Background

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.

Methods

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.

Results

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).

Conclusions

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: 1100P

RMST at 60 Mo and cure-rate analysis

Clinical trial identification

COMBI-AD (NCT01682083), conducted in accordance with Study Protocol BRF115532.

Editorial acknowledgement

Medical editorial assistance was provided by Zareen Khan, PhD, from ArticulateScience LLC and funded by Novartis Pharmaceuticals Corporation (East Hanover, NJ), in accordance with Good Publication Practice (GPP3) (https://www.ismpp.org/gpp3) guidelines and International Committee of Medical Journal Editors recommendations.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

J.M. Kirkwood: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Research grant/Funding (institution), Travel/Accommodation/Expenses: Checkmate Pharmaceuticals; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis Pharmaceuticals Corporation; Research grant/Funding (institution): Castle Biosciences; Research grant/Funding (institution): Immunocore; Research grant/Funding (institution): Iovance. R. Dummer: Advisory/Consultancy: Novartis; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Roche; Advisory/Consultancy: Amgen; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Sun Pharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Catalym GmbH; Advisory/Consultancy: Second Genome; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Alligator Bioscience. A. Hauschild: Advisory/Consultancy: Almirall Hermal GmbH; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: OncoSec; Advisory/Consultancy, Research grant/Funding (institution): Philogen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Provectus Biopharmaceuticals; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Regeneron; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Sanofi Genzyme; Advisory/Consultancy: Sun Pharma. V. Atkinson: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Honoraria (self), Speaker Bureau/Expert testimony: Novartis; Travel/Accommodation/Expenses: OncoSec; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Roche. V. Chiarion Sileni: Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Serono; Advisory/Consultancy: Merck, Sharp & Dohme; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Speaker Bureau/Expert testimony: Sanofi. M.S. Nyakas: Honoraria (self): Bristol-Myers Squibb; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre. A.M. Haydon: Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre. C. Dutriaux: Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre. J. Schachter: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Roche. C. Robert: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Biothera Pharmaceuticals; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Sanofi. L. Mortier: Travel/Accommodation/Expenses: Novartis. H. Banerjee: Full/Part-time employment: Novartis. T. Haas: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis Pharma AG. M. Tan: Full/Part-time employment: Novartis. M. Lau: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. D. Schadendorf: Honoraria (self), Advisory/Consultancy: 4SC; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Array BioPharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy: Immunocore; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck EMD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (institution), Advisory/Consultancy: Nektar Therapeutics; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Regeneron; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi. G.V. Long: Advisory/Consultancy: Aduro Biotech; Advisory/Consultancy: Amgen; Advisory/Consultancy: Array BioPharma; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: OncoSec Medical; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Roche; Advisory/Consultancy: Sandoz. M. Mandala': Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Sanofi. All other authors have declared no conflicts of interest.