PD-L1 subpopulations of metastatic urothelial carcinoma demonstrate heterogeneity to chemotherapy: an integrated analysis of digitized trial results.

Efforts to translate advances in immunology into anti-cancer immunotherapies have progressed rapidly in recent years. Six antibodies acting on programmed death ligand 1 or programmed death 1 pathways were approved in 75 cancer indications between 2015 and 2021. Several of these therapies were granted accelerated approval for specific cancer indications based on evidence from single-arm phase II clinical trials. In the absence of randomization, however, patient prognosis for progression-free and overall survival may not have been studied under standard chemotherapies for PD-1 and PD-L1 biomarker subpopulations. In 2021, two immunotherapies were withdrawn from accelerated approval applications for treatment of metastatic urothelial carcinoma after randomized phase III trials failed to demonstrate evidence for survival advantage over standard of care. This re-analysis uses digitized data to quantify PD-L1 heterogeneity in chemotherapy response, extending prior meta-analyses by incorporating digitized data and design simulation. The findings of the IMvigor210 (NCT02108652) and IMvigor211 (NCT02302807) trials of atezolizumab are reviewed to elucidate the statistical implications of PD-L1 subpopulation heterogeneity. To place the findings into the context of external evidence, digitization software is used to combine results from journal articles of eleven trials that assigned metastatic urothelial carcinoma patients to the same chemotherapy agents administered in the IMvigor211 control arm. This article defines the extent to which PD-L1 IC2/3 subpopulations appeared to outperform historical expectations in the IMvigor211 study based on external evidence from digitized data. Given the extent of PD-L1 heterogeneity suggested by this analysis, trial simulation is applied to define the probability that IMvigor211 would have resulted in a positive trial based on its actual design and alternative designs that enrolled more IC2/3 patients or had longer durations.