Exploration of a Novel Intermediate Response Endpoint in Immunotherapy Clinical Studies

Purpose: Both objective response rate (ORR) and progression-free survival as defined by RECIST are weakly associated with overall survival (OS) in trials evaluating immunotherapy drug products.  We proposed a novel intermediate response endpoint (IME) for evaluating immunotherapies.  Experimental Design: We defined IME response as having no non-target lesion progression, no new lesion appearance, and reaching a target lesion response determined by baseline tumor burden, tumor reduction depth, and tumor change dynamic within one year after randomization. Database used consisted of data from randomized active-controlled immunotherapy trials. Criterion for IME was developed based on patient level data from a training dataset, and further evaluated using independent testing dataset. A patient level responder analysis comparing OS between patients with and without an IME response was conducted using combined data.  Association between trial level OS hazard ratio (HR) and IME odds ratio was analyzed using a weighted linear regression model. Results: A total of 5806 patients from 9 randomized studies were included in the database. At patient level, patients with IME response had improved OS compared to non-responders (HR 0.09). At trial level, association between OS and IME was moderate (R2 = 0.68). Conclusion: The IME was moderately associated with OS, and the association appeared to be stronger than the association observed between RECIST-defined ORR and OS.  However, the analyses conducted in this research are exploratory and further evaluation is needed before using this endpoint in future studies.

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