Association Between Biomarkers And Clinical Outcomes Of Lenvatinib (L) Plus Pembrolizumab (P) In Advanced Endometrial Cancer (Ec): Results From Keynote-146/Study 111

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. 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 (TcellinfGEP) 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 TcellinfGEP and TMB. Microsatellite stable (MSS) status was determined by MSI Analysis System. Clinical data cutoff was Aug 18, 2020. 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, TcellinfGEP was not associated with ORR (P=0.749) or PFS (P=0.934), nor were the other 11 signatures before or after adjustment for TcellinfGEP. 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. TcellinfGEP and TMB were uncorrelated in all pts and in pts with MSS (Spearman’s ρ, −0.01 and −0.03, respectively). 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.