title: Differences in Treatment Effect Size Between Overall Survival and Progression-Free Survival in Immunotherapy Trials: A Meta-Epidemiologic Study of Trials With Results Posted at ClinicalTrials.gov.
abstract: Purpose We aimed to compare treatment effect sizes between overall survival (OS) and progression-free survival (PFS) in trials of US Food and Drug Administration-approved oncology immunotherapy drugs with results posted at ClinicalTrials.gov . Methods We searched ClinicalTrials.gov for phase II to IV cancer trials of Food and Drug Administration-approved immunotherapy drugs and selected those reporting results for both OS and PFS. For each trial, we extracted the hazard ratios (HRs) with 95% CIs for both outcomes and evaluated the differences by a ratio of HRs (rHRs): the HR for PFS to that for OS. We performed a random effects meta-analysis across trials to obtain a summary rHR. We also evaluated surrogacy of PFS for OS by the coefficient of determination and the surrogacy threshold effect, the minimal value of HR for PFS to predict a non-null effect on OS. Results We identified 51 trials assessing 14 drugs across 15 conditions. Treatment effect sizes were 17% greater, on average, with PFS than with OS (rHR, 0.83; 95% CI, 0.79 to 0.88; I2= 34.4%; P = .01; τ2= 0.0129). Nearly one half of the trials (n = 23, 45%) showed statistically significant benefits for PFS but not for OS. Differences were great for trials of obinutuzumab (rHR, 0.21; 95% CI, 0.08 to 0.54), bevacizumab (rHR, 0.75; 95% CI, 0.67 to 0.84), and rituximab (rHR, 0.79; 95% CI, 0.64 to 0.98). The coefficient of determination was 38% and the surrogacy threshold effect was 0.50. Conclusion Treatment effect sizes in trials of immunotherapy drugs were greater for PFS than for OS, with important differences for some drugs, which is consistent with surrogacy metrics. Caution must be taken when interpreting PFS in the absence of OS data.
authors.affiliation: Aidan Tan and Philippe Ravaud, Mailman School of Public Health, Columbia University, New York, NY; Aidan Tan, National University Hospital, Singapore; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris; Raphael Porcher, Philippe Ravaud, and Agnes Dechartres, Université Paris Descartes, Sorbonne Paris Cité; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Centre de Recherche Epidémiologie et Statistique, INSERM U1153; and Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Cochrane France, Paris, France.
authors.forename: Aidan
authors.initials: A
authors.lastname: Tan
authors.affiliation: Aidan Tan and Philippe Ravaud, Mailman School of Public Health, Columbia University, New York, NY; Aidan Tan, National University Hospital, Singapore; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris; Raphael Porcher, Philippe Ravaud, and Agnes Dechartres, Université Paris Descartes, Sorbonne Paris Cité; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Centre de Recherche Epidémiologie et Statistique, INSERM U1153; and Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Cochrane France, Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Porcher
authors.affiliation: Aidan Tan and Philippe Ravaud, Mailman School of Public Health, Columbia University, New York, NY; Aidan Tan, National University Hospital, Singapore; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris; Raphael Porcher, Philippe Ravaud, and Agnes Dechartres, Université Paris Descartes, Sorbonne Paris Cité; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Centre de Recherche Epidémiologie et Statistique, INSERM U1153; and Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Cochrane France, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Crequit
authors.affiliation: Aidan Tan and Philippe Ravaud, Mailman School of Public Health, Columbia University, New York, NY; Aidan Tan, National University Hospital, Singapore; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris; Raphael Porcher, Philippe Ravaud, and Agnes Dechartres, Université Paris Descartes, Sorbonne Paris Cité; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Centre de Recherche Epidémiologie et Statistique, INSERM U1153; and Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Cochrane France, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravaud
authors.affiliation: Aidan Tan and Philippe Ravaud, Mailman School of Public Health, Columbia University, New York, NY; Aidan Tan, National University Hospital, Singapore; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris; Raphael Porcher, Philippe Ravaud, and Agnes Dechartres, Université Paris Descartes, Sorbonne Paris Cité; Raphael Porcher, Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Centre de Recherche Epidémiologie et Statistique, INSERM U1153; and Perrine Crequit, Philippe Ravaud, and Agnes Dechartres, Cochrane France, Paris, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Dechartres
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D018572:Disease-Free Survival; D016021:Epidemiologic Studies; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000706:statistics & numerical data; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D015996:Survival Rate
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C543332:obinutuzumab