What are the recommended immunotherapy regimens, dosing, duration, and safety considerations for a patient with unresectable stage III or IV melanoma, including options for high disease burden, adjuvant therapy after complete resection of high‑risk stage III disease, second‑line treatment after anti‑PD‑1 failure, and targeted therapy for BRAF V600E/K mutations?

Melanoma Immunotherapy: Comprehensive Treatment Algorithm

First-Line Treatment for Unresectable Stage III/IV Melanoma

For patients with unresectable stage III or IV melanoma, treatment selection depends critically on BRAF mutation status, disease burden, and symptomatology, with anti-PD-1 therapy (nivolumab or pembrolizumab) serving as the backbone for all patients and combination regimens reserved for specific clinical scenarios. 1

Mandatory Pre-Treatment Testing

• All patients must undergo BRAF V600 mutation testing (specifically V600E and V600K) before initiating any systemic therapy, as this directly determines therapeutic options. 1, 2
• Testing should be performed on metastatic tissue when available, or primary tumor tissue if metastatic samples are unavailable. 3
• For patients testing wild-type at V600, comprehensive sequencing for other BRAF class II/III mutations, NRAS, and c-KIT is recommended to confirm true wild-type status. 2

BRAF Wild-Type Disease: Treatment Options

For BRAF wild-type patients, four evidence-based first-line regimens are available, all with strong recommendation strength and high-quality evidence:

• Nivolumab monotherapy: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks 1
• Pembrolizumab monotherapy: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks 1
• Nivolumab plus relatlimab: 480 mg nivolumab + 160 mg relatlimab IV every 4 weeks, offering median PFS of 10.12 months versus 4.63 months with nivolumab alone 1, 4
• Nivolumab plus ipilimumab: Nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks 1

BRAF V600E/K Mutant Disease: Treatment Options

For BRAF-mutant patients, six first-line options exist—the four immunotherapy regimens above plus three BRAF/MEK inhibitor combinations:

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

Clinical Decision Algorithm for BRAF-Mutant Patients

The choice between immunotherapy and targeted therapy in BRAF-mutant disease depends on disease tempo and patient factors:

• Select BRAF/MEK inhibitors when: Rapidly progressive disease, high symptomatic burden (especially visceral metastases causing organ dysfunction), or need for rapid disease control due to high tumor burden 1, 3, 5
• Select anti-PD-1 immunotherapy when: Low-volume asymptomatic disease, desire for durable responses after treatment completion, or lower treatment discontinuation rates (8-10% vs 26% for targeted therapy) 2, 5
• Select nivolumab/ipilimumab combination when: High disease burden requiring maximal response rates, absence of contraindications to dual checkpoint blockade, or presence of asymptomatic brain metastases 1, 4, 3

Comparative Efficacy and Toxicity Data

Nivolumab/ipilimumab combination provides superior progression-free survival but carries significantly higher toxicity:

• Grade 3-4 adverse events: 55-59% for nivolumab/ipilimumab versus 14.4-14.7% for anti-PD-1 monotherapy versus 41% for dabrafenib/trametinib 1, 2, 4
• Objective response rate: 31% for combination versus lower rates for monotherapy 6
• Median PFS: Combination therapy superior to monotherapy, with hazard ratio 0.54 for checkpoint inhibitors versus control 7

For BRAF/MEK inhibitors, combination therapy is mandatory—never use monotherapy:

• Dabrafenib/trametinib yields 69% response rate and median PFS 11.0 months, with 3-year RFS gain of 19% in adjuvant setting 1, 2, 3
• MEK inhibitor monotherapy has poor efficacy (22% response rate, median PFS 2.8 months) and should never be used 3

Adjuvant Therapy for Resected Stage III Disease

For patients with completely resected stage IIIA-D melanoma, three equally effective adjuvant options exist for 52 weeks of treatment:

BRAF Wild-Type Stage III

• Nivolumab: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks for 52 weeks (RFS HR 0.66) 1, 2
• Pembrolizumab: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks for 52 weeks (RFS HR 0.57,3-year RFS gain 14%) 1, 2

BRAF V600E/K Mutant Stage III

All three options above plus:

• Dabrafenib 150 mg PO twice daily + trametinib 2 mg PO once daily for 52 weeks (RFS HR 0.47,3-year RFS gain 19%, OS HR 0.57) 1, 2

Special Considerations for Stage IIIA Disease

• Patients with stage IIIA disease with sentinel node metastasis <1 mm were excluded from pivotal trials and have relatively better prognosis (lower relapse risk). 1
• For these patients, treatment decisions should weigh the 20% 10-year mortality risk against treatment toxicity, though adjuvant therapy remains a reasonable option. 1, 2

Stage IIID-Specific Recommendations

• Adjuvant radiation to the nodal basin should be strongly considered for stage IIID disease with N3 involvement due to high-risk nodal disease. 2
• Adjuvant therapy must be initiated within 13 weeks post-surgery, with complete surgical resection and negative margins mandatory before starting. 2

Second-Line Treatment After Anti-PD-1 Failure

After progression on first-line anti-PD-1 monotherapy, treatment selection depends on BRAF status:

BRAF Wild-Type After Anti-PD-1 Failure

• Ipilimumab-containing regimens (ipilimumab monotherapy or nivolumab/ipilimumab combination if not previously used) should be offered. 1
• Ipilimumab plus anti-PD-1 yields 31% objective response rate, median OS 20.4 months, and median PFS 3.0 months in anti-PD-1-resistant patients. 6
• Grade 3-5 toxicity occurs in 31% with combination versus 33% with ipilimumab monotherapy, making combination therapy the preferred option. 6

BRAF V600E/K Mutant After Anti-PD-1 Failure

• Switch to BRAF/MEK inhibitor combination therapy (dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib) as described in first-line recommendations. 1
• Alternatively, ipilimumab-containing regimens may be offered if targeted therapy is contraindicated. 1

After BRAF/MEK Inhibitor Failure

• Switch to anti-PD-1-based therapy (nivolumab, pembrolizumab, or nivolumab/ipilimumab combination) as described in first-line recommendations. 1
• Patients who progressed rapidly on first-line BRAF inhibitors derive minimal benefit from second-line BRAF/MEK combinations. 3

Special Clinical Scenarios

Asymptomatic Brain Metastases

For patients with asymptomatic brain metastases, nivolumab/ipilimumab combination is the preferred first-line regimen, even in BRAF-mutant disease. 3

• If ≤5-10 small (<3 cm) asymptomatic lesions are present, upfront stereotactic radiosurgery is an acceptable alternative. 3
• In all other cases, systemic therapy should be initiated first, reserving SRS for non-responding lesions. 3

Injectable Cutaneous/Subcutaneous Lesions

• Talimogene laherparepvec (T-VEC) may be offered for unresectable stage IIIB/C or IVM1a disease with injectable lesions, either as primary therapy when systemic options are declined or for disease control in limited stage IV disease. 1, 3

Oligometastatic Resectable Stage IV Disease

• Surgical resection or stereotactic irradiation should be considered in fit patients with locoregional recurrence or single distant metastasis, preferentially combined with adjuvant systemic therapy. 1

Treatment Duration and Monitoring

Duration of Therapy

• Nivolumab: May be continued beyond 2 years in responding patients, though optimal duration remains undefined. 3
• Pembrolizumab: Typically limited to 2 years (approximately 35 cycles) based on pivotal trial design. 4, 3
• BRAF/MEK inhibitors: Continue until progression or unacceptable toxicity; no defined maximum duration. 1

Monitoring Requirements

For immunotherapy:

• Imaging surveillance with CT chest/abdomen/pelvis every 2-3 months initially to assess response. 4
• Brain MRI at baseline and during follow-up due to melanoma's propensity for CNS metastases. 4
• Monitor for immune-related adverse events: colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities. 2, 4

For BRAF/MEK inhibitors:

• Monitor for pyrexia, skin rash, hepatic dysfunction, and cardiac toxicity. 2
• Regular ECG and echocardiogram monitoring for cobimetinib-containing regimens due to cardiac toxicity risk. 1

Complete Response Management

• For patients achieving complete response on immunotherapy, median time from CR to therapy discontinuation is 10 months (IQR 1-17). 8
• Five-year PFS after CR is 79% and 5-year OS is 83%, with most patients having S100 normalization at time of CR. 8
• Late immune-related toxicities occur in 25% of patients after CR, most being cutaneous. 8

Critical Pitfalls to Avoid

Never use these inferior or contraindicated regimens:

• Ipilimumab monotherapy as first-line treatment due to CheckMate 067 showing superior outcomes with anti-PD-1 monotherapy or combination therapy. 3
• BRAF inhibitor monotherapy unless combination therapy is absolutely contraindicated. 3
• MEK inhibitor monotherapy due to poor efficacy (22% response rate, median PFS 2.8 months). 3
• High-dose interferon or biochemotherapy in the adjuvant setting due to inferior efficacy and significant toxicity. 2
• Chemotherapy (dacarbazine or temozolomide) as first-line treatment; reserve only for after failure of both immunotherapy and targeted therapy. 1, 3

Critical testing and sequencing errors to avoid:

• Do not postpone BRAF testing until after immunotherapy has begun; testing must be completed before finalizing therapy selection. 2
• Only V600E and V600K mutations are actionable for dabrafenib/trametinib; other BRAF variants lack proven benefit. 2
• Consider retesting for BRAF mutations at progression, as false-negative results can rarely occur. 4

Toxicity management considerations:

• Prior grade 3-4 immune-related adverse effects from ipilimumab do not predict nivolumab toxicities; 62% of such patients achieved CR/PR/SD at 24 weeks on nivolumab. 9
• High numbers of myeloid-derived suppressor cells (MDSC) are associated with poor survival on nivolumab and may help assess expected benefit. 9