1737MO - Tumor and immune features associated with disease-free survival with adjuvant nivolumab in the phase III CheckMate 274 trial

Background

CheckMate 274 (NCT02632409), a phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection, demonstrated improved disease-free survival (DFS) with adjuvant NIVO vs PBO in the intent-to-treat (ITT) and tumor PD-L1 expression ≥ 1% populations. We report exploratory analyses (minimum follow-up, 11.0 months) of associations between pre-treatment tumor and immune features and DFS to identify patients (pts) who may potentially benefit most from adjuvant NIVO.

Methods

Pts were randomized 1:1 to NIVO 240 mg IV every 2 weeks or PBO for ≤ 1 year of adjuvant treatment. Pre-treatment tumor tissue from the most recently resected site or the transurethral resection yielding MIUC diagnosis was provided for biomarker analyses. Tumor mutation burden (TMB; mutations/MB) was measured by whole exome sequencing. CD8+ immune cell infiltration was measured with digital immunohistochemistry (IHC). Gene signature scores were computed from RNA-seq data. Cox proportional hazards models were used to assess association between DFS and biomarkers (continuous scale) and estimate treatment-effect hazard ratios (HRs; NIVO vs PBO) for biomarker tertile subgroups.

Results

Of 709 randomized pts, 458, 445, and 323 were evaluable for TMB, CD8 IHC, and RNA-seq. TMB, and CD8 T cell infiltration and IFN-γ signature scores (Table) were positively associated with DFS in the NIVO arm. The associations appeared more pronounced in pts with PD-L1 ≥ 1%. Of these 3 biomarkers, evidence that association with DFS differed between arms was strongest for the IFN-γ signature.

Conclusions

Biomarkers associated with preexisting antitumor immunity were associated with improved DFS with NIVO vs PBO, reinforcing the mechanism for benefit with immunotherapy and extending prior findings in metastatic UC to the adjuvant setting. Multivariable modeling is ongoing. Further validation of these exploratory analyses is warranted. Table: 1737MO

^aTwo patients were not evaluable for PD-L1.CI, confidence interval; IFN-γ, interferon gamma.

Clinical trial identification

NCT02632409.

Editorial acknowledgement

Professional medical writing assistance was provided by Nicolette Belletier, PhD, of Parexel, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

A. Necchi: Financial Interests, Personal, Other, Steering Committee Member: Astellas, AstraZeneca, Bayer, Janssen, Merck, Roche; Non-Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Gilead, Merck, Ipsen; Financial Interests, Personal, Invited Speaker, Steering Committee Member: Clovis Oncology; Non-Financial Interests, Personal, Other, Coordinating PI: Incyte; Non-Financial Interests, Personal, Other, Local PI: Pfizer; Non-Financial Interests, Personal, Leadership Role: Global society of Rare Genitourinary Tumors (GSRGT). D.F. Bajorin: Financial Interests, Personal, Advisory Board, Advisory board member: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, DSMC member: Merck; Non-Financial Interests, Institutional, Other, Local PI: AstraZeneca, Merck, Inc.; Non-Financial Interests, Institutional, Other, Trial Chair: Bristol Myers Squibb. Y. Tomita: Financial Interests, Personal, Invited Speaker: Astellas, Bristol Myers Squibb, Merck, Ono; Financial Interests, Institutional, Research Grant: Chugai, Ono; Non-Financial Interests, Personal, Other, Advisory Role: Eisai, Ono. D. Enting: Financial Interests, Institutional, Other, Bladder Cancer Preceptorship: Astellas; Financial Interests, Institutional, Advisory Board, Ra223 adboard: Bayer; Financial Interests, Institutional, Invited Speaker, Janssen Prostate Cancer UK Summit: Janssen. A. Peer: Financial Interests, Personal, Advisory Board: Astellas, Bristol Myers Squibb, Bayer, Janssen, Medison pharma, MSD, Takeda, Teva; Financial Interests, Personal, Invited Speaker: Astellas, Bristol Myers Squibb, Exelixis, MSD; Financial Interests, Personal, Expert Testimony, and invited speaker: Roche; Non-Financial Interests, Institutional, Research Grant: Sanofi aventis. M. Milowsky: Financial Interests, Personal, Other, Co-Editori-in-Cheif, Clinical Genitourinary Cancer: Elsevier; Financial Interests, Personal, Advisory Board: Loxo/Lilly; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Merck, Pfizer; Financial Interests, Institutional, Other, local PI: Alliance for Clinical Trials in Oncology, Alliance Foundation Trials, Arvinas, Bristol Myers Squibb, Clovis Oncology, G1 Therapeutics, Incyte, Merck, Mirati Therapeutics, Regeneron, Roche/Genentech, Seagen. M. Grimm: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen Pharma, Merck Serono, MSD, Pfizer, Roche, Takeda; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Bristol Myers Squibb, Ipsen Pharma, Merck Serono, MSD, Pfizer; Financial Interests, Personal, Member of the Board of Directors: Deutsche Gesellschaft fur Urologie; Financial Interests, Personal and Institutional, Other, Coordinating PI: Bristol Myers Squibb; Financial Interests, Institutional, Other, Local PI: Intuitive Surgical, Novartis. F. Stenner-Liewen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Ipsen, MSD, Pfizer, Roche; Non-Financial Interests, Institutional, Other, Coordinating PI, translational research support within a study: Bristol Myers Squibb; Non-Financial Interests, Personal, Principal Investigator: Bristol Myers Squibb. J.M. David: Financial Interests, Personal and Institutional, Full or part-time Employment, Employee of BMS: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Ownership Interest, I own shares of the BMS company: Bristol Myers Squibb; Non-Financial Interests, Institutional, Proprietary Information, I am an employee of BMS company: Bristol Myers Squibb. J. Li: Financial Interests, Personal, Full or part-time Employment, full time employee of BMS: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, Own BMS stocks: Bristol Myers Squibb. S.D. Chasalow: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. F. Nasroulah: Financial Interests, Personal, Full or part-time Employment, I am a full time employee of BMS: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, I own stock of BMS: Bristol Myers Squibb. A. Apfel: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, own stock in BMS: Bristol Myers Squibb. K. Unsal-Kacmaz: Financial Interests, Institutional, Full or part-time Employment, Was an employee of BMS at the time of this study: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. M.D. Galsky: Financial Interests, Personal, Advisory Board: Alligator, Astellas, AstraZeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Incyte, Janssen, Merck, Pfize, Seagen; Other, Personal, Other, Consultant: Rappta Therapeutics; Financial Interests, Institutional, Other, Coordinating PI: AstraZeneca, Jazz; Financial Interests, Institutional, Other, Steering Committee Member: Bristol Myers Squibb, Genentech, Merck; Financial Interests, Institutional, Other, Local PI: Seagen. All other authors have declared no conflicts of interest.