Non-Small Cell Lung Cancer (NSCLC)

Lung cancers are generally divided into two main categories: small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancers. Histologically, NSCLC is divided further into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma. (See Pathophysiology.)

Lung cancer was a rare entity in the early 1900s but has since become far more prevalent. The prevalence of lung cancer is second only to that of prostate cancer in men and breast cancer in women. By the end of the 1900s, lung cancer had become the leading cause of preventable death in the United States,[5] and recently, it surpassed heart disease as the leading cause of smoking-related mortality.

Lung cancer is the leading cause of cancer-related mortality in both men and women not only in the United States but also throughout the world. In 2022, the disease is expected to cause over 130,000 deaths in the United States—about as many as colorectal, breast, and prostate cancers combined.[6] The types of lung cancer in the United States, as well as in many other countries, have also changed in the past few decades: the frequency of adenocarcinoma has risen, and that of SCC has declined. (See Epidemiology.)

Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. The need to diagnose lung cancer at an early and potentially curable stage is thus obvious. (See Prognosis.) In addition, most patients who develop lung cancer have been smokers and have smoking-related damage to the heart and lungs, making aggressive surgical or multimodality therapies less viable options.

Lung cancer is often insidious, producing no symptoms until the disease is well advanced. In approximately 7-10% of cases, lung cancers are diagnosed incidentally in asymptomatic patients, when a chest radiograph performed for other reasons reveals the disease. Numerous pulmonary signs may be associated with NSCLC. Systemic findings may include unexplained weight loss and low-grade fever. (See Presentation.)

Because of the importance of stage in the therapeutic decision-making process, all patients with NSCLC must be staged adequately. A complete staging workup for NSCLC should be carried out to evaluate the extent of disease. (See Workup.)

Treatment primarily involves surgery, chemotherapy, or radiation therapy. Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment of patients with NSCLC. (See Treatment.)

Go to Small Cell Lung Cancer for complete information on this topic. 

Both exposure (environmental or occupational) to particular agents and an individual’s susceptibility to these agents are thought to contribute to one’s risk of developing lung cancer. In the United States, active smoking is responsible for approximately 90% of lung cancer cases. Occupational exposures to carcinogens account for approximately 9-15% of lung cancer cases.

Exposure to carcinogens

Tobacco smoke contains more than 300 harmful substances with at least 40 known potent carcinogens. Polyaromatic hydrocarbons and nicotine-derived nitrosamine ketone (NNK) are known to cause DNA damage by forming DNA adducts in animal models. Benzo-A-pyrine also appears to induce molecular signaling such as AKT, as well as inducing mutations in p53 and other tumor suppressor genes.

The most common occupational risk factor for lung cancer is exposure to asbestos. Studies have shown radon exposure to be associated with 10% of lung cancer cases, while outdoor air pollution accounts for perhaps 1-2%.[7] In addition, preexisting nonmalignant lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and tuberculosis have all been shown to be associated with increased lung cancer rates.

The current multiple hit theory suggests that a series of toxic cellular insults disrupts orderly genetic reproduction. Symptoms ultimately develop from the uncontrolled disorganized growth that interferes with local or distant anatomy or physiologic processes.[7]

A study by Ito et al assessed the shift in histologic types of lung cancer in Japan and the United States in relation to the shift from nonfiltered to filtered cigarettes.[8] The study determined that the shift in cigarette types only altered the most frequent type of lung cancer, which shifted from SCC to adenocarcinoma.

Genetic susceptibility

Advanced molecular techniques have identified amplification of oncogenes and inactivation of tumor suppressor genes in NSCLC. The most important abnormalities detected are mutations involving the ras family of oncogenes. The ras oncogene family has 3 members: H-ras, K-ras, and N-ras. These genes encode a protein on the inner surface of the cell membrane with guanosine triphosphatase activity and may be involved in signal transduction.

Studies performed on mice suggest the involvement of ras mutations in the molecular pathogenesis of NSCLC. Studies in humans suggest that ras activation contributes to tumor progression in persons with lung cancer. The ras gene mutations occur almost exclusively in adenocarcinoma and are found in 30% of such cases. These mutations were not identified in adenocarcinomas that developed in persons who do not smoke. The K-ras mutation appears to be an independent prognostic factor.

Studies are ongoing to develop management plans according to the presence or absence of ras gene mutations.

Other molecular abnormalities found in NSCLC include mutations in the oncogenes c-myc and c-raf and in the tumor suppressor genes retinoblastoma (Rb) and p53.

Two studies have documented early and extensive mutations in lung cancers that result in pronounced intratumor heterogeneity by the time these cancers manifest clinically—thus helping to explain why these cases so often fail to respond to treatment. A study by Zhang and colleagues identified 20 of 21 known cancer gene mutations in all regions of 11 localized lung adenocarcinomas. On follow-up, patients who had postsurgical relapse had significantly larger fractions of subclonal mutations in their primary tumors.[9]

Similarly, a study by de Bruin and colleagues in seven operable NSCLCs determined that there was a long period of tumor latency between early mutations and clinical symptoms, which appeared after new mutations triggered rapid disease growth. In some former smokers, the initial mutations dated back to when they were smoking cigarettes, two decades earlier. Over time, however, those mutations became less important, with more recent mutations resulting from a new process controlled by a protein called APOBEC.[10]

Classification of lung cancer

Lung cancers are generally divided into 2 main categories: SCLC and NSCLC. NSCLC accounts for approximately 85% of all lung cancers. NSCLC is divided further into adenocarcinoma, SCC, and large cell carcinoma. All share similar treatment approaches and prognoses but have distinct histologic and clinical characteristics.

Adenocarcinoma

Adenocarcinoma, arising from the bronchial mucosal glands, is the most common NSCLC cancer in the United States, representing 35-40% of all lung cancers. It is the subtype observed most commonly in persons who do not smoke. It usually occurs in a peripheral location within the lung, in some cases at the site of pre-existing scars, wounds, or inflammation (ie, a “scar carcinoma”).

Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with a classic manifestation as an interstitial lung disease on chest radiograph. Bronchoalveolar carcinoma arises from type II pneumocytes and grows along alveolar septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease, or a rapidly progressing pneumonic form. A characteristic finding in persons with advanced disease is voluminous watery sputum.

Squamous cell carcinoma

SCC accounts for 25-30% of all lung cancers. Whereas adenocarcinoma tumors are peripheral in origin, SCC is found in the central parts of the lung (see the image below). The classic manifestation is a cavitary lesion in a proximal bronchus. This type is characterized histologically by the presence of keratin pearls and can be detected with cytologic studies because it has a tendency to exfoliate. It is the type most often associated with hypercalcemia.

View Media Gallery

Large-cell carcinoma

Large-cell carcinoma accounts for 10-15% of lung cancers, typically manifesting as a large peripheral mass on chest radiograph. Histologically, this type has sheets of highly atypical cells with focal necrosis, with no evidence of keratinization (as is typical of SCC) or gland formation (as is typical of adenocarcinomas).

With improved histopathologic procedures and the use of electron microscopy, most NSCLCs that would previously have been classified as large-cell carcinomas are identified as undifferentiated adenocarcinomas or, less frequently, as SCCs.[11] Large-cell undifferentiated cancers carry the same prognosis as do adenocarcinomas and are combined with them in clinical trials.

Causes of lung cancer include the following:

• Smoking (78% in men, 90% in women)
• Radon exposure
• Asbestos exposure
• Halogen ether exposure
• Chronic interstitial pneumonitis
• Inorganic arsenic exposure
• Radioisotope exposure, ionizing radiation
• Atmospheric pollution
• Chromium, nickel exposure
• Vinyl chloride exposure

Unlike many other malignancies, whose causes are largely unknown, lung cancer is known to be caused by tobacco smoking in as many as 90% of patients. However, two studies have reported rising NSCLC rates in persons who have never smoked: In a United States study, rates increased from 8.9% in 1990–1995 to 19.5% in 2011–2013, while a study from the United Kingdom reported an increase from 13% to 28% during a 6-year period.[12]

Because not all smokers develop lung cancer and not all lung cancer patients have a history of smoking, other factors (eg, genetic susceptibility [see Pathophysiology], arsenic exposure, radiation exposure, and other environmental carcinogens[13] ) also play a causative role, either independently or in conjunction with smoking. Genetic factors probably contribute in all populations, but the contribution of other factors is population-specific.

A study by Bagnardi et al determined that alcohol use is not an independent factor in the etiology of lung cancer.[14]

Smoking

Smoking prevalence in the United States has gradually declined over last 4 decades. In 2020, there were an estimated 30.8 million active adult smokers in the United States. Overall smoking prevalence declined from 20.9% in 2005 to 12.5% in 2020.[15]

Worldwide, there were an estimated 1.14 billion current smokers in 2019. Although the prevalence of smoking in persons aged 15 years and older decreased significantly from 1990 to 2019 (by 27.5% in males and by 37.7% in females), population growth led to a significant increase in the total number of smokers, from 0.99 billion in 1990.[16]

The development of lung cancer is directly related to number of cigarettes smoked, length of smoking history, and the tar and nicotine content of the cigarettes. Risk is highest among current smokers and lowest among nonsmokers. A large trial showed that persistent smokers had a 16-fold elevated lung cancer risk, which was further doubled in those who started smoking when younger than 16 years.[17] The age-adjusted incidence rates range from 4.8-20.8 per 100,000 among nonsmokers to 140-362 per 100,000 among active smokers.

Although tobacco smoking is the major cause of lung cancer, it is now believed that males and females may differ in their susceptibility to the carcinogenic effects of tobacco smoke. This difference may be due to differences in DNA repair mechanisms. Although still considered controversial, it is well known that women are more likely to develop adenocarcinomas and that, stage for stage, women survive longer. In addition, differences in response to certain biologic therapies (eg, epidermal growth factor receptor [EGFR] inhibitors) and antiangiogenic agents have been observed between sexes.

The risk of lung cancer declines slowly after smoking cessation. Long-term follow-up studies show that the relative risk remains high in the first 10 years after cessation and gradually declines to 2-fold approximately 30 years after cessation. This long-term risk explains the development of almost 50% of United States lung cancer cases in past smokers.

Strong cardiorespiratory fitness might help reduce lung cancer risk in men who smoke or used to smoke, accordng to the findings from a study that assessed 1602 former smokers (40 pack-years) and 1377 current smokers (43 pack-years). All were men, aged 42 to 76 years, who were free from lung cancer at baseline. Over a follow-up period of 4.6 to 18.6 years, 46 former smokers and 53 current smokers developed lung cancer. Of this group, 40 former smokers and 39 current smokers died. Men who had higher fitness levels at baseline, measured with a maximal treadmill exercise test, had a lower incidence of lung cancer during follow-up and had better survival if they did get lung cancer.[18]

Secondhand smoking

Cigarette smoke containing the carcinogenic N-nitrosamines and aromatic polycyclic hydrocarbons can be inhaled passively by nonsmokers (secondhand smoke); urinary levels of these carcinogens in nonsmokers are 1-5% of those found in active smokers. As many as 25% of the lung cancers in persons who do not smoke are believed to be caused by secondhand smoke.[19]

The US Environmental Protection Agency has recognized passive smoking as a potential carcinogen. About 3000 cases of lung cancer appear to be related to passive exposure. This awareness has led to local ordinances restricting smoking in enclosed public places, including restaurants and government buildings.

Lung cancer in never-smokers

A minority of lung cancers develop in persons who have never smoked. These lung cancers are genetically distinct from smoking-related NSCLC, and this distinction may have therapeutic implications. The observed genetic differences include a lower frequency of K-ras and a higher frequency of mutations in the EGF receptor and likely are responsible for the higher efficacy of EGF receptor inhibitors in this patient population.

Asbestos exposure

The silicate type of asbestos fiber is an important carcinogen. Asbestos exposure has been shown to be strongly associated with the causation of lung cancer, malignant pleural mesothelioma, and pulmonary fibrosis. Asbestos exposure increases the risk of developing lung cancer by as much as 5 times.

Tobacco smoke and asbestos exposure act synergistically, and the risk of developing lung cancer for persons who currently smoke tobacco and have a history of asbestos exposure approaches 80-90 times that of control populations.

Radon exposure

Radon is an inert gas produced as a result of uranium decay. Radon exposure is a well-established risk factor for lung cancer in uranium miners. Approximately 2-3% of lung cancers annually are estimated to be caused by radon exposure. Household exposure to radon, however, has never been clearly shown to cause lung cancer.

The US National Research Council’s report of the Sixth Committee on Biological Effects of Ionizing Radiation has estimated that radon exposure causes 2100 new lung cancers each year, while it contributes to lung cancer causation in approximately 9100 persons who smoke.

HIV infection

Persons with HIV infection have a higher lung cancer risk than those without HIV infection, with relative risk estimates ranging from 2 to 11. In persons with HIV infection, lung cancer is the most common and most fatal non-AIDS-associated malignancy, accounting for about 16% of deaths.[20] A majority of these cases are adenocarcinomas. In most, but not all, studies the incidence and risk of lung cancer in HIV-infected persons did not change significantly with the advent of highly active antiretroviral therapy.[21]

Lung cancer in HIV-infected persons develops almost exclusively in smokers, but HIV infection appears to increase lung cancer risk independent of smoking status, by a factor of at least 2.5-fold. Compared with lung cancer patients in the general population, HIV-infected patients with lung cancer are significantly younger. Most patients with HIV infection and lung cancer present with advanced-stage disease and have significantly shorter median survival.[20]

Other environmental agents

Beryllium, nickel, copper, chromium, and cadmium have all been implicated in causing lung cancer.

Dietary fiber and vegetables have been suggested as protective from lung cancer. Although diets rich in fruits and vegetables appear to be associated with lower rates of lung cancer, trials of supplemental beta-carotene, alone or in combination with vitamin E or retinyl palmitate, in persons at high risk for lung cancer found that this supplementation actually increased the incidence of lung cancers.[22]

United States statistics

In the United States, lung cancer is the second most common cancer, after prostate cancer in men and breast cancer in women, but the most common cause of cancer deaths. The American Cancer Society projects that 238,340 cancers of the lung and bronchus will be diagnosed in the United States in 2023, with 127,070 deaths. Approximately 81% of those cases are expected to be NSCLC.[6]

Incidence rates of lung cancer follow those of tobacco smoking, with a lag of several decades. Since about 2006, the incidence rate of lung cancer has decreased 2.6% per year in men and 1.1% per year in women. Because women took up cigarette smoking in large numbers later and were slower to quit, declines began later and have been slower in women than in men. This has resulted in a narrowing of the sex gap in lung cancer incidence, from more than 3-fold higher rates in men in the 1970s to just 24% higher in 2018.[6]  

Lung cancer death rates for US women are among the highest in the world. Although in the United States, death rates are higher in men than in women, rates for US men are still lower than rates for men in several other countries.[23] These trends in US death rates parallel trends in smoking prevalence over the past 50 years.[6]

However, lung cancer death rates in the US have been decreasing at an accelerated rate. In men, lung cancer death rates fell 3% per year during 2005-2014 and 5% per year during 2014-2020; in women, the decreases during those periods were 2% and 4% per year, respectively. This reduction outpaces declines in incidence and likely reflects advances in treatment, as well as earlier detection, facilitated by lung cancer screening, which has been recommended for persons at high risk for lung cancer since 2013.[6]

International statistics

Lung cancer is the second most commonly diagnosed cancer worldwide, after breast cancer, and its incidence continues to grow. In 2020, an estimated 2.2 million new cases of lung cancer were diagnosed globally, accounting for approximately 11.4% of the global cancer burden. An estimated 1.8 million lung cancer deaths occurred in 2020.[24] Among all cancers, lung cancer is currently the most common cause of cancer deaths in most countries, with industrialized regions such as North America and Europe having the highest rates.

Several differences exist in lung cancer incidence according to geographic area. The highest incidence occurs in Polynesia (37.3 cases per 100,000 population per year). The lowest incidence rate is in western Africa (approximately 2.2 cases per 100,000 population per year).[24] With increased smoking in developing countries, the incidence is expected to increase in the next few years, notably in China and India.

Generally, global lung cancer trends have followed the trends in smoking, with a lag time of several decades. Lung cancer incidence has been declining in several countries, including the United States, Canada, the United Kingdom, and Australia, following the decreasing rate of smoking. Lung cancer incidence among women, however, continues to increase in several parts of the globe, although it has begun to plateau in the United States. Notably, despite a very low rate of smoking, Chinese women have a higher incidence of lung cancer than European women.

Age and sex distribution

Lung cancer occurs predominately in persons aged 50-70 years. The probability of developing lung cancer remains very low until age 39 years in both sexes. It then slowly starts to rise and peaks among those older than 70 years. The risk of developing lung cancer remains higher among men in all age groups after age 40 years.

Overall, lung cancer is more common in men than in women. In the United States, Northern Europe, and Western Europe, the prevalence of lung cancer has been decreasing in men. In Eastern and Southern European countries, the incidence of lung cancer has been rapidly increasing. Most Western countries have encountered a disturbing trend of increasing prevalence in women and younger patients. Women have a higher incidence of localized disease at presentation and of adenocarcinoma and typically are younger when they present with symptoms.

Over the past two decades, the incidence of lung cancer has generally decreased in both men and women 30 to 54 years of age in all races and ethnic groups. However, the incidence has declined more steeply in men. As a result, lung cancer rates in younger women have become higher than those in younger men. In non-Hispanic whites and Hispanics ages 44 to 49 years, for example, the female-to-male rate ratio for lung cancer incidence rose from 0.88 during 1995-1999 to 1.17 during 2010-2014.[25]

This reversal can be explained in part by increased rates of cigarette smoking in women born since 1965. However, while the difference in smoking rates in that age group has narrowed, rates in women have generally not exceeded the rates in men, so other factors may be playing a role. For example, women may be more susceptible to the oncogenic effects of smoking.[25]

Incidence and survival by race

Whereas lung cancer incidence rates are similar among African-American and white women, lung cancer occurrence is approximately 45% higher in African-American men than in white men.[23] This increased incidence has been attributed to differences in smoking habits; however, recent evidence suggests a slight difference in susceptibility.

From 1995-2001, the 5-year relative survival rate was 13% lower in African Americans compared with white individuals.[23] This racial gap persisted within each stage at diagnosis for both men and women.

Trends in 5-year survival rates in lung cancer from 1975-2003 revealed that while modest gains occurred in 5-year survival rates among whites, survival rates remained unchanged in the African-American population. Current 5-year survival rates are estimated to be 16% among whites and 13% among non-whites.

Lung cancer is highly lethal. In Europe, the 5-year overall survival rate is 12.3%. The highest recorded 5-year patient survival rates are observed in the United States. US data collected from 2012–2018 indicate that the 5-year relative survival rate for lung cancer was 22.9%, reflecting a steady but slow improvement from 12.5% in 1975.[23, 26] However, the 5-year relative survival rate varies markedly, depending on how advanced the disease is at diagnosis, as follows[26] :

• 61.2% for localized disease
• 33.5% for regional disease
• 7.0% for distant-metastasis disease

Prognostic factors for NSCLC are summarized in the image below.

A retrospective Surveillance, Epidemiology, and End Results (SEER) data analysis suggests that the number of lymph nodes with cancer may be predictive of survival. Mean lung cancer-specific survival decreased from 8.8 years for patients with one positive lymph node to 3.9 years for patients with more than eight positive lymph nodes.[27]

Patients with in situ and stage I lung cancer may respond to surgery. Their prognosis is far better than that of patients with more advanced disease. In patients with radiologically occult lung neoplasms, the 5-year survival rate is 24-26%; in those with abnormal chest radiographic findings, the rate is 12%. If the cancer is nonresectable, the prognosis is poor, with a mean survival rate of 8-14 months.

Mostertz et al found that in some patient populations, the oncogenic pathway activation profile of the tumor can have prognostic significance.[28] Retrospective analysis of 787 patients with predominantly early-stage NSCLC, using gene expression profiling, showed the following:

• In patients younger than 70 years, high-risk patients, with the shortest recurrence-free survival, demonstrated increased activation of the Src and tumor necrosis factor (TNF) pathways.

• In women, high-risk patients demonstrated increased activation of the invasiveness and signal transducer and activator of transcription 3 (STAT3) pathways.

• Multivariate analyses confirmed the independent clinical relevance of the pathway-based subphenotypes in women and patients younger than 70 years.

A meta-analysis by Parsons et al suggests that smoking cessation after diagnosis of early-stage lung cancer may improve prognosis, probably by reducing cancer progression. Life table modelling on the basis of data from 9 studies gave an estimated 5-year survival rate of 33% in 65-year-old patients with early-stage NSCLC who continued to smoke compared with 70% in those who quit smoking.[29]

In an analysis of data on 4200 patients who participated in the National Comprehensive Cancer Network's NSCLC Database Project, patients who were current smokers at the time of diagnosis had worse survival compared with patients who never smoked, and among younger patients with stage IV disease, current smokers had worse survival compared with former smokers who quit smoking more than 12 months before being diagnosed.[30]

Secondary analyses of the Women’s Health Initiative (WHI) randomized, placebo-controlled trial demonstrated an association between the use of daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) and NSCLC. Women who used CEE plus MPA for more than 5 years were at increased risk for NSCLC, and women using CEE plus MPA who were diagnosed with NSCLC had higher mortality than women with NSCLC who do not take hormone therapy.[31]

The WHI analyses included 16,608 multiethnic postmenopausal women aged 50-79 years. Confirmation of lung cancers was completed by medical record review. This area deserves more attention and study to determine the risks and benefits of hormone therapy for postmenopausal women who smoke.

In contrast, a study by Bouchardy et al found that patients who had received antiestrogen treatment for breast cancer had a lower lung cancer mortality rate. However, use of antiestrogens did not significantly lower standardized incidence ratios for lung cancer.[32]

A review of eight trials by Rothwell et al found that allocation to daily aspirin reduced death caused by a variety of cancers, including adenocarcinoma of the lung (but no other form of lung cancer). A latent period of 5 years was observed before risk of death was decreased for lung cancer, but 20-year risk of cancer death remained lower in the aspirin groups. Benefit was unrelated to aspirin dose (75 mg or higher), sex, or smoking, but increased with age, with the absolute reduction in 20-year risk of cancer death reaching 7.08% at age 65 years and older.[33]

Although tumor-node-metastasis (TNM) staging is the best prognostic factor for NSCLC, a study by Hofman et al concluded that preoperative detection of circulating tumor cells (CTCs) has prognostic significance.[34] The results showed that the presence and level of 50 or more circulating nonhematologic cells (CNHC) were associated with worse survival among patients with resectable NSCLC. Although CTCs are potentially interesting, the significance of their presence is still being debated.[35]

Risk of recurrence

In a 2012 retrospective review of 1402 consecutive stage I-III (N0-N1) NSCLC patients who underwent complete resection without adjuvant radiation therapy, significant risk factors for local recurrence included surgical procedure (single/multiple wedges + segmentectomy versus lobectomy + bilobectomy + pneumonectomy), visceral pleural invasion, and tumor size > 2.7 cm. Significant risk factors for regional recurrence included pathologic N1 stage, lymphovascular space invasion, and visceral pleural invasion.[36]

In a study of 452 cases of stage I lung adenocarcinoma, thyroid transcription factor–1 (TTF-1) expression independently predicted the risk of disease recurrence. The 5-year cumulative incidence of recurrence was 40% for patients with negative TTF-1 expression, versus 15% for those with positive TTF-1 expression (P < 0.001.[37]

According to a 2013 retrospective analysis of 734 patients with stage I adenocarcinoma no larger than 2 cm, recurrence of small, early-stage adenocarcinoma after limited lung resection is three times more likely when the micropapillary component of the tumor is 5% or greater. In the 258 study patients who underwent wedge resection or segmentectomy, after adjustment for both vascular and lymphatic invasion, the presence of a micropapillary component of 5% or greater was independently associated with a 5-year cumulative incidence of recurrence (hazard ratio = 3.11). Micropapillary status was not significantly associated with recurrence in the 476 patients who underwent lobectomy.[38]

Advise patients that smoking cessation is the most important measure for preventing lung cancer; it may also improve prognosis in patients with early-stage lung cancer.[29] Smoking cessation by others who share the patient’s home, car, or both is also important. According to published data, the use of nicotine alternatives (eg, gum, patch, spray) instead of cigarettes reduces the incidence of lung cancer, although it does not affect the incidence of ischemic heart disease.

Advise the patient to avoid asbestos exposure. Consider prophylactic administration of retinoids, such as beta-carotene.

Where appropriate, patient education should include a discussion of lung cancer screening. Current American Cancer Society guidelines recommend annual lung cancer screening with a low-dose computed tomography (LDCT) scan for asymptomatic individuals at higher risk for lung cancer who meet all of the following conditions[39] :

• Aged 50 to 80 years and in fairly good health
• Currently smoke or previously smoked
• Have at least a 20-pack-year smoking history

In addition, individuals who are going to be screened should:

• Receive smoking cessation counseling if they are current smokers
• Have been involved in informed/shared decision making about the benefits, limitations, and harms of screening with LDCT scans,
• Have access to a high-volume, high-quality lung cancer screening and treatment center

See also Workup/Screening. For patient education information, see Lung Cancer.

Lung cancer is often insidious, producing no symptoms until the disease is well advanced. In approximately 7-10% of cases, lung cancer is diagnosed in asymptomatic patients when a chest radiograph performed for other reasons reveals the disease. At initial diagnosis, 20% of patients have localized disease, 25% of patients have regional metastasis, and 55% of patients have distant spread of disease.

Signs and symptoms of lung cancers may be due to the primary tumor, locoregional spread, metastatic disease, or ectopic hormone production (see the image below). Cough is reported to be the most common presenting symptom of lung cancer. Other respiratory symptoms include dyspnea, chest pain, and hemoptysis. Hemoptysis has been described as the one symptom often prompting more rapid presentation.[40]

Symptoms due to primary tumor

The symptoms produced by the primary tumor depend on its location (ie, central, peripheral).[1] Central tumors are generally squamous cell carcinomas (SCCs) and produce cough, dyspnea, atelectasis, postobstructive pneumonia, wheezing, and hemoptysis.

Most peripheral tumors are adenocarcinomas or large cell carcinomas and, in addition to causing cough and dyspnea, can cause symptoms due to pleural effusion, and severe pain as a result of infiltration of parietal pleura and the chest wall. Because of their peripheral location, adenocarcinomas may not call attention to themselves until they have produced extrathoracic metastases. For example, patients may present with clinical signs of bone spread or intracranial metastatic disease.

Symptoms due to locoregional spread

Symptoms due to locoregional spread can include superior vena cava obstruction, paralysis of the recurrent laryngeal nerve, and phrenic nerve palsy, causing hoarseness and paralysis of the diaphragm; pressure on the sympathetic plexus, causing Horner syndrome; dysphagia resulting from esophageal compression; and pericardial effusion.

Superior sulcus tumors (Pancoast tumors) can cause compression of the brachial plexus roots as they exit the neural foramina, resulting in intense, radiating neuropathic pain in the ipsilateral upper extremity.

Symptoms by location of cancer

Endobronchial cancers may produce the following signs:

• Cough (45-75% of patients)
• Hemoptysis (57%)
• Bronchial obstruction
• Postobstructive complications (eg, pneumonitis, pneumonia, effusion)

Mediastinal cancers may produce the following signs and symptoms:

• Dyspnea
• Postprandial coughing (esophageal)
• Wheezing
• Stridor (upper airway obstruction, 2-18%)
• Hoarseness (left vocal cord paralysis due to recurrent laryngeal nerve impingement, 2-18%)
• Chylothorax (thoracic duct)
• Palpitations (pericardial)
• Dysphagia (enlargement of the subcarinal lymph nodes can cause dysphagia by compressing the middle third of the esophagus)

Pleural cancers may produce the following signs and symptoms:

• Chest pain (27-49%)
• Dyspnea (37-58%)
• Cough (45-75%)

Neurologic signs and symptoms include the following:

• Arm weakness and paresthesias (brachial plexus impingement)
• Miosis, ptosis, and anhidrosis (cervical sympathetic chain, Horner syndrome)
• Dyspnea (secondary to phrenic nerve paralysis)

Metastatic cancer may produce the following signs (8-68%):

• Weight loss
• Cachexia

Central nervous system (CNS) signs and symptoms include the following:

• Headache
• Altered mental status
• Seizure
• Meningismus
• Ataxia
• Nausea and/or vomiting

Vascular signs include the following:

• Phlebitis
• Thromboembolism (Trousseau syndrome)

Musculoskeletal manifestations include the following:

• Bone pain (6-25%)
• Spinal cord impingement

Paraneoplastic syndromes occur in 10-20% of patients. Most paraneoplastic syndromes are caused by small cell lung cancer (SCLC). However many paraneoplastic syndromes also occur in non–small cell lung cancer (NSCLC) patients. Some examples include:

• Hypercalcemia due to parathyroid-like hormone production occurs most commonly in patients with SCCs

• Clubbing and hypertrophic pulmonary osteoarthropathy and Trousseau syndrome of hypercoagulability are caused more frequently by adenocarcinomas

• The syndrome of inappropriate antidiuretic hormone production (SIADH) is more common in SCLC but can also occur in NSCLC.

• Cushing syndrome from ectopic adrenocorticotropic hormone (ACTH) production is more likely to occur in SCLC or bronchial carcinoid[41]

Numerous signs may be associated with NSCLC (see the image below). Extrapulmonary findings may include adenopathy and clubbing. Systemic findings may include unexplained weight loss and low-grade fever.

In approximately two thirds to three fourths of patients, the cancer is not diagnosed until it has reached an advanced stage; patients may have lost weight and may have obvious respiratory distress. Subtle findings on physical examination may provide clues for early detection.

About one third of patients present with symptoms as a result of distant metastases. The most common sites of distant metastasis from lung cancer are as follows:

• Bone
• Liver
• Adrenal glands and intra-abdominal lymph nodes
• Brain and spinal cord
• Lymph nodes and skin

Lung cancer can metastasize to virtually any bone, although the axial skeleton and proximal long bones are most commonly involved.

Head and neck

Commonly, no signs are found upon examination of the head and neck regions. However, when the cancer has spread to the supraclavicular lymph nodes, careful examination may reveal enlargement of involved nodes, which helps in the clinical staging process.

Superior sulcus tumors (Pancoast tumors), because of their presence at the apex of the lung, can compress the cervical sympathetic plexus, causing classic Horner syndrome. Findings involve ipsilateral ptosis, miosis, enophthalmos, and anhidrosis (ie, lack of sweating).

The superior vena cava syndrome (SVCS) results from obstruction of blood flow to the heart from the head and neck regions and upper extremities as a consequence of compression of the superior vena cava, either from direct invasion by the primary tumor into the mediastinum or from lymphatic spread with enlarged right paratracheal lymph nodes. It is commonly caused by SCLC but can result from any centrally located tumor or mediastinal spread.

Signs of SVCS include the following:

• Feeling of fullness in the head
• Dyspnea
• Cough
• Dilated neck veins
• Prominent venous pattern on the face and the chest
• Upper extremity and facial edema
• Papilledema
• Facial cyanosis
• Plethora
• Conjunctival edema (possibly)

Respiratory system

Findings are variable and depend on tumor location and spread. Centrally located obstructing tumors can cause collapse of the entire lung with an absence of breath sounds on the side of the lesion. Peripheral lesions can cause individual segments or lobes to collapse, leading to findings of dullness to percussion and/or decreased breath sounds.

Pleural effusions give rise to characteristic findings of dullness and decreased breath sounds, depending on the size.

Respiratory insufficiency is signaled by dyspnea and increased work of breathing, retractions, orthopnea, and cyanosis. Upper airway obstruction is manifested by stridor and wheezing. Lower airway obstruction is manifested by asymmetric breath sounds, pleural effusion, pneumothorax, infiltrate, and post obstructive processes.

Cardiovascular system

Cardiac findings are usually noted when the tumor causes a pericardial effusion. Findings can range from simple effusion to tamponade. Direct cardiac involvement may also occur.

Gastrointestinal tract

The most common site of metastatic spread is the liver, which may manifest as tender hepatomegaly. In addition, Ogilvie intestinal pseudo-obstruction may occur, as manifested by the following:

• Nausea
• Vomiting
• Early satiety
• Abdominal discomfort
• Weight loss
• Change in bowel habits

Musculoskeletal system

Bone is another common site of spread for lung carcinomas. Patients may report bone pain, and tender spots may be found during examination.The examination should include fist percussion of the spine to look for tender spots, which may suggest vertebral column metastases.

A Pancoast tumor may give rise to any of the following:

• Pain (eg, in the shoulder, medial forearm, arm, scapula)
• Bone destruction
• Hand muscle atrophy

Central nervous system

A neurologic examination should be performed to assess for focal neurological deficits caused by brain metastases and for signs of spinal cord compression. The skeletal system is a common site of spread of lung cancer, and metastatic lesions in the spine may grow and compress the spinal cord. Patients usually report back pain and neurological symptoms in the form of decreased sensation in the lower half of the body, decreased strength, loss of bowel control, and urinary incontinence or retention. A careful neurologic examination usually localizes the level of compression.

Suspected spinal cord compression is an emergency. Patients should immediately receive an adequate dose of a corticosteroid (usually intravenous dexamethasone, 10 mg followed by 4 mg q6h) and should undergo an immediate MRI scan of the vertebral column. If documented, spinal cord compression should be treated emergently with radiation therapy, and steroids should be tapered slowly.

A study by Fadel et al found that en bloc resection can achieve good long-term survival in highly selected patients with NSCLC that invades the thoracic inlet and spine. Factors that independently affected survival were incomplete resection and subclavian artery involvement.[42]

Paraneoplastic syndromes

Paraneoplastic syndromes are more likely to occur in small cell lung cancer than in NSCLC. Nevertheless, findings indicative of the following paraneoplastic syndromes may be noted[43] :

• Cushing syndrome

• Lambert-Eaton myasthenic syndrome - Gradual onset of proximal lower extremity weakness; proximal upper extremity weakness is usually less noticeable; the syndrome may be worse in the morning and improve during the day; although extraocular muscle involvement is uncommon, ptosis is often found.

• Hypercalcemia

• Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

• Enlargement of the extremities, and painful, swollen joints (hypertrophic osteoarthropathy)

Paraneoplastic syndromes are unrelated to the size of the primary tumor. Sometimes paraneoplastic syndromes precede the diagnosis of a malignancy, sometimes they occur late in the disease, and sometimes they are the first signs of a recurrence.

In a patient with a long history of smoking or other risk factors for lung cancer, the presence of persistent respiratory symptoms should prompt a chest radiograph. Because benign conditions and metastatic malignancies can mimic lung cancer on radiographs, histologic confirmation is necessary. This can be achieved by sputum cytologic studies, bronchoscopy, or computed tomography (CT)-guided transthoracic needle biopsy of the mass, depending on the location of the tumor (see the image below).

Staging workup

Because of the importance of stage in the therapeutic decision-making process, all patients with non–small cell lung cancer (NSCLC) must be staged adequately. A complete staging workup for NSCLC should be carried out to evaluate the extent of disease. In the United States, the standard staging workup for NSCLC includes 7 main components (see the table below).

Information obtained from these tests can then be used to guide further testing (eg, imaging studies). Invasive staging procedures such as mediastinoscopy and mediastinotomy may be required to assess mediastinal lymph nodes in patients who are candidates for potentially curative surgical resection. Positron emission tomography (PET) scans may be useful in the detection of involved nodes, the presence of which may influence decisions about operability.

A study by Annema et al determined that among patients with suspected NSCLC, a combination of endosonography and surgical staging had a greater sensitivity for mediastinal nodal metastases than surgical staging alone.[45] This resulted in fewer unnecessary thoracotomies.

See Non-Small Cell Lung Cancer Staging for summary tables.

See Lung Cancer Staging -- Radiologic Options, a Critical Images slideshow, to help identify stages of the disease process.

Other procedures

An electrocardiogram (ECG) is helpful in establishing baseline findings and differentiating clinical symptoms (eg, chest pain, dyspnea). Changing lung hemodynamics often alter ECG wave patterns.

Bedside tests for peak expiratory flow provide good indicators of significant airflow obstruction. Lung cancer is more closely linked to chronic obstructive pulmonary disease with airflow compromise than to the disease without significant airway obstruction.

For staging purposes, a complete blood count (CBC) should be obtained in every patient, especially before instituting chemotherapy. In an emergency setting, a CBC is not helpful in the initial evaluation. Obtain a CBC in patients with widely metastatic disease to aid in determining whether an infiltrate is potentially infectious. Obtain a CBC in patients with fever who have a recent history of chemotherapy to check for neutropenia (absolute neutrophil count < 1000/μL).

Lung cancers have a propensity to cause paraneoplastic syndromes (see the table below). Appropriate studies in such patients may include assays of serum electrolytes, blood urea nitrogen (BUN), creatinine, calcium, and magnesium.

The most common metabolic abnormality associated with NSCLC is hypercalcemia, which usually occurs with squamous cell carcinoma and results from secretion of parathyroid hormone–related peptide (PTH-rP) by the tumor. This can be distinguished from hyperparathyroidism by confirmation of normal serum parathyroid hormone (PTH) levels.

Other electrolyte abnormalities can include hyponatremia, in which case the syndrome of inappropriate antidiuretic hormone secretion (SIADH) should be considered. The combination of hyponatremia, serum osmolality < 280 mOsm/kg, and high urine osmolality is the hallmark of SIADH.

Liver function tests (aspirate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], prothrombin time [PT]/international normalized ratio [INR]) and alkaline phosphatase level are usually not helpful initially. In patients with advanced disease, however, elevated results may be an indication of hepatic metastasis and bone metastasis, respectively.

Arterial blood gas (ABG) levels are useful in the detection of respiratory failure (eg, acidosis, hypercarbia, hypoxia) in sick patients. Obtain ABG levels in patients with active systemic diseases or abnormal labored breathing.

A chest radiograph is usually the first test ordered in patients in whom a lung malignancy is suggested. Clues from the chest radiograph may suggest the diagnosis of lung cancer, but may not be helpful in identifying a histologic subtype. If the tumor is clearly visible and measurable, chest radiography can sometimes be used to monitor response to therapy.

Chest radiographs may show the following:

• Pulmonary nodule, mass, or infiltrate (see the first image below)
• Mediastinal widening
• Atelectasis
• Hilar enlargement
• Pleural effusion (see the second image below)

  Non–small cell lung cancer. Bronchoscopy. A large central lesion was diagnosed as non–small cell carcinoma.

Popcorn calcification is usually a radiologic characteristic of benign lesions.

The percentage of patients found to have lung cancer incidentally through chest radiographs has been consistently low. Randomized controlled trials have shown that the use of screening chest radiographs does not reduce lung cancer mortality.[46, 47]

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

A chest CT scan (see the image below) is the standard for staging. The findings of CT scans of the chest and clinical presentation usually allow a presumptive differentiation between NSCLC and small cell lung cancer (SCLC). Massive lymphadenopathy and direct mediastinal invasion are commonly associated with small cell carcinoma. A mass in or adjacent to the hilum is a particular characteristic of SCLC and is seen in about 78% of cases.[48]

Common sites of spread of NSCLC include the liver and adrenals; hence, CT scanning of the chest and upper abdomen that includes the liver and adrenals is the minimum standard for a staging workup for a person newly diagnosed with NSCLC. Lung nodules incidentally detected on abdominal CT are often benign.[49]

A CT scan or magnetic resonance imaging (MRI) scan of the brain may be required if neurologic symptoms or signs (eg, mental status change) are present. Most thoracic surgeons perform imaging of the brain before attempting definitive resection of a lung malignancy.

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

MRI is most useful when evaluating a patient in whom spinal cord compression is suggested. In addition, brain MRI has a greater sensitivity than CT scan for detection of central nervous system (CNS) metastasis. MRI may be used when findings of superior sulcus and brachial plexus tumors are equivocal on CT scans.

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

The skeletal system is common site of metastases for lung cancers. If patients report bone pain or if their serum calcium and/or alkaline phosphatase levels are elevated, a bone scan should be obtained to search for bone metastases (see the image below).

PET scanning (see the image below) using fluoro-18–2-deoxyglucose (FDG) has proven to be an excellent modality for evaluating solitary pulmonary nodules and has been approved by the US Food and Drug Administration (FDA) for this indication. The average sensitivity and specificity of FDG-PET scanning for detecting a malignancy was reported to be 0.97 and 0.78, respectively.[50] However, a meta-analysis by Deppen and colleagues found that FDG-PET had lower specificity for diagnosing malignancies in areas with endemic infectious lung disease compared with areas with nonendemic disease.[51]

Studies also suggest that PET scanning is useful for searching for systemic spread if other diagnostic modalities cannot clarify an abnormality that may change the treatment of the patient’s condition. However, false-positive and false-negative results occur.

Additional data have emerged that underscore the importance of PET scanning in patients with NSCLC. PET scans appear to be more sensitive, specific, and accurate than CT scans for staging mediastinal disease. Whereas radiographs and CT scans show images of structures, PET scans reveal the nature of the area under study. PET scans often detect abnormalities not demonstrated on CT scans.

Published reports suggest that staging of NSCLC may be influenced by PET scan results in up to 60% of the cases and that as many as 25% of cases may be upstaged after PET scanning.

Caution is required when interpreting the results of PET scans in patients who may be denied potentially curative surgical resection based on PET results.

Go to Imaging in Non-Small Cell Lung Cancer for complete information on this topic.

Centrally located endobronchial tumors may exfoliate malignant cells into sputum. (This location and tendency to exfoliate are most common in squamous cell carcinomas [SCCs].) Therefore, sputum cytology can be a quick and inexpensive diagnostic test if results are positive. The false-positive rate for sputum cytology is 1%, but the false-negative rate is as high as 40%.

Sputum cytology does not provide reliable distinction between different histologic subtypes. Discordant results are often observed between cytologic and histologic findings of specimens obtained from bronchoscopy or transthoracic biopsy.

The diagnostic accuracy of sputum cytology depends on rigorous specimen sampling (at least 3 specimens) and preservation techniques, as well as on the location (central vs peripheral) and size of the tumor.[52] The test detects 71% of central tumors but less than 50% of peripheral tumors; therefore, further testing must always follow a negative result.

Several large studies have not revealed that screening with sputum cytology and chest radiography is cost-effective in early detection. In one small study, a cytologic specimen was used to measure EGFR and KRAS mutations; however, this practice still needs to be validated.[53]

Sputum cytology is suggested for high-risk patients in whom semi-invasive procedures such as bronchoscopy or transthoracic needle aspiration (see below) might pose a higher risk. Currently, however, with the development of advanced x-ray imaging techniques and biopsy procedures, sputum cytology is not commonly employed in the diagnosis of NSCLC.

When a lung cancer is suggested, bronchoscopy provides a means for direct visualization of the tumor, allows determination of the extent of airway obstruction, and allows collection of diagnostic material under direct visualization with direct biopsy of the visualized tumor, bronchial brushings and washing, and transbronchial biopsies.

The decision whether to pursue a diagnostic bronchoscopy for a lesion that is suspected of being lung cancer largely depends on the location of the lesion (central vs peripheral).[54] Bronchoscopy is the study of choice in patients with central tumors, with a combined sensitivity of 88%. The addition of transbronchial needle aspiration with endobronchial ultrasound to obtain cytology or histology samples when there is submucosal tumor spread or peribronchial tumor causing extrinsic compression further increases the sensitivity of bronchoscopy.[55]

Transthoracic needle biopsy, guided by CT or fluoroscopy, is preferred for tumors located in the periphery of the lungs because peripheral tumors may not be accessible through a bronchoscope. A positive finding for cancer is reliable; however, the false-negative rate is high at 26%, and, thus, transthoracic biopsy is generally not useful in ruling out cancer.

Diagnostic material can also be obtained from other abnormal sites (eg, enlarged palpable lymph nodes, liver, pleural or pericardial effusions, accessible bone lesions).

Needle thoracentesis is both diagnostic and therapeutic in patients presenting with respiratory distress. Thoracentesis has a sensitivity of only 80% with a specificity greater than 90%. In patients suspected of having lung cancer who have an accessible pleural effusion, if the pleural fluid cytology finding is negative (after at least 2 thoracenteses), thoracoscopy is recommended as the next step to aid in diagnosis.

Thoracoscopy is usually reserved for tumors that remain undiagnosed after bronchoscopy or CT-guided biopsy. Thoracoscopy is also an important tool in the management of malignant pleural effusions.

Video-assisted thoracoscopy (VATS) is a newer modality that may be used to sample small peripheral tumors (less than 2 cm in diameter), pleural tumors, or pleural effusions for diagnostic or staging purposes.[55] It is safe and can provide a definitive diagnosis with a high degree of accuracy and minimal risk to the patient. The reported sensitivity rate ranges between 0.80 and 0.99, the specificity rate ranges between 0.93 and 1, and the negative predictive value ranges between 0.93 and 0.96.[55] Survival with assisted VATS is comparable to complete VATS and can be cost-effective.[56]

Mediastinoscopy

Mediastinoscopy may be used to obtain tissue from cancer that has infiltrated into the mediastinum.[57] It is usually performed to evaluate the status of enlarged mediastinal lymph nodes (seen on CT scan) before attempting definitive surgical resection of lung cancer.

Molecular testing forms an important part of the full pathologic evaluation of patients with metastatic non–small cell lung cancer (NSCLC), because very effective, less toxic, targeted treatments have become available for NSCLC with specific molecular abnormalities. Testing should include the following:

• Epidermal growth factor receptor ( EGFR) mutation
• Anaplastic lymphoma kinase ( ALK) rearrangement
• BRAF V600E  mutation
• RET rearrangement
• ROS-1 rearrangement
• NTRK 1/2/3 gene fusion
• MET exon 14 skipping
• KRAS G12C mutation
• Programmed death ligand 1 (PD-L1) expression

According to international evidence-based guidelines jointly published by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP), all lung cancer patients with adenocarcinomas should be tested for the genetic abnormalities that indicate suitability for treatment with targeted agents, irrespective of clinical variables such as sex, ethnicity, or smoking status.[58]  Clinical trial data demonstrate that patients who are tested for these abnormalities and treated with the appropriate targeted therapy have better outcomes.[58]  

Testing for driver mutations (eg, fusion, amplification, deletion) in the above-listed genes can be used to determine whether targeted therapy is appropriate. PD-L1 expression is based on the tumor proportion score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. Certain PD-L1 inhibitors may indicated in cases where the TPS is 1% or greater (eg, pembrolizumab), while others may be indicated in patients with a TPS of 50% or greater (eg, cemiplimab).

In 2013, the US Food and Drug Administration (FDA) approved the cobas EGFR Mutation Test, a companion diagnostic for erlotinib.[59] This is the first FDA-approved companion diagnostic that can detect EGFR gene mutations. The mutation test allows physicians to identify patients with NSCLC who are candidates for receiving erlotinib as first-line therapy.

The safety and effectiveness of the cobas EGFR Mutation Test was established with clinical data from the EURTAC study and showed progression-free survival in patients with NSCLC who had specific types of EGFR mutations (exon 19 deletions or exon 21 [L858R] substitution mutations) for 10.4 months when they received erlotinib treatment, compared with 5.4 months for those who received standard therapy.[60]

For more information, see Genetics of Non-Small Cell Lung Cancer.

The updated World Health Organization (WHO) classification of lung cancer is widely used. Non–small cell lung cancer (NSCLC) includes squamous cell carcinoma (SCC), adenocarcinoma, and large cell carcinoma. Some lung cancers exhibit two or more histologic patterns. SCC was previously the most common type of NSCLC, but adenocarcinoma appears to be increasing in incidence, especially in women.

SCC has a distinct dose-response relationship to tobacco smoking and usually develops in proximal airways, progressing through stages of squamous metaplasia to carcinoma in situ. Well-differentiated SCCs contain keratin pearls, while poorly differentiated SCCs may stain positive for keratin. Microscopic examination reveals cells with large, irregular nuclei and coarse nuclear chromatin with large nucleoli. Cells are arranged in sheets, and the presence of intercellular bridging is diagnostic.

Histologically, adenocarcinomas form glands and produce mucin. Mucin production can be identified with mucicarmine or periodic acid-Schiff staining. The WHO classification of lung cancer divides adenocarcinomas into (1) acinar, (2) papillary, (3) bronchoalveolar, and (4) mucus-secreting. Bronchoalveolar carcinoma is a distinct clinicopathologic entity that appears to arise from type II pneumocytes and may manifest as a solitary peripheral nodule, multifocal disease, or a pneumonic form, which can spread rapidly from one lobe to another.

Stage for stage, adenocarcinomas are associated with worse prognoses than SCCs, with the exception of T1 N0 M0 tumors.

Large cell carcinoma is the least common of all NSCLCs. It is composed of large cells with prominent nucleoli, and no mucin production or intercellular bridging is identified. Many tumors previously diagnosed as large cell carcinomas are identified as poorly differentiated adenocarcinomas or SCCs after advanced immunohistochemical staining, electron microscopy, and monoclonal antibody studies.

A variant of large cell carcinoma has been identified; it contains neuroendocrine features and is called large cell neuroendocrine carcinoma. Large cell neuroendocrine carcinomas are associated with a worse prognosis than large cell carcinomas.

WHO classification of epithelial lung tumors

WHO divides epithelial lung tumors into preinvasive lesions and invasive malignant lesions. Preinvasive lesions include the following:

• Squamous dysplasia/carcinoma in situ

• Atypical adenomatous hyperplasia

• Diffuse idiopathic pulmonary neuroendocrine hyperplasia

Invasive malignant lesions include the following:

• Squamous cell carcinoma – Variants, papillary, clear cell, small cell, basaloid

• Small cell carcinoma – Variant, combined small cell carcinoma

• Adenocarcinoma – Acinar, papillary, bronchoalveolar, nonmucinous (Clara cell/type II pneumocyte) type, mixed mucinous and nonmucinous (Clara cell/type II pneumocyte and goblet cell) type or intermediate cell type, solid adenocarcinoma with mucin formation, adenocarcinoma with mixed subtypes, variants, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet-ring adenocarcinoma, clear cell adenocarcinoma

• Large cell carcinoma – Variants, large cell neuroendocrine carcinoma, combined large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepitheliomalike carcinoma, clear cell carcinoma, large cell carcinoma with rhabdoid phenotype

• Adenosquamous carcinoma

• Carcinoma with sarcomatoid, pleomorphic, or sarcomatous elements - Carcinoma with spindle or giant cells, pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, pulmonary blastoma

• Carcinoid tumors - Typical carcinoid, atypical carcinoid

• Carcinoma of salivary gland type - Mucoepidermoid carcinoma, adenoid cystic carcinoma, others

• Unclassified

The most important prognostic indicator in lung cancer is the extent of disease and lymph node involvement. The American Joint Committee for Cancer Staging and End Results Reporting has developed the TNM (tumor-node-metastasis) staging system, which takes into account the degree of spread of primary tumor, the extent of regional lymph node involvement, and the presence or absence of distant metastases (see the table below).[61] The TNM system is used for all lung carcinomas except SCLCs.

AJCC TNM staging and grouping system

Primary tumor (T) involvement is as follows:

• TX - Primary tumor cannot be assessed

• T0 - No evidence of primary tumor

• Tis - Carcinoma in situ; squamous cell carcinoma in situ; adenocarcinoma in situ; adenocarcinoma with pure lepidic pattern, 3 cm or less in greatest dimension

• T1 - Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (not in the main bronchus)

• T1mi - Minimally invasive adenocarcinoma: adenocarcinoma (3 cm or less in greatest dimension) with a predominantly lepidic pattern and 5 mm or less invasion in greatest dimension

• T1a - Tumor 1 cm or less in greatest dimension

• T1b - Tumor more than 1 cm but 2 cm or less

• T1c - Tumor more than 2 cm but 3 cm or less

• T2 - Tumor more than 3 cm but 5 cm or less, or one with any of the following features:(1) Involves the main bronchus, regardless of distance to the carina, but without involvement of the carina; (2) Invades visceral pleura (PL1 or PL2); (3) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung

• T2a - Tumor more than 3 cm but 4 cm or less

• T2b - Tumor more than 4 cm but 5 cm or less

• T3 - Tumor more than 5 cm but 7 cm or less, or one that invades any of the following: : parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary 

• T4 - Tumor more than 7 cm, or of any size that invades one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary

Lymph node (N) involvement is as follows:

• NX - Regional nodes cannot be assessed

• N0 - No regional node metastasis

• N1 - Metastasis in ipsilateral peribronchial and/or ipsilateral hilar nodes and intrapulmonary nodes, including involvement by direct extension

• N2 - Metastasis in ipsilateral mediastinal and/or subcarinal node

• N3 - Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene node, or supraclavicular node

Metastatic (M) involvement is as follows:

• MX - Distant metastasis cannot be assessed

• M0 - No distant metastasis

• M1 - Distant metastasis

• M1a - Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion

• M1b - Single extrathoracic metastasis in a single organ (including involvement of a single nonregional node)

• M1c - Multiple extrathoracic metastases in one or more organs

AJCC prognostic groups for NSCLC comprise 4 stages, with further subdivision of stages into subtypes. These stages have important therapeutic and prognostic implications, which are discussed later.

Stage grouping of the TNM system is as follows:

• Stage 0 - TisN0M0
• Stage IA1- T1miN0M0 / T1aN0M0
• Stage IA2 - T1bN0M0
• Stage IA3 - T1cN0M0
• Stage IB - T2aN0M0
• Stage IIA - T2bN0M0
• Stage IIB - T1aN1M0 / T1bN1M0 / T1cN1M0 / T2aN1M0 / T2bN1M0 /  T3N0M0
• Stage IIIA - T1aN2M0 / T1bN2M0 / T1cN2M0 / T2aN2M0 / T2bN2M0 /T3N1M0 / T4N0M0 / T4N1M0
• Stage IIIB - T1aN3M0 / T1bN3M0 / T1cN3M0 / T2aN3M0 / T2bN3M0 / T3N2M0 / T4N2M0 
• Stage IIIC - T3N3M0 / T4N3M0
• Stage IVA - Any T, any N, M1a or M1b
• Stage IVB - Any T, any N, M1c
• M1a designates metastasis within the thoracic cavity
• M1b designates a single extrathoracic metastasis
• M1c designates multiple extrathoracic metastases

Go to Imaging in Lung Cancer Staging and Non-Small Cell Lung Cancer Staging for complete information on this topic.

See also Lung Cancer Staging -- Radiologic Options, a Critical Images slideshow, to help identify stages of the disease process.

Patients with CNS metastasis, immunosuppression, superior vena cava syndrome (SVCS), Pancoast tumor, and/or Ogilvie intestinal pseudo-obstruction may require specific workup, as described below. If no pathologic process is present, discharge the patient with a prescription for continuous analgesic use until follow-up care can be arranged with the patient’s personal physician.[62]

Patients with CNS metastasis and known cancer

Head CT scanning, with and without contrast enhancement to depict masses, may be indicated. Obtain a neurosurgical consultation. Admit patients for possible whole-brain irradiation or resection.

Headache and brain edema may respond to dexamethasone (10 mg IV). Seizures are treated with anticonvulsants, but patients with brain metastases and no history of seizures do not generally require anticonvulsant therapy.[63]

Immunosuppressed patients with cancer and infections

Obtain a CBC for evaluation of neutropenia and other blood cell derangements. Assess electrolyte levels for signs of dehydration. The chest radiograph may show only subtle infiltrate. If diarrhea is present, perform urinalysis with a culture, blood cultures with samples from peripheral sites, cultures with samples from any indwelling catheters, and stool cultures for Clostridium difficile.

Administer broad-spectrum empiric antibiotics (eg, piperacillin, gentamicin, second- or third-generation cephalosporin) and an aminoglycoside. If the patient has a penicillin allergy, replace penicillin with carbapenem (if mild penicillin allergy) or aztreonam.

Treatment with granulocyte colony-stimulating factor (G-CSF) may be appropriate for raising neutrophil levels. Consultation with an oncologist is indicated to begin G-CSF therapy.

Patients with Pancoast tumor

An MRI is superior to a CT scan in depicting superior sulcus tumors. Admit the patient for transthoracic needle aspiration. Perform bronchoscopy if endobronchial involvement is present.

Patients with SVCS

Lung cancer accounts for 60-80% of SVCS. Head elevation, cautious administration of fluids, and supplemental oxygen is indicated. Diuretics and glucocorticoids (methylprednisolone 125 mg IV) may help with symptoms, but their roles are unclear. Definitive treatment is usually by radiotherapy or chemotherapy and/or vena caval stenting.

Patients with Ogilvie intestinal pseudo-obstruction

Abdominal radiograph shows massive dilation of the colon and small intestine, with or without air-fluid levels. Check electrolyte levels and correct abnormalities. Place a nasogastric tube and rectal tube.

Admit the patient for possible colonic decompression and treatment of the underlying cause (eg, lung cancer producing autoantibodies to the myenteric neural plexus). For cancer patients with severe pain and advanced disease, administer opioid analgesics. Nasogastric tube and rectal tube placement may help with pain.

Since the publication of the National Lung Screening Trial results in 2011, which demonstrated that annual low-dose computed tomography (LDCT) allows for early detection and reduces lung cancer mortality by 20%,[64] screening for lung cancer in patients at high risk has become the standard of care in the United States.[47] Over time, the trend has been to increase screening eligibility to a larger number of patients, by extending the age range and reducing the smoking history for screening eligibility. Currently, guidelines from the American Cancer Society (ACS), American College of Chest Physicians (CHEST), National Comprehensive Cancer Network (NCCN), and U.S. Preventive Services Task Force (USPSTF) provide similar criteria sets for offering annual screening with LDCT scanning (see the table below).[39, 65, 47, 66]

Table. Criteria for lung cancer screening (Open Table in a new window)

American Cancer Society guidelines exclude patients from screening if they have any of the following[39] :

• Health conditions that may increase harm or hinder further evaluation, surgery, or other treatment for lung cancer.
• Comorbid conditions that limit life expectancy to less than 5 years
• Unwillingness to accept treatment for cancer detected by screening

In addition to smoking, the NCCN guidelines include the presence of one or more of the following additional factors as an indication of high risk[65] :

• Radon exposure (documented sustained and substantially elevated)
• Occupational exposure to carcinogens (eg, silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel fumes, nickel, coal smoke, soot)
• Cancer history (eg, lymphomas, head and neck cancer; however, patients with previous lung cancer are ineligible for screening)
• Family history of lung cancer in first-degree relatives
• Disease history (chronic obstructive pulmonary disease [COPD] or pulmonary fibrosis)
• Second-hand smoke exposure

The NCCN recommends using a risk calculator to enhance determination of risk status.

The NCCN notes that evidence from randomized trials supports screening up to age 77 years, but screening beyond age 77 years may be considered as long as the patient's functional status and comorbidity allow consideration for curative-intent therapy.[65]

Using data from the National Health Interview Survey, Cheung et al estimated the number of US smokers eligible for screening on the basis of either USPSTF criteria or the Lung Cancer Risk Assessment Tool and the number of lung cancer deaths preventable with each method. They determined that with risk-based screening, more people would be screened and more deaths prevented. In 2015, risk-based screening would have prevented 5000 more lung cancer deaths than USPSTF-based screening.[67]  However, an analysis by Kumar et al concluded that risk-based screening provides only attenuated and modest benefits with respect to life-years, quality-adjusted life-years, and cost-effectiveness.[68]

A randomized trial designed to assess the value of prolonged lung cancer screening beyond 5 years found LDCT screening benefit improved beyond the 5th year of screening, with a 58% reduced risk of lung cancer mortality (HR 0.42; 95% CI 0.22–0.79), and 32% reduction of overall mortality (HR 0.68; 95% CI 0.49–0.94).[69]

Limitations of screening

In a 2013 analysis of data on 53,452 individuals at high risk for lung cancer, derived from the National Lung Screening Trial, Patz et al determined that performing lung screens with LDCT scanning carries a 22.5% probability of NSCLC overdiagnosis (ie, detection of indolent cancers), as well as an 18.5% probability of overdiagnosis for lung cancer in general. Patz et al concluded that overdiagnosis—which can lead to increases in treatment costs, anxiety, and treatment-related morbidity—should be a consideration when physicians are discussing the risks of LDCT lung cancer screening.[70]

Subsequently, in a retrospective cohort analysis of data from the National Lung Screening Trial participants, Patz et al reported that patients whose initial LDCT scan is negative have a lower incidence of lung cancer and lung cancer-specific mortality. These authors proposed that a longer interval between screens might be warranted in patients whose initial LDCT screening scan is negative.[71]

In this study, lung cancer incidence per 100,000 person-years was 371.88 in the 19,066 participants with a negative LDCT, versus 661.23 in the overall cohort of 26,231 participants. Lung cancer–related mortality rates per 100 000 person-years were 185.82 versus 277.20 for the two cohorts, respectively.[71]

In a study by Kinsinger et al of lung cancer screening in 2106 patients at Veterans Health Administration medical centers, LDCT identified nodules in 59.7% of screened patients, but just 1.5% of patients had lung cancer diagnosed within 330 days. The rate of false-positive test results was 97.5%. These authors concluded that implementing a lung cancer screening program for Veterans Health Administration patients "would potentially require substantial resources and effort by clinical staff and facilities for an uncertain benefit of reduced mortality from lung cancer."[72]

Risk models for screening

A study by researchers from the National Cancer Institute (NCI) and the American Cancer Society that reviewed nine risk prediction models determined that the following four models were more accurate than the others for predicting lung cancer risk and for selecting patients who had ever-smoked for lung cancer screening:

• Bach model
• Ovarian Cancer Screening Trial Model 2012 (PLCO-M2012)
• Lung Cancer Risk Assessment Tool (LCRAT)
• Lung Cancer Death Risk Assessment Tool (LCDRAT)

Although the researchers concluded that that any of those models could be used to select US smokers who are at the greatest risk for lung cancer incidence or death, all the models have limitations. The Bach model does not account for race/ethnicity, family history of lung cancer, or presence of chronic obstructive pulmonary disease; the PLCO-M2012 model underestimated lung cancer risk in people of Hispanic descent by a factor of 2 to 3, and the LCRAT and LCDRAT models both underestimated risk in the "Asian/other" subgroup.[73]

Biomarker screening

A collaborative study has identified and validated a panel of circulating protein biomarkers that may improve lung cancer risk assessment and may be used to define eligibility for CT screening.[74] Using prediagnostic blood samples from patients at high risk for lung cancer, the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium for Early Detection of Lung Cancer created a risk assessment tool consists of a panel of the following proteins:

• Cancer antigen 125
• Carcinoembryonic antigen
• Cytokeratin-19 fragment
• The precursor of surfactant protein B

In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls, an integrated risk prediction model that combined smoking exposure with the biomarker panel score identified 40 of the 63 lung cancer cases, corresponding to a sensitivity of 0.63. By comparison, the US Preventive Services Task Force screening criteria demonstrated a sensitivity of 0.42 for these cases.[74]

Surgery is the treatment of choice for patients with non–small cell lung cancer (NSCLC) stages I through IIIA.[11] In addition, patients with resected lung cancer have a high risk of relapse and so are treated with adjuvant chemotherapy.[75] Patients with stage IIIB and IV NSCLC are usually offered chemotherapy with the option of surgery. Molecular-targeted therapy plays an increasingly important role in the treatment of advanced NSCLC.

The success of molecular-targeted therapy in advanced NSCLC has raised interest in preoperative therapy of resectable early-stage NSCLC.[76] In March 2022, the US Food and Drug Administration (FDA) approved the neoadjuvant use of the immune checkpoint inhibitor nivolumab, in combination with platinum-doublet chemotherapy, for patients with resectable NSCLC (tumors ≥4 cm or node positive). Approval was based on results of the CheckMate 816 trial, which included patients with stage IB, II, or IIIA NSCLC.[77, 78] Studies of other biologic agents for neoadjuvant therapy are currently in progress.

Radiation is a reasonable option for treatment in patients who are not candidates for surgery. The role of adjuvant radiation therapy after resection of the primary tumor remains controversial.

See Non-Small Cell Lung Cancer Treatment Protocols for details of treatment regimens. Go to Oncology Decision Point for expert commentary on NSCLC treatment decisions and related guidelines. To view multidisciplinary tumor board case discussions, see the Memorial Sloan Kettering e-Tumor Boards Stage IV NSCLC with Brain Metastases and Spindle Cell NSCLC with Recurrence of Previously Resected Tumor.

Because most NSCLC cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of treatment. Increasing evidence supports offering palliative care concurrently with standard oncologic care at the initial diagnosis of advanced NSCLC.[79]

For example, a clinical trial found that patients with metastatic NSCLC randomized to early palliative care had a better quality of life and, surprisingly, longer median survival than those randomized to standard oncologic care alone. The palliative care group also had less depressive symptoms, and fewer patients in this group received aggressive end-of-life care.[80]

Outline of treatment options by stage 

Treatment of NSCLC by stage is as follows:

• Stage IA - Surgery only; no adjuvant chemotherapy
• Stage IB-IIIA - Surgery followed by adjuvant chemotherapy with four cycles of a cisplatin-based regimen and, in cases with an EGFR  exon 19 deletion or exon 21 L858R mutation, adjuvant osimertinib
• Stage II-IIIB - If surgically unresectable, chemoradiation plus durvalumab for one year if chemoradiation results in a partial or complete response 
• Stage IV - Treat on the basis of histology (squamous or non-squamous) and molecular profile and biomarkers

Treatment of stage IV squamous NSCLC is as follows:

• Cisplatin-based chemotherapy
• If programmed death ligand 1 (PD-L1) expression is 1-49%, chemotherapy plus pembrolizumab
• If PD-L1 expression is > 50%, pembrolizumab alone

Treatment of stage IV non-squamous NSCLC is as follows:

• If PD-L1 expression is 1-49%, cisplatin-based chemotherapy plus pembrolizumab
• If PD-L1 expression is > 50%, pembrolizumab alone
• Cisplatin-based chemotherapy plus bevacizumab is also a reasonable option
• Oral tyrosine kinase inhibitor or other targeted therapy for tumors with treatable driver mutations (eg,  EGFR, ALK, ROS1, RET, BRAF, NTRK gene fusion, MET exon 14 skipping; see Workup/Molecular Testing)

Emergency treatment

All patients thought to have lung cancer should be encouraged to obtain follow-up care with their primary care physician. In almost all cases, document the possible diagnosis and discuss it with the patient. Definitive treatment of the underlying cancer is not the purview of the emergency department (ED).

Emergency treatment is based on symptoms. In cases of upper airway obstruction, admit the patient to the intensive care unit (ICU), prepare for intubation and/or cricothyrotomy, and obtain otolaryngologic and/or surgical consultation for fiberoptic laryngoscopy or intraoperative tracheostomy.

If hemoptysis is noted, administer supplemental oxygen and perform suctioning. If a threat of imminent demise exists, consider placing a double-lumen endotracheal tube. Position the patient with the bleeding hemithorax in a dependent position. Perform arterial blood gas (ABG) and complete blood count (CBC) (type and crossmatching) coagulation studies if the bleeding is more than trivial. A pulmonologist may have to perform fiberoptic bronchoscopy. Admit patients, except those with the most minor bleeding, to the ICU.

Surgical resection remains the mainstay of treatment for all patients with stage I and II NSCLC—that is, those patients with no evidence of mediastinal disease or invasion of local organs. Lobectomy is the procedure of choice. Outcomes are better when the procedure is performed by a surgeon with specialty training, or is done in a higher-volume center or in a teaching facility.[81]

A study of patients who underwent planned resection after an unexpected finding of N2 disease at the time of thoracoscopy or thoracotomy found that proceeding with lobectomy did not appear to compromise outcomes if adjuvant chemotherapy with or without radiation therapy was administered following surgery.[82]

The role of surgery for stage III disease is controversial. (See Stage-Based Management.) Patients with completely resectable primary tumors (ie, T4 N0) have a much better prognosis than those with spread to ipsilateral mediastinal or subcarinal lymph nodes (ie, N2), signifying that spread beyond the primary tumor is associated with a poor prognosis. Patients with stage IIIB or IV tumors are almost never surgical candidates.

Preoperative evaluation

Preoperative evaluation should include a careful assessment of resectability, cardiopulmonary reserve, and perioperative risk. High-resolution computed tomography (CT) and positron emission tomography (PET) scanning are helpful for preoperative planning in early-stage lung cancer.[83]

As a general guideline, most patients with a preoperative forced expiratory volume in one second (FEV1) of greater than 2.5 L are able to tolerate pneumonectomy. With an FEV1 of 1.1-2.4 L, a lobectomy is possible. Patients with an FEV1 of less than 1 L are not considered candidates for surgery. These factors are further modified by the presence of cardiac disease or other comorbid conditions.

Lobectomy and pneumonectomy

The standard surgical approach remains a lobectomy, which helps preserve pulmonary function while allowing a good resection. Hilar and other proximal tumors may require more extensive surgery, including a pneumonectomy, which carries significant operative mortality and long-term morbidity. In such patients, alternative approaches such as sleeve resection may be of value.[84]

Retrospective data from the Surveillance, Epidemiology, and End Results (SEER) database show that lobectomy and segmentectomy result in similar survival among patients with small lung cancers (< 1 cm).[85] A phase III trial in 697 patients with peripheral stage IA NSCLC, with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, reported that on median follow-up of 7 years, sublobar resection was noninferior to lobar resection with respect to disease-free survival, and that overall survival was similar with the two procedures.[86]

For more information, see Pneumonectomy.

Wedge resection/segmentectomy

Sublobar resections are used for patients with poor pulmonary reserve and are increasingly being used in conjunction with video-assisted thoracoscopic surgery (VATS). An older Lung Cancer Study Group trial, of stage IA cancers randomized to standard lobectomy versus sublobar resections, suggested a much higher local recurrence rate (75%), with a near-significant trend towards an increased cancer-specific mortality of 50%.[87]

However, a review of SEER data from 1988-2008 found that the survival benefit of lobectomy over sublobar resection for stage I NSCLCs ≤ 2 cm in size decreased over that time. By 2005-2008, both wedge resections and segmentectomies were equivalent to lobectomy.[88] A Cancer and Leukemia Group B (CALGB) phase III trial randomizing patients to lobectomy or limited resection for small peripheral IA lesions is ongoing, and should provide more clarity in this area.[87]

In patients older than 74 years with stage IA NSCLC, Okami et al found no significant difference in 5-year survival after sublobar resection versus standard lobectomy, although locoregional recurrence rates were higher after sublobar resection.[89] A study by Wolf et al showed that sublobar resection is a reasonable option for elderly patients with compromised cardiopulmonary status.[90]

For more information, see Thoracoscopic Wedge Resection and Lung Segmentectomy and Limited Pulmonary Resection.

Video-assisted thoracoscopic surgery

Video-assisted thoracoscopic surgery (VATS) is a minimally invasive surgical modality being used for both diagnostic and therapeutic lung cancer surgery. It offers low perioperative morbidity and mortality as well as decreased pain and hospitalization.

Recurrence rates and 5-year and long-term overall survival appear similar to those with traditional open thoracotomies. This approach is also better tolerated in older populations.[91] Finally, patients treated with VATS appear to have fewer delays and dose reductions in adjuvant chemotherapy. Practice guidelines suggest that VATS is feasible as long as adequate resection is possible.[92, 93]

For more information, see Video-Assisted Thoracoscopic Surgery (VATS).

Mediastinal lymphadenectomy

The role of routine mediastinal lymphadenectomy versus lymph node sampling remains controversial. The authors of a large randomized trial recommend that an adequate mediastinal lymphadenectomy should include exploration and removal of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right-side cancers and stations 4L, 5, 6, 7, 8, and 9 for left-side cancers.[94]

For details on this procedure, see Mediastinal Lymphadenectomy.

Postoperative evaluation and complications

Residual pulmonary function after surgical resection is estimated using pulmonary function tests and radionuclide lung scans.

A study by Allen et al assessed curative-intent resections in a major US metropolitan area. The study found that most resections did not achieve good quality surgical resection (GQR) standards.[95] Although surgical sampling of mediastinal (level 2) lymph nodes was most lacking, evaluation of level 1 lymph nodes was also suboptimal. Further studies are indicated to assess surgical practices in order to achieve minimum standards for accurate staging, prognostication, and eligibility for clinical trials.

An understanding of post-surgical quality of life can help surgeons provide lung cancer patients with important information regarding postoperative outcomes. A study that measured health-related quality of life (HRQOL) in patients who underwent lung cancer surgery found that survivors exhibited clinically meaningful worse dyspnea, coughing, chest pain, and financial problems than the general population.[96]

The perioperative mortality rate is 6% for pneumonectomy, 3% for lobectomy, and 1% for segmentectomy. These rates reflect improvements in anesthesia and surgical techniques.

In the treatment of stage I and stage II NSCLC, radiation therapy alone is considered only when surgical resection is not possible because of limited pulmonary reserve or the presence of comorbidities.[2] Radiation is a reasonable option for lung cancer treatment in patients who are not candidates for surgery.[3] Radiation therapy alone as local therapy, in patients who are not surgical candidates, has been associated with 5-year cancer specific survival rates of 13-39% in early-stage NSCLC (ie, T1 and T2 disease).[97]

This inferior survival reflects the poor functional status of these patients, as well as the likelihood of these patients actually having a higher stage, given the known limitations of clinical staging. Survival appears to be enhanced by the use of hyperfractionation schedules, such as continuous hyperfractionated accelerated radiotherapy (CHART) at 1.5 Gy 3 times a day for 12 days, as opposed to conventional radiation therapy at 60 Gy in 30 daily fractions. Overall survival at 4 years was 18% vs 12%.

A study by Jeremić et al assessed independent prognosticators of outcome for hyperfractionated radiation therapy treatment.[98] The study found that female sex, lower Karnofsky performance score (KPS), less pronounced weight loss, squamous histology, lower stage, shorter interfraction interval, and treatment independently predicted better overall survival and progression-free survival. Age did not influence overall survival or progression-free survival.

A retrospective study of 722 patients with NSCLC undergoing radiotherapy who were taking beta blockers for another condition found that these patients had better overall survival, disease-free survival, and distant metastasis–free survival than patients not taking these drugs. Data showed a 22% improvement in overall survival in the beta-blocker group. However, there was no improvement in locoregional progression-free survival, which suggests that beta blockers affect the metastatic tumors rather than the primary tumor.[4]

In a population-based study of 10,376 elderly patients with unresectable stage III NSCLC who were not candidates for chemotherapy, treatment with radiotherapy alone (specifically, complex radiotherapy) was associated with significantly improved survival. Median overall survival was found to be 9 months in the radiation-treated group (n=6468) and 7 months in the untreated patient group.[99]

However, this was benefit was seen only in patients treated with complex radiotherapy, not in those who received intermediate complexity radiotherapy. In addition, patients treated with radiation were more likely to be hospitalized with pneumonitis or esophagitis.

Stereotactic body radiotherapy (SBRT) is another technique for nonoperative treatment of early-stage lung cancers. SBRT uses precise targeting of high-dose radiation to the tumor, typically in 1-2 fractions, while minimizing toxicity to normal tissues. Patients best suited for SBRT include those with a peripheral node-negative tumor that is less than 5 cm, in whom definitive surgery is contraindicated.

In a phase II study by Timmerman et al, use of SBRT in patients with inoperable NSCLC resulted in a 3-year survival rate of 55.8% (versus the 20%-35% seen with current management), high rates of local tumor control, and moderate treatment-related morbidity.[100] A large Japanese retrospective analysis showed that patients treated with SBRT at doses higher than 100 Gy had a local recurrence rate of 8.4%, and a 5-year overall survival of 70.8%.[101] Randomized studies of SBRT are being conducted by the Radiation Therapy Oncology Group (RTOG).

SBRT was associated with shorter overall survival but similar recurrence rates and cause-specific mortality in a nonrandomized study by Grills et al. The study compared outcomes in patients with stage T1-2N0M0 NSCLC who were ineligible for lobectomy and thus underwent either wedge resection or, if deemed medically inoperable, SBRT.[102]

Radiofrequency ablation (RFA) has also been used for inoperable patients who have peripheral tumors that are less than 3 cm in size, and occasionally in a palliative setting. In a single small nonrandomized prospective study, 2-year overall survival with stage I NSCLC was 75% (45-92%). This may be an option for patients in whom both surgery as well as traditional external beam radiation therapy may be contraindicated.[103]

Planning 4-dimensional computed tomography (4DCT) scans can be used to minimize target volumes for lung cancer radiotherapy, but 4DCT results may not be fully representative of patient movement during radiotherapy. Dutch investigators have reported that megavoltage cinema images can identify patients in whom planning 4DCT scans are not representative and thus could be helpful in the treatment of small lesions.[104]

Adjuvant radiation therapy

The role of adjuvant radiation therapy after resection of the primary tumor remains controversial.[105, 106] Radiation therapy reduces local failures in completely resected (stages II and IIIA) NSCLC but has not been shown to improve overall survival rates. In one study, 5-year overall survival was actually worse (30% vs 53%). A retrospective SEER analysis also showed that survival was lower for this population.

A single phase III study using small fractions, with 3D treatment planning, showed a 5-year survival benefit in the radiation treatment arm (67% vs 58%).[107] This finding has not been replicated; hence, at this time, postoperative radiation therapy for stage I and II lung cancer is reserved for cases with positive margins, until further trials are conducted with modern radiation therapy planning and delivery.

The treatment of NSCLC has drastically changed over the past few years, with the advent of molecular-targeted agents. Nevertheless, cytotoxic chemotherapy retains a role in management..

Only 30-35% of patients with NSCLC present with sufficiently localized disease at diagnosis that curative surgical resection may be attempted (stages IA and IB, IIA and IIB, and IIIA). Furthermore, approximately 50% of patients who undergo surgical resection experience local or systemic relapse. Thus, approximately 80% of all patients with lung cancer are considered for chemotherapy at some point during the course of their illness.

At present, chemotherapy alone has no role in potentially curative therapy for NSCLC. Some trials have shown a survival benefit with adjuvant chemotherapy (ie, chemotherapy given after surgery) in resected stage IIA, IIB, and IIIA NSCLC, with a survival advantage of 5-10%.[108, 109] However, adjuvant chemotherapy in elderly patients with resected stage IIIA NSCLC is not associated with survival advantage.[110]

Two small, randomized trials have suggested that neoadjuvant chemotherapy (ie, chemotherapy given prior to surgery) prolongs survival in subjects with stage IIIA disease. Other similarly designed trials failed to confirm this.

Chemotherapy may be considered as part of multimodality therapy for locally advanced NSCLC and is used alone in the palliative treatment of stage IIIB NSCLC (owing to malignant pleural effusion) and stage IV NSCLC.[65] In advanced NSCLC, patients with good performance status (ie, 0-2 on the Zubrod or Eastern Cooperative Oncology Group [ECOG] scale) or greater than 70% on the Karnofsky scale; see the table below), and less than 10% body weight loss are good candidates for chemotherapy.

Large meta-analyses from 16 randomized trials showed a significant survival advantage to patients getting chemotherapy as opposed to best supportive care. One-year survival in the chemotherapy arm was 29% as opposed to 20% in those receiving supportive care alone. This survival benefit was present irrespective of age or histology. There appears to be no detriment in quality of life in the patients treated with chemotherapy; hence, palliative chemotherapy should be offered to all patients who are willing and able to receive chemotherapy.[111, 112]

NSCLC is only moderately sensitive to chemotherapy, with single-agent response rates in the range of 15% or better. Newer agents (eg, gemcitabine, pemetrexed, docetaxel, vinorelbine) have shown promising single-agent activity, with response rates from 20-25%.

A study by Wanders et al found that patients with stage III NSCLC who are 75 years and older could have improved survival if they are provided treatment with curative intent (eg, radiotherapy only, sequential chemotherapy and radiation).[113] In an observational cohort study of patients aged 65 years or older, the benefit of adjuvant chemotherapy was similar to that seen with younger patients. However, a subset analysis of patients aged 80 years or older suggested that adjuvant chemotherapy might have more adverse effects in this population.[114]

Platinum-based regimens

Cisplatin has been the cornerstone of most combination regimens studied in advanced NSCLC.[115] A meta-analysis of 16 trials comparing platinum-based regimens to nonplatinum agents showed a statistically significant improved response rate as well as 1-year survival favoring cisplatin. A beneficial trend was noted with carboplatin-based combinations but this was not significant. Gastrointestinal toxicity was higher with cisplatin.[116]

American Society of Clinical Oncology (ASCO) guidelines recommend that first-line treatment for NSCLC should include a platinum combination. In younger patients, with a good performance status or in the adjuvant setting, cisplatin is preferred, but in older patients or those with significant comorbidities, carboplatin may be substituted. Some trials have studied nonplatinum combinations such as gemcitabine with a taxane, which have shown noninferiority, and may be an option for selected patients.

Several randomized controlled trials have failed to show a clear superiority of one platinum-containing combination over another. A landmark ECOG trial comparing cisplatin-gemcitabine, cisplatin-paclitaxel, cisplatin-docetaxel, and carboplatin-paclitaxel, suggested similar overall response rates (approximately 19%), and median survival (7.9 mo). One- and 2-year overall survival was also similar at 33% and 11%, respectively.[117]

In 2012, the FDA approved protein-bound paclitaxel (Abraxane) for locally advanced or metastatic NSCLC, as first-line treatment in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. Approval was based on a single-phase, multicenter, randomized open-label study in which patients with advanced NSCLC received either weekly protein-bound paclitaxel plus carboplatin every 3 weeks or solvent-based paclitaxel plus carboplatin every 3 weeks.[118]

Patients who received the protein-bound paclitaxel demonstrated a statistically significantly higher overall response rate (ORR) compared with those in the solvent-based paclitaxel arm (33% vs 25%; P = 0.005). In patients with squamous histology, the ORR was also statistically superior in the protein-bound paclitaxel group (41% vs 24%; P < 0.001). There was no statistically significant difference in overall survival between the 2 study arms.[118]

The cisplatin-gemcitabine combination did appear to have an increased progression-free survival, compared with the standard treatment arm of cisplatin-paclitaxel (4.2 mo vs 3.4 mo), with increased kidney toxicity. This finding was confirmed by 2 Italian and Japanese studies, which showed similar efficacy of these combinations as measured by response rates or survival.

However, a meta-analysis comparing cisplatin-gemcitabine with other platinum-containing regimens suggested an improved median survival (9 vs 8.2 mo), and an absolute improvement in 1-year overall survival of 3.9% as compared with nongemcitabine combinations. This effect was not sustained when compared against other third-generation cisplatin combinations.[119]

A study by Quoix et al found that platinum-based doublet chemotherapy was associated with survival benefits among elderly patients with NSCLC compared with vinorelbine or gemcitabine monotherapy, despite increased toxic effects.[120] A separate study by Pallis et al found that chemotherapy treatment among older patients with NSCLC is feasible, with no significant differences in response compared with younger patients, although increased toxicity is noted.[121]

Histologic factors in chemotherapy responsiveness

For some time, NSCLC histology was thought to not impact chemotherapy responsiveness. A phase III trial comparing upfront cisplatin-pemetrexed with cisplatin-gemcitabine in stage III and IV NSCLC showed similar response rates (30.6% vs 28.2%), median survival (10.3 mo each), and 2-year overall survival (18.9% vs 14%). These were statistically similar.

However, in a preplanned subset analysis, median survival in patients with nonsquamous histology was significantly better with cisplatin-pemetrexed than with cisplatin-gemcitabine: 12.6 vs 10.9 mo for patients with adenocarcinoma and 10.4 vs 6.7 mo for those with large cell histology. In contrast, the patients with squamous cell histology did better with the cisplatin-gemcitabine combination: 10.8 vs 9.4 mo. Cisplatin-pemetrexed is now the preferred combination for adenocarcinoma.[122]

Genetic factors in resistance to platinum compounds

Although platinum-based chemotherapy is currently standard of care in NSCLC, data suggest that certain individual tumors may have inherent resistance to platinum compounds. Excision repair cross-complementation group 1 (ERCC1) is one such genetic abnormality, and high levels of ERCC1 messenger RNA in tumor tissue have been associated with resistance to platinum.

Holm et al found that, in patients receiving carboplatin and gemcitabine for inoperable NSCLC, the expression of ERCC1 had different effects on survival in men and women. In a retrospective study in 163 patients, men whose tumors were ERCC1 negative survived significantly longer than men with ERCC1 -positive tumors (median survival, 11.8 mo vs 7.9 mo). Conversely, ERCC1 status had no effect on survival in women.[123]

As with ERCC1, increased expression of ribonucleotide reductase subunit 1 (RRM1) has been associated with decreased response to gemcitabine and platinum.

Adjunct therapy after chemotherapy

In 2021, the FDA approved the programmed death ligand 1 (PD-L1) inhibitor atezolizumab for adjuvant treatment in patients with stage II to IIIA NSCLC and PD-L1 expression of 1% or higher, following resection and platinum-based chemotherapy. Approval was based on the phase III IMpower010 trial, in which median disease-free survival was not reached in patients on the atezolizumab arm compared with 35.3 months on the best supportive care arm.[124]

In January 2023, the FDA approved the PD-L1 inhibitor pembrolizumab for adjuvant treatment following resection and platinum-based chemotherapy in patients with stage IB (T2a, ≥ 4 cm), II, or IIIA NSCLC, at all levels of PD-L1 expression. Approval was based on results of the KEYNOTE-091 trial, in which median disease-free survival was 58.7 months in the pembrolizumab arm versus 34.9 months in the placebo arm.[117]

Second-line chemotherapy

Selected patients with good responses to first-line chemotherapy, good performance status, and a long disease-free period between initial chemotherapy and relapse may be candidates for second-line chemotherapy. Docetaxel and pemetrexed have been approved by the FDA in this clinical setting, but other drugs (eg, gemcitabine, vinorelbine), if not used in the first-line regimen, may result in similar palliation and clinical benefit.

Ramucirumab (Cyramza), a monoclonal antibody, approved in combination with docetaxel for metastatic NSCLC with disease progression on or after platinum-based chemotherapy. 

Approval was based on improved overall survival (OS) in a multicenter, double-blind, placebo-controlled study (n = 1253) in patients with previously treated metastatic NSCLC. Patients were randomized to receive either ramucirumab (10 mg/kg q3wk) in combination with docetaxel (75 mg/m2 q3wk) on day 1 of a 21-day cycle (n=628) or matching placebo plus docetaxel (n=625). Results showed a statistically significant prolonged OS and PFS in patients treated with ramucirumab plus docetaxel.[125]

A phase III study published in 2009 compared immediate and delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced NSCLC and found a statistically significant improvement in progression-free survival when docetaxel was administered immediately after front-line gemcitabine plus carboplatin, without increasing toxicity or decreasing quality of life. The increase in overall survival was not statistically significant.[126]

Another phase III trial of pemetrexed versus docetaxel showed similar efficacy for both agents in recurrent NSCLC when administered as single-agent chemotherapy in second-line settings. Response rates (9.1% vs 8.8%) and overall survival (8.3 mo vs 7.9 mo) were similar.[127]

In a phase III study comparing docetaxel and docetaxel/aflibercept, the addition of ziv-aflibercept to standard docetaxel therapy did not improve overall survival in platinum-pretreated patients with advanced or metastatic nonsquamous NSCLC.[128]

Complications

Chemotherapy can give rise to various adverse effects, as follows:

• Febrile neutropenia or bleeding from bone marrow suppression
• Hyponatremia or hypomagnesemia from cisplatin nephrotoxicity
• Acute kidney injury or ototoxicity from cisplatin
• Peripheral neuropathy from cisplatin, paclitaxel, and vinorelbine

The current standard of care in the management of good-risk (ie, Karnofsky performance score of 70-100, minimal weight loss) patients with locally advanced unresectable (stage IIIA) NSCLC is combined-modality therapy consisting of platinum-based chemotherapy in conjunction with radiation therapy. This combination results in statistically significant improvement in both disease-free and overall survival rates compared with either modality used alone.[129, 130]

Randomized studies show longer survival in patients with unresectable stage III disease when treated with concurrent (rather than sequential) platinum-based chemotherapy and radiation therapy.[131, 132] In a Radiation Therapy Oncology Group (RTOG) study that compared cisplatin/vinblastine either given concurrently with radiation therapy or followed by radiation therapy, the concurrent group showed better median survival as well as overall survival (17 vs 14.6 mo and 21% vs 12%, respectively).[133, 134, 135]

Chemotherapy regimens that have been studied in combination with radiation therapy include cisplatin/vinblastine and cisplatin/etoposide (5-y survival of 15%).[131] In elderly patients or those with comorbidities and contraindications to cisplatin, weekly carboplatin/paclitaxel may be used, based on a phase II study that showed a median survival of 16.7 months.[136, 137, 138]

Consolidation chemotherapy after chemoradiation had initially been shown to be beneficial in phase II studies, with docetaxel after chemoradiation with cisplatin/etoposide showing a median survival of 26 months and a 5-year survival of 29%. In phase III testing, however, this regimen did not show improved survival and it proved to be more toxic, so it is no longer recommended outside a clinical trial setting.[139]

In a phase III study of 610 patients, treatment with a combination of cisplatin, etoposide, and radiation conferred significant overall survival. These researchers concluded that this regimen should be the standard in patients with stage III lung cancer.[140]

Consolidation therapy with the anti–programmed death ligand 1 (PD-L1) antibody durvalumab following concomitant chemoradiation has shown significant benefit. In the phase III PACIFIC study, in 713 patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy, median progression-free survival was 16.8 months with durvalumab versus 5.6 months with placebo, and the 18-month progression-free survival rate was 44.2% versus 27.0%.[141] The 36-month overall survival rates were 57.0% with durvalumab versus 43.5% with placebo.[142]

The high locoregional failure rate with chemoradiation alone has led to study of chemoradiation followed by surgical resection.[106, 108, 143] Uncontrolled phase II studies suggested possible survival benefit from this approach, but a phase III study showed only a nonsignificant trend toward better 5-year overall survival (27% vs 20%) despite an improvement in progression-free survival. The postoperative mortality rate was higher in those patients undergoing surgical resection.

A European Organization for Research and Treatment of Cancer (EORTC) study failed to show any benefit of resection over radiation therapy after neoadjuvant chemotherapy in patients with stage IIIA (N2) disease.[144]

In a small study in patients who were node negative with T3 and T4 NSCLC, neoadjuvant chemoradiation followed by surgery led to better survival.[145]

In recent years, the increased understanding of molecular abnormalities in lung cancer, identification of molecular targets, and development of molecular-targeted therapies have produced a paradigm shift. The treatment of NSCLC has entered a new era. The steadily growing success of biologic agents in the treatment of advanced NSCLC has inspired exploration of their use as preoperative therapy in early-stage NSCLC.[76]

The possibility of finding a mutation that is susceptible to molecular-targeted therapy is driving more frequent mutation testing in NSCLC. However, the likelihood of a mutation depends on the histologic subtype of the cancer. Consequently, histologic testing should precede mutation testing.[92]

All patients with NSCLC should have their tumor tissue tested for mutations, such as in the genes that code for epidermal growth factor receptor (EGFR), KRAS, anaplastic lymphoma kinase (ALK), ROS1, and for programmed death ligand–1 (PDL-1). The results will help determine the patient's eligibility for treatment with specific molecular-targeted agents.

EGFR testing, which identifies sensitivity to EGFR-directed tyrosine kinase inhibitors (TKIs), includes assessment for exon 19 deletions or the L858R point mutation. The T790M and exon 20 insertion mutations have been associated with low response or acquired resistance to TKIs. In patients with adenocarcinomas that have EGFR mutations consistent with TKI sensitivity, options for single-agent targeted therapy without chemotherapy (first-, second-, or subsequent-line) include the following:

• Osimertinib (Tagrisso)
• Erlotinib (Tarceva)
• Afatinib (Gilotrif)
• Gefitinib (Iressa)
• Dacomitinib (Vizimpro)

NCCN guidelines recommend osimertinib as the preferred category 1 option for first-line therapy in patients who have EGFR mutations documented before first-line chemotherapy and as category 2A with EGFR mutations such as exon 19 deletion or L858R discovered during first-line systemic therapy. For exon 20 insertion, amivantamab (Rybrevant) is indicated.[92]  American Society of Clinical Oncology (ASCO) guidelines recommend the use of osimertinib in patients with stage IB, II, and IIIA NSCLC that has sensitizing EGFR mutations (exon 19 deletions or L858R).[146]  

Human epidermal growth factor receptor 2 (HER2 ) has emerged as a biomarker for NSCLC. Mutations in the gene encoding HER2 drive approximately 3% of nonsquamous NSCLCs and are associated with female sex, never-smoking history, and a poor prognosis, as well as with a slightly younger age and higher incidence of brain metastases than NSCLC without HER2 mutations or with other mutations.[147]  For unresectable or metastatic HER2-mutant NSCLC in patients who have received a prior systemic therapy, targeted therapy is with trastuzumab deruxtecan (Enhertu).

The presence of a KRAS mutation is prognostic of poor survival and has been associated with reduced responsiveness to EGFR TKI therapy.[92]  KRAS G12C accounts for approximately 50% of KRAS mutations in NSCLC and is present in approximately 14% of patients with NSCLC.[148]  For patients with KRAS G12C–mutated locally advanced or metastatic NSCLC who have received 1 or more prior systemic therapies, consider sotorasib (Lumakras) or adagrasib (Krazati).[92]  

NSCLC adenocarcinoma with ALK rearrangements more commonly occurs in light smokers or non-smokers. These patients do not benefit from treatment with EGFR-directed TKIs. Instead, first-line therapy is with one of the following:

• Alectinib (Alecensa) 
• Brigatinib (Alunbrig) 
• Lorlatinib (Lobrena) 
• Crizotinib (Xalkori) if the ALK rearrangement is discovered during first-line systemic therapy (eg, pembrolizumab/chemotherapy)
• Ceritinib (Zykadia)

Treatment for NSCLC with BRAF mutation is with dabrafenib (Tafinlar) in combination with trametinib (Mekinist).

For patients with RET fusion-positive NSCLC, the following agents are used:

• Selpercatinib (Retevmo) [preferred]
• Pralsetinib (Gavreto) [preferred]
• Cabozantinib (Cabometyx) 
• Vandetanib (Capresla)

For patients with ROS1 mutations, the following agents are used:

• Crizotinib (Xalkori)(preferred)
• Entrectinib (Rozyltrek)(preferred) ^{[149, 150]}
• Ceritinib (Zykadia) 
• Repotrectinib (Augtyro) 

For patients who are NTRK gene fusion positive, the following agents are used:

• Larotrectinib (Vitrakvi)(preferred)
• Entrectinib (Rozlytrek)(preferred)

For patients with MET exon 14 skipping mutation, the following agents are used:

• Capmatinib (Tabrecta) (preferred)
• Tepotinib (Tepmetko) (preferred)
• Crizotinib if the mutation is discovered during first-line systemic therapy

Immune checkpoint inhibitors (ICIs) generally should be reserved for NSCLC patients whose tumors have a PD-L1 expression ≥1% and do not have any of the treatment-susceptible molecular variants (eg, EGFR, ALK, ROS1), although in select settings they can be used regardless of PD-L1 expression. Targeted therapy should take precedence over ICIs in patients with those molecular variants.[92]

FDA-approved first-line therapies for metastatic NSCLC with PD-L1 expression and no presence of any of the molecular variants (eg, EGFR, ALK, ROS1) are pembrolizumab (Keytruda), atezolizumab (Tecentriq), and cemiplimab (Libtayo).[151]  These agents may be used in combination with chemotherapy or as a single agent in first-line or subsequent therapies. Another ICI is nivolumab (Opdivo), which is indicated in combination with ipilimumab for first-line treatment, in combination with ipilimumab and platinum doublet chemotherapy for first-line treatment regardless of PD-L1 expression, and as monotherapy in patients with progression of metastatic NSCLC on or after platinum-based chemotherapy.

If PDL-1 expression is ≥50%, the following immunotherapy alone or with chemotherapy may be offered:

• Atezolizumab or cemiplimab alone (preferred)
• Pembrolizumab with or without carboplatin or cisplatin and pemetrexed (preferred)
• Atezolizumab/carboplatin/albumin-bound paclitaxel
• Nivolumab/ipilimumab with or without pemetrexed and carboplatin or cisplatin

If PDL-1 expression is ≥1% to 49%, immunotherapy with standard chemotherapy may be offered, as follows:

• Pembrolizumab with or without carboplatin or cisplatin and pemetrexed (preferred)
• Atezolizumab with carboplatin/paclitaxel/bevacizumab
• Nivolumab/ipilimumab with or without pemetrexed and carboplatin or cisplatin

EGFR mutations

Overexpression of EGFR is common in NSCLC. Cancers overexpressing EGFR have been shown to have increased resistance to chemotherapy and increased metastatic potential, and thus a poorer prognosis.

Stimulation of the EGFR pathway leads to increased autophosphorylation of a tyrosine kinase pathway associated with EGFR. This leads to a series of intracellular events culminating in increased mitotic and growth potential, increased ability to metastasize, and increased angiogenesis (new blood vessel formation) in the cancer cells.

Rosell et al evaluated the feasibility of large-scale screening for EGFR mutations in patients with advanced NSCLC. EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were found more frequently in women (69.7%), patients who had never smoked (66.6%), and those with adenocarcinomas (80.9%). These researchers concluded that large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment.[152]

The NCCN guidelines note that EGFR mutations are present in adenocarcinomas in approximately 10% of Western patients and up to 50% of Asian patients, and that the EGFR mutation frequency is higher in nonsmokers, women, and patients with non-mucinous cancers. In squamous cell carcinomas, however, the observed incidence of EGFR mutations is 2.7% and the true incidence can be confidently posited as less than 3.6%—too low to justify routine testing of all tumor specimens.[92]

EGFR-directed therapies are described below, in the order of their FDA approval.

Afatinib

Afatinib (Gilotrif) is a TKI that was approved by the FDA in 2013 for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by the diagnostic companion test therascreen EGFR RGQ PCR kit. Approval was based on data from the LUX-Lung 3 trial, in which progression-free survival (PFS) in patients receiving afatinib was 11.1 months, compared with 6.9 months for those treated with pemetrexed/cisplatin.[153] In 2018, the indication for first-line use in metastatic NSCLC was expanded to include 3 additional nonresistant EGFR mutations (ie, L861Q, G719X, S768I).[154]

Additionally, in patients with tumors expressing the two most common EGFR mutations (Del19 or L858R), PFS was 13.6 months in those who received afatinib, versus 6.9 months for those in the chemotherapy arm.[153]

In 2016, the FDA approved afatinib for metastatic squamous NSCLC that has progressed after platinum-based chemotherapy. Approval was based on the LUX-Lung 8 clinical trial. Compared with erlotinib, afatinib significantly delayed progression of lung cancer, reducing the risk of progression by 18%. Also observed was a significant improvement in overall survival (OS)(P=0.0077), reducing the risk of death by 19%. A significantly improved disease control rate was also shown (51% vs 40%; P=0.002).[155]

The most common serious adverse events in patients receiving afatinib included diarrhea (6.6%), vomiting (4.8%), dyspnea, fatigue, and hypokalemia (1.7%). Fatal adverse events included pulmonary toxicity/interstitial lung disease (1.3%), sepsis (0.43%), and pneumonia (43%).[153]

Gefitinib

Gefitinib represents a class of EGFR TKIs that act intracellularly to block activation of the EGFR pathway.[156, 157]

In 2015, gefitinib returned to the United States market following restricted availability. It was approved by the FDA as first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Approval as first-line treatment for metastatic NSCLC is based on data from the IFUM (IRESSA Follow-Up Measure) clinical trial, which showed an overall response rate (ORR) of about 50% with a median duration of response of 6 months.[158]

The IFUM results were supported by the most recent analysis of the IPASS (IRESSA Pan-ASia Study) study, which assessed gefitinib vs carboplatin/paclitaxel as a first-line treatment in these patients. The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive by the same clinical trial assay as used in IFUM and had radiographic scans available for a retrospective assessment. IPASS showed an ORR of 67% with a median duration of response of 9.6 months in gefitinib-treated patients vs 41% ORR with a median duration of response of 5.5 months for the carboplatin/paclitaxel group. Mean PFS was 10.8 months in the gefitinib group vs 5.4 months for the carboplatin/paclitaxel patients.[159]

Two large phase II trials led to the expedited original approval of gefitinib in the United States as a third-line therapy. However, the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, a large phase III randomized trial that compared gefitinib with placebo in patients whose cancer had progressed following first-line chemotherapy, found no significant improvement in median survival (5.6 vs 5.1 months) overall and also in the adenocarcinoma subset (6.3 vs 5.4 months). Planned subset analyses in patients who had never been smokers and those of Asian ethnicity showed significantly longer survival (8.9 vs 6.1 months and 9.5 vs 5.5 months, respectively) than with placebo.[157]

The INTEREST trial studied gefitinib versus docetaxel in the second-line setting and found no significant difference in survival (7.6 vs 8 mo). Based on those data, gefitinib was removed from the United States market for use in new patients and was only available by a restricted access program.

Mok et al conducted a large phase III study that compared gefitinib with carboplatin-paclitaxel in the first-line setting in Asian patients who had adenocarcinoma and had never smoked or were former light smokers (none in last 15 years). Patients receiving gefitinib had a higher response rate (43% vs 32%), with similar median survival (18.6 vs 17.3 mo). Of patients whose tumors were positive for the EGFR gene mutation, those in the gefitinib group had significantly longer PFS than those in the carboplatin-paclitaxel group. Conversely, patients who were negative for the mutation had significantly longer PFS with carboplatin-paclitaxel.[160]

In an early IPASS study, EGFR mutation was found to be the strongest predictor of PFS and response to gefitinib.[161]

Erlotinib

A second EGFR TKI, erlotinib, improved survival rates compared with placebo in the second- and third-line setting.[162, 163] Erlotinib demonstrated improved response rates (8% vs < 1%), and overall survival (6.7 vs 4.6 mo). This led to the initial FDA approval of erlotinib in the second-line setting. In late 2016, approval was extended to use for first-line treatment, maintenance treatment, or second- or subsequent-line treatment after progression following at least 1 prior chemotherapy regimen in patients with NSCLC that has EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. as detected by an FDA-approved test.

In an open-label, randomized, phase III trial of Chinese patients with adenocarcinoma of the lung with an EGFR mutation, PFS was longer in patients treated with erlotinib than in those receiving standard chemotherapy with gemcitabine plus carboplatin (13.1 vs 4.6 months).[164]

An open-label randomized phase III trial in European patients with NSCLC also found erlotinib to be superior to standard chemotherapy for first-line treatment of NSCLC with EGFR mutations. In this study, PFS in patients with either EGFR exon 19 deletions or exon 21 [L858R] substitution mutations was 9.7 months with erlotinib treatment, compared with 5.2 months for those who received standard therapy.[60]

Similar to the experience with gefitinib, no benefit was seen when erlotinib was combined with chemotherapy. Earlier studies also showed better response rates and survival with females, Asian persons, nonsmokers, and particularly those with adenocarcinoma histology (especially bronchioalveolar cancer), as was seen with gefitinib.

In contrast, a study in 760 unselected patients with advanced NSCLC found that first-line treatment with erlotinib followed at disease progression by cisplatin-gemcitabine was significantly inferior in terms of overall survival compared with the standard sequence of chemotherapy with cisplatin-gemcitabine followed by erlotinib.[165]

A study by Herbst et al found no benefit when erlotinib was combined with bevacizumab compared with erlotinib alone in patients who experienced a failure of standard first-line chemotherapy.[166] A separate study by Hirsch et al compared the use of erlotinib alone or intercalated with chemotherapy among chemotherapy-naïve patients with advanced NSCLC that was positive for EGFR protein expression, had a high EGFR gene copy number, or both. The study results did not support combined chemotherapy and erlotinib in this setting; patients with tumors harboring EGFR mutations had better outcomes with erlotinib alone.[167]

In contrast, the phase III RELAY trial demonstrated a benefit when erlotinib was combined with ramucirumab for metastatic NSCLC in treatment-naïve patients (n=449) whose tumors have EGFR exon 19 deletion or exon 21 L858R mutations. In RELAY, patients who received erlotinib plus ramucirumab had a significantly longer median PFS compared with those who received erlotinib plus placebo (19.4 months vs. 12.4 months, respectively; hazard ratio [HR] 0.59; 95% CI, 0.46-0.79).[168] On the basis of the RELAY trial results, the FDA approved ramucirumab in combination with erlotinib for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

Osimertinib

Osimertinib (Tagrisso) is an irreversible EGFR-TKI inhibitor designed to inhibit both EGFR-sensitizing and EGFR T790M–resistance mutations, with clinical activity against central nervous system (CNS) metastases. In 2017, the FDA approved osimertinib for EGFR T79M–positive NSCLC in patients whose disease progressed on or after EGFR TKI therapy.[169]

Efficacy was demonstrated in the open-label AURA3 trial, in which 419 patients with previously treated EGFR T790M mutation–positive metastatic NSCLC received either osimertinib or platinum-based doublet chemotherapy. PFS was significantly longer in the osimertinib arm than in the chemotherapy arm. There was no statistically significant difference in overall survival (OS) between the two study arms.

In 2018, approval of osimertinib was extended to first-line treatment of metastatic NSCLC in patients whose tumors express EGFR exon 19 deletions or exon 21 L858R mutations. Approval was based on the phase III FLAURA study (n=556), which demonstrated significantly longer survival with osimertinib than with a standard EGFR TKI (gefitinib or erlotinib): PFS was 18.9 versus 10.2 months, respectively, while OS was 38.6 versus 31.8 months, respectively.[169, 170]

In 2020, osimertinib was further approved as adjuvant therapy for early-stage NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations following tumor resection. Approval was based on the results from the phase III ADAURA trial, in which 682 patients with stage IB to IIIA NSCLC were randomized to osimertinib (n=339) or placebo (n=343). At 24 months, disease-free survival (DFS) rates in the patients with stage II to IIIA NSCLC were 90% in the osimertinib group and 44% in the placebo group. In the overall study population, DFS rates were 89% versus 52%, respectively. OS data were immature at the time of analysis.[171]  

The ADAURA trial continued and the planned final analysis of OS was published in 2023. In patients with stage II to IIIA disease, 5-year OS was 85% in the osimertinib group and 73% in the placebo group (P < 0.001). In the overall study population, 5-year OS was 88% in the osimertinib group and 78% in the placebo group (P < 0.001).[172]   

Dacomitinib

Dacomitinib (Vizimpro) is an irreversible kinase inhibitor of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR-activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). It is indicated for first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.

Approval of dacomitinib was based on the ARCHER 1050 trial (n=452), in which median PFS was 14.7 months with dacomitinib compared with 9.2 months with gefitinib (hazard ratio, 0.59; P < 0.0001).[173] Overall survival analysis showed slight improvement with dacomitinib: 34.1 months, versus 26.8 months with gefitinib.[174]

Cetuximab

Cetuximab, a monoclonal antibody that binds the EGFR receptor, is also used in colorectal cancer and squamous cell cancer (SCC) of the head and neck. It was studied in the first-line setting, in combination with cisplatin-vinorelbine, compared with cisplatin-vinorelbine alone, in patients with NSCLC that expressed EGFR by immunohistochemistry.[175]

The chemotherapy regimen was given in combination with cetuximab for up to 6 cycles, and in responding patients, the cetuximab was continued until progression. Patients receiving cetuximab had a higher response rate (36% vs 29%), and longer median survival (11.3 vs 10.1 mo). Whites appeared to benefit more than Asian patients, who seemed to do worse with this regimen.

A phase III study found that the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC provided a survival benefit in patients with high EGFR expression (immunohistochemistry score ≥ 200), increasing overall survival from a median of 9.6 to 12.0 months. No corresponding survival benefit was seen in those with low EGFR expression.[176]

The cetuximab/cisplatin/vinorelbine chemotherapy regimen is not recommended by NCCN guidelines due to small benefit of 1 month, along with the fact that most of these patients have multiple comorbid conditions and poor tolerance of this regimen.[92]  

Amivantamab

Amivantamab is a bispecific antibody directed against EGF and MET receptors. In 2021, the FDA granted accelerated approval of amivantamab for treatment of adult patients with locally advanced or metastatic NSCL with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. It is administered as an IV infusion.[177]  

Mobocertinib

Mobocertinib, an orally administered TKI, gained accelerated approval from the FDA in September 2021 for the treatment of adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.[178] In October 2023, the manufacturer announced the voluntary withdrawal of mobocertinib from the US market, based on the agent's failure to meet the primary endpoint of improved PFS in the phase III EXCLAIM-2 trial.[179]

HER2 mutations

The antibody drug conjugate trastuzumab deruxtecan is the first HER2-directed treatment for unresectable or metastatic HER2-mutant NSCLC based on presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens in previously treated patients. Mutations in the gene encoding HER2 drive approximately 3% of nonsquamous NSCLCs and are associated with female sex, never-smoking history, and a poor prognosis, as well as with a slightly younger age and higher incidence of brain metastases than NSCLC without HER2 mutations or with other mutations.[147]  

Accelerated approval was granted by the FDA in August 2022 based on results from the phase II DESTINY-Lung02 trial. Of the 52 patients in the primary efficacy population, the objective response rate (ORR) was 58% and the duration of response was 8.7 months.[180]     

KRAS mutations 

Sotorasib and adagrasib are indicated for KRAS G12C–mutated locally advanced or metastatic NSCLC in adults who have received 1 or more prior systemic therapies. Sotorasib and adagrasib form an irreversible, covalent bond with the unique cysteine of KRAS G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. 

Sotorasib

Accelerated approval was supported by the CodeBreak 100 phase II trial. An objective response was observed in 46 of 124 patients (37.1%) who had measurable disease at baseline, including 4 patients who had a complete response and 42 with a partial response. Disease control occurred in 100 patients (80.6%) and median overall survival was 12.5%.[181]  

Adagrasib

Adagrasib (Krazati) also gained accelerated approval from the FDA in December 2022 that is contingent on results from a phase III confirmatory trial. Accelerated approval was supported by evidence from the KRYSTAL-1 phase II trial, in which 48 of 112 patients (42.9%) with measurable disease at baseline had a confirmed objective response. The median duration of response was 8.5 months and the median PFS was 6.5 months. On median follow-up of 15.6 months, the median OS was 12.6 months. Additionally, in 33 patients with previously treated, stable CNS metastases, the intracranial confirmed ORR was 33.3%.[182]

ROS1 mutations

Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation.

Repotrectinib

Repotrectinib, approved by the FDA in November 2023, is indicated for adults with locally advanced or metastatic ROS1-positive NSCLC. It is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 and tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. 

Approval was based on the TRIDENT-1 study, an open-label, single-arm, phase I/II trial that included both TKI-naïve and TKI-pretreated patients. In TKI-naïve patients (n = 71), the primary endpoint of objective response rate (ORR) was 79%. The median duration of response (mDOR) was 34.1 months. Among patients pretreated with 1 prior ROS1 TKI and no prior chemotherapy (n = 56), the ORR was 38% and the mDOR was 14.8 months. Among those who had measurable CNS metastases at baseline, responses in intracranial lesions were observed in 7 of 8 TKI-naïve patients (n = 71) and 5 of 12 (77%; 95% CI 64–88)TKI-pretreated patients (n = 56).[183]   

Entrectinib

Entrectinib was approved in 2019 for treatment of ROS1-positive metastatic NSCLC, as well as for treatment of NTRK gene fusion–positive NSCLC. An integrated analysis of three phase I-II trials in patients with locally advanced or metastatic ROS1 fusion–positive NSCLC reported that 41 of 53 patients (77%) had an objective response, and mDOR was 24.6 months.[149]

Crizotinib

Crizotinib was initially approved for treatment of ALK-positive NSCLC. In 2016 the FDA expanded use of crizotinib to include patients with metastatic NSCLC whose tumors harbor a ROS1 gene mutation. Study results showed crizotinib exhibited marked antitumor activity in this population with an objective response rate of 66% by an independent radiology review. There was 1 complete response and 32 partial responses. The median duration of response was 18.3 months.[184]

Squamous Cell NSCLC

For patients with metastatic squamous cell lung cancer it is important to test for EGFR mutation. If EGFR mutation is present, chemotherapy with cisplatin and gemcitabine and necitumumab should be prescribed. Other options could include oral EGFR inhibitors.

Necitumumab

Necitumumab is another monoclonal antibody that binds to human EFGR and blocks the interaction between EGFR and its ligands. It was approved in 2015 for first-line treatment of metastatic squamous NSCLC in combination with gemcitabine and cisplatin. 

However, current NCCN guidelines recommend against use of this regimen, based on the opinion that the addition of necitumumab to the regimen is not beneficial based on toxicity, cost, and limited improvement in efficacy when compared with cisplatin/gemcitabine. Specifically, the NCCN panel notes that the addition of necitumumab resulted in only a slight improvement in overall survival and an increase in grade 3 or higher adverse events.[92]

Pembrolizumab

Pembrolizumab, a PD-1 inhibitor, gained approval in 2018 as a first-line treatment option for metastatic squamous NSCLC in combination with carboplatin and either paclitaxel or nab-paclitaxel. Approval was supported by the KEYNOTE-407 study. In the trial, the combination of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel) significantly improved overall survival (OS) compared with chemotherapy alone, at a median of 15.9 months compared with 11.3 months (hazard ratio [HR], 0.64; P = 0.0017).[185]

Vandetanib

A randomized, double-blind, phase III trial assessed the use of vandetanib, a once-daily oral inhibitor of vascular EGFR and EGFR signaling.[186] This second-line therapy did not meet the primary end point of statistically significant improvement in PFS. However, the combination of vandetanib (100 mg/d) plus pemetrexed (500 mg/m2) produced a significantly higher objective response rate and a significant delay in time to worsening of symptoms compared with placebo. The combination also had an acceptable safety profile. This indication is not yet approved by the FDA.

Non-Squamous NSCLC: VEGF inhibitors

In adenocarcinoma and large cell lung cancers that lack mutations in EGFR, ROS1, or ALK, combination chemotherapy and targeted therapy may be offered.

Bevacizumab

In an Eastern Cooperative Oncology Group (ECOG) study, addition of the anti-angiogenesis agent bevacizumab to standard first-line carboplatin-paclitaxel resulted in significant prolongation of survival. Bevacizumab was continued in patients who appeared to respond to four to six cycles of chemotherapy. The median overall survival (OS) was improved (12.3-10.3 mo), as was the response rate (35% vs 15%) compared with chemotherapy alone.[187]

Patients with squamous cell histology, brain metastases, clinically significant hemoptysis, and ECOG performance status of greater than 1 were excluded.[187] Despite increased hemorrhagic complications and treatment-related deaths, bevacizumab has been approved for use in this setting in combination with chemotherapy.

Bevacizumab has also been studied in combination with cisplatin-gemcitabine as first-line therapy for nonsquamous NSCLC, with improved response rates (34.1% vs 20.1%) and modest improvement in PFS (6.7 vs 6.1 mo). OS was not different.[188]

A 2012 systematic review and meta-analysis of randomized phase II/III trials concluded that the addition of bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced NSCLC significantly prolonged OS and PFS. The effects of bevacizumab on OS were significantly greater in patients with adenocarcinoma versus other histologies. No unexpected toxicity was observed.[189]

In 2017, the FDA approved Mvasi (bevacizumab-awwb) as a biosimilar to Avastin (bevacizumab) to treat non-squamous NSCLC. It is used in combination with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent or metastatic disease. The approval was based on evidence from animal study data, human pharmacokinetic and pharmacodynamics data, and clinical immunogenicity data.[190]

Ramucirumab

Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. A phase III trial in patients with stage IV NSCLC that had progressed during or after first-line platinum-based chemotherapy reported a 1-month survival benefit with ramucirumab plus docetaxel compared with docetaxel plus placebo.[191]

ALK-directed targeted therapies

Chromosomal rearrangement of ALK occurs in about 5% of NSCLC cases. In most of these patients, treatment is initiated with crizotinib. This agent is also indicated for NSCLC with ROS-1 mutations. Second-line agents for ALK-positive NSCLC are brigatinib, ceritinib, and alectinib.

Crizotinib

Crizotinib (Xalkori) was approved by the FDA in 2011 for the treatment of locally advanced or metastatic NSCLC that is ALK positive, as detected by the Vysis ALK Break Apart FISH Probe test (Abbott Molecular). Approval was based on 2 multicenter trials (n=255) in which median response duration ranged from 41.9-48.1 weeks.[192]

In a study of patients with previously treated advanced NSCLC who had ALK gene rearrangement, treatment with crizotinib was superior to standard chemotherapy.[193] Risk of progression was reduced by 50% with crizotinib. Study participants with locally advanced or metastatic ALK-positive lung cancer treated with one previous platinum-based regimen were randomized to oral crizotinib 250 mg twice daily or to chemotherapy with intravenous pemetrexed (500 mg/m²) or docetaxel (75 mg/m²) every 3 weeks. As part of a separate analysis, patients in the chemotherapy group with disease progression were allowed to cross over to crizotinib.[193]

Median PFS was longer with crizotinib treatment (7.7 mo) than with chemotherapy (3.0 mo). The hazard ratio for progression or death with crizotinib was 0.49 (95% confidence interval [CI], 0.37-0.64; P< 0.001), and the response rate was higher in the crizotinib group (65%) than in the chemotherapy group (20%) (P< 0.001). Overall survival was similar in the two groups.[193]

Brigatinib

Brigatinib (Alunbrig) was approved in 2017 for ALK-positive metastatic NSCLC in patients whose disease has progressed on or who are intolerant of crizotinib. Approval was based on the noncomparative, open-label, multicenter ALTA clinical trial. After a median follow-up of 8 months, median duration of response was 13.8 months in patients randomized to receive brigatinib at oral doses of either 90 mg once daily (n = 112) or 180 mg once daily following a 7-day lead-in at 90 mg once daily (n = 110).[194]

Ceritinib

Ceritinib, an ALK inhibitor, received accelerated approval from the FDA in 2014 for patients with ALK-positive metastatic NSCLC whose disease had progressed or who had intolerance to crizotinib, based on a blinded independent review committee (BIRC)–assessed ORR of 44% among 163 patients in a single-arm trial. A phase I study found that ceritinib at the dose of 400 mg daily provided a response rate of 58%, with a median PFS of 7 months. Dose-limiting toxicity included diarrhea, vomiting, dehydration, elevated aminotransferase level, and hypophosphatemia. In this study, ceritinib was effective for both crizotinib-naive patients and those who had tumor progression with crizotinib.[195]

In  2017, ceritinib was granted regular approval for patients with metastatic NSCLC whose tumors are ALK positive, as detected by an FDA-approved test. This approval also included use as first-line treatment. Approval was based on data from ASCEND-4, a randomized, multicenter, open-label, active-controlled trial conducted in patients with untreated ALK-positive NSCLC. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) test performed through central laboratory testing.

ASCEND-4 randomized 376 patients to receive either ceritinib (n=189) 750 mg orally once daily until disease progression or platinum-pemetrexed doublet chemotherapy (n=187). Patients in the chemotherapy arm received pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC 5-6) on day 1 of every 21-day cycle for up to 4 cycles, followed by pemetrexed maintenance therapy. Results demonstrated improved PFS as assessed by BIRC, with a hazard ratio (HR) of 0.55 (P < 0.0001). The estimated median PFS was 16.6 months in the ceritinib arm and 8.1 months in the chemotherapy arm. Confirmed ORR was 73% and 27% in the ceritinib and chemotherapy arms, respectively. Estimated median response durations were 23.9 months and 11.1 months in the ceritinib and chemotherapy arms, respectively. Overall survival data are immature.[196]

In the ASCEND-8 trial, 137 patients receiving ceritinib 450 mg or 600 mg daily with food (~100-500 calories and 1.5-15 grams of fat) or 750 mg daily under fasted conditions, there was no clinically meaningful difference in the systemic steady-state exposure of ceritinib (AUC) for the 450 mg with food arm compared with the 750 mg fasted arm. The steady-state AUC increased by 24% and the peak plasma concentration increased by 25% in the 600 mg with food arm compared to the 750 mg fasted arm.[197]

Alectinib

In 2017, the FDA approved alectinib (Alecensa), a TKI that targets ALK and RET, for the first-line treatment of patients with ALK-positive metastatic NSCLC. In addition to granting this new indication, the FDA also converted alectinib’s indication for patients with ALK-positive NSCLC that has progressed on crizotinib from accelerated approval to full approval. Alectinib is indicated for ALK-positive, metastatic NSCLC in patients whose disease has progressed on crizotinib or who are intolerant to crizotinib.

Approval was primarily based on findings from the phase III ALEX study. In that trial, treatment-naïve patients were randomly assigned to alectinib 600 mg PO BID or crizotinib 250 mg PO BID. Median PFS, as determined by an independent review committee, was 25.7 months in the alectinib arm versus 10.4 months in the crizotinib arm. The ORR with alectinib was 79% versus 72% with crizotinib. The complete response rates were 13% versus 6%, respectively, and the partial response rate was 66% in both arms. Eighty-two percent of patients receiving alectinib had a response duration ≥6 months, with 64% and 37%, having response durations ≥12 months and ≥18 months, respectively. The corresponding rates in the crizotinib arm were 57%, 36%, and 14%.[198]

A separate phase III study, the Japanese phase III J-ALEX trial, also demonstrated the benefit of crizotinib in ALK-positive NSCLC. In J-ALEX, 207 Japanese patients with ALK-positive advanced or recurrent NSCLC who had not been previously treated with an ALK inhibitor were randomized to alectinib 300 mg PO BID or 250 mg of crizotinib 250 mg PO BID. The median PFS was 25.9 months in the alectinib arm versus 10.2 months in the crizotinib arm. Alectinib reduced the risk of progression in the CNS by 81% in patients without brain metastases at baseline, and by 49% in patients with brain metastases at baseline.[199]

Lorlatinib

Lorlatinib (Lorbrena) was approved in March 2021 for patients with metastatic NSCLC whose tumors are ALK positive. It previously received accelerated approval in 2018 for the second- or third-line treatment of ALK-positive metastatic NSCLC.[200]

Approval was based on data from the CROWN study, a phase III, multicenter, open-label, active-controlled trial evaluating 296 patients with ALK-positive metastatic NSCLC who had not received prior systemic therapy for metastatic disease. Patients were randomized to receive lorlatinib (n=149) or crizotinib (n=147). The median PFS was not estimable in the lorlatinib arm and was 9.3 months (95% CI: 7.6, 11.1) for those treated with crizotinib. Overall survival data were immature at the PFS analysis. The intracranial ORR was 82% in the lorlatinib arm and 23% in the crizotinib arm, with intracranial responses lasting at least 12 months in 79% of the lorlatinib arm and 0% of the crizotinib arm.[201]

Programmed cell death–1 inhibitors

ICIs such as programmed cell death (PD-1) inhibitors have gained increasing importance in cancer therapy. PD-1 is expressed on the surface of activated CD8+ T cells, and cancers that express PD-1 ligand (PDL-1) can inactivate these T cells and thus avoid attack by them. PD-1 inhibitors bind to PD-1, preventing the interaction with PD-1 ligand but not inactivating the T cell, so the T cells maintain their ability to target the cancer cells.

Nivolumab

Nivolumab is a monoclonal antibody inhibitor of PD-1. It is the first immunotherapy approved for NSCLC and may be used in nonsquamous and squamous cell NSCLC.

In 2020, nivolumab combined with ipilimumab was approved for metastatic NSCLC in patients whose tumors express PD-L1 (≥1%), with no EGFR or ALK tumor aberrations. The approval was based on the open-label CheckMate-227 trial, in which 793 patients with metastatic or recurrent NSCLC and no prior anticancer therapy were randomized to receive either nivolumab plus ipilimumab or platinum-doublet chemotherapy. The median OS was 17.1 months in the nivolumab plus ipilimumab arm compared with 14.9 months in the platinum chemotherapy arm.[202] On 4-year minimum follow-up, with all patients off immunotherapy for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable efficacy.[203]

Also in 2020, nivolumab in combination with ipilimumab and two cycles of platinum-doublet chemotherapy was approved for the first-line treatment of adult patients with metastatic or recurrent NSCLC whose tumors have no EGFR or ALK aberrations, regardless of PD-L1 expression. In CheckMate 9LA, an international open-label phase III trial, this regimen yielded significantly longer OS compared with chemotherapy only (15.6 months versus 10.9 months, at median 13.2 months follow-up).[204]

Nivolumab is also approved for second-line therapy of metastatic NSCLC that has progressed on or after platinum-based chemotherapy. Patients with EGFR or ALK tumor aberrations should have had disease progression on FDA-approved therapy for those aberrations.[205]

In 2022, nivolumab was approved for neoadjuvant treatment of resectable NSCLC (tumors ≥4 cm or node positive), in combination with platinum-doublet chemotherapy. Approval was based on findings from the phase III CheckMate 816 study, which demonstrated a statistically significant improvement in event-free survival (EFS) with nivolumab plus platinum-doublet chemotherapy compared with chemotherapy alone in patients with stage IB, II, or IIIA NSCLC. Risk of progression, recurrence, or death was 37% lower in the nivolumab plus chemotherapy arm (HR, 0.63; P = 0.0052). Pathologic complete responses were achieved in 24% of the nivolumab plus chemotherapy group compared with 2.2% of the chemotherapy alone group (95% CI, 0.6%-5.6%; P < 0.0001).[77]

Pembrolizumab

A second PD-1 inhibitor, pembrolizumab, was first approved for metastatic NSCLC in 2015, based on data from the KEYNOTE-001 trial.[206] In 2016, pembrolizumab was approved as monotherapy for first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] ≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. This expanded approval was based on results from the KEYNOTE-024 trial, which showed significantly longer PFS and OS and fewer adverse events with pembrolizumab than with platinum-based chemotherapy. Median PFS was 10.3 months (95% CI, 6.7 to not reached) in the pembrolizumab group compared with 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P < 0.001).[207]

The above indication was expanded in 2019 to include patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or with metastatic NSCLC, and whose tumors express PD-L1 (TPS ≥1%) with no EGFR or ALK genomic tumor aberrations. Approval was based on the KEYNOTE-042 trial (n=1274) that compared pembrolizumab with the investigator’s choice of platinum-based chemotherapy. The results suggest that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic NSCLC without sensitizing EGFR or ALK alterations and with low PD-L1 TPS. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (ie, ≥50%, ≥20%, and ≥1%).[208]

First-line combination treatment including pembrolizumab was approved in 2017 for metastatic nonsquamous NSCLC. Approval was based on data from the KEYNOTE-021 trial (Cohort G1) in 123 previously untreated patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations and irrespective of PD-L1 expression. In this trial, pembrolizumab plus pemetrexed and carboplatin demonstrated an ORR that was nearly double the ORR of pemetrexed/carboplatin (55% vs 29% respectively; all responses were partial responses). Among patients who received pembrolizumab plus pemetrexed/carboplatin, 93% had a duration of response of 6 months or more (range 1.4+ to 13.0+ months) compared with 81% who received pemetrexed/carboplatin alone (range 1.4+ to 15.2+ months). PFS was also longer (median 13.0 months [95% CI]) versus 8.9 months (95% CI) with pemetrexed/carboplatin alone.[209]

In the KEYNOTE-010 trial, pembrolizumab was compared with docetaxel in 1034 patients with previously treated NSCLC who had PD-L1 expression on at least 1% of tumor cells; pembrolizumab resulted in longer overall survival and had a more favorable benefit-to-risk profile. In this randomized, open-label trial, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel.[210]

In the KEYNOTE-189 trial, the addition of pembrolizumab to standard chemotherapy with pemetrexed and a platinum-based agent resulted in significantly longer overall and progression-free survival. Metastatic nonsquamous NSCLC patients (n=616) with no EGFR or ALK and no previous treatment received pemetrexed and a platinum-based drug with either pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy.[211]

Approval for treatment of metastatic squamous NSCLC with pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel was supported by the KEYNOTE-407 study. The combination of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel) significantly improved overall survival compared with chemotherapy alone, at a median of 15.9 months compared with 11.3 months (hazard ratio [HR], 0.64; P = 0.0017).[185]

Atezolizumab

Another monoclonal antibody to PD-L1, atezolizumab was approved for patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab. Approval was based on the phase III OAK and phase II POPLAR studies. In the OAK study, survival benefit of atezolizumab was compared with docetaxel chemotherapy, regardless of PD-L1 status. Patients receiving atezolizumab lived a median 4.2 months longer than those treated with docetaxel chemotherapy.[212, 213]

In 2020, atezolizumab was also FDA-approved for first-line treatment of metastatic NSCLC in patients whose tumors have high PD-L1 expression (PD-L1 stained ≥50% of tumor cells [TC ≥50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥10% of the tumor area [IC ≥10%]). Approval was based on the phase III IMpower110 trial, a multicenter, international, randomized, open-label trial. Patients were randomized to receive either atezolizumab or a platinum-based chemotherapy. Median overall survival was 20.2 months in the atezolizumab arm and 13.1 months in the chemotherapy arm, which was a 7.1-month improvement in overall survival in the atezolizumab arm.[214]

Current ASCO guidelines recommend adjuvant atezolizumab after cisplatin-based chemotherapy for patients with stages IIA, IIB, and IIIA NSCLC with PD-L1 ≥1%—except for those with sensitizing EGFR mutations, in whom osimertinib is recommended.[146]

Cemiplimab

Like nivolumab and pembrolizumab, cemiplimab is a monoclonal antibody to PD-1. Cemiplimab was granted accelerated approval for first-line therapy in metastatic NSCLC patients with high PD-L1 expressed (TPS ≥50%) tumors and no EFGR, ALK, or ROS-1 mutations.

Efficacy was evaluated in Study 1624, a multicenter, open-label trial that enrolled 710 patients with localized advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation, or with metastatic NSCLC. Patients were randomly assigned to receive either cemiplimab or a platinum-based chemotherapy. The cemiplimab arm had significantly higher median OS and PFS (22.1 months, 6.2 months) compared with the chemotherapy arm (14.3 months, 5.6 months).[151]

Durvalumab

In 2018, the FDA approved durvalumab for unresectable stage III NSCLC in patients whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. Approval was based on a randomized trial of 713 patients whose NSCLC had not progressed after completing chemotherapy and radiation. Median PFS for patients taking durvalumab was 16.8 months compared with 5.6 months for patients receiving a placebo (P < 0.001). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs 14.6 months; P< 0.001).[141]  

Durvalumab plus tremelimumab

In October 2022, the FDA approved tremelimumab in combination with durvalumab and platinum-based chemotherapy for adults with metastatic  NSCLC with no sensitizing EGFR mutation or ALK genomic tumor aberrations. The POSEIDON phase III trial showed that adding 2 immune checkpoint inhibitors to platinum-based chemotherapy significantly improved PFS and OS compared with 1 immunotherapy agent (durvalumab) plus chemotherapy, or chemotherapy alone.[215]  

BRAF-directed therapy

Testing for BRAF mutations should be done. If the BRAF V600E mutation is found, treatment with the combination of dabrafenib and trametinib is indicated.

Dabrafenib with trametinib

In 2017, the FDA approved the combination of dabrafenib (a selective BRAF kinase inhibitor) and trametinib (an MEK1 inhibitor) for targeted treatment of metastatic NSCLC with BRAF V600E mutation.[216] Approval was based on a phase II open-label, nonrandomized study in patients who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily in continuous 21-day cycles until disease progression.

Of the 93 patients in the study, 36 had received no prior systemic therapy for metastatic NSCLC, and 57 had demonstrated disease progression despite receiving at least one platinum-based chemotherapy regimen. In the previously treated group, the overall response rate (ORR) was 63% and the median duration of treatment response was 9.0 months. The overall disease control rate was 79% when patients who had stable disease for 12 weeks or more were included.[216]

RET inhibitors

Selpercatinib is the first targeted therapy to be approved by the FDA for tumors that have rearranged during transfection (RET) mutations. It is indicated for metastatic RET-fusion–positive NSCLC. 

Accelerated approval in 2020 for use in NSCLC was based on the open-label LIBRETTO-001 phase I/II clinical trial (n = 144). ORR was 64% in treatment-experienced patients (n = 105) and 85% in treatment-naïve patients (n = 39). The phase III confirmatory trial (LIBRETTO-431) is under way.[217]

Another RET inhibitor, pralsetinib (Gavreto) was granted accelerated approval in 2020 for use in metastatic RET-fusion–positive NSCLC. Its efficacy for this indication was based on a multicenter, open-label, multi-cohort clinical trial, ARROW (n=87). The ORR was 57%; 80% of responding patients had responses lasting 6 months or longer. The ORR for patients who were never systemically treated was 70%; 58% of responding patients had responses lasting 6 months or longer.[218]

MET Inhibitors

Capmatinib

Resistance to EGFR TKI therapy can result from mesenchymal-epithelial transition (MET) exon 14 skipping. In 2020, the FDA approved capmatinib (Tabrecta) for treatment of adults with metastatic NSCLC with exon 14 skipping. Approval was based on a study in which the ORR in treatment-naïve patients (n=28) was 68% (complete response in 4%, partial response in 64%) and the ORR in previously treated patients (n=69) was 41%, with all having a partial response. Median duration of response was 12.6 months in treatment-naïve patients and 9.7 months in previously treated patients.[219]

The FDA also approved a companion diagnostic for capmatinib, the FoundationOne CDx assay (F1CDx). F1CDx is a next-generation sequencing–based, in vitro diagnostic device that detects MET exon 14 skipping mutations, as well as other mutations.[219]

Tepotinib

Another oral MET inhibitor, tepotinib (Tepmetko) was recommended by the NCCN panel and also granted accelerated approval by the FDA for treatment of metastatic NSCLC in patients with MET exon 14 skipping mutation.

Efficacy was evaluated in the multicenter, open-label, single-arm, VISION trial enrolling 152 metastatic or advanced NSCLC patients with the MET exon 14 skipping alterations received tepotinib until disease progression or unacceptable toxicity. The ORR was 43% in treatment naïve and previously treated patients. The median response duration for treatment-naïve and previously treated patients was 10.8 months and 11.1 months, respectively.[220]

Immunotherapy-related toxicity

Immune-mediated adverse effects are a common complication of checkpoint inhibitor therapy, with autoimmune toxicity of any grade occurring in approximately 30% of patients and grade 3-5 toxicity occurring in up to 10% of patients. Dermatologic, pulmonary, gastrointestinal, endocrine, neurologic, cardiovascular, and musculoskeletal involvement have all been reported.[221]

A study by Berner et al in 73 patients with NSCLC who received anti–PD-1 therapy with nivolumab or pembrolizumab found that autoimmune skin toxic effects were more frequent in patients with complete remission or partial remission (68.2%) than in those with progressive or stable disease (19.6%). These authors identified nine T-cell antigens that were present in both tumor tissue and skin and were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were present in autoimmune skin lesions and tumors of patients who responded to anti–PD-1 therapy.[222]

Treatment of immunotherapy-related toxicity depends on its severity and the organ system involved. Corticosteroid therapy is indicated for most symptomatic toxicity. Holding immunotherapy may be indicated.[223]

National Comprehensive Cancer Network (NCCN) guidelines include the following recommendations on initiation of corticosteroid therapy for specific immunotherapy-related toxicities[223] :

• Maculopapular rash – Severe (grade 3-4); prednisone 0.5–1 mg/kg/day
• Pruritus – Severe (grade 3); prednisone/methylprednisolone 0.5–1 mg/kg/day
• Bullous dermatitis – Moderate (grade 2); prednisone/methylprednisolone 0.5–1 mg/kg/day
• Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) – Severe (grade 3) or life-threatening (grade 4); prednisone/methylprednisolone 1–2 mg/kg/day
• Diarrhea/colitis – Moderate (grade 2); prednisone/methylprednisolone 1 mg/kg/day
• Transaminitis without elevated bilirubin – If moderate (grade 2; 3-5 times the upper limit of normal [UNL]), consider prednisone 0.5–1 mg/kg/day; if severe (grade 3; > 5-20 x ULN), initiate prednisone 1–2 mg/kg/day
• Transaminitis > grade 1 with bilirubin >1.5 x ULN (unless Gilbert syndrome) – Prednisone/methylprednisolone 2 mg/kg/day
• Acute pancreatitis – Moderate (grade 3), prednisone/methylprednisolone 0.5–1 mg/kg/day; severe (grade 4), 1-2 mg/kg/day
• Primary adrenal insufficiency – Steroid replacement with hydrocortisone 20 mg in AM, 10 mg in PM, then slowly titrating doses down according to symptoms, or  prednisone 7.5 mg or 10 mg starting dose, then reduce to 5 mg daily as appropriate, and fludrocortisone can be started 0.1 mg every other day; then titrated up or down based on blood pressure, symptoms, lower-extremity edema, and labs
• Pneumonitis – Moderate (grade 2); prednisone/methylprednisolone 1–2 mg/kg/day
• Elevated serum creatinine/acute renal failure – Moderate (grade 2; creatinine 2–3x above baseline); start prednisone 0.5–1 mg/kg/day if other causes are ruled out
• Anterior uveitis or episcleritis – Grade 2; treatment guided by ophthalmology to include ophthalmic and systemic prednisone/methylprednisolone
• Myasthenia gravis – Moderate (grade 2), consider low-dose oral prednisone 20 mg daily, increase by 5 mg every 3–5 days to a target dose of 1 mg/kg/day but not more than 100 mg daily (steroid taper based on symptom improvement); severe (grade 3-4), methylprednisolone 1–2 mg/kg/day (steroid taper based on symptom improvement)
• Peripheral neuropathy – Moderate (grade 2); Initial observation or initiate prednisone 0.5–1 mg/kg orally (if progressing from mild); if progression occurs, initiate methylprednisolone 2–4 mg/kg/day and consider Guillain-Barré syndrome
• Encephalitis – Trial of methylprednisolone 1–2 mg/kg/day; if severe or progressing symptoms or oligoclonal bands present, consider pulse steroids, methylprednisolone 1 g IV daily for 3–5 days plus IVIG
• Transverse myelitis –  Methylprednisolone pulse dosing 1 g/day for 3–5 days
• Cardiovascular (myocarditis,  pericarditis, arrhythmias, impaired ventricular function) – Severe (grade 3) or life-threatening (grade 4); consider methylprednisolone pulse dosing 1 g/day for 3–5 days
• Inflammatory arthritis - Mild; if nonsteroidal anti-inflammatory drugs (NSAIDs) ineffective, consider low-dose prednisone 10–20 mg daily x 4 weeks; if not improving, treat as moderate; moderate, prednisone 0.5 mg/kg/day x 4–6 weeks; if no improvement, treat as severe; severe, prednisone/methylprednisolone 1 mg/kg/day
• Myalgias or myositis – Moderate, severe, or life-threatening; prednisone 1–2 mg/kg/day

Stage IA/IB (T1aN0M0 , T1bN0M0, T2aN0M0)

Surgery is the treatment of choice for stage I NSCLC. A careful assessment of residual pulmonary reserve should be carried out as part of surgical planning. Although lobectomy is generally considered to be the optimal procedure, patients with limited pulmonary reserve may be considered for more limited surgical intervention with either a segmental or a wedge resection.[224]

Video-assisted thoracoscopic surgery (VATS) may be used for surgical resection. VATS offers apparently similar resection capability and decreased postoperative morbidity.

Patients with insufficient pulmonary reserve to undergo a resection may be treated with radiation therapy alone with curative intent. Retrospective data report a 5-year survival ranging from 10-25% with radiation therapy alone in this setting. Selected patients may be candidates for either stereotactic body radiotherapy or radiofrequency ablation for isolated lesions.

The role of postoperative radiation has been explored and a meta-analysis of 9 randomized trials revealed a reduction in overall survival with postoperative radiation therapy in stage I and II NSCLC. However, it remains to be seen whether the use of modern radiation techniques with better definition of target volume and cardiac sparing could alter these outcomes.

Adjuvant chemotherapy has been extensively explored in NSCLC.[225] A meta-analysis concluded that adjuvant cisplatin-based therapy improved survival in resected stage IB, II, and III NSCLC. The absolute benefit in survival at 5 years was 6.9%, but in subset analyses, the benefit in stage IB was not statistically significant. No impact of age, sex, histology, or type of surgery was noted. The CALGB 9633 study randomized resected stage IB patients to 4 cycles of carboplatin-paclitaxel versus observation.

This study initially showed improved overall survival at 4 years (71% vs 59%), but a longer term follow-up at 74 months showed no change in overall survival, except in patients with a tumor size greater than 4 cm.[226]

This contrasted with the results of a Canadian study that showed significantly improved 5-year survival for stage IB and II patients treated with adjuvant cisplatin-vinorelbine for 4 cycles. Patients with resected stage IB NSCLC should, therefore, be counseled about risks and benefits of adjuvant chemotherapy and may be offered either 4 cycles of platinum-based doublet chemotherapy, preferably cisplatin, or observation.

Stage IIA/IIB (T2bN0M0, T1aN1M0, T1bN1M0, T1bN1M0, T2aN1M0, T2bN1M0, T3N1M0)

Surgical resection is the treatment of choice for stage II NSCLC, except for those patients who are not surgical candidates because of comorbid conditions or poor pulmonary reserve.

Long-term survival of 10-25% has been reported in patients with radiation therapy alone delivered with curative intent. In such cases, however, the dose of radiation therapy should be approximately 60 Gy, with careful planning to define tumor volume and avoid critical structures. Frequently a cone-down boost is used to enhance local control.

Patients with resected stage II disease are candidates for platinum-based adjuvant chemotherapy and should be offered four cycles of platinum-based adjuvant chemotherapy plus osimertinib if their tumor has an EGFR exon 19 deletion or exon 21 L858R mutation.

Stage IIIA (T1aN2M0, T1bN2M0, T2aN2M0, T3N1M0, T3N2M0, T4N1M0)

The management of stage IIIA NSCLC is quite controversial. Surgical resection, chemotherapy, radiation therapy, or a combination of any of these modalities may be the optimal choice, depending on the clinical situation. Overall 5-year survival of stage IIIA (N2) ranges from 10-15%, as resectability rates are low and very few patients (5-10%) achieve long-term benefit with radiation therapy alone. Consequently, stage IIIA has been an area of active research.

Patients who have mediastinal node involvement (N2 or N3 stage) have poor results from surgery and hence should be considered for definitive chemoradiation therapy. Cisplatin-based combinations (eg, with etoposide) are preferred, with carboplatin an acceptable alternative in patients with contraindications to cisplatin. Radiation is usually given in daily fractions for a total of 60 Gy. A cone-down boost may be useful.

Hyperfractionation schedules appear to be better, but are not widely available. Further chemotherapy or surgery does not appear to provide significant survival benefit for in patients treated upfront with chemoradiation.

A large randomized trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) compared surgery versus radiation therapy following neoadjuvant chemotherapy and found no significant difference between the two approaches in stage IIIA N2 disease. Neoadjuvant chemotherapy followed by surgery may, however, be considered for younger patients with stage IIIA disease who have good performance status.

Patients with stage III (T3-4, N1) disease of the superior sulcus are usually treated with neoadjuvant chemotherapy followed by surgical resection Two-year survival in this group is 50-70%.

Patients with stage IIIA (T3, N1) disease who are candidates for surgical resection should be offered adjuvant chemotherapy after a definitive surgical resection, based on the results of the International Adjuvant Lung Trial (IALT) and meta-analysis of adjuvant chemotherapy trials showing a hazard ratio of 0.87 with adjuvant chemotherapy. These patients should also undergo a mediastinal node dissection. In patients with positive margins, radiation therapy may be considered concurrently with chemotherapy.

Several retrospective series have suggested that postoperative radiation therapy may improve local control in patients with involved mediastinal nodes. Prospective trials have yielded conflicting results with regard to reduction in local recurrence with postoperative radiation therapy. A meta-analysis of 9 randomized trials of postoperative radiation therapy did not find a survival benefit in the entire group or in the subgroup with N2 disease.

Two small reports have shown improvement in disease-free and overall survival rates with neoadjuvant cisplatin-based chemotherapy for stage IIIA NSCLC; this approach may be considered in patients with good performance status. This approach may also be employed for patients who have tumors that are too large for a radiation port, prior to definitive chemoradiation.

A phase III trial compared prophylactic cranial irradiation (PCI) versus observation in patients with stage III NSCLC.[227] The study determined that among patients with stage III disease who did not have progression of disease after treatment with surgery or radiation therapy, PCI decreased the rate of brain metastasis but did not improve overall survival or disease-free survival. No significant differences in global cognitive function or quality of life were noted after PCI; however, a significant decline in memory was noted at 1 year.[228]

Stage IIIB (T1aN3M0, T1bN3M0, T2aN3M0, T2bN3M0, T3N3M0, T4N2M0, T4N3M0)

Patients with satellite lesions (T4 N0-1) should undergo a surgical resection if possible, followed by adjuvant chemotherapy. All other patients with stage IIIB disease are usually not candidates for surgical resection and are best managed with chemotherapy, combined chemoradiation therapy, or radiation therapy alone, depending on extent of disease, sites of involvement, and performance status of the patient. Patients who have malignant pleural effusion are not candidates for radiation therapy and are managed as stage IV (see below).

In an open-label, phase III study in chemotherapy-naive patients with stage IIIB NSCLC (n=676), cetuximab combined with first-line taxane/carboplatin chemotherapy did not reach statistically significant improvement for progression-free survival or overall survival; however, significant improvement was shown in overall response rate.[229]

The NVALT3 study found that chemotherapy in patients aged 70 years or older treated with carboplatin/paclitaxel or carboplatin/gemcitabine did not have a decline in their quality of life.[230]

A meta-analysis of 10 randomized trials of combined chemoradiation therapy revealed a 10% reduction in risk of death with combined modality therapy compared with radiation alone. It appears that in appropriate candidates (with good performance status), chemotherapy given concurrently with radiation results in superior survival compared with chemotherapy followed by radiation therapy.

Patients with stage IIIB NSCLC and poor performance status are not good candidates for chemotherapy or a combined-modality approach. These patients may benefit from radiation therapy alone to palliate the symptoms of shortness of breath, cough, and hemoptysis. Patients with invasive airway obstruction may be candidates for palliative endobronchial curettage or stenting to relieve obstructive atelectasis and dyspnea.

Stage IV (Any T, any N, M1a; Any T, any N, M1b)

Patients with advanced NSCLC should be evaluated for the presence of distant metastases. Patients with solitary brain lesions may benefit from a surgical resection, or stereotactic radiosurgery, if their primary disease is well controlled. Isolated adrenal masses should be resected, since many adrenal masses are benign and even oligometastatic adrenal disease can occasionally be well controlled.

In a small study, patients with isolated adrenal metastasis from lung cancer treated with surgical resection compared with nonoperative management have a better 5-year survival (34% vs 0%).[231]

Isolated synchronous nodules (either in the same or the opposite lung) should be treated as two separate primaries. These patients may need PET scanning to identify occult metastases or serial scans prior to definitive surgical resection that may be counterproductive.

In first-line systemic therapy for stage IV disease, cisplatin-based regimens have provided clear evidence of improved median survival and reductions in risk of death. Patients with good performance status should be offered chemotherapy with a platinum-based combination. Older patients (>70 y) or those with contraindications may be treated with a carboplatin-based regimen, such as carboplatin-paclitaxel. Younger patients (< 70 y) with nonsquamous histology may be candidates for treatment with cisplatin-pemetrexed, which appears to be somewhat better than cisplatin-gemcitabine.

Patients with nonsquamous histology, absence of cranial metastases, and no hemoptysis may be candidates for treatment with bevacizumab, which has been studied in combination with carboplatin-paclitaxel and cisplatin-gemcitabine. Antiangiogenic therapy is very expensive and potentially toxic even in carefully selected patients; hence, a detailed discussion with patients about its modest benefits versus the risks and costs is important.

Two-drug combinations have been found to be superior to single-agent treatment. However, no therapeutic advantage is obtained with the use of three drugs.

No clear survival benefit is observed from maintenance non–cross-resistant chemotherapy, though this is being studied with agents such as pemetrexed. For example, a randomized, placebo-controlled, double-blind phase 3 study of maintenance therapy with pemetrexed in 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy found that although pemetrexed therapy was associated with toxic effects, it significantly improved progression-free survival and overall survival compared with placebo.[232]

In other randomized, double-blind, placebo-controlled studies, quality of life during maintenance therapy with pemetrexed was similar to that seen with placebo, although a small increase in loss of appetite was observed. Pemetrexed maintenance therapy significantly delayed worsening of pain and hemoptysis and was associated with improvements in overall and progression-free survival, making it a treatment option for patients with advanced nonsquamous NSCLC who have not progressed after induction therapy with platinum-based regimens.[233, 234]

Small-molecule EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib may benefit nonsmokers with adenocarcinomas, particularly bronchoalveolar carcinoma; women of Asian origin are particularly likely to benefit. In such patients, it may be helpful to evaluate for EGFR mutations and use these agents first line.

Similarly, patients with EGFR expression and absence of K-ras mutations may be considered for the addition of cetuximab to first-line chemotherapy. However, the combination of anti–vascular endothelial growth factor (VEGF) agents such as bevacizumab with anti-EGFR antibodies appears to detrimental in other settings, and its use in NSCLC should be avoided.

Patients with progressive disease and good performance status may be candidates for treatment with single cytotoxic drugs such as docetaxel, pemetrexed, or gemcitabine, if they were not exposed to these drugs in the first-line setting. Selected patients can also be treated with erlotinib, though this is typically used in the third-line setting.

Patients with ECOG/Zubrod performance scores greater than 2 should be considered for palliative care, focused on symptom control. These patients should be recommended for enrollment in hospice care programs.

American Society of Clinical Oncology (ASCO) guidelines on systemic therapy for stage IV disease provide separate recommendations for tumors with and without genetic alterations that allow targeted therapy. See Guidelines/Treatment of Stage IV Disease.[235, 236, 237]

Patients with large-cell neuroendocrine carcinoma should receive platinum plus etoposide or the same treatment as other patients with nonsquamous carcinoma.

A patient's activity level, as measured by a performance status scale (eg, Zubrod, Karnofsky) is an important prognostic factor. Patients should be encouraged to remain active during and after treatment for lung cancer. A declining activity level usually signifies progressive or recurrent disease but also may be due to adverse effects of treatment.

 

Smoking cessation

Cigarette smoking is the most common etiologic factor for lung cancer; thus, the primary way to decrease the prevalence of lung cancer is to decrease the prevalence of smoking. Some measures for doing so include the following:

• Public education about the hazards of smoking

• More stringent legislation for tobacco control, including the increase of tax levies

• Banning of tobacco smoking in public areas - Exposure to second-hand smoke and other respiratory toxins in the workplace has decreased as a result of federal legislation

• Offering comprehensive strategies for smoking cessation to smokers, which include behavioral counseling, pharmaceutical aids such as varenicline, bupropion, and nicotine replacement therapy (eg, gum, transdermal patches)

Combining nicotine replacement, bupropion, and social or behavioral support can increase the quit rate to 35%.[238]

Although the relative risk of cancer does not decline to baseline levels for as long as 10 years after cessation, linked conditions (eg, chronic bronchitis, chronic obstructive pulmonary disease) show more rapid improvement or stabilization.[239]

Other measures

Workers exposed to asbestos or radioactive materials should always wear required safety equipment.

Some studies have shown a reduction in lung cancer incidence with daily use of aspirin. This reflects similar studies showing an association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and a reduced incidence of colorectal cancer and adenoma.[240]

Screening

Prevention is the more effective modality for decreasing the prevalence of NSCLC. However, several organizations recommend screening with low-dose computed tomography in patients at high risk for lung cancer. See Workup/Screening.

The management of lung cancer is best achieved with a multidisciplinary approach; therefore, after diagnosis, consultations should be sought from the following specialists:

• Thoracic surgeon
• Radiation oncologist
• Medical oncologist
• Pulmonologist
• Social worker

To address complications caused by spread of the disease, consultation with one or more of the following services may be needed:

• Otolaryngology
• General surgery
• Orthopedic surgery
• Vascular surgery
• Neurosurgery
• Neurology

Recommendations from the National Comprehensive Cancer Network (NCCN) regarding cancer surveillance in survivors of NSCLC include the following[92] :

• History and physical examination (H&P) and chest computed tomography (CT) scan with or without contrast every 6-12 months for 2-3 years, then an H&P and noncontrast chest CT scan annually
• Assessment of smoking status at each visit, with counseling and referral for smoking cessation as needed

Other NCCN recommendations for long-term monitoring include the following[92] :

• Annual influenza vaccination; pneumococcal vaccination with revaccination as appropriate; herpes zoster vaccination
• Counseling regarding health promotion and wellness (eg, regular physical activity, healthy diet)
• Routine health monitoring

Guidelines on the following aspects of managing non–small cell lung cancer (NSCLC) have been issued:

• Lung cancer screening ^{[39, 47, 65, 66]}
• Lung cancer diagnosis ^{[81, 92, 241]}
• Molecular testing ^{[58, 92, 242]}
• Treatment of stage I-III NSCLC ^{[1, 81, 146, 224, 241]}
• Radiation therapy for locally advanced NSCLC ^{[243, 244, 245]}
• Treatment of stage IV NSCLC ^{[92, 235, 236, 237, 246]}
• Post-treatment surveillance ^{[92, 247]}

For more information, see Non–Small Cell Lung Cancer (NSCLC) Guidelines.

Chemotherapy is used as an adjuvant to surgery in selected patients with non–small cell lung cancer (NSCLC). Unresectable NSCLC is treated with chemotherapy or a combination of chemotherapy and radiation therapy. Molecularly targeted treatments have also become standard of care.

Aggressive antiemetic support and growth-factor support, when appropriate, are other integral parts of medical treatment of these patients. Antibiotics are commonly required for treatment of infectious complications but are not discussed in this article. Aggressive antiemetic support to prevent, not treat, nausea and vomiting is essential because of the highly emetogenic potential of chemotherapy drugs and the doses used in the treatment of NSCLC. This holds especially true for platinum-based chemotherapeutic regimens. The most common and effective agents are corticosteroids and the serotonin receptor antagonists, which include ondansetron, granisetron, and dolasetron.

Class Summary

Antineoplastic agents are used either to prolong survival or to palliate symptoms in advanced or unresectable lung cancer.

Carboplatin

Carboplatin has a mechanism of action similar to that of cisplatin. It is approved for ovarian cancer but is used commonly in squamous cell carcinoma (SCC) of the head, neck, cervix, and lungs. Its main advantages over cisplatin include less nephrotoxicity and ototoxicity (not requiring extensive prehydration) and reduced likelihood of inducing nausea and vomiting. It is more likely to induce myelotoxicity.

Vinorelbine (Navelbine)

Vinorelbine is a semisynthetic vinca alkaloid that inhibits tubulin polymerization during the G2 phase of cell division, thereby inhibiting mitosis. Vinorelbine alone or in combination with cisplatin is indicated as first-line treatment of ambulatory patients with unresectable, advanced NSCLC and for stage IV NSCLC. In stage III NSCLC, vinorelbine is indicated in combination with cisplatin.

Paclitaxel

Paclitaxel is a naturally occurring chemical derived from the Pacific yew tree (Taxus brevifolia). It inhibits tubulin depolymerization in the spindle during cell division. Paclitaxel is used in combination with cisplatin for the first-line treatment of NSCLC in patients who are not candidates for potentially curative surgery or radiation therapy.

Paclitaxel protein bound (Abraxane)

Protein-bound paclitaxel is a microtubular inhibitor (albumin-conjugated formulation). It is a natural taxane, and it prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition. It is indicated for locally advanced or metastatic NSCLC, as first-line treatment in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Cisplatin

Cisplatin is an alkylating agent that causes intrastrand and interstrand cross-linking of DNA, leading to strand breakage. It has a very broad range of antitumor activity and is approved for use in testicular, ovarian, and transitional cell carcinomas. It forms the basis of currently available approved combination chemotherapy regimens for NSCLC. Administer it as a single-dose intravenous (IV) infusion or in divided doses over several days; this can be repeated only after complete hematologic recovery; cycles are typically separated by 3-4 wk.

Gemcitabine (Gemzar)

Gemcitabine is an antimetabolite that acts as an inhibitor of DNA synthesis. It is cell-cycle specific for the S phase. Gemcitabine is used as first-line treatment of patients with inoperable, locally advanced (stage IIIA or IIIB), or metastatic (stage IV) NSCLC in combination with cisplatin.

Docetaxel (Taxotere)

Docetaxel is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking disassembly of microtubules, thereby preventing cancer cell division, leading to cell death. It is indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior platinum-based chemotherapy when used alone. It can be used in combination with cisplatin for the treatment of patients with unresectable, locally advanced, or metastatic NSCLC who have not previously received chemotherapy for this condition.

Pemetrexed disodium (Alimta)

Pemetrexed disrupts folate-dependent metabolic processes essential for cell replication. It specifically inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in de novo biosynthesis of thymidine and purine nucleotides. It is indicated for nonsquamous NSCLC as follows:

1) Initial treatment in combination with pembrolizumab and platinum chemotherapy for patients with metastatic disease with no EGFR or ALK genomic tumor aberrations

2) Initial treatment in combination with cisplatin for patients with locally advanced or metastatic disease

3) Single agent for maintenance in patients with locally advanced or metastatic disease that has not progressed after 4 cycles of platinum-based first-line chemotherapy

4) Single agent for treatment of patients with recurrent metastatic disease after prior therapy

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards; as an alkylating agent, the mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Doxorubicin

Doxorubicin is an anthracycline that inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA; the combination of these 2 events can, in turn, inhibit the growth of neoplastic cells.

Vincristine

Vincristine is a vinca alkaloid whose mechanism of action is uncertain. It may involve a decrease in reticuloendothelial cell function or an increase in platelet production. However, neither of these mechanisms fully explains the effect in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. The antineoplastic effects of vincristine are related to its binding to tubulin and inhibition of microtubule formation.

Etoposide

Etoposide inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early G2 portion of cell cycle; do not administer IT.

Class Summary

Testing for ALK rearrangement is recommended in patients with metastatic NSCLC adenocarcinoma to determine if a therapy targeted toward ALK would be beneficial.

Crizotinib (Xalkori)

Inhibitor of receptor tyrosine kinases including, anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-Met), and recepteur d'origine nantais (RON). The gene's expression and signaling that contribute to increased cell proliferation and survival of the tumors becomes activated following the expression of ALK oncogenic fusion proteins. Indicated for locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK positive as detected by an FDA-approved test. It is also indicated for NSCLC tumors positive for the ROS-1 gene mutation.

Ceritinib (Zykadia)

Ceritinib is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK), insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. It is indicated for ALK-positive, metastatic NSCLC.

Alectinib (Alecensa)

Tyrosine kinase inhibitor that targets ALK and RET. The major active metabolite of alectinib, M4, showed similar in vitro potency and activity. In nonclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations.. It is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic NSCLC as detected by an FDA-approved test.

Brigatinib (Alunbrig)

Brigatinib inhibits autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. It is indicated for ALK-positive metastatic NSCLC in patients who have progressed on or are intolerant to crizotinib.

Lorlatinib (Lorbrena)

ALK/ROS1 tyrosine kinase inhibitor indicated for ALK-positive metastatic NSCLC

Class Summary

PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells. Under normal conditions, PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells; therefore, inhibiting the ligand binding will enhance T-cell mediated immune response.

Nivolumab (Opdivo)

Monoclonal antibody to programmed cell death-1 protein (PD-1). It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Restores cytokine secretion and T cell activity. It is indicated for metastatic squamous and nonsquamous (including adenocarcinoma) NSCLC with progression on or after platinum-based chemotherapy. It is also indicated, in combination with ipilimumab, for metastatic NSCLC in patients whose tumors express PD-L1 (≥1%), with no EGFR or ALK tumor aberrations; and, in combination with ipilimumab and two cycles of platinum-doublet chemotherapy, for the first-line treatment of metastatic or recurrent NSCLC in patients whose tumors have no EGFR or ALK aberrations, regardless of PD-L1 expression. In addition to metastatic NSCLC, it is also indicated for resectable (tumors ≥4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy.

Pembrolizumab (Keytruda)

Pembrolizumab is a monoclonal antibody to programmed cell death-1 protein (PD-1). It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is indicated as a single agent for first-line treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC whose tumors express PD-L1 (Tumor Proportion Score [TPS] ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. Pembrolizumab is also indicated as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.

Pembrolizumab is indicated in combination with pemetrexed and carboplatin for first-line treatment of patients with metastatic nonsquamous NSCLC irrespective of PD-L1 expression. It is also indicated first-line in combination with carboplatin and either paclitaxel or nab-paclitaxel for patients with metastatic squamous NSCLC.

Atezolizumab (Tecentriq)

Atezolizumab is a monoclonal antibody to PD-L1. It is indicated for patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab. It is also indicated for first-line treatment for metastatic NSCLC in patients whose tumors have high PD-L1 expression (PD-L1 stained ≥50% of tumor cells [TC ≥50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥10% of the tumor area [IC ≥10%]).

Durvalumab (Imfinzi)

Human IgG1 kappa monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, and therefore overcoming/preventing PD-L1-mediated inhibition/suppression of T-cell activation. It is indicated for unresectable, Stage III NSCLC in patients whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. 

Also indicated in combination with tremelimumab and platinum-based chemotherapy for adults with metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. 

Cemiplimab (Libtayo, Cemiplimab-rwlc)

Cemiplimab is a recombinant human IgG4 monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L1, releasing the PD-1 pathway-mediated inhibition of the immune response, including antitumor immune response, thereby decreasing tumor growth. Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. It is approved for first-line treatment of NSCLC who tumors have high PD-L1 expression [TPS ≥50%] with no EGFR, ROS-1, or ALK mutations.

Ipilimumab (Yervoy)

Recombinant, human cytotoxic T-lymphocyte antigen. Proposed mechanism of action is indirect, possibly through inhibition of CTLA-4 signaling, which can in turn reduce T-regulatory cell function and may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response. It is indicated in combination with nivolumab, for metastatic NSCLC in patients whose tumors express PD-L1 (≥1%), with no EGFR or ALK tumor aberrations.

Class Summary

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking monoclonal antibody blocks the interaction with its ligands CD80 and CD86. This action releases CTLA-4-mediated inhibition of T-cell activation. 

Tremelimumab (Imjudol)

Indicated in combination with durvalumab for and platinum-based chemotherapy for adults with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

Class Summary

EGFR is expressed on the cell surface of both normal and cancer cells and plays a role in the processes of cell growth and proliferation.

Osimertinib (Tagrisso)

EGFR kinase inhibitor, which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion). It is indicated for metastatic EGFR T790M mutation–positive NSCLC in patients whose disease has progressed on or after EGFR TKI therapy. It is also used as first-line treatment for metastatic NSCLC in patients with EGFR exon 19 deletions or exon 21 L858R mutations, and as adjuvant therapy after tumor resection in NSCLC patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.

Gefitinib (Iressa)

Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signalling and blocking EGFR-dependent proliferation. It is indicated for the treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

Erlotinib (Tarceva)

Erlotinib is pharmacologically classified as an HER1/EGFR tyrosine kinase inhibitor (TKI). EGFR is expressed on the cell surface of normal cells and cancer cells. It is approved for NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test for first-line treatment, maintenance treatment, or as second- or greater-line treatment after progression following at least 1 prior chemotherapy regimen. It also is indicated in combination with ramucirumab for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

Afatinib (Gilotrif)

Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. It demonstrates inhibition of autophosphorylation and in vitro proliferation of cell lines expressing wild-type EGFR or those expressing selected EGFR exon 19 deletion mutations or exon 21 L858R mutations, including some with a secondary T790M mutations

Afatinib is indicated for first-line treatment of patients with metastatic NSCLC whose tumors have non-resistant EGFR mutations as detected by an FDA-approved test. Additionally, afatinib is indicated for first-line use in metastatic NSCLC for 3 additional nonresistant EGFR mutations (L861Q, G719X, S768I). It is also indicated for metastatic squamous NSCLC that has progressed after platinum-based chemotherapy.

Dacomitinib (Vizimpro)

Irreversible kinase inhibitor of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR-activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). It is indicated for first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.

Amivantamab (Amivantamab-vmjw, Rybrevant)

Bispecific antibody that binds to the extracellular domains of EGFR and MET; indicated for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, in adults whose disease has progressed on or after platinum-based chemotherapy. It is administered as an IV infusion. 

Class Summary

Mutations in the gene encoding HER2 drive approximately 3% of nonsquamous NSCLCs and are associated with female sex, never-smoking history, and a poor prognosis, as well as with a slightly younger age and higher incidence of brain metastases than NSCLC without HER2 mutations or with other mutations.[147]

Trastuzumab deruxtecan (Enhertu)

Indicated for unresectable or metastatic HER2-mutant NSCLC based on presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens in patients who have received prior systemic therapy. 

Class Summary

BRAF genes direct protein production which induces signal transmission along the RAS/MAPK pathway. RAS/MAPK pathway regulates cell growth, cell differentiation, cell migration, and apoptosis. BRAF mutations can cause dysregulation of cell growth, resulting in tumor progression[248]

Dabrafenib (Tafinlar)

Dabrafenib selectively inhibits multiple mutated BRAF kinases, BRAF V600E, BRAF V600K, and BRAF V600D. BRAF kinase inhibition primarily stunts cells growth. The combination of dabrafenib with trametinib targets two different kinases in the RAS/MEK pathway, causing greater growth inhibition of tumors with the BRAF V600 mutation.  

Entrectinib (Rozlytrek)

Entrectinib and its major metabolite inhibit tropomyosin receptor tyrosine kinases (TRKs), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). It is indicated for metastatic NSCLC in adults whose tumors are ROS1-positive. Entrectinib is also indicated for NTRK genetic fusion solid tumors in pediatric and adult patients for whom there are no effective treatments.

Larotrectinib (Vitrakvi)

Larotrectinib is an oral tyrosine kinase inhibitor that binds to tropomyosin receptor kinase (TrK), preventing TrK activation. This induces cellular apoptosis and inhibition of cell growth in tumors. It is currently indicated for solid tumors that have an NTRK gene fusion in adults and pediatric patients without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.

Repotrectinib (Augtyro)

Indicated for adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. 

Class Summary

Genomic alterations in rearranged during transfection (RET) kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth.

Selpercatinib (Retevmo)

Selpercatinib is a kinase inhibitor of wild-type rearranged during transfection (RET) and multiple mutated RET isoforms, as well as vascular endothelial growth factor receptors (VEGFR1, VEGFR3). It is indicated for metastatic RET fusion-positive NSCLC. 

Pralsetinib (Gavreto)

Pralsetinib is a selective inhibitor of RET alterations and resistant mutations; specifically designed to spare VEGFR2 and other kinases with the potential to drive off-target toxicity. This RET inhibitor exhibited antitumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations. It is Indicated for metastatic RET gene-positive NSCLC.

Class Summary

Mitogen extracellular signal-regulated kinase (MEK) protein acts downstream from Ras in the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway regulates cell growth, cell differentiation, cell migration, and apoptosis.[248]  Blockage of MEK protein may affect tumors with mutated Ras proteins or other proteins influenced by MAPK pathway.

Capmatinib (Tabrecta)

Capmatinib is a kinase inhibitor that targets mesenchymal-epithelial transition (MET) , including the exon 14 skipping mutation. MET tyrosine kinase stimulates cell scattering, invasion, protection from apoptosis, and angiogenesis. A variety of cancers (eg, lung, gastric) are associated with dysregulation of MET, owing to MET amplifications and exon 14 skipping mutations. Capmatinib is indicated for metastatic NSCLC in adults whose tumors have a mutation that leads to exon 14 skipping.

Tepotinib (Tepmetko)

Tepotinib is an inhibitor of MET tyrosine kinase, which selectively binds to MET tyrosine kinase and disrupts MET signal transduction pathways. Therefore, this disruption may induce apoptosis in tumor cells overexpressing this kinase. It is indicated for metastatic NSCLC in patients with MET exon 14 skipping mutation.

Trametinib (Mekinist)

Trametinib is a selective reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity BRAF V600E mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib inhibits cell growth in BRAF V600 mutation positive tumors in vitro and in vivo. It is indicated, in combination with dabrafenib, for the treatment of patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test.

Class Summary

KRAS G12C proteins continuously regenerate, so continuous inhibition is needed to prevent downstream signaling. Sotorasib and adagrasib form an irreversible, covalent bond with the unique cysteine of KRAS G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. These inhibitors block KRAS signaling, inhibit cell growth, and promote apoptosis only in KRAS G12C tumor cell lines. 

Adagrasib (Krazati)

It is indicated for KRAS G12C- mutated locally advanced or metastatic NSCLC in adults who have received 1 or more prior systemic therapies.

Sotorasib (Lumakras)

Indicated for KRAS G12C-mutated locally advanced or metastatic NSCLC in adults who have received 1 or more prior systemic therapies. 

Bevacizumab (Avastin, Mvasi)

Bevacizumab is a murine-derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). It inhibits new blood vessel formation, denying blood, oxygen, and other nutrients needed for tumor growth. It is indicated in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC. Mvasi has been FDA-approved as a biosimilar to Avastin but not as an interchangeable product.

Ramucirumab (Cyramza)

Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, it inhibits ligand-stimulated activation of VEGF2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. It is indicated in combination with erlotinib for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

Class Summary

Antiemetic agents are useful in the treatment of symptomatic nausea caused by chemotherapy.

Ondansetron (Zofran, Zuplenz)

Ondansetron blocks serotonin 5-HT3 receptor antagonists. It is not clear whether the effect is mediated centrally, peripherally, or both. Ondansetron is indicated in the prevention of chemotherapy-induced nausea and vomiting.

Granisetron (Granisol, Sancuso, Sustol)

Granisetron blocks serotonin 5-HT3 receptor antagonists. It is not clear whether the effect is mediated centrally, peripherally, or both. Granisetron is indicated in the prevention of chemotherapy-induced nausea and vomiting.

Dolasetron (Anzemet)

Dolasetron blocks serotonin 5-HT3 receptor antagonists. It is not clear whether the effect is mediated centrally, peripherally, or both. Dolasetron is indicated in the prevention of chemotherapy-induced nausea and vomiting.

Palonosetron (Aloxi)

Palonosetron is a selective 5-HT3 receptor antagonist with a long half-life (40 h). It is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of chemotherapy. It blocks 5-HT3 receptors peripherally and centrally in the chemoreceptor trigger zone.

Dexamethasone

Dexamethasone is a synthetic adrenocortical steroid with multiple indications. It is widely used in prevention of nausea and vomiting caused by highly emetogenic agents (eg, cisplatin) in combination with serotonin receptor antagonists.