Correlation between treatment effects on response rate and progression-free survival and overall survival in trials of targeted therapies in molecularly enriched populations.

Background: The number of randomized trials of agents targeting oncogene-addicted tumors has surged in the past 10 years. Using a meta-analysis, we explored whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in progression-free survival (PFS) or overall survival (OS) in populations with oncogene-addicted cancer.
Patients and Methods: Using commercial text mining software I2E, we searched ClinicalTrials.gov and MEDLINE databases for randomized, phase III trials based on prospectively defined criteria, including (i) use of agents targeting EGFR activating mutations, ALK rearrangements, BRAF V600E or V600K mutations, and BCR-ABL fusion protein; (ii) molecularly enriched trial population or subpopulation; (iii) control arm only randomized to chemo/cytotoxic therapy. Correlative analyses were performed using ORR, OS, and PFS data from trials that met these criteria.
Results: A total of 62 trials were identified; 15 met all of the prespecified criteria. The ORR effect size (both the difference in ORR between arms and the log odds ratio) and log PFS hazard ratio were strongly correlated: -0.78 (P = 0.0007) for the ORR difference model; -0.74 (P = 0.0017) for the log odds ratio model. ORR effect size was positively correlated with the log OS hazard ratio, but more weakly: -0.67 (P = 0.013) for the ORR difference model and -0.58 (P = 0.036) for the log odds ratio model. Analysis of the treatment effects between OS and PFS found no correlation.
Conclusions: These analyses identified a strong correlation between treatment effects on ORR and PFS in randomized clinical trials investigating agents targeting oncogene-driven cancers. A weaker correlation was observed between ORR and OS. These meta-analysis results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.
Competing Interests: Disclosure BJS reports personal fees from Loxo Oncology, during the conduct of the study; personal fees from AstraZeneca, Novartis, Roche/Genentech, Bristol Myers Squibb, Merck, Gritstone Oncology, Amgen, Sanofi/Regeneron, and grants and personal fees from Pfizer, all outside the submitted work. HHL reports personal fees for Advisory Board participation from Bayer, Boehringer Ingelheim, Celgene, and Eli Lilly; personal fees for Advisory Board and Speaker’s Bureau participation and research funding from Novartis; personal fees for Speaker’s Bureau participation from Guardant Health and Eisai; travel support and research funding from Merck; research funding from Mundipharma, and travel support from Pfizer. YS reports personal fees from Eli Lilly, Roche, AstraZeneca, Takeda, Pfizer, and Merck. ZMT, PF, BKL, and AS report employment and stock ownership with Eli Lilly. JW reports Advisory Board and lecture fees from AbbVie, Amgen, AstraZeneca, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, Ignyta, Janssen, Eli Lilly, Loxo Oncology, Merck, Novartis, Pfizer, Roche, and Takeda; and research support to the institution from Bristol Myers Squibb, Johnson and Johnson, Novartis, and Pfizer. JC-HY reports honoraria for speeches and Advisory Boards from Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Merck, Pfizer, Novartis, Bristol Myers Squibb, and Ono Pharmaceutical; and honoraria for Advisory Boards from AstraZeneca, Astellas, Merck Serono, Celgene, Merrimack, Yuhan Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, and Blueprint Medicines. AD reports honoraria from Advisory Board participation from Ignyta/Genentech/Roche, Loxo Oncology/Bayer/Eli Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare therapeutics; associated research support paid to the institution by Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences; royalties from Wolters Kluwer; and other support from Merck, Puma, Merus, and Boehringer Ingelheim.
(Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)