Restricted Mean Survival Time (Rmst) And Cure-Rate Modeling In Estimating Survival Benefit With Adjuvant Dabrafenib (D) Plus Trametinib (T) Treatment In Melanoma

Kaplan-Meier and Cox regression time-to-event analyses have traditionally been used to estimate relapse-free survival (RFS) and assess adjuvant treatment effects in high-risk melanoma. However, these methods do not account for nonproportional hazards and/or the potential that a fraction of patients (pts) may never have disease relapse. To overcome these limitations, we evaluated treatment effects using RMST, which assesses area under the survival curve and cure-rate analysis in COMBI-AD. COMBI-AD (NCT01682083) is a randomized phase III trial that compared 12 mo of adjuvant D 150 mg twice daily + T 2 mg once daily vs 2 matched placebos (PBO) in pts with resected stage III BRAF V600E/K–mutant melanoma, stratified by BRAF V600E or K status and disease stage (by AJCC 7 criteria). RMST truncated at 60 mo and a mixed Weibull cure-rate model were used to estimate treatment effect and long-term RFS rates. Median follow-up was 60 mo and 58 mo in the D+T and PBO arms. At the data cutoff (Nov 8, 2019), RMST across all stages was 41.5 mo (95% CI, 39.4-43.6 mo) with D+T vs 28.7 mo (95% CI, 26.3-31.2 mo) with PBO (representing a gain in RFS of 12.8 mo with D+T over 60 mo). The overall cure rate was 51% (95% CI, 46%-56%) with D+T vs 35% (95% CI, 30%-40%) with PBO, meaning an absolute increase of 16% in the fraction of pts who remain relapse free long term with D+T. RMST and cure rate were improved with D+T across AJCC 7 substages, with the greatest benefit observed in pts with high-risk baseline stage IIIB or IIIC (Table). RMST and cure-rate models complement conventional statistical methods for 5-year COMBI-AD analysis, demonstrating significant clinical benefit with adjuvant D+T across all stage III substages in pts with melanoma. These analyses may assist oncologists with presenting adjuvant stage III options to their pts.Table: 1100PRMST at 60 Mo and cure-rate analysisStage IIIAStage IIIBStage IIICD+T (n = 83)PBO (n = 71)D+T (n = 169)PBO (n = 187)D+T (n = 181)PBO (n = 166)RMST (95% CI), mo50.4 (46.7-54.2)42.2 (36.4-47.9)41.2 (37.7-44.7)29.0 (25.4-32.6)38.0 (34.6-41.3)22.8 (18.9-26.8)RMST difference (95% CI), mo8.2 (1.4-15.1)12.2 (7.2-17.2)15.1 (10.0-20.3)Cure rate (95% CI), %63 (49-77)52 (33-71)54 (46-62)33 (26-40)43 (35-51)28 (21-36) Open table in a new tab