# Melanoma Immunotherapy and Targeted Therapy

## Molecular Biology of Melanoma

### Key Driver Mutations

**BRAF** is mutated in approximately 50 percent of cutaneous melanomas, with V600E accounting for 80 to 90 percent of BRAF mutations and V600K for 10 to 15 percent. BRAF activates the MAPK/ERK pathway (RAS to RAF to MEK to ERK to cell proliferation) and is more common in intermittent sun exposure sites, younger patients, and superficial spreading melanoma. **NRAS** is mutated in 15 to 20 percent of melanomas and activates both the MAPK and PI3K/AKT pathways. NRAS-mutant melanomas are associated with thicker tumors, nodular melanoma, and worse prognosis, and there is no approved targeted therapy for them, though MEK inhibitors have limited activity. **KIT** is mutated or amplified in 15 to 30 percent of acral, mucosal, and chronically sun-damaged melanomas, and imatinib has shown activity in KIT-mutant disease. **NF1** is mutated in 10 to 15 percent of melanomas, often in older patients with sun-damaged skin, where loss of neurofibromin leads to RAS pathway activation. **GNAQ/GNA11** mutations occur in approximately 80 percent of uveal melanomas but are not found in cutaneous melanoma.

| Gene | Frequency | Pathway | Key Associations | Targeted Therapy |
|------|-----------|---------|-----------------|-----------------|
| BRAF | ~50% | MAPK/ERK | Intermittent UV, younger patients, SSM | BRAF/MEK inhibitors |
| NRAS | 15–20% | MAPK + PI3K/AKT | Thicker tumors, nodular melanoma | MEK inhibitors (limited) |
| KIT | 15–30% (acral/mucosal) | Multiple | Acral, mucosal, CSD melanoma | Imatinib |
| NF1 | 10–15% | RAS | Older patients, CSD skin | None approved |
| GNAQ/GNA11 | ~80% (uveal only) | PLCβ/PKC | Uveal melanoma | None standard |

### Molecular Classification

Melanomas are classified as BRAF-mutant, RAS-mutant, NF1-mutant, or triple wild-type. This classification guides therapy selection and clinical trial eligibility. All advanced melanomas should undergo molecular testing, with BRAF testing at minimum and comprehensive genomic profiling increasingly becoming standard.

## BRAF/MEK Inhibitor Combinations

### Approved Regimens

Three BRAF/MEK inhibitor combinations are approved: **dabrafenib plus trametinib** (COMBI trials), **vemurafenib plus cobimetinib** (coBRIM trial), and **encorafenib plus binimetinib** (COLUMBUS trial).

| BRAF Inhibitor | MEK Inhibitor | Pivotal Trial |
|---------------|---------------|---------------|
| Dabrafenib | Trametinib | COMBI-d / COMBI-v |
| Vemurafenib | Cobimetinib | coBRIM |
| Encorafenib | Binimetinib | COLUMBUS |

### Efficacy in Metastatic BRAF V600-Mutant Melanoma

These combinations achieve overall response rates of 65 to 70 percent with complete responses in 15 to 20 percent. Median progression-free survival is 11 to 15 months, median overall survival is 22 to 33 months, and 5-year overall survival is approximately 30 to 34 percent. A key advantage is rapid onset of response (median 1 to 2 months), which is particularly important for patients with symptomatic or high-burden disease.

### Mechanism of Action

BRAF inhibitors block mutant BRAF kinase activity. However, single-agent BRAF inhibition causes paradoxical MAPK activation in BRAF wild-type cells, explaining the development of cutaneous SCCs as a side effect. Adding a MEK inhibitor blocks this paradoxical pathway activation, improves efficacy, and reduces cutaneous toxicity.

### Toxicity Profile

**Pyrexia** occurs in approximately 50 percent of patients on dabrafenib/trametinib and can be severe, managed with drug hold and rechallenge. Cutaneous toxicity includes rash, photosensitivity, and keratoacanthomas or cutaneous SCCs, though these are reduced with combination therapy. Cardiac effects include decreased left ventricular ejection fraction from MEK inhibitors, requiring baseline and periodic echocardiography. Ocular toxicity includes central serous retinopathy and uveitis. Hepatotoxicity manifests as liver function test elevations requiring regular monitoring. Arthralgia, fatigue, and diarrhea are common.

### Resistance Mechanisms

Resistance develops through MAPK pathway reactivation (via NRAS mutations, MEK mutations, BRAF amplification, or BRAF splice variants), PI3K/AKT pathway activation, and phenotype switching to mesenchymal or dedifferentiated states. The median time to resistance is 9 to 12 months.

<image>Diagram of the MAPK signaling pathway showing points of inhibition by BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) and MEK inhibitors (trametinib, cobimetinib, binimetinib) in BRAF V600-mutant melanoma</image>

## Immune Checkpoint Inhibitors

### Anti-PD-1 Antibodies

**Nivolumab** and **pembrolizumab** block the PD-1 receptor on T cells, preventing PD-L1-mediated immune evasion. They are first-line therapy for advanced melanoma regardless of BRAF status. As monotherapy in metastatic melanoma, overall response rates are approximately 40 to 45 percent with complete responses of 15 to 20 percent. Median overall survival is 30 to 36 months, and 5-year overall survival reaches 40 to 44 percent. Responses are characteristically durable, with the majority of responders maintaining their response at 5 years. Pseudoprogression, where tumors initially appear to enlarge before responding, occurs in approximately 5 to 10 percent of cases.

### Anti-CTLA-4

**Ipilimumab** blocks CTLA-4 on T cells, enhancing T-cell activation and priming. It was the first checkpoint inhibitor to improve overall survival in melanoma (2010). As monotherapy, it achieves an overall response rate of 15 to 20 percent and 5-year overall survival of approximately 20 percent. It is now mainly used in combination with anti-PD-1.

### Combination Immunotherapy: Nivolumab + Ipilimumab

The landmark **CheckMate 067 trial** compared nivolumab plus ipilimumab, nivolumab monotherapy, and ipilimumab monotherapy. The 7.5-year update showed median overall survival of 72 months for the combination (7.5-year OS approximately 49 percent), 37 months for nivolumab alone (7.5-year OS approximately 42 percent), and 20 months for ipilimumab alone (7.5-year OS approximately 26 percent). However, Grade 3 to 4 adverse events occurred in 59 percent of combination patients compared to 23 percent with nivolumab and 28 percent with ipilimumab. Treatment-related deaths occurred in approximately 1 to 2 percent with the combination.

| Regimen | Median OS | 7.5-yr OS | Grade 3–4 AEs |
|---------|-----------|-----------|---------------|
| Nivolumab + Ipilimumab | 72 months | ~49% | 59% |
| Nivolumab alone | 37 months | ~42% | 23% |
| Ipilimumab alone | 20 months | ~26% | 28% |

### Immune-Related Adverse Events (irAEs)

Checkpoint inhibitors produce a characteristic spectrum of immune-related toxicities. **Dermatologic** irAEs include maculopapular rash, pruritus, vitiligo (a positive prognostic sign), and lichenoid dermatitis. **Gastrointestinal** irAEs include colitis and diarrhea (the most common serious irAE with ipilimumab) and hepatitis. **Endocrine** irAEs include thyroiditis and hypothyroidism (the most common endocrine irAE), hypophysitis (especially with ipilimumab), adrenal insufficiency, and type 1 diabetes. **Pulmonary** involvement includes pneumonitis, **renal** involvement includes nephritis, **neurologic** complications include peripheral neuropathy, myasthenia gravis, and encephalitis, and **cardiac** myocarditis, though rare, carries approximately 50 percent mortality. Management follows a grade-based approach: Grade 1 is managed with continued therapy and monitoring, Grade 2 with holding therapy and considering corticosteroids, Grade 3 with holding therapy and high-dose corticosteroids (1 to 2 mg/kg prednisone), and Grade 4 with permanent discontinuation, high-dose corticosteroids, and consideration of infliximab for colitis or mycophenolate for hepatitis.

<image>Infographic summarizing major immune-related adverse events from checkpoint inhibitor therapy organized by organ system with corresponding management strategies</image>

## Anti-LAG-3: Relatlimab

### Relatlimab + Nivolumab (Opdualag)

This combination was FDA-approved in 2022 for first-line treatment of unresectable or metastatic melanoma. The **RELATIVITY-047 trial** showed median progression-free survival of 10.1 months with the combination versus 4.6 months with nivolumab alone. Grade 3 to 4 adverse events occurred in 19 percent versus 10 percent, reflecting lower toxicity than the nivolumab plus ipilimumab combination. This regimen is positioned as an option between nivolumab monotherapy and nivolumab plus ipilimumab, offering intermediate efficacy and toxicity.

## Adjuvant Therapy

### Stage III (Resected, Node-Positive)

**Nivolumab** (CheckMate 238) demonstrated improved recurrence-free survival versus ipilimumab and is FDA-approved. **Pembrolizumab** (KEYNOTE-054) improved recurrence-free survival versus placebo and is also FDA-approved. **Dabrafenib plus trametinib** (COMBI-AD) improved recurrence-free survival versus placebo in BRAF-mutant stage III melanoma, with 5-year RFS of 52 percent versus 36 percent. All regimens are given for 1 year.

### Stage IIB/IIC (Resected, High-Risk Primary, Node-Negative)

**Pembrolizumab** (KEYNOTE-716) improved recurrence-free survival versus placebo and was FDA-approved in 2022. Stage IIB/IIC melanomas have comparable or worse outcomes compared to some stage IIIA tumors, justifying adjuvant treatment. **Nivolumab** (CheckMate 76K) also improved recurrence-free survival versus placebo in stage IIB/IIC and is FDA-approved.

### Neoadjuvant Therapy

The practice-changing **SWOG S1801 trial** compared neoadjuvant pembrolizumab (3 cycles before surgery) plus adjuvant pembrolizumab versus adjuvant pembrolizumab alone for resectable stage III to IV melanoma. Two-year event-free survival was 72 percent versus 49 percent, a significant improvement, with pathologic complete response in approximately 25 percent of the neoadjuvant arm. This trial establishes neoadjuvant immunotherapy as a new standard for resectable stage III to IV melanoma. The **OpACIN-neo trial** evaluated neoadjuvant ipilimumab plus nivolumab (2 cycles) in stage III melanoma, achieving pathologic response rates of approximately 77 percent. Patients with pathologic response may not require adjuvant therapy.

<image>Timeline diagram illustrating the evolution of melanoma systemic therapy from dacarbazine era through targeted therapy and immunotherapy with key clinical trials and FDA approvals marked</image>

## Special Populations

### Uveal Melanoma

Uveal melanoma is driven by GNAQ/GNA11 mutations, rendering BRAF/MEK inhibitors ineffective. Metastases are hepatotropic. **Tebentafusp**, a bispecific T-cell engager targeting gp100, was FDA-approved in 2022 for HLA-A*02:01-positive uveal melanoma and demonstrated improved overall survival versus investigator's choice.

### Mucosal Melanoma

Mucosal melanoma has a higher frequency of KIT mutations and limited response to immunotherapy (overall response rate approximately 20 to 25 percent). It carries a worse prognosis than cutaneous melanoma stage for stage.

### Acral Melanoma

Acral melanoma has a higher KIT mutation rate but lower tumor mutational burden and lower BRAF mutation rate. Immunotherapy response rates are lower than in non-acral cutaneous melanoma.

## Targeted vs. Immunotherapy Sequencing

### The Ongoing Debate

For BRAF-mutant melanoma, both targeted therapy and immunotherapy are viable first-line options. The **DREAMseq trial** compared nivolumab plus ipilimumab first versus dabrafenib plus trametinib first and found 2-year overall survival of 72 percent versus 52 percent, establishing that **immunotherapy first is now preferred** in most BRAF-mutant patients. Exceptions favoring targeted therapy first include symptomatic high tumor burden requiring rapid response, brain metastases requiring rapid cytoreduction, autoimmune diseases precluding immunotherapy, and organ transplant recipients.

## Biomarkers of Response

**PD-L1 expression** correlates with response but is not used to exclude patients, as PD-L1-negative patients still respond. **Tumor mutational burden** (TMB), when high, is associated with better immunotherapy response. **Interferon-gamma gene signature** correlates with response. **ctDNA** (circulating tumor DNA) clearance early during treatment predicts favorable outcomes. **Vitiligo development** during immunotherapy is a strong positive prognostic indicator.

## Clinical Pearls

All patients with advanced melanoma should undergo BRAF mutation testing at minimum, and comprehensive genomic profiling is increasingly standard. The DREAMseq trial established that immunotherapy first is preferred over targeted therapy first in most BRAF-mutant melanoma patients, even though targeted therapy produces faster responses. Neoadjuvant immunotherapy (SWOG S1801) is a paradigm shift: 3 cycles of pembrolizumab before surgery significantly improves event-free survival in resectable stage III to IV melanoma. Checkpoint inhibitor-induced vitiligo is a favorable prognostic sign and should not be treated. Immune-related myocarditis, though rare (less than 1 percent), carries approximately 50 percent mortality -- any new cardiac symptoms in a patient on checkpoint inhibitors requires urgent troponin, ECG, and cardiology consultation.

## References
- Larkin J, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546
- Long GV, et al. Dabrafenib plus trametinib in patients with BRAF V600-mutant melanoma: 5-year survival. J Clin Oncol. 2022;40(15):1717-1726
- Patel SP, et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma (S1801). N Engl J Med. 2023;388(9):813-823
- Atkins MB, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma (DREAMseq). Lancet Oncol. 2023;24(3):e108-e117
- Tawbi HA, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma (RELATIVITY-047). N Engl J Med. 2022;386(1):24-34