International real-world study of combination immunotherapy sequences in metastatic melanoma

Immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, with programmed cell death protein 1 (PD-1) inhibitors-alone or in combination with cytotoxic T-lymphocyte-associated protein 4 or lymphocyte-activation gene 3 inhibitors-demonstrating significant efficacy. However, there is a critical lack of robust data to determine the optimal sequencing of these therapies for individual patients. In particular, the role of relatlimab+nivolumab (rela/nivo) within treatment sequences remains poorly defined. Choosing the right sequence is strategic, as an inappropriate order may compromise the effectiveness of subsequent treatments and limit long-term benefits.

This multicenter retrospective and prospective study evaluated 190 patients across three treatment arms: rela/nivo followed by ipilimumab+nivolumab (ipi/nivo) (arm A, N=40), ipi/nivo followed by rela/nivo (arm B, N=71), and anti-PD-1 followed by rela/nivo (arm C, N=79). The study assessed the impact of treatment sequencing on outcomes including response rate, progression-free survival, and overall survival (OS).

The overall response rate to second treatment was highest in arm C (30.4%), followed by arm B (28.1%) and arm A (17.5%). Patients with secondary resistance to first-treatment ICIs had better responses to second-treatment ICIs than those with primary resistance, particularly in arm B (p=0026). Median OS from date of first ICI treatment was significantly longer in arms B (40.9 months) and C (42.5 months) compared with arm A (16.3 months).

Our findings indicate that rela/nivo may remain active following anti-PD-1 or ipi/nivo therapy. Additionally, our results suggest that sequencing ipi/nivo before rela/nivo may yield better outcomes than starting with rela/nivo. Patients who respond to the first combination regimen appear to derive greater benefit from the second. Further efforts are needed to optimize sequencing strategies in advanced melanoma, and future studies should consider the impact of prior treatment outcomes.