What are the treatment implications for a melanoma tumor with a TERT promoter mutation, microsatellite stability (MSS), and a tumor mutational burden (TMB) of 4.7 mutations per megabase, without alterations in BRAF, NF1, or NRAS?

Treatment Implications for BRAF/NRAS/NF1 Wild-Type Melanoma with TERT Promoter Mutation

This melanoma should be treated with immune checkpoint inhibitor therapy, specifically anti-PD-1 monotherapy (pembrolizumab or nivolumab) or combination ipilimumab plus nivolumab, as the absence of BRAF, NRAS, and NF1 mutations eliminates targeted therapy options and the low TMB (4.7 mutations/Mb) suggests limited but not absent immunotherapy benefit. 1

Key Molecular Findings and Their Clinical Significance

Triple Wild-Type Status

• Your tumor lacks actionable driver mutations in BRAF, NRAS, and NF1, placing it in the "triple wild-type" (tWT) category, which represents 5-10% of all melanomas. 2
• This molecular profile eliminates BRAF/MEK inhibitor combinations (vemurafenib, dabrafenib/trametinib) as treatment options since these require documented BRAF V600 mutations. 1
• The absence of NRAS mutations means MEK inhibitor monotherapy is also not indicated. 3

TERT Promoter Mutation (C228T)

• The TERT promoter mutation C228T is associated with increased telomerase activity and is one of the most common noncoding mutations in melanoma, occurring in approximately 70% of cutaneous melanomas. 4
• This mutation correlates with more aggressive disease behavior, increased invasion potential, and historically poorer prognosis. 4
• However, TERT promoter mutations were equally distributed among patients receiving different immunotherapy regimens and did not independently predict response to checkpoint inhibitors. 2

Microsatellite Stability (MSS)

• Your tumor is microsatellite stable (MSS), which means it does NOT qualify for the highly responsive MSI-high/dMMR immunotherapy indication. 1
• MSS tumors generally have lower response rates to immunotherapy compared to MSI-high tumors across cancer types. 1

Low Tumor Mutational Burden (TMB = 4.7 mutations/Mb)

• Your TMB of 4.7 mutations/Mb is classified as LOW (below the 10 mutations/Mb threshold for TMB-high designation). 1, 5
• This is significantly below the median TMB for melanoma (typically ~20 mutations/Mb) and places your tumor in the lowest TMB category. 6
• Low TMB is associated with reduced likelihood of response to immunotherapy, as higher mutation burden correlates with increased neoantigen presentation and better checkpoint inhibitor efficacy. 5
• Pembrolizumab's FDA approval for TMB-high (≥10 mutations/Mb) solid tumors does NOT apply to your case. 1

Recommended Treatment Approach

First-Line Systemic Therapy

Anti-PD-1 monotherapy (pembrolizumab or nivolumab) is the recommended first-line treatment, despite the low TMB, because:

• Immunotherapy remains the only systemic option with potential for durable responses in BRAF/NRAS/NF1 wild-type melanoma. 1
• The 2023 ASCO guidelines establish PD-1 blockade as standard of care for all patients with advanced melanoma regardless of BRAF status. 1
• Even with low TMB, some melanoma patients achieve meaningful responses to checkpoint inhibitors. 6

Combination ipilimumab plus nivolumab is an alternative first-line option that may be considered for:

• Patients with higher disease burden or more aggressive disease tempo. 1
• Those who can tolerate the increased toxicity profile of dual checkpoint inhibition. 1

Expected Outcomes and Realistic Expectations

Patients with triple wild-type melanoma have shorter progression-free and overall survival with immunotherapy compared to melanomas with known driver mutations:

• Median PFS with anti-PD-1 monotherapy: approximately 4 months (95% CI: 2.9-8.5 months). 2
• Median PFS with ipilimumab plus nivolumab: approximately 6.2 months (95% CI: 4-9 months). 2
• Median OS with either approach: 24-29 months. 2
• These outcomes are considerably shorter than reported for BRAF-mutant or NRAS-mutant melanomas. 2

Second-Line and Beyond

If first-line anti-PD-1 monotherapy fails:

• Switch to ipilimumab plus nivolumab combination if not used initially. 1
• Clinical trial enrollment should be strongly prioritized given limited standard options. 1
• Cytotoxic chemotherapy (dacarbazine, temozolomide, paclitaxel-based regimens) may provide modest palliation but has limited efficacy. 1

Critical Caveats and Pitfalls

Testing Considerations

• Consider retesting for BRAF mutations if disease progresses, as false-negative results can rarely occur, though this is uncommon. 1
• Expanded molecular profiling may identify rare actionable alterations such as KIT mutations (more common in acral/mucosal melanomas) or NTRK fusions (extremely rare at ~0.2% in cutaneous melanoma). 1

Performance Status Matters

• If performance status is poor primarily due to tumor burden, initiate immunotherapy promptly as clinical improvement may occur with tumor response. 1
• If poor performance status is due to comorbidities, carefully weigh risks of immune-related adverse events. 1

Immune-Related Toxicity Management

• Maintain high suspicion for immune-related adverse events (pneumonitis, colitis, hepatitis, endocrinopathies, etc.). 1
• Follow ASCO guidelines for identification and management of immune-related toxicities. 1

Brain Metastases

• If brain metastases develop, ipilimumab plus nivolumab can be used even in asymptomatic brain metastases, potentially delaying local therapy until intracranial progression. 1

Bottom Line

Your melanoma's molecular profile—lacking BRAF, NRAS, and NF1 mutations with low TMB and MSS status—represents a challenging subset with limited treatment options and historically poorer outcomes. Immunotherapy with anti-PD-1 antibodies remains the standard approach, but realistic expectations should be set regarding response rates and durability. Clinical trial participation should be actively pursued given the unmet need in this population. 1, 2