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

Treatment Approach for Metastatic Melanoma with TERT Promoter Mutation, MSS Status, Low TMB, and Triple Wild-Type (BRAF/NRAS/NF1 Negative)

What This Genomic Profile Means

Your tumor is classified as "triple wild-type" melanoma, which means you lack the three most common targetable mutations (BRAF, NRAS, NF1), eliminating targeted therapy options and making immune checkpoint inhibitors your primary treatment backbone. 1, 2

Key Molecular Findings

• TERT promoter mutation (C228T): This is the most common noncoding mutation in melanoma, present in the majority of cases, and is associated with increased telomerase activity and more aggressive disease behavior 3. However, this mutation does not currently have FDA-approved targeted therapies, though it represents a potential therapeutic vulnerability being explored in clinical trials 4.

• Triple wild-type status (no BRAF/NRAS/NF1 mutations): This eliminates BRAF/MEK inhibitor combinations as treatment options entirely 1. Your tumor falls into the fourth genetic subtype defined by The Cancer Genome Atlas, which accounts for approximately 15-20% of melanomas 5, 6.

• Microsatellite stable (MSS) status: This means your tumor does not qualify for the highly responsive MSI-high/dMMR immunotherapy indication, and generally predicts lower (but not absent) response rates to immunotherapy compared to MSI-high tumors 1, 7.

• Low tumor mutational burden (TMB 4.7 mutations/Mb): This is below the typical threshold of 10 mutations/Mb considered "high," suggesting your tumor may have a somewhat reduced likelihood of responding to immunotherapy, though TMB alone should not exclude you from checkpoint inhibitor therapy 1.

First-Line Treatment Recommendations

Anti-PD-1 monotherapy with pembrolizumab (200 mg IV every 3 weeks) or nivolumab (240 mg IV every 2 weeks or 480 mg every 4 weeks) is the recommended first-line treatment for your triple wild-type melanoma. 1, 2, 7

Treatment Selection Algorithm

If you have symptomatic, bulky metastases, rapidly progressive disease, or high disease burden (elevated LDH, multiple organ involvement, poor performance status):

• Consider combination ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) IV every 3 weeks for 4 doses, followed by nivolumab 240 mg IV every 2 weeks 8, 2, 7
• This combination offers the highest response rates (~70%) and most rapid disease control 8, 7
• However, grade 3-4 treatment-related adverse events occur in approximately 55-59% of patients 7

If you have good performance status, slower disease tempo, or desire to balance efficacy with tolerability:

• Start with anti-PD-1 monotherapy (pembrolizumab or nivolumab) 1, 2, 7
• This provides significant overall survival benefit with the lowest toxicity profile (grade 3-4 adverse events in ~15-20%) 7
• Alternatively, consider nivolumab (480 mg) plus relatlimab (160 mg) IV every 4 weeks, which showed median PFS of 10.12 months versus 4.63 months with nivolumab alone, with lower toxicity than ipilimumab/nivolumab combination 7

If you are elderly, have multiple comorbidities, or strongly prefer lower toxicity:

• Single-agent pembrolizumab or nivolumab is the clear choice 7

Why Immunotherapy Despite Low TMB and MSS Status

While your low TMB (4.7 mutations/Mb) and MSS status suggest potentially reduced immunotherapy responsiveness, anti-PD-1 therapy remains the standard of care and has demonstrated significant survival benefit across all molecular subsets of melanoma, including those with low TMB 8, 1. TMB is not powerful enough to exclude patients from anti-PD-1 treatment 8.

Treatment Duration and Monitoring

• Continue treatment until maximum response is reached, confirmed progression, or unacceptable adverse effects occur 2
• Consider stopping anti-PD-1 therapy after 2 years in the case of partial response or complete response 2
• Imaging surveillance with CT chest/abdomen/pelvis every 2-3 months initially to assess response 7
• Brain MRI at baseline and during follow-up is necessary due to melanoma's propensity for CNS metastases 7
• Monitor for immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities 2

Second-Line Treatment After Progression

If first-line anti-PD-1 monotherapy fails, switch to ipilimumab plus nivolumab combination, which has shown an overall response rate of 21% and 12-month overall survival of 55% in this setting. 2, 7

If first-line combination therapy fails, clinical trial enrollment should be strongly prioritized given limited standard options beyond first-line immunotherapy. 1, 2, 7

Critical Caveats and Pitfalls to Avoid

Expanded Molecular Testing Considerations

• Retesting for BRAF mutations should be considered if disease progresses, as false-negative results can rarely occur 1, 2, 7
• Expanded molecular profiling may identify rare actionable alterations such as KIT mutations (especially in acral/mucosal melanomas) or NTRK fusions that could open targeted therapy options 1, 2, 7
• KIT mutations occur in approximately 10-15% of acral and mucosal melanomas and may respond to KIT inhibitors 8, 9

Treatment Timing

• Do not delay immunotherapy initiation—starting treatment promptly after diagnosis optimizes outcomes 2
• Do not rely on chemotherapy as first-line treatment, as immunotherapy has dramatically superior outcomes 2
• Chemotherapy (dacarbazine, temozolomide, taxanes, fotemustine) is considered only as second-line or bridging treatment after immunotherapy failure 8, 2, 7

Special Clinical Scenarios

If brain metastases develop:

• Checkpoint inhibitors, including ipilimumab plus nivolumab, can be safely used and have shown significant efficacy in brain metastases 2, 7
• Stereotactic radiotherapy is preferred over whole brain irradiation for brain metastases 2
• Ipilimumab plus nivolumab can be used even in asymptomatic brain metastases, potentially delaying local therapy until intracranial progression 1

If limited resectable disease is present:

• Complete surgical resection should be strongly considered first if technically feasible 2
• Following complete resection, adjuvant nivolumab or pembrolizumab is recommended 2

Multidisciplinary Management Requirements

• All stage IV melanoma patients should be treated and discussed in an interdisciplinary tumor board at centers with broad experience in melanoma 2
• Palliative radiotherapy should be considered for symptomatic brain or localized painful bone metastases 2

Future Therapeutic Considerations

The TERT promoter mutation in your tumor represents a potential therapeutic vulnerability currently being explored in clinical trials 3, 4. While no FDA-approved therapies directly target TERT mutations yet, this remains an active area of investigation, particularly for NRAS-mutant melanomas where TERT dependency has been demonstrated 4. Clinical trial enrollment should be strongly considered given your triple wild-type status and limited standard options. 1, 2