IKCS 2022: Choosing Endpoints and Designs of Future Trials: OS vs PFS and Comparator Cohorts

(UroToday.com) The 2022 IKCS North American annual meeting featured a Regulatory for New Trials session and a presentation by Dr. Joe Lee discussing an overview of drug development in renal cell carcinoma (RCC) focusing on clinical trial endpoints and the clinical significance of different endpoints. Using the paradigm of 1L therapy decisions in metastatic renal cell carcinoma (RCC), Dr. Lee highlighted the roles of different clinical trial endpoints in understanding treatment efficacy.



Given the lack of rigorously-validated predictive biomarkers to guide 1L therapy, oncologists use clinical judgment and shared decision-making to select IO/IO or IO/TKI. There will likely never be head-to-head comparisons of these approaches, and it is unclear how best to assess long-term efficacy taking into account the impact of subsequent therapies.

In terms of near-term endpoints, Dr. Lee highlighted ORR with a special focus on CR and PD, both of which may be short-term surrogates of longer-term outcomes. 



Moving onto middle-term outcomes, Dr. Lee discussed that just as for ORR, comparison of PFS across trials is challenging due to patient heterogeneity. Furthermore, PFS (or PFS1) may not capture the true long-term benefit (or inadequacy) of 1L therapy.

He discussed the emerging endpoint PFS2, which quantifies the duration of time from initiation of 1L therapy through progression of 1L therapy all the way to progression on 2L therapy. He asserted that PFS2 better recapitulates OS data, though this correlation also reflects longer follow-up of these patients. He highlighted a meta-analysis of solid tumor trials showing better correlation between PFS2 and OS than between PFS1 and OS, though modestly so.

Dr. Lee highlighted the work of his colleague, Dr. Kelly Fitzgerald, who presented data showing a very strong correlation between depth of response and overall survival with both IO/IO as well as with IO/TKI. Interestingly patients achieving only SD fare about the same as those with primary PD.







Dr. Lee noted that PFS2 could be a useful endpoint particularly to address questions around combination versus sequencing, as is the critical question regarding COSMIC-313 where PFS2 is a reasonable endpoint that may yield readout more expeditiously than OS. He highlighted the value of PFS2 in interpreting the efficacy of IO/TKI in CLEAR.



Presented by: Chung-Han “Joe” Lee, MD, PhD, Memorial Sloan Kettering Cancer Center

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