796P - Association between biomarkers and clinical outcomes of lenvatinib (L) + pembrolizumab (P) in advanced endometrial cancer (EC): Results from KEYNOTE-146/study 111

Background

L + P had antitumor activity and a manageable safety profile in previously treated advanced EC in KEYNOTE-146/study 111 (NCT02501096). In this exploratory analysis, we evaluated the association between gene expression signatures and tumor mutational burden (TMB) and clinical outcomes.

Methods

Pts with advanced EC treated with L 20 mg PO QD + P 200 mg IV Q3W with evaluable RNA-sequencing data for the 18-gene T-cell–inflamed gene expression profile (Tcell_infGEP) and 11 other signatures (angiogenesis; glycolysis; gMDSC; hypoxia; mMDSC; MVD; MYC; proliferation; RAS; stroma/EMT/TGFβ; WNT) and whole exome sequencing (WES) data for TMB were analyzed. Association between each signature score and ORR and PFS per immune-related RECIST was evaluated using logistic regression and Cox proportional hazards. P values were adjusted for multiplicity using the Hochberg step-up procedure; significance was prespecified at α = 0.05. Spearman’s ρ was used to correlate Tcell_infGEP and TMB. Microsatellite stable (MSS) status was determined by MSI Analysis System. Clinical data cutoff was Aug 18, 2020.

Results

RNA sequencing and WES data were available for 93 (75%) and 79 (64%) pts, respectively, of 124. Of 93 pts with RNA sequencing data, 83 (89%) had MSS disease; 10 (11%) were MSI-H. The prevalence of TMB ≥175 mut/exome was 16% in all pts and 6% in pts with MSS. In all pts, Tcell_infGEP was not associated with ORR (P=0.749) or PFS (P=0.934), nor were the other 11 signatures before or after adjustment for Tcell_infGEP. Response (ORR) was achieved regardless of TMB status (TMB ≥175 vs TMB <175 mut/exome): 77% (10/13) vs 33% (22/66) in all pts and 100% (4/4) vs 34% (22/64) in pts with MSS; TMB trended higher in responders vs nonresponders. Tcell_infGEP and TMB were uncorrelated in all pts and in pts with MSS (Spearman’s ρ, −0.01 and −0.03, respectively).

Conclusions

In this exploratory analysis of pts with advanced EC enrolled in KEYNOTE-146/study 111 treated with L + P, clinically meaningful responses were achieved regardless of biomarker status, including TMB status, and no gene expression signatures were associated with clinical outcomes.

Clinical trial identification

NCT02501096; EudraCT 2017-000300-26.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Dominic Singson, MD, and Holly C. Cappelli, PhD, CMPP, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA.

Disclosure

V. Makker: Financial Interests, Personal, Other, Honoraria: Merck, MSD, Eisai, Karyopharm, IBM Watson ; Financial Interests, Personal, Advisory Role: Merck, MSD, Eisai, Karyopharm, IBM Watson ; Financial Interests, Personal, Speaker’s Bureau: Onc Live, ASCO Post; Financial Interests, Personal, Other, Travel Expenses: Eisai, Merck, Karyopharm; Financial Interests, Institutional, Research Grant: Eisai, Merck, MSD, GSK, AstraZeneca, Karyopharm, Lilly, Moreo, Faeth, Dicephra, Clovis, Takeda, Zymeworks, Genentech. M.H. Taylor: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Eisai Inc, Novartis, Merck, Pfizer, Bayer, Sanofi/Genzyme, Regeneron, Bayer, Array Biopharma, Loxo Oncology, Blueprint Medicines, Arqule; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Eisai Inc, Novartis, Merck, Pfizer, Bayer, Sanofi/Genzyme, Regeneron, Bayer, Array Biopharma, Loxo Oncology, Blueprint Medicines, Arqule; Financial Interests, Personal, Speaker’s Bureau, Expert Testimony: BMS, Merck, Eisai Inc, Bayer, Blueprint Medicines; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb, Merck Sharp & Dohme Corp., Pharmacyclics, AstraZeneca, Eisai, Incyte, EMD Serono, Novartis, Seattle Genetics, AbbVie, Genentech, Eli Lilly, Roche, Acerta Pharma, Genzyme Corporation, Pfizer. C. Aghajanian: Financial Interests, Personal, Advisory Role: Tesaro, Eisai/Merck, Mersana Therapeutics, Roche/Genetech, Abbvie, AstraZeneca/Merck, Repare; Financial Interests, Institutional, Funding: Clovis, Genentech, Abbvie, AstraZeneca. M.S. Brose: Financial Interests, Personal, Other, Honoraria: Easai; Financial Interests, Personal, Advisory Role: Easai; Financial Interests, Personal, Research Grant: Easai. A. Cao: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Institutional, Stocks/Shares: Merck; Financial Interests, Personal, Stocks/Shares: BMS. L. Suttner: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck. A. Loboda: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal and Institutional, Stocks/Shares: Merck, BMS. R. Cristescu: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal, Stocks/Shares: Merck. P. Jelinic: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal and Institutional, Stocks/Shares: Merck. A. Snyder: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal and Institutional, Stocks/Shares: Merck. M. Nebozhyn: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal and Institutional, Stocks/Shares: Merck. J. Lunceford: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal and Institutional, Stocks/Shares: Merck; Financial Interests, Personal, Other, Patent: Self. R. Orlowski: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal and Institutional, Stocks/Shares: Merck. L. Dutta: Financial Interests, Personal and Institutional, Full or part-time Employment: Eisai. J. Matsui: Financial Interests, Personal and Institutional, Full or part-time Employment: Eisai. C. Dutcus: Financial Interests, Personal and Institutional, Full or part-time Employment: Eisai. Y. Minoshima: Financial Interests, Personal and Institutional, Full or part-time Employment: Eisai; Financial Interests, Personal and Institutional, Stocks/Shares: Eisai. All other authors have declared no conflicts of interest.