Nivolumab, a programmed death (PD)-1 inhibitor, demonstrated efficacy in a single-arm phase II study in patients (pts) with metastatic or surgically unresectable urothelial carcinoma (UC) (CheckMate 275; Sharma et al. 2017). The current analysis explores the potential association between pretreatment tumor mutation burden (TMB) and response to nivolumab.
Tumor DNA from pretreatment archival tumor tissue and matched whole blood samples was profiled by whole exome sequencing. TMB was defined as the total number of missense somatic mutations per tumor, and was evaluated as a continuous variable and by tertiles (missense count: high ≥167, medium 85–166, low
139 (51%) of 270 pts had evaluable TMB. Baseline characteristics, ORR, PFS, and OS were similar between all treated pts and the TMB subgroup. ORR, PFS and OS in all pts and TMB/PD-L1 subgroups are shown in the Table. TMB showed a statistically significant positive association with ORR (P=0.002) and PFS (P=0.005), and a strong association with OS (P=0.067), even when adjusted for baseline tumor PD-L1 expression, liver metastasis status, and serum hemoglobin. High TMB had the greatest impact on survival in pts with
These exploratory findings suggest that TMB may enrich for response to nivolumab and may provide complementary prognostic/predictive information beyond PD-L1. Further analyses in randomized trials are warranted to define the prognostic/predictive value of TMB in the context of other biomarkers in UC pts treated with immunotherapy.
Clinical trial identification
Legal entity responsible for the study
M.D. Galsky: Received research funding from Bristol-Myers Squib, Novartis, and Merck and has served on advisory boards for Genentech, Merck, EMD-Serono, and AstraZeneca. A. Saci: Reports being an employee of Bristol-Myers Squibb during the conduct of the study. A. Azrilevich: Reports being an employee of the sponsor, Bristol-Myers Squibb. C. Horak: Reports being an employee and stockholder of Bristol-Myers Squibb A. Lambert: Reports employment and stock owner from Bristol-Myers Squibb, outside the submitted work. A. Siefker-Radtke: Reports being on the Scientific advisory board for AstraZeneca, Bristol-Myers Squibb, Eisai, EMD Serono, Genentech, Inovio, Janssen, and Merck, outside the submitted work. A. Necchi: Reports consulting or advisory role from AstraZeneca, Bayer, Roche, Merck & Co. Inc., and Pfizer; Reports research funding from Amgen, AstraZeneca, and Merck & Co. Inc., outside the submitted work. P. Sharma: Reports being a consultant for Bristol-Myers Squibb, Glaxo Smith Kline, AstraZeneca, Amgen, Constellation, Jounce, Kite Pharma, Neon, Evelo, EMD Sereno, Astellas; stock from Jounce, Kite Pharma, Evelo, Constellation, Neon, outside the submitted work. All other authors have declared no conflicts of interest.