Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials
| Autor: | 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. Quinn, Jacqueline Vuky, Nicholas J. Vogelzang, Razvan Cristescu, Jared Lunceford, Assieh Saadatpour, Andrey Loboda, Junshui Ma, Mohini Rajasagi, James Luke Godwin, Blanca Homet Moreno, Petros Grivas |
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| Přispěvatelé: | Medical Oncology |
| Rok vydání: | 2022 |
| Předmět: |
Male
Carcinoma Transitional Cell Cancer Research Antibodies Monoclonal Humanized B7-H1 Antigen All institutes and research themes of the Radboud University Medical Center Urinary Bladder Neoplasms SDG 3 - Good Health and Well-being Oncology Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] Antineoplastic Combined Chemotherapy Protocols Biomarkers Tumor Tumor Microenvironment Humans Female |
| Zdroj: | Clinical Cancer Research, 28, 10, pp. 2050-2060 Clinical Cancer Research, 28(10), 2050-2060. American Association for Cancer Research Inc. Clinical Cancer Research, 28, 2050-2060 |
| ISSN: | 1078-0432 2050-2060 |
| Popis: | 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 α = 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. |
| Databáze: | OpenAIRE |
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