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  • / Association of TMB and PD-L1 with efficacy of first-line pembrolizumab (pembro) or pembro + chemotherapy (chemo) versus chemo in patients (pts) with advanced urothelial carcinoma (UC) from KEYNOTE-361.

Association of TMB and PD-L1 with efficacy of first-line pembrolizumab (pembro) or pembro + chemotherapy (chemo) versus chemo in patients (pts) with advanced urothelial carcinoma (UC) from KEYNOTE-361.

Abstract Video & Slides Poster

Authors

Rafael Morales-Barrera, Sr

Rafael Morales-Barrera

Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

Rafael Morales-Barrera , Thomas Powles , Mustafa Ozguroglu , Tibor Csoszi , Yohann Loriot , Aude Flechon , Nobuaki Matsubara , Alejo Rodriguez-Vida , Lajos Geczi , Susanna Y. Cheng , Yves Fradet , Stephane Oudard , Seyda Gunduz , Junshui Ma , Mohini Rajasagi , Amir Vajdi , Razvan Cristescu , Kentaro Imai , Blanca Homet Moreno , Ajjai Shivaram Alva

Organizations

Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, Barts Cancer Centre, St Bartholomew’s Hospital, Barts Cancer Institute, Barts Health NHS Trust, Queen Mary University of London, London, United Kingdom, Cerrahpaşa School of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey, County Oncology Centre, Hetényi Géza Hospital, Szolnok, Hungary, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France, Centre Léon Bérard, Lyon, France, National Cancer Center Hospital East, Chiba, Japan, Hospital del Mar, Barcelona, Spain, National Institute of Oncology, Budapest, Hungary, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada, CHU de Québec - Université Laval, Québec City, QC, Canada, Georges Pompidou European Hospital, University of Paris, Paris, France, Memorial Antalya Hospital and Minimally Invasive Therapeutics Laboratory, Mayo Clinic, Antalya, Turkey, Merck & Co., Inc., Kenilworth, NJ, University of Michigan Health System, Ann Arbor, MI

Research Funding

Pharmaceutical/Biotech Company

Background: The 3-arm, open-label, phase 3 KEYNOTE-361 study (NCT02853305) evaluated first-line pembro ± chemo vs chemo in advanced UC regardless of PD-L1 status. The trial did not meet its primary end points of superior PFS and OS with pembro + chemo vs chemo and thus analysis of pembro monotherapy (mono) vs chemo was exploratory. We explored the association of TMB status and PD-L1 combined positive score (CPS) with clinical outcomes in KEYNOTE-361. Methods: In pts with TMB and/or PD-L1 data, the association between TMB (via whole exome sequencing) and PD-L1 (via PD-L1 IHC 22C3 pharmDx) and clinical outcomes (ORR, PFS, and OS) was evaluated. In each treatment arm, the hypotheses regarding the associations were evaluated using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS), and 1-sided (pembro; pembro + chemo) and 2-sided (chemo) P values were calculated; significance was prespecified at α = 0.05 without multiplicity adjustment. Clinical utility was assessed using prespecified cutoffs of 175 mut/exome (TMB) and CPS 10 (PD-L1). Clinical data cutoff was April 29, 2020. Results: 820/993 pts (82.6%) had evaluable TMB data (pembro, 252; pembro + chemo, 282; chemo, 286). TMB (log10) was significantly positively associated with ORR, PFS, and OS for pembro (P < 0.001, < 0.001, and 0.007, respectively) and PFS and OS for pembro + chemo (P= 0.007 and 0.010, respectively). The area under the receiver operating characteristics (AUROC) curve (95% CI) for discriminating response was 0.64 (0.56-0.71) for pembro, 0.53 (0.46-0.60) for pembro + chemo, and 0.52 (0.45-0.59) for chemo. Efficacy by TMB cutoff is reported in the Table. All 993 pts had PD-L1 data (pembro, 302; pembro + chemo, 349; chemo, 342). PD-L1 was significantly positively associated with PFS for pembro (P= 0.006) and ORR for pembro + chemo (P= 0.042) but not chemo. Efficacy by PD-L1 CPS is reported in the Table. Conclusions: Strong associations were observed between TMB and all 3 clinical outcomes (ORR, PFS, and OS) with pembro mono in the first-line setting and a reduced association was observed between TMB and clinical outcomes with pembro + chemo. No consistent associations were observed between PD-L1 and clinical outcomes with pembro mono or pembro + chemo. Clinical trial information: NCT02853305.

TMB ≥175TMB ≥175TMB < 175TMB < 175
P (n = 78) vs
C (n = 85)		P+C (n = 86) vs
C (n = 85)		P (n = 74)
vs
C (n = 201)
P+C (n = 196) vs
C (n = 201)
PFS, HR (95% CI)0.81 (0.54-1.21)0.70
(0.48-1.02)
1.37 (1.09-1.74)0.80
(0.63-1.00)
OS, HR (95% CI)0.69 (0.45-1.04)0.77
(0.53-1.14)
0.92
(0.73-1.16)
0.79
(0.63-0.99)
CPS ≥10CPS ≥10CPS < 10CPS < 10
P (n = 156)
vs
C (n = 153)
P+C (n = 158) vs
C (n = 153)		P (n = 146)
vs
C (n = 189)
P+C (n = 191) vs
C (n = 189)
PFS, HR (95% CI)1.32 (1.01-1.74)0.76
(0.58-1.01)
1.28 (1.00-1.65)0.76
(0.60-0.97)
OS, HR (95% CI)1.03 (0.78-1.35)0.83
(0.62-1.09)
0.83
(0.64-1.07)
0.82
(0.65-1.03)

HRs adjusted for ECOG PS.

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Abstract Details

Meeting

2022 ASCO Genitourinary Cancers Symposium

Session Type

Poster Session

Session Title

Poster Session B: Urothelial Carcinoma

Track

Urothelial Carcinoma

Sub Track

Translational Research, Tumor Biology, Biomarkers, and Pathology

Clinical Trial Registration Number

NCT02853305

Citation

J Clin Oncol 40, 2022 (suppl 6; abstr 540)

DOI

10.1200/JCO.2022.40.6_suppl.540

Abstract #

540

Poster Bd #

Online Only

Abstract Disclosures

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