Abstract 1105P
Background
Immune-checkpoint inhibitors nivolumab (NIVO) and ipilimumab (IPI), alone and in combination, have demonstrated durable long-term survival patterns in previously untreated patients with advanced melanoma in the CheckMate 067 trial (NCT01844505). Plateaus in overall survival (OS) and progression-free survival (PFS) data can be attributed to survival heterogeneity, which can be better captured by mixture models.
Methods
We assumed that a subset of patients can be classified as long-term survivors (LTSs) and that their survival trend follows that of the general population, with no excess mortality due to melanoma. A cohort-level background survival distribution was derived using mortality rates from the World Health Organization and demographic information from CheckMate 067. After assessing the suitability of mixture models by comparing hazard functions for the 5-year data in the entire trial population and the general population, we fit mixture models to the OS and PFS data to estimate the proportion of LTSs in each treatment arm. Time-to-event outcomes of non-LTSs were modeled by parametric survival functions, the forms of which were varied to obtain a range for the proportions of LTSs and to test the robustness of the results.
Results
Regardless of the data source (OS or PFS), ranges of estimated proportions of LTSs did not overlap across the treatment arms. Based on OS analyses, ranges of estimated proportions of LTSs were 38–46% for NIVO, 49–54% for NIVO+IPI, and 16–26% for IPI. Based on PFS analyses, ranges were 29–33% for NIVO, 38–40% for NIVO+IPI, and 9–13% for IPI. As these ranges represent only a span of point estimates of LTSs across model choices, a formal statistical assessment of the significance of LTSs among the treatment arms would require a comparison of confidence intervals.
Conclusions
Mixture models adequately captured the survival plateaus in CheckMate 067 and suggested a higher proportion of LTSs with NIVO and NIVO+IPI than with IPI. These methods may be used in the indirect estimation of auxiliary outcomes, such as time to subsequent treatment and impact of subsequent treatments on LTSs.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Bristol-Myers Squibb Company.
Funding
Bristol-Myers Squibb Company.
Disclosure
P. Mohr: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: Merk KGaA; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: Novartis. J. Larkin: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Achilles; Research grant/Funding (self): Aveo; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Nektar; Research grant/Funding (self): Covance; Research grant/Funding (self): Immunocore; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Boston Biomedical; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: EUSA Pharma; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy: Imugene; Honoraria (self), Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy: iOnctura; Honoraria (self), Advisory/Consultancy: Kymab; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Pfizer; Honoraria (self), Advisory/Consultancy: Secarna; Honoraria (self), Advisory/Consultancy: Vitaccess. V.F. Paly: Advisory/Consultancy, Full/Part-time employment, Employee of ICON Plc., which provides consulting and research services: ICON Plc. A. Remiro Azocar: Advisory/Consultancy, Full/Part-time employment: IQVIA; Advisory/Consultancy: ICON plc. G. Baio: Research grant/Funding (self): Merck Sharp & Dohme; Advisory/Consultancy: ICON plc.; Advisory/Consultancy: Parexel; Advisory/Consultancy: IQVIA. M. Kurt: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb Company; Full/Part-time employment: Merck. A. Amadi: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb Pharmaceuticals Ltd. J.I. Rizzo: Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Bristol-Myers Squibb Company. H.M. Johnson: Advisory/Consultancy, Full/Part-time employment: Bristol-Myers Squibb Pharmaceuticals Ltd. A. Moshyk: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb Company. S. Kotapati: Leadership role, Research grant/Funding (self), Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb Company. M. Middleton: Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Millenium; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunocore; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb Company; Research grant/Funding (institution), Non-remunerated activity/ies, Member of IDSMC: Eisai; Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies, Member of IDSMC: Merck/Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution), Acquired by Merck Sharp & Dohme: Rigontec; Research grant/Funding (institution): Regeneron; Advisory/Consultancy, Research grant/Funding (institution): BiolineRx; Advisory/Consultancy, Research grant/Funding (institution), Acquired by Pfizer: Array Biopharma; Research grant/Funding (institution), Travel/Accommodation/Expenses: Replimune; Advisory/Consultancy: Kineta; Advisory/Consultancy: Silicon Therapeutics.