Status:
Completed
Clinicaltrials.gov identifier:
Sponsor:
N/A (Merck sponsored KEYNOTE studies but not this current analysis of biomarkers)
Study Design:
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.
Rationale:
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.
Endpoints:
The primary endpoint was to test if the biomarkers (tested as continuous variables) were associated with clinical outcomes (OS, ORR, progression-free survival (PFS)).
Comments:
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.
Results:
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.
