Non-Small Cell Lung Cancer (NSCLC) Treatment & Management

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. ^[74] 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. ^[75] 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 (tumors ≥4 cm or node positive) NSCLC. Approval was based on results of the CheckMate 816 trial, which included patients with stage IB, II, or IIIA NSCLC. ^[76] 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. 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. ^[77]

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. ^[78]

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. ^[79]

A study 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. ^[80]

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. ^[81]

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. ^[82]

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). ^[83] This needs to be validated in a randomized phase III study.

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%. ^[84]

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. ^[85] 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. ^[84]

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. ^[86] A study by Wolf et al showed that sublobar resection is a reasonable option for elderly patients with compromised cardiopulmonary status. ^[87]

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. ^[88] 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. ^{[89, 90]}

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. ^[91]

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. ^[92] 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. ^[93]

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). ^[94]

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. ^[95] 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. ^[96]

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. ^[97] 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%. ^[98] 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. ^[99]

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. ^[100]

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. ^[101]

Adjuvant radiation therapy

The role of adjuvant radiation therapy after resection of the primary tumor remains controversial. ^{[102, 103]} 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%). ^[104] 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%. ^{[105, 106]} However, adjuvant chemotherapy in elderly patients with resected stage IIIA NSCLC is not associated with survival advantage. ^[107]

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. ^[64] 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. ^{[108, 109]}

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). ^[110] 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. ^[111]

Platinum-based regimens

Cisplatin has been the cornerstone of most combination regimens studied in advanced NSCLC. ^[112] A recent 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. ^[113]

American Society for 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 recent 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.

In October 2012, the US Food and Drug Administration (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. ^[114]

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. ^[114]

The cisplatin-gemcitabine 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 renal 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. ^[115]

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. ^[116] 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. ^[117]

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. ^[118]

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. ^[119]

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

In the future, therapy for NSCLC may need to be tailored on the basis of the genetic characteristics of individual tumors. Gene expression profiling has been studied for accurate classification of NSCLC histology as well as prognostication, but this remains experimental.

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 US Food and Drug Administration (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. ^[120]

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. ^[121]

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. ^[122]

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. ^[123]

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
• Renal failure 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) non–small cell lung cancer (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. ^{[124, 125]}

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. ^{[126, 127]} 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). ^{[128, 129, 130]}

Chemotherapy regimens that have been studied in combination with radiation therapy include cisplatin/vinblastine and cisplatin/etoposide (5-y survival of 15%). ^[126] 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. ^{[131, 132, 133]}

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. ^[134]

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. ^[135]

More recently, consolidation therapy with the anti-programmed death ligand–1 antibody durvalumab following concomitant chemoradiation has shown significant benefit. In a 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%. ^[136]

The high locoregional failure rate with chemoradiation alone has led to study of chemoradiation followed by surgical resection. ^{[103, 105, 137]} 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. ^[138]

In a small study in patients who were node negative with T3 and T4 NSCLC, neoadjuvant chemoradiation followed by surgery led to better survival. ^[139]

The pacific trial, a phase 3 trial for locally advanced patients who have unresectable lung cancer, who were treated with chemoradiation, those with no progression of disease on scans were randomized to placebo or durvalumab for 1 year. Ot the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). The 24 month overall survival was 665.3% in the durvalumab group and 55.6% in the placebo arm. Durvalumab significantly prolonged overall survival. updated survival shows 17.2 months compared to placebo of 5.6 months. The median time to death or distant metastasis was 28.3 months in the durvalumab arma dn 16.2 months for the placebo group. ^[136]  

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. ^[75]

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. ^[89]

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.

EGFRtesting, 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. ^[89]  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). ^[140]  

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. ^[141]  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. ^[89]  KRAS G12C accounts for approximately 50% of KRAS mutations in NSCLC and is present in approximately 14% of patients with NSCLC. ^[142]  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). ^[89]  

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 ROS-1 mutations, the following agents are used:

• Crizotinib (Xalkori)(preferred)
• Entrectinib (Rozyltrek)(preferred) ^{[143, 144]}
• Ceritinib (Zykadia)

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. ^[89]

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). ^[145]  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. ^[146]

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. ^[89]

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. ^[147] In 2018, the indication for first-line use in metastatic NSCLC was expanded to include 3 additional nonresistant EGFR mutations (ie, L861Q, G719X, S768I). ^[148]

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. ^[147]

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). ^[149]

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%). ^[147]

Gefitinib

Gefitinib represents a class of EGFR TKIs that act intracellularly to block activation of the EGFR pathway. ^{[150, 151]}

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. ^[152]

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. ^[153]

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. ^[151]

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. ^[154]

In an early IPASS study, EGFR mutation was found to be the strongest predictor of PFS and response to gefitinib. ^[155]

Erlotinib

A second EGFR TKI, erlotinib, improved survival rates compared with placebo in the second- and third-line setting. ^{[156, 157]} 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). ^[158]

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. ^[59]

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. ^[159]

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. ^[160] 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. ^[161]

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). ^[162] 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. ^[163]

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, osimertinib was also approved for 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. ^{[163, 164]}

Osimertinib was also approved as an adjuvant therapy for NSCLC patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations following tumor resection. Approval was based on the results from the phase III ADAURA trial trial, in which stage II to IIIA patients (n=682) were randomized to osimertinib or placebo. Differences in disease-free survival (DFS) in the overall study population were 11% DFS events in osimertinib arm compared with 46% in the placebo arm. Median DFS was not reached after 2 years in both the stage II-IIIA and overall population. Overall survival data were immature at the time of analysis. ^[165]

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). ^[166] Overall survival analysis showed slight improvement with dacomitinib: 34.1 months, versus 26.8 months with gefitinib. ^[167]

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. ^[168]

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. ^[169]

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 to this regimen. ^[89]  

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. ^[170]  

Mobocertinib

Similar to amivantamab, mobocertinib is a kinase inhibitor indicated 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. It is the first orally administered TKI that targets EGFR exon 20. This indication gained accelerated approval from the FDA in September 2021, based on overall response rate and duration of response (DOR) in the phase I/II EXCLAIM study, an open-label trial of 114 patients treated with mobocertinib 160 mg once daily. Investigator-assessed overall response rate was 35% (95% CI: 26, 45) with a median DOR of 11.2 months, with responses lasting longer than 6 months in 63% of these patients. ^[171]  

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. ^[141]  

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. ^[172]     

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%. ^[173]  

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%. ^[174]   

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. ^[89]

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). ^[175]

Vandetanib

A randomized, double-blind, phase III trial assessed the use of vandetanib, a once-daily oral inhibitor of vascular EGFR and EGFR signaling. ^[176] 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. ^[177]

Patients with squamous cell histology, brain metastases, clinically significant hemoptysis, and ECOG performance status of greater than 1 were excluded. ^[177] 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. ^[178]

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. ^[179]

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. ^[180]

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. ^[181]

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. ^[182]

In a study of patients with previously treated advanced NSCLC who had ALK gene rearrangement, treatment with crizotinib was superior to standard chemotherapy. ^[183] 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. ^[183]

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. ^[183]

In 2016 the FDA expanded use of crizotinib to include patients with metastatic NSCLC whose tumors harbor a ROS-1 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]

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). ^[185]

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. ^[186]

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. ^[187]

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. ^[188]

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%. ^[189]

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. ^[190]

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. ^[191]

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. ^[192]

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. ^[193] 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. ^[194]

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). ^[195]

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. ^[196]

In March 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). ^[76]

Pembrolizumab

A second PD-1 inhibitor, pembrolizumab, was first approved for metastatic NSCLC in 2015, based on data from the KEYNOTE-001 trial. ^[197] 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). ^[198]

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%). ^[199]

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. ^[200]

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. ^[201]

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. ^[202]

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). ^[175]

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. ^{[203, 204]}

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. ^[205]

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. ^[140]

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). ^[145]

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). ^[136]  

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. ^[206]  

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. ^[207] 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. ^[207]

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. ^[208]

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. ^[209]

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. ^[210]

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. ^[210]

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. ^[211]

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. ^[212]

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. ^[213]

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. ^[214]

National Comprehensive Cancer Network (NCCN) guidelines include the following recommendations on initiation of corticosteroid therapy for specific immunotherapy-related toxicities ^[214] :

• 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 intervention with either a segmental or a wedge resection. The risk of local recurrence is higher with limited resection, but no adverse effect on overall survival was reported in a randomized trial by the Lung Cancer Study Group.

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. ^[215] 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. ^[216]

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 (see below) 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. ^[217] 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. ^[218]

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. ^[219]

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. ^[220]

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%). ^[221]

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. ^[222]

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. ^{[223, 224]}

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. ^{[225, 226, 227]}

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%. ^[228]

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. ^[229]

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. ^[230]

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 non–small cell lung cancer (NSCLC) include the following ^[89] :

• 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 ^[89] :

• 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