What is the recommended first‑line immunotherapy regimen for an adult with unresectable stage III or IV melanoma, including dosing, duration, and considerations for combination therapy and BRAF mutation status?

Immunotherapy for Melanoma

First-Line Treatment for Unresectable Stage III or IV Melanoma

PD-1 blockade (nivolumab or pembrolizumab) or the combination of nivolumab plus ipilimumab are standard of care for all patients with unresectable stage III or IV melanoma, regardless of BRAF mutation status, in the first-line setting. 1

Mandatory Pre-Treatment Testing

• BRAF V600 mutation testing is mandatory before initiating treatment, as this determines whether targeted therapy (BRAF/MEK inhibitors) is an additional option for patients with BRAF-mutant disease. 1
• Testing should be performed on metastatic tissue (preferred) or the primary tumor to detect BRAF V600 mutations (V600E, V600K, or other variants). 1, 2

Treatment Options by BRAF Status

For BRAF Wild-Type Disease

Three evidence-based first-line options exist, all with Level I, Grade A evidence: 1, 3

• Nivolumab monotherapy: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks 1, 3
• Pembrolizumab monotherapy: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks 1, 3
• Nivolumab plus ipilimumab combination: Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks 1, 3, 4

For BRAF V600-Mutant Disease

Six evidence-based first-line options exist: 1, 2

All three immunotherapy options listed above for BRAF wild-type disease, plus:

• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily 1, 2
• Encorafenib 450 mg PO once daily plus binimetinib 45 mg PO twice daily 1, 2
• Vemurafenib 960 mg PO twice daily plus cobimetinib 60 mg PO once daily (21 days on, 7 days off) 1, 2

Clinical Decision Algorithm for BRAF-Mutant Patients

The choice between immunotherapy and BRAF/MEK inhibitors depends on disease tempo and symptom burden: 3, 2

• Select BRAF/MEK inhibitor combinations when: The patient has rapidly progressive disease, high tumor burden requiring rapid response, or symptomatic metastases requiring immediate disease control. 3, 2

• Select immunotherapy (anti-PD-1 ± ipilimumab) when: The patient has low-volume disease, asymptomatic metastases, or preference for potential durable responses after treatment completion. 3, 2

Choosing Between Anti-PD-1 Monotherapy vs. Nivolumab/Ipilimumab Combination

The combination of nivolumab plus ipilimumab provides superior progression-free survival but carries significantly higher toxicity: 3, 2

• Select nivolumab/ipilimumab combination when: The patient has high disease burden, symptomatic disease requiring rapid response, good performance status, and ability to comply with intensive monitoring for immune-related adverse events. Grade 3-4 adverse events occur in approximately 55-59% of patients. 3, 2

• Select anti-PD-1 monotherapy (nivolumab or pembrolizumab) when: The patient is elderly, has multiple comorbidities, prefers lower toxicity profile, or has concerns about treatment tolerability. Grade 3-4 adverse events occur in approximately 14-15% of patients. 3, 5, 2

Treatment Duration

• Nivolumab: Can be continued beyond 2 years in responding patients, though optimal duration is not definitively established. 1, 2
• Pembrolizumab: Typically limited to 2 years (35 cycles) based on pivotal trial design. 1, 2
• Nivolumab/ipilimumab combination: Ipilimumab is given for 4 doses only, followed by nivolumab maintenance until disease progression or unacceptable toxicity. 4, 6
• BRAF/MEK inhibitors: Continued until disease progression or unacceptable toxicity. 2

Special Considerations for Brain Metastases

For patients with asymptomatic brain metastases, the nivolumab/ipilimumab combination is the preferred first-line treatment, even in BRAF-mutant patients. 1

• For patients with a small number of asymptomatic metastases (<5-10 lesions), non-bulky disease (<3 cm), stereotactic radiosurgery (SRS) upfront is an alternative option. 1
• Other patients should receive systemic treatment first, reserving SRS for non-responding lesions. 1

Second-Line Treatment After Progression

After progression on first-line anti-PD-1 monotherapy: 1

• For BRAF wild-type patients: Switch to ipilimumab or ipilimumab-containing regimens (such as nivolumab/ipilimumab if not previously used). 1
• For BRAF-mutant patients: Switch to BRAF/MEK inhibitor combination therapy if not previously used, or ipilimumab-containing regimens. 1, 2

After progression on BRAF/MEK inhibitors: 2

• Switch to anti-PD-1-based immunotherapy (nivolumab, pembrolizumab, or nivolumab/ipilimumab). 2
• Patients who progressed rapidly on first-line BRAF inhibitors derive minimal benefit from second-line BRAF/MEK combinations. 2

Alternative Option for Injectable Lesions

For patients with unresectable stage IIIB/C or IVM1a disease with injectable cutaneous, subcutaneous, or nodal lesions, talimogene laherparepvec (T-VEC) is an option. 1, 2

• T-VEC may be offered as primary therapy if patients are not eligible for or decline systemic therapies, or for disease control in limited stage IV disease. 2

Critical Monitoring Requirements

For immunotherapy, monitor for immune-related adverse events including: 5

• Colitis, hepatitis, pneumonitis, endocrinopathies (thyroid dysfunction, hypophysitis, adrenal insufficiency), and dermatologic toxicities. 5

For BRAF/MEK inhibitor combinations, monitor for: 5

• Pyrexia (very common with dabrafenib), skin rash, hepatic dysfunction, and cardiac toxicity (decreased ejection fraction). 5

Imaging surveillance: 3

• CT chest/abdomen/pelvis every 2-3 months initially to assess response. 3
• Brain MRI at baseline and during follow-up due to melanoma's propensity for CNS metastases. 3

Common Pitfalls to Avoid

• Never use ipilimumab monotherapy as first-line treatment due to inferior outcomes compared to anti-PD-1 monotherapy or combination therapy. 2
• Never use BRAF inhibitor monotherapy unless combination therapy is absolutely contraindicated; BRAF/MEK combination is vastly superior. 2
• Never use MEK inhibitor monotherapy due to poor efficacy (response rate 22%, median PFS 2.8 months). 2
• Do not use chemotherapy (dacarbazine or temozolomide) as first-line therapy; it should only be considered after immunotherapy and targeted therapy failure. 1