What is the treatment approach for a melanoma tumor with a TERT promoter mutation, microsatellite stability (MSS), low tumor mutational burden (TMB), and no alterations in BRAF, NF1, or NRAS?

Melanoma Genomic Profile Interpretation and Treatment Approach

What These Results Mean

Your melanoma is "triple wild-type" (lacking BRAF, NRAS, and NF1 mutations) with a TERT promoter mutation, microsatellite stability, and low tumor mutational burden—this profile indicates aggressive disease biology but eliminates targeted therapy options, making immune checkpoint inhibitors your only standard treatment option. 1, 2

Key Molecular Findings

• TERT promoter mutation (C228T): This is a Tier 1/2 actionable mutation associated with aggressive disease, poor prognosis, and increased metastasis risk according to ESMO guidelines 1, 3

• Triple wild-type status (BRAF/NRAS/NF1 negative): The absence of BRAF V600 mutations eliminates BRAF/MEK inhibitor combinations as treatment options 2, 4. This triple wild-type pattern occurs in only 5-10% of melanomas and is associated with worse outcomes compared to melanomas with known oncogenic mutations 5

• Microsatellite stable (MSS): Your tumor does not qualify for the highly responsive MSI-high immunotherapy indication, and MSS tumors generally have lower response rates to immunotherapy 2

• Low tumor mutational burden (4.7 mutations/Mb): This is classified as low TMB (≤5 mutations/Mb), which predicts reduced but not absent benefit from immunotherapy 6, 7. Low TMB combined with BRAF wild-type status increases recurrence risk (hazard ratio 3.43) 7

First-Line Treatment Recommendation

Start with anti-PD-1 monotherapy (pembrolizumab or nivolumab) as your first-line treatment. 2, 8, 4

Treatment Algorithm

For standard disease burden:

• Pembrolizumab 200mg IV every 3 weeks OR nivolumab 240mg IV every 2 weeks 9, 10
• Anti-PD-1 monotherapy is the recommended first-line treatment for all patients with advanced melanoma regardless of BRAF status 2, 8
• Continue treatment for up to 2 years if achieving partial response, or until progression or unacceptable toxicity 8

For symptomatic, bulky, or rapidly progressive disease:

• Consider ipilimumab plus nivolumab combination therapy upfront 2, 8
• Response rate approximately 70% but with significantly higher toxicity (grade ≥3 adverse events in 41% vs 14% with anti-PD-1 monotherapy) 4, 2
• This combination may be particularly important given your low TMB, as elevated TMB is associated with better response to dual checkpoint inhibition 6

Critical Caveat About Expected Outcomes

Triple wild-type melanomas have considerably shorter progression-free survival (PFS) and overall survival (OS) with checkpoint inhibitors compared to melanomas with known oncogenic mutations. 5

• Expected median PFS with anti-PD-1 monotherapy: 4 months (95% CI: 2.9-8.5) 5
• Expected median OS: 29.18 months (95% CI: 17.5-46.2) 5
• These outcomes are substantially worse than the general melanoma population treated with checkpoint inhibitors 5

Second-Line and Subsequent Treatment

If first-line anti-PD-1 monotherapy fails, switch to ipilimumab plus nivolumab combination therapy. 2, 8, 4

• Overall response rate of 21% with 12-month OS of 55% in the second-line setting 8
• Treatment duration and monitoring remain the same as first-line 8

Clinical trial enrollment should be strongly prioritized given limited standard options after immunotherapy failure. 2, 8

Essential Additional Testing and Monitoring

Request expanded molecular profiling to identify rare actionable alterations:

• Test for KIT mutations (particularly if acral or mucosal melanoma) 2, 8
• Test for NTRK fusions and other rare kinase fusions 2, 11
• Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 30% derived clinical benefit lasting ≥6 months from genomically matched targeted therapy 11

Consider retesting for BRAF mutations if disease progresses:

• False-negative results can rarely occur, though this is uncommon 2
• Mutation testing should be performed in an accredited laboratory with appropriate quality controls 4

Special Clinical Scenarios

If brain metastases develop:

• Checkpoint inhibitors including ipilimumab plus nivolumab can be safely used even in asymptomatic brain metastases 8
• Stereotactic radiotherapy is preferred over whole brain irradiation 8, 4
• Close disease monitoring by MRI is recommended to add stereotactic radiosurgery when indicated 4

If limited resectable disease:

• Complete surgical resection should be strongly considered first if technically feasible 8
• Following complete resection, adjuvant nivolumab or pembrolizumab is recommended 4, 8

Critical Pitfalls to Avoid

• Do not delay immunotherapy initiation—starting treatment promptly after diagnosis optimizes outcomes 8
• Do not rely on chemotherapy as first-line treatment—immunotherapy has dramatically superior outcomes 8
• Do not assume your low TMB means immunotherapy won't work—while response rates are lower, meaningful responses still occur 6, 7
• Do not fail to discuss clinical trial options early—given your triple wild-type status and low TMB, novel therapeutic approaches may offer better outcomes than standard therapy 2, 8

Multidisciplinary Management

All stage IV melanoma patients should be treated and discussed in an interdisciplinary tumor board at centers with broad experience in melanoma. 8

• Monitor for immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities 8
• Palliative radiotherapy should be considered for symptomatic brain or localized painful bone metastases 8