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Published on: February 8, 2018
LAG3-PD1 or CTLA4-PD1 Inhibition in Advanced Melanoma: Indirect Cross Comparisons of the CheckMate-067 and
Bai-Wei Zhao1, Fei-Yang Zhang1, Yun Wang2
1Department of Gastric Surgery & Melanoma Surgical Section, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Abstract:
Objective: To compare the inhibition of LAG3-PD1 versus the inhibition of CTLA-4-PD1 in patients with previously untreated advanced melanoma. Methods: The individual participant data (IPD) 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. 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 plus relatlimab (LAG3 inhibitor) versus nivolumab plus ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab plus relatlimab versus nivolumab was 2.35 (95% CI 0.77-3.94) months, compared with 1.87 (95% CI, 0.25-3.49) months for nivolumab plus ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab plus relatlimab had earlier PFS benefits than those with nivolumab plus ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab plus relatlimab and 55.0% of patients using nivolumab plus ipilimumab. Conclusions: These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and LAG3-PD1 inhibition exhibited earlier survival benefit and lesser TRAEs.
Insights
Comparing immune checkpoint inhibitors in advanced melanoma, LAG3-PD1 blockade showed similar progression-free survival to CTLA-4-PD1 blockade but offered earlier survival benefits and fewer treatment-related adverse events.
Area of Science:
- Immunotherapy
- Oncology
- Melanoma Research
Background:
- Immune checkpoint inhibitors (ICIs) like PD-1, CTLA-4, and LAG-3 blocking antibodies have revolutionized melanoma treatment.
- Dual ICI blockade, such as CTLA-4 and PD-1 inhibition, has demonstrated superior efficacy compared to single-agent therapy.
- The combination of LAG-3 and PD-1 inhibition represents a novel therapeutic strategy for advanced melanoma.
Purpose of the Study:
- To compare the efficacy and safety of LAG3-PD1 inhibition versus CTLA-4-PD1 inhibition in previously untreated advanced melanoma patients.
- To analyze overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) between the two treatment arms.
Main Methods:
- Individual participant data (IPD) were reconstructed from published Kaplan-Meier plots of relevant clinical trials (CheckMate-067 and RELATIVITY-047).
- Statistical analyses included log-rank tests, Cox proportional hazard models, Bayesian hierarchical models with time-varying hazard ratios, and restricted mean survival time (RMST).
- Hazard ratios (HRs) and RMST were calculated to estimate survival benefits, and incidence of Grade 3 or 4 TRAEs was compared.
Main Results:
- The hazard ratio for nivolumab plus relatlimab (anti-LAG3 plus anti-PD1) versus nivolumab plus ipilimumab (anti-CTLA-4 plus anti-PD1) was 1.19 (95% CI, 0.96-1.48), indicating similar PFS.
- Restricted mean survival time at 24 months favored nivolumab plus relatlimab (2.35 months) over nivolumab plus ipilimumab (1.87 months) when compared to nivolumab monotherapy.
- Bayesian modeling suggested earlier PFS benefits with LAG3-PD1 inhibition. Grade 3/4 TRAEs were significantly lower with nivolumab plus relatlimab (18.9%) compared to nivolumab plus ipilimumab (55.0%).
Conclusions:
- Progression-free survival between LAG3-PD1 and CTLA-4-PD1 inhibition strategies in advanced melanoma appears comparable.
- LAG3-PD1 inhibition demonstrated an earlier survival benefit and a more favorable safety profile with significantly fewer high-grade treatment-related adverse events.
- These findings support LAG3-PD1 inhibition as a promising alternative treatment for advanced melanoma, offering comparable efficacy with improved tolerability.
