Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials

Joaquim Bellmunt, Ronald de Wit, Yves Fradet, Miguel A. Climent, Daniel P. Petrylak, Jae Lyun Lee, Lawrence Fong, Andrea Necchi, Cora N. Sternberg, Peter H. O’Donnell, Thomas Powles, Elizabeth R. Plimack, Dean F. Bajorin, Arjun V. Balar, Daniel Castellano, Toni K. Choueiri, Stephane Culine, Winald Gerritsen, Howard Gurney, David I. QuinnJacqueline Vuky, Nicholas J. Vogelzang, Razvan Cristescu, Jared Lunceford, Assieh Saadatpour, Andrey Loboda, Junshui Ma, Mohini Rajasagi, James Luke Godwin, Blanca Homet Moreno, Petros Grivas

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Purpose: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell–inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC). Patients and Methods: Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at a ¼ 0.05. Results: In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment. Conclusions: Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.

Original languageEnglish (US)
Pages (from-to)2050-2060
Number of pages11
JournalClinical Cancer Research
Issue number10
StatePublished - May 15 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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