Researchers suggested these findings may assist in better selection and prioritization of immune checkpoint inhibitor agents for testing in randomized clinical trials based on phase 2 single arm randomized clinical trial results.
A 6-month progression-free survival (PFS) for 12-month overall survival (OS) model developed in a systematic review and meta-analysis published in JAMA Network Open reliably estimated 12-month OS from 6-month PFS using a larger validation data set.
Researchers suggested these findings could assist in better selection and prioritization of immune checkpoint inhibitor (ICI) agents for testing in randomized clinical trials based on phase 2 single arm randomized clinical trial results.
“Importantly, our work may serve as a platform for future estimation models that incorporate multiple surrogate end points, including molecular surrogates and pharmacodynamic markers for a more sophisticated estimation of OS with ICI therapy,” the authors wrote.
Researchers searched electronic databases, including Medline, EMBASE, and the Cochrane Central Register of Controlled Trials, for ICI randomized clinical trials published between January 2000 and June 2019. Studies deemed eligible were phase 2 and phase 3 ICI randomized clinical trials in advanced solid cancers that reported objective response rate (ORR), PFS, and OS.
Overall, 99 articles from 60 randomized clinical trials with 74 experimental ICI arms were selected.Further, the development data set included 25 arms from studies published in January 2000 to January 2017.
The estimation model for 12-month OS using 6-month PFS was (1.06 x PFS6) + 0.16 + (0.04 x melanoma) − (0.03 x non-small cell lung cancer [NSCLC]) + (0 x other tumors); PFS6 indicates 6-month PFS. The estimation model for 12-month OS using ORR was (0.15 x ORR) + 0.52 + (0 x melanoma) − (0.02 x NSCLC) − (0.01 x other tumors).
In total, 49 arms from studies published after January 2017 to June 2019 composed the validation data set. When the models were applied on this set, calibration between the 6-month PFS model estimated versus observed 12-month OS was good (r = 0.89; Brier score, 0.008), though poor for the ORR model (r = 0.47; Brier score, 0.03). Notably, these findings were comparable across all of the studied subgroups.
“This study has several important implications. The ability to accurately estimate for OS from observed 6-month PFS using our model may allow smaller future ICI studies with shorter follow-up and earlier results saving resources,” the authors explained. “It may help better select and prioritize ICI agents, either as monotherapy or in combination with other treatments, for testing in phase 3 [randomized clinical trials] and reduce failure rates.”
“Where phase 3 [randomized clinical trials] are not feasible owing to limitations, such as small sample size in rare cancers, 6-month PFS results that estimate for promising 12-month OS outcomes may assist regulators, policy makers, and funding bodies to better assess treatment efficacy even if evidence is limited to smaller, non-randomized trials,” the authors added.
Importantly though, the researchers were unable to account for differences in follow-up time, which ranged from 4 to 48 months in the included studies. Therefore, the conclusions drawn from this study are only relevant to the particular landmark times (ie, 6 months and 12 months).
Kok P, Cho D, Yoon W, et al. Validation of Progression-Free Survival Rate at 6 Months and Objective Response for Estimating Overall Survival in Immune Checkpoint Inhibitor Trials. JAMA Network Open. doi: 10.1001/jamanetworkopen.2020.11809.