TY - JOUR
T1 - Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer
T2 - Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials
AU - Bellmunt, Joaquim
AU - de Wit, Ronald
AU - Fradet, Yves
AU - Climent, Miguel A.
AU - Petrylak, Daniel P.
AU - Lee, Jae Lyun
AU - Fong, Lawrence
AU - Necchi, Andrea
AU - Sternberg, Cora N.
AU - O’Donnell, Peter H.
AU - Powles, Thomas
AU - Plimack, Elizabeth R.
AU - Bajorin, Dean F.
AU - Balar, Arjun V.
AU - Castellano, Daniel
AU - Choueiri, Toni K.
AU - Culine, Stephane
AU - Gerritsen, Winald
AU - Gurney, Howard
AU - Quinn, David I.
AU - Vuky, Jacqueline
AU - Vogelzang, Nicholas J.
AU - Cristescu, Razvan
AU - Lunceford, Jared
AU - Saadatpour, Assieh
AU - Loboda, Andrey
AU - Ma, Junshui
AU - Rajasagi, Mohini
AU - Godwin, James Luke
AU - Moreno, Blanca Homet
AU - Grivas, Petros
N1 - Publisher Copyright:
©2022 American Association for Cancer Research
PY - 2022/5/15
Y1 - 2022/5/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-3089
DO - 10.1158/1078-0432.CCR-21-3089
M3 - Article
C2 - 35247908
AN - SCOPUS:85130381507
SN - 1078-0432
VL - 28
SP - 2050
EP - 2060
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -