Sequencing immune checkpoint inhibitors and BRAF/MEK inhibitors in advanced melanoma: A meta-analysis of Kaplan-Meier-reconstructed individual level data

Objectives: Optimal sequencing of immune checkpoint inhibitors (ICI) and BRAF inhibitors (BRAFi) for BRAFV600-mutant advanced melanoma remains uncertain. We conducted a meta-analysis of Kaplan-Meier (KM)-reconstructed individual-patient data (IPD) comparing two clinically used sequences: First-line ICI followed by BRAFi (ICI-BRAFi) versus first-line BRAFi followed by ICI (BRAFi-ICI). Methods: We searched MEDLINE, Embase, and Cochrane for phase II/III studies reporting KM curves for stage III/IV melanoma patients treated with either ICI-BRAFi or BRAFi-ICI. Outcomes were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were toxicity and brain-metastasis-free survival (BMFS). Reconstructed IPD were analyzed with Cox proportional hazards (PH) models. We additionally estimated restricted mean survival time (RMST) up to 24 months (m) (Grambsch-Therneau test, p<0.05). Results: Six studies with 832 patients were included, of which 426 patients received ICI-BRAFi, and 406 BRAFi-ICI. Median PFS was approximately 12 m for both groups (p=0.1, log-rank). PFS at 24 m was 42.8 and 29 m for ICI-BRAFi and BRAFi-ICI, respectively. The PFS RMST difference at 24 m was 0.32 m (95% CI: -1.1 - 1.8 months; p=0.66). Median OS was 58.2 m for ICI-BRAFi and 40.3 m for BRAFi-ICI. OS at 24 m was 65.9% and 60.7% for ICI-BRAFi and BRAFi-ICI groups, respectively (p=0.4; log-rank). The RMST revealed a slight and nonsignificant OS difference of -0.49 m (95% CI: -1.64 - 0.67 months; p=0.41). In a pooled analysis including the only two randomized studies SECOMBIT and DREAMseq, we found a median PFS of 31.5 m for ICI and 13.1 m for BRAFi (p=0.003); and median OS was NA and 32.7 m for ICI and BRAFi (p=0.005). Conclusion: ICI-BRAFi led to significantly longer PFS and OS than BRAFi-ICI when evaluating only randomized clinical trials, supporting ICI-first sequencing. $$table_{CF128EEB-D4BD-4130-95C0-74E89761CA49}$$ Survival data in ICI-BRAFi vs BRAFi-ICI cohorts ICI–BRAFi BRAFi–ICI p value Overall median PFS 12.5 months (9.6-23.3) 12 (10.7-14) 0.1 PFS at 24 months 42.8 months (36.9-49.7) 29 months (24.2-34.4) - Median PFS with RCT only 31.5 months (13.9-44.1) 13.1 months (11.3-16.7) 0.003 Overall median OS 58.2 months (37.5-NA) 40.3 months (32.4-NA) 0.4 Os at 24 months 65.9 % (60.2-72.1 %) 60.7 % (55.6-66.2 %) - Median OS with RCT only NA (55.5-NA) 32.7 (23.1-59.7) 0.005