Abstract 3705
Background
Unlike biomarkers of dichotomous genetic mutations/fusions required for response, biomarkers for checkpoint inhibitors are continuous biologic variables with context specific cutpoints. Selecting the cutpoint of a continuous biomarker for higher response rate in a given therapy decreases the number of biomarker positive patients (prevalence). To facilitate interpretation of biomarkers in IO, we introduce a framework for understanding how cutpoints, response rate and prevalence are interrelated.
Methods
Objective response rate (ORR) in biomarker positive patients is the product of ORR in all patients and the fraction of responding patients who are biomarker positive (FR+), divided by the prevalence. FR+ depends on the difference in biomarker distributions between responding and nonresponding patients. Biomarker [PD-L1 IHC, tumor mutation burden (TMB), T-cell activated gene expression profile (GEP)] and response data were pooled from 595 patients in 7 clinical trials of pembrolizumab monotherapy across 16 tumor types. A Bayesian model was used to estimate biomarker distributions in responders and nonresponders for each biomarker assuming normality.
Results
ORR prevalence data generated by varying the cutpoint were fit well by the biomarker distribution model for all 3 biomarkers. Individual biomarker ORR prevalence curves and 95% credible intervals overlapped substantially with each other, consistent with indistinguishable areas under the receiver operating characteristics curve (AUROC) for PD-L1, TMB and GEP in this pan tumor population. Thus, although PD-L1 or GEP identify populations only partially overlapping with that of TMB, the predictive ability is similar for all 3 biomarkers.Table: 99P
Value (95% CI) | ||||
---|---|---|---|---|
Biomarker | ORR @ 60% Prevalence | ORR @ 30% Prevalence | ORR @ 10% Prevalence | AUROC |
PD-L1 | 15.5 (12.0, 19.0) | 21.5 (15.8, 27.4) | 33.6 (22.3, 45.7) | 0.69 (0.63, 0.76) |
GEP | 17.5 (14.1, 21.2) | 24.8 (19.2, 30.1) | 33.5 (24.2, 44.1) | 0.76 (0.70, 0.82) |
TMB | 15.0 (11.7, 18.6) | 21.5 (15.7, 27.7) | 35.9 (24.0, 49.0) | 0.67 (0.59, 0.74) |
CI = Credible interval for ORR and confidence interval for AUROC
Conclusions
A model using biomarker distributions in responding and nonresponding patients accounts for the relationships among cutpoints, response rate and prevalence, and may provide a framework for interpretation of biomarker response data in IO.
Clinical trial identification
Legal entity responsible for the study
Merck Sharp & Dohme, Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme, Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Editorial Acknowledgement
Joanne Tomassini, Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
J.L. Evelhoch: Employee and stock owner: Merck Sharp & Dohme Corp. R. Mogg, R. Cristescu, D. Aurora-Garg, C.H. Poehlein, A. Joe, S.M. Keefe, P. Kang, V. Karantza, J. Cheng, E.H. Rubin: Employee and stock owner/stock options: Merck Sharp & Dohme Corp. L.Q. Chow: Advisory board honoraria: Merck & Co., Inc., Sanofi-Genzyme; Institutional grant funding: Merck & Co., Inc., Bristol Myers Squibb, Lily/Imclone; Consulting honoraria: Amgen, Incyte, VentiRx; Institutional research grant and advisory board honoraria: Novartis, Genentech, AstraZeneca, Pfizer, Seattle Genetics. S. Loi: Grants: Merck Sharp & Dohme, Puma Biotechnology, Bristol-Myers Squibb, Novartis, Pfizer; Grants and non-financial support: Roche-Genentech. D.V.T. Catenacci: Consultant: Eli Lilly, Roche/Genentech, Amgen, Taiho, Five Prime Therapeutics; Speaker bureau: Eli Lilly; Institutional research funding: Amgen, Genentech. U.A. Matulonis: Funding: Merck & Co., Inc., Novartis; Consulting/advisor fees: Merck & Co., Inc., Lilly, Geneos, 2X Oncology, Myriad Genetics, Clovis Oncology, Fujifilm. P.A. Ott: Consulting or advisory role: Amgen, Bristol-Myers Squibb, Alexion, CytomX Therapeutics, Celldex, Genentech, Novartis, Pfizer, Neon Therapeutics; Speaking fees: Merck & Co., Inc.; Research funding: Bristol-Myers Squibb, Merck & Co., Inc., Astra Zeneca/MedImmune, Celldex, Neon Therapeutics, Pfizer, CytomX, ARMO BioSciences (to institution). E.S. Antonarakis: Consulting or advisory role: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas Pharma, Merck & Co., Inc., AstraZeneca, Clovis Oncology; Travel fees: Sanofi, Dendreon, Medivation; Co-inventor of a biomarker technology that has been licensed to Qiagen; Honoraria: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Asstellas Pharma, Merck & Co., Inc., AstraZeneca, Clovis Oncology; Research funding: Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Aragon Pharma, Exelixis, Millennium, Genentech, Novartis, Astellas Pharma, Tokai Pharmaceuticals, Merck & Co., Inc., AstraZeneca, Clovis Oncology, Constellation Pharmaceuticals (received by institution).