Sequential therapy in BRAF-mutant melanoma: Comparison of combination immunotherapy anti-CTLA4 and anti–PD-1 versus anti–PD-1 monotherapy after targeted treatment failure.

e21527 Background: The optimal immunotherapy strategy for patients with BRAF-mutant advanced melanoma who progress on first-line BRAF/MEK inhibitors remains undefined. While anti–PD-1 monotherapy is commonly used, combination ipilimumab/nivolumab (Ipi/Nivo) offers potentially superior efficacy but with a higher toxicity burden. This study directly compares these two standard approaches in this patient population in routine practice. Methods: A retrospective, multicenter observational analysis of adult patients with BRAF V600–mutant advanced melanoma who progressed on BRAF/MEK inhibitors and were managed at two Russian centers (N.N. Blokhin NMRCO and Moscow Oncology City Hospital No. 62) from 2019 to 2023. This retrospective analysis included 63 patients with advanced melanoma who received first-line (1L) combined targeted therapy (e.g., BRAF/MEK inhibitors) and, upon progression, initiated second-line (2L) immunotherapy. Patients received either ipilimumab plus nivolumab (Ipi/Nivo) (n = 46) or anti–PD-1 monotherapy (n = 17). Results: Treatment assignment information was available for all 63 patients (Ipi/Nivo combination, n = 46; anti-PD-1 monotherapy, n = 17). The median age of all included patients was 50.4 years; 54.3% were male. Metastatic stage at treatment initiation differed between groups (M1d: 50.0% vs 35.3%; M1c: 28.3% vs 35.3%), respectively. The median duration of follow-up after second-line treatment initiation was 26.9 months. The objective response rate (ORR; complete and partial responses) to second-line immunotherapy was 19.0%. Combination immunotherapy did not increase ORR compared with monotherapy (19.6% with ipilimumab/nivolumab vs 17.0% with anti–PD-1 therapy). The majority of patients (85.7%) had documented disease progression on 2L therapy, confirming an aggressive, treatment-resistant population The median progression-free survival (mPFS) was 5.5 months (95% CI, 3.00–13.6) in the ipilimumab/nivolumab group and 4.7 months (95% CI, 3.33–23.8) in the anti–PD-1 therapy group. The median overall survival (OS) was 28.7 months (95% CI, 12.03–45.4) in the ipilimumab/nivolumab group and 35.8 months (95% CI, 25.1–46.5) in the anti–PD-1 therapy group, with a hazard ratio (HR) of 0.98 (95% CI, 0.49–1.95; p = 0.956). Conclusions: Second-line immunotherapy provided modest disease control with a high primary progression rate. No significant efficacy difference was observed between anti–PD-1 monotherapy and ipilimumab/nivolumab combination as a 2L strategy, suggesting limited benefit from intensification to combination immunotherapy after targeted therapy failure in this setting. These results need to be interpreted with caution given the retrospective nature of the analysis and the small number of patients in the treatment groups.