What is the best systemic therapy for a patient with BRAF (B-Raf proto-oncogene) negative, PD-L1 (Programmed Death-Ligand 1) inhibitor-resistant metastatic melanoma?

Best Systemic Therapy for BRAF-Negative, PD-L1 Inhibitor-Resistant Metastatic Melanoma

For BRAF wild-type metastatic melanoma patients who have progressed on anti-PD-1 therapy, ipilimumab or ipilimumab-containing regimens (such as nivolumab plus ipilimumab) should be offered as the next line of treatment. 1

Primary Recommendation

• Ipilimumab-based therapy is the guideline-recommended option after anti-PD-1 progression in BRAF wild-type melanoma, though the evidence quality is acknowledged as low and the recommendation strength is weak 1
• The specific regimen options include:
  • Ipilimumab 3 mg/kg IV every 3 weeks for 4 doses 1
  • Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks 2

Critical Context and Limitations

• No high-quality randomized trial data exist specifically for BRAF wild-type patients who have progressed on modern anti-PD-1 therapy (pembrolizumab or nivolumab), as the pivotal ipilimumab trials enrolled patients previously treated with chemotherapy or IL-2, not anti-PD-1 agents 1
• The ASCO guideline explicitly states this recommendation is based on "informal consensus" with "no evidence" quality, reflecting the lack of direct trial data in this specific population 1
• Despite the weak evidence base, ipilimumab remains FDA-approved for previously treated metastatic melanoma based on historical trials 1

Alternative Option for Injectable Lesions

• Talimogene laherparepvec (T-VEC) may be offered to patients with injectable cutaneous, subcutaneous, or nodal lesions as an alternative or adjunct to systemic therapy 1, 2
• This option is particularly relevant for patients seeking local disease control or those who cannot tolerate additional systemic immunotherapy 1

Important Clinical Considerations

Toxicity Profile

• Ipilimumab monotherapy carries lower risk of grade ≥3 immune-related adverse events compared to combination nivolumab/ipilimumab (approximately 20-30% vs 65%) 2
• Patients must have adequate performance status (ECOG 0-2) and organ function to tolerate additional immunotherapy 1
• Prior anti-PD-1 toxicity history should inform decision-making about retreatment with ipilimumab-containing regimens 2

Disease Characteristics That Influence Treatment Selection

• Rapidly progressive or symptomatic disease: These patients may benefit from clinical trial enrollment rather than standard ipilimumab, given the modest response rates expected 1
• Brain metastases: Ipilimumab can be safely used in patients with brain metastases, though stereotactic radiosurgery should be considered for progressive CNS lesions 1
• High tumor burden with elevated LDH: These poor prognostic features predict limited benefit from salvage ipilimumab 3

Critical Pitfalls to Avoid

• Never use single-agent ipilimumab as first-line therapy in treatment-naïve patients, as it is inferior to anti-PD-1 monotherapy or combination immunotherapy 1, 2
• Do not rechallenge with anti-PD-1 monotherapy after clear progression on pembrolizumab or nivolumab, as cross-resistance is expected 1
• Avoid chemotherapy as the next line unless all immunotherapy options have been exhausted or are contraindicated, as chemotherapy provides only short-lived responses without survival benefit 1

Clinical Trial Enrollment

• Strongly consider clinical trial enrollment for all patients with PD-1-refractory, BRAF wild-type melanoma, as this represents an area of significant unmet need with limited evidence-based options 1
• Novel combinations under investigation include ipilimumab plus novel checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses 4, 5

Monitoring and Response Assessment

• Perform imaging at 12 weeks after initiating ipilimumab-based therapy, then every 6-8 weeks to assess response 1, 2
• Continue treatment through initial progression if clinically stable, as pseudoprogression can occur with immunotherapy 1
• Discontinue permanently if symptomatic progression, rapidly progressive disease, or grade 3-4 immune-related adverse events that do not resolve with immunosuppression 2