Malignant Melanoma Treatment Protocols

Treatment protocols for malignant melanoma are provided below, including recommendations for the following:

• Treatment by stage
• Combination treatment for advanced or metastatic disease
• Treatment for disease progression following ipilimumab and BRAF inhibitor treatment

Treatment recommendations for patients with malignant melanoma based on stage

Stage 0 in situ and IA ^[1] :

• For patients with stage 0 and stage IA melanoma (< 0.8 mm thick, no ulceration) wide-excision surgery is recommended as primary treatment

• For patients with stage IA with one or more adverse features (eg, very high mitotic index ≥2/mm², particularly in a young patient; lymphovascular invasion), discuss and consider sentinel lymph node biopsy (SLNB) in addition to wide-excision surgery

Stage IB and IIA ^{[1, 2]} :

• Wide-excision surgery; also discuss and offer SLNB

Stage IIB or IIC ^[2] :

• Surgery is recommended for stage IIB or IIC; also discuss or offer SLNB

• If SLNB is performed and is node positive, then complete dissection of nodal basin should be performed

• Alternative recommendations are observation, clinical trial enrollment, or interferon alfa; use of interferon alfa is based on lower level of clinical evidence, and its use should be individualized

Stage III ^{[2, 1]} :

• For stage III (clinically positive nodes), surgical excision is recommended with complete lymph node dissection; adjuvant therapy includes clinical trials, observation, or biologic therapy; pembrolizumab or nivolumab are currently favored for biologic therapy, as they have a better toxicity profile than interferon or ipilumimab.

• Consider radiation therapy to nodal basin for stage IIIC disease with multiple nodes involved or macroscopic extranodal extension

• Biologic therapy for stage III melanoma is selected on the basis of the toxicity profile and results of randomized trials

• PD-1 inhibitors are commonly used today rather than ipilumimab and interferon formulations due to lesser toxicity with these agents.

• Pembrolizumab is indicated for adjuvant treatment of resected, high-risk stage 3 melanoma; level one evidence showed pembrolizumab (200 mg q3wk for 1 year) had a significantly prolonged 1-year recurrence-free survival compared with placebo (75.4% vs 61%; P < 0.001) In April 2020, FDA approved additional dosing of 400 mg q6wk for up to 1 year. ^[3] ​ ^[4]

• Nivolumab is indicated for adjuvant treatment of resected stage III or IV melanoma; level one evidence shows that recurrence-free survival is better with nivolumab (3 mg/kg q2wk for 1 year) than with ipilimumab ^[5]

• Ipilimumab is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes > 1 mm who have undergone complete resection, including total lymphadenectomy; the recommended regimen is 10 mg/kg IV q3wk for 4 doses followed by 10 mg/kg q12wk for up to 3 years ^[6]

• Peginterferon alfa-2b has been approved for adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 d of definitive surgical resection including complete lymphadenectomy; dosing recommendations are 6 μg/kg/wk SC for eight doses followed by 3 μg/kg/wk SC for up to 5 years

• Interferon alfa-2b (20 million IU/m² IV five times weekly for 4 wk, then 10 million IU/m² SC three times weekly for 48 wk; treat for a total of 1 year) ^[7]

For patients with stage III in-transit disease, primary treatment options include the following:

• Complete resection (preferred, if feasible)

• SLNB for resectable disease

• Hyperthermic perfusion/infusion with melphalan for localized multiple lesions in a single extremity or recurrent lesions in a single limb

• Talimogene laherparepvec is a genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery ^[8] It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. Dosage and volume of the injection(s) depend on whether it is the initial dose, second dose, or subsequent doses and by lesion size.

• Clinical trial

Combination-treatment recommendations for advanced or metastatic melanoma

Combination treatment provides better response and control of the disease and is often used in patients with advanced or metastatic disease who clinically are able to tolerate this approach. Considerations are as follows:

• Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable)

• For limited disease, resection is recommended, followed by nivolumab ^[5]

• Other options for treatment for limited disease includes clinical trial or systemic therapy with interleukin-2 (IL-2) or temozolomide, dacarbazine for two to three cycles, ipilumimab q3wk four times, and then assessment for response; if stable, continue treatment (see below for drug regimens)

Stage IV with diffuse metastasis:

For patients who have unresectable or metastatic melanoma with BRAF V600E or V600K mutation:

• Trametinib 2 mg PO qd plus dabrafenib 150 mg PO BID for BRAF V600E or V600K mutations ^[9] or

• Cobimetinib 60 mg PO qd on days 1-21 plus vemurafenib 960 mg PO BID on days 1-28 of a 28-day cycle ^[10] or

• Encorafenib 450 mg PO qd plus binimetinib 45 mg PO BID until disease progression or unacceptable toxicity ^[11]

• Vemurafenib 960 mg PO BID plus  cobimetinib 60 mg PO qd for 21 days followed by atezolizumab 840 mg IV (Day 1 and 15), vemurafenib 720 mg BID, and cobimetinib 60 mg qd (21 days on–7 days off)

Other approaches are as follows:

• For patients with unresectable disease without brain metastases, treatment includes systemic therapy; patients with brain metastases require treatment of the central nervous system disease

• For stage IV disease in one limb, recommendations include surgery plus  lymph perfusion treatment plus options such as observation, clinical trial, or treatment with interferon alfa

Previously untreated unresectable or metastatic melanoma: 

• Nivolumab/relatlimab 480 mg/160 mg IV q4wk over 30 min until disease progression or unacceptable toxicity ^[12]  

For previously untreated patients with BRAF V600 wild-type, unresectable or metastatic melanoma:

• Nivolumab 1 mg/kg IV over 30 min followed by ipilimumab 3 mg/kg IV over 90 min administered on the same day q3wk for 4 doses; subsequent single-agent nivolumab doses are 240 mg q2wk or 480 mg q4wk over 30 min until disease progression or unacceptable toxicity ^{[13, 14]} or

• Dacarbazine 220 mg/m² IV on days 1-3 plus carmustine 150 mg/m² IV on day 1 plus cisplatin 25 mg/m² IV on days 1-3; repeat cycle with dacarbazine and cisplatin q21 days; repeat cycle of carmustine q42days or

• Interferon alfa-2b (15 million IU/m² IV on days 1-5, 8-12, and 15-19 as induction therapy or  10 million IU/m² SC 3 times weekly after induction therapy) plus  dacarbazine 200 mg/m² IV on days 22-26

Single-agent treatment recommendations for advanced or metastatic melanoma or second-line therapy

Stage IV ^{[15, 16, 17, 18, 19, 20, 21]} :

• Clinical trial is preferred

• Pembrolizumab 200 mg IV q3wk or 400 mg q6wk until disease progression or unacceptable toxicity; it is indicated as first-line treatment for unresectable or metastatic malignant melanoma; note that the trial used a higher dose of pembrolizumab than the dose approved by the FDA, which is 2 mg/kg q3wk  ^[22]  or

• Ipilimumab 3 mg/kg IV over 90 min; q21 d for a total of four doses ^[23] or

• Dacarbazine 2-4.5 mg/kg/day IV for 10 days; may repeat q4wk; or  250 mg/m² IV on days 1-5; may repeat q3wk or

• Temozolomide 150 mg/m² PO on days 1-5; repeat q28 days; may increase dose to 200 mg/m² PO on days 1-5 or

• Interleukin-2 600,000 U/kg IV q8h (maximum 14 doses); following nine days of rest, repeat for another 14 doses (not to exceed 28 doses per course, as tolerated; FDA-approved recommendation) or

• Nivolumab 240 mg IV q2wk or 480 mg IV q4wk over 30 min until disease progression or unacceptable toxicity; single agent in the first-line treatment of unresectable or metastatic BRAF V600 wild-type or mutation-positive melanoma ^[14]

• Vemurafenib 960 mg PO q12h (for patients with BRAF V600E mutation); not indicated for wild-type BRAF melanoma

• Dabrafenib 150 mg PO BID (for BRAF V600E mutation); not indicated for wild-type BRAF melanoma

• Trametinib 2 mg PO qd (for BRAF V600E or V600K mutations); not indicated in patients who have received prior BRAF inhibitor therapy

• Imatinib 400 mg PO qDay (for activating KIT mutations) ^{[2, 24]}

• Larotrectinib 100 mg PO BID until disease progression or until unacceptable toxicity (for NTRK gene fusions) ^[25]

• Entrectinib 600 mg PO BID until disease progression or until unacceptable toxicity (for NTRK gene fusions) ^[26]

• Binimetinib 45 mg PO BID until disease progression or until unacceptable toxicity (for NRAS mutations) ^[27]

Disease progression following ipilimumab treatment

Treatment options for unresectable or metastatic melanoma and disease progression following ipilimumab treatment are as follows:

• Pembrolizumab 200 mg IV q3wk over 30 min until disease progression or unacceptable toxicity; if BRAF V600 mutation positive, a BRAF inhibitor (dabrafenib, vemurafenib) ^[28]

• Nivolumab 240 mg IV q2wk or 480 mg IV q4wk over 30 min until disease progression or unacceptable toxicity; if BRAF V600 mutation positive, a BRAF inhibitor ^[29]

Uveal melanoma

For HLA-A*02:01–positive patients with uveal melanoma, tebentafusp-tebn is administered weekly by intravenous infusion, as follows ^[30] :

• 20 mcg on Day 1
• 30 mcg on Day 8
• 68 mcg on Day 15
• 68 mcg once weekly thereafter, until disease progression or unacceptable toxicity