Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria based objective response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Experimental Design: Thirteen randomized, multicenter, active control trials containing immunotherapeutic agents submitted to FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS and OS were evaluated at individual and trial-levels. Patient-level responder analysis was performed for PFS and OS. Results: The coefficient of determination (R2) measured the strength of associations, where values near 1 imply surrogacy and values close to zero suggest no association. At the trial-level, associations between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 - 0.1, and individual level correlations were approximately 0.6. HRs of PFS and OS for responders versus non-responders were 0.129 (95% CI: 0.11, 0.15) and 0.118 (95% CI: 0.11, 0.13), respectively. Conclusions: While responders exhibited longer survival and PFS than non-responders, the trial-level and individual level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations.
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