Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials
| العنوان: | Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials |
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| المؤلفون: | 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 |
| المساهمون: | Medical Oncology |
| المصدر: | 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 |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1078-0432 2050-2060 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f9a033eea1a8dbe8ea54e8402e4eed44 https://repository.ubn.ru.nl/handle/2066/250670 |
| Rights: | RESTRICTED |
| رقم الانضمام: | edsair.doi.dedup.....f9a033eea1a8dbe8ea54e8402e4eed44 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10780432 20502060 |
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