N/A (Merck sponsored KEYNOTE studies but not this current analysis of biomarkers)
Patients with biomarker data were identified from each trial and the majority of patients had PD-L1 data but only 50-55% of patients had stromal signature data. The association of these biomarkers with clinical outcomes such as overall survival (OS) and overall response rate (ORR) was analyzed. Of note, KEYNOTE-045 included patients with urothelial cancer and progressive disease after platinum-based chemotherapy while KEYNOTE-052 included patients with unresectable or metastatic urothelial cancer who were ineligible for systemic chemotherapy. The KEYNOTE-045 patients received pembrolizumab salvage thearpy while KEYNOTE-052 patients received first-line pembrolizumab therapy.
This publication is an exploratory analysis performed retrospectively on the cohorts for both of these clinical trials to determine any association of putative biomarkers (PD-L1, tumor mutational burden (TMB), T-cell inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of patients treated with pembrolizumab monotherapy in locally advanced or metastatic urothelial cancer.
The primary endpoint was to test if the biomarkers (tested as continuous variables) were associated with clinical outcomes (OS, ORR, progression-free survival (PFS)).
It appears increasingly evident that biomarkers other than PD-L1 may be important to understanding potential outcomes with immunotherapy. PDL-1 was not important in the second line setting in the randomized KEYNOTE-045 trial, but maintained importance in untreated patients in KEYNOTE-052 and possibly also in other larger randomized trials, where the FDA and EMA stopped accrual in first line setting of patients who were PDL-1 negative. There is clearly much more to learn from evaluating these and other biomarkers.
In KEYNOTE-052, PD-L1, TMB, TcellinfGEP were associated with improved clinical outcomes while higher stromal signature was associated with worse outcomes. In KEYNOTE-045, TMB and TcellinfGEP were significantly associated with improved clinical outcomes. Of note, PD-L1 was not significantly associated with improved outcomes. Furthermore, stromal signature was not associated with worse outcomes.