LAG3-PD1 or CTLA4-PD1 Inhibition in Advanced Melanoma: Indirect Cross Comparisons of the CheckMate-067 and RELATIVITY-047 Trials

OBJECTIVE To compare the inhibition of lymphocyte-activation gene 3 (LAG3) plus programmed cell death 1 (PD-1) versus the inhibition of cytotoxic T-lymphocyte antigen 4 (CTLA-4) plus PD-1 in patients with previously untreated advanced melanoma. DESIGN A meta-analysis of individual participant data (IPD). DATA SOURCES PubMed, Web of Science and Embase were searched from January 1, 2015, to January 14, 2022, for eligible studies. ELIGIBILITY CRITERIA FOR STUDY SELECTION Data from randomized controlled trials reporting on the use of dual LAG3-PD1 inhibitors or dual CTLA4-PD1 inhibitors which assigned PD1 inhibitor alone as their control arm and provided corresponding Kaplan-Meier (KM) curves of treatment outcomes for previously untreated advanced melanoma were retrieved. METHODS The IPD data were extracted from the KM plots using a graphical reconstructive algorithm. Log-rank, Cox proportional hazard model, Bayesian hierarchical model with time-varying hazard ratio (HR) effect, and restricted mean survival time (RMST) were performed to estimate survival benefits. The primary endpoint was progression-free survival. RESULTS The CheckMate-067 (N = 630) and RELATIVITY-047 (N = 714) trials were included for analysis. The graphical reconstructive algorithm showed that IPD had similar HRs and log-rank values as the original plots. The HR of nivolumab-relatlimab (LAG3 inhibitor) versus nivolumab-ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab-relatlimab versus nivolumab alone was 2.35 (95% CI 0.77 to 3.94) months, compared with 1.87 (95% CI 0.25-3.49) months for nivolumab-ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab-relatlimab had earlier PFS benefits than those with nivolumab-ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab-relatlimab and 55.0% of patients using nivolumab-ipilimumab. CONCLUSION These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and that LAG3-PD1 inhibition tended to exhibit earlier survival benefit and lesser TRAEs.