Outcomes of systemic treatment in advanced melanoma after progression on anti–PD-1 therapy: a real-world study with literature review

INTRODUCTION: Currently, a substantial proportion of patients are still treated with first-line anti-PD-1 immunotherapy (ICI). After disease progression, treatment options, especially for patients with BRAF-negative tumors, are limited. One regimen used in real-world practice in this setting is ipilimumab monotherapy (anti-CTLA-4). This study aimed to assess the efficacy of ipilimumab monotherapy after progression on anti-PD-1 monotherapy. Moreover, the observed progression-free survival (PFS) and overall survival (OS) were compared with the efficacy of potential new drugs used in second-line treatment. MATERIAL AND METHODS: This retrospective analysis included patients who had received prior anti-PD-1 monother­apy and subsequently developed disease progression, after which ipilimumab was administered as second-line ICI. The primary outcome measures were objective response rate (ORR), PFS, and OS. Kaplan–Meier and Cox analyses were performed. RESULTS: A total of 120 patients were enrolled in the study. The ORR was 10.8%, with 1 (0.8%) patient achieving a complete response (CR) and 12 (10%) achieving a partial response (PR). Another 21 (17.5%) patients achieved stable disease (SD). In contrast, in85 (70.8%) patients had the best overall response of progressive disease (PD) to ipilimumab. The median PFS was 3 months (95% CI 2.6–3.7). At 6 months after the first dose, PFS was 29.9% (95% CI 22.7–39.5), and at 12 months it was 10.9% (95% CI 6.4–18.5). The median OS was 7.6 months (95% CI 6.2–10.1), with 1- and 2-year OS rates of 32.39% (95% CI 24.9–42.2) and 14.01% (95% CI 8.9–22), respectively. Male sex and increased lactate dehydrogenase (LDH) activity were significantly associated with worse PFS and OS. CONCLUSIONS: This study demonstrated that the real-world efficacy of ipilimumab monotherapy as second-line therapy in patients with advanced melanoma is similar to that reported in clinical trials. The observed ORR, PFS, and OS were relatively low; however, a small group of patients benefited from sequential anti-PD-1/anti-CTLA-4 ther­apy, raising the question of how to identify these patients upfront. The nivolumab-ipilimumab combination should be offered as a first-line treatment option in eligible patients.