Abstract 2140: Association between gene expression signatures and outcomes of pembrolizumab (pembro) and paclitaxel (pac) in advanced gastric cancer (GC): Exploratory analysis from KEYNOTE-061
Authors: Shitara Kohei , Bartolomeo Maria Di , Mandala Mario , Ryu Min-Hee , Caglevic Christian , Olesinski Tomasz , Chung Hyun C. , Muro Kei , Goekkurt Eray , McDermott Raymond S. , Mansoor Wasat , Wainberg Zev A. , Shih Chie-Schin , Kobie Julie , Nebozhyn Michael , Cristescu Razvan , Cao Z. Alexander , Loboda Andrey , Özgüroğlu Mustafa 
Published: June 2022

Abstract
Background: In the phase 3 KEYNOTE-061 study (NCT02370498), second-line pembro did not significantly prolong OS vs pac in patients with PD-L1-positive (CPS ≥1) GC (N = 395) but did elicit a longer DOR and offered a favorable safety profile. We explored the association between tumor gene expression signatures and clinical outcomes.
Methods: In patients with tumor RNA-sequencing data, we analyzed the association of the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 other signatures (angiogenesis, glycolysis, gMDSC, hypoxia, mMDSC, MYC, proliferation, RAS, stroma/EMT/TGFβ, WNT) on a continuous scale with outcomes using logistic (ORR) and Cox proportional hazards (PFS; OS) regression. For TcellinfGEP, 1-sided (pembro) and 2-sided (pac) P values were calculated (prespecified significance, α = 0.05). For the 10 non-TcellinfGEP signatures, 1-sided (pembro) and 2-sided (pac) multiplicity-adjusted P values were calculated (prespecified significance, α = 0.10). Clinical data cutoff was October 26, 2017.
Results: There were 274 patients with tumor RNA-sequencing data (n = 137 in each arm). Association with clinical outcomes for gene expression signatures are reported in the Table.
Conclusions: In this exploratory analysis of patients with previously treated GC from KEYNOTE-061, tumor TcellinfGEP showed some association with clinical outcomes for pembro (ORR and PFS) but not pac (ORR, PFS, and OS). The TcellinfGEP-adjusted mMDSC signature was negatively associated with clinical outcomes for pembro (ORR, PFS, and OS), while the TcellinfGEP-adjusted glycolysis, MYC, and proliferation signatures were negatively associated with OS for pac. This exploratory biomarker analysis suggests that myeloid-driven suppression may play a role in resistance to PD-1 inhibition and supports a strategy of considering immunotherapy combinations intended to target this myeloid axis.
Association between clinical outcomes and TcellinfGEP and non-TcellinfGEP signatures adjusted for TcellinfGEP Pembrolizumabn = 137 Paclitaxeln = 137 ORR PFS OS ORR PFS OS TcellinfGEPa 0.041 0.026 0.178 0.822 0.207 0.644 Angiogenesisb 0.077 0.298 0.623 0.220 0.462 0.263 Glycolysisb 0.934 0.861 0.956 0.223 0.097 0.018 gMDSCb 0.626 0.573 0.623 0.694 0.352 0.263 Hypoxiab 0.934 0.861 0.956 0.223 0.220 0.440 mMDSCb 0.077 0.057 0.033 0.694 0.932 0.263 MYCb 0.934 0.861 0.956 0.223 0.327 0.057 Proliferationb 0.934 0.861 0.956 0.223 0.071 0.002 RASb 0.934 0.861 0.956 0.223 0.327 0.440 Stroma/EMT/TGFβb 0.306 0.366 0.522 0.694 0.462 0.263 WNTb 0.934 0.861 0.956 0.097 0.327 0.440 aBolded P values (1-sided for pembrolizumab with hypothesized positive association and 2-sided for paclitaxel with no hypothesized association) indicate nominal statistical significance (α = 0.05); model includes additional covariates of ECOG PS. bBolded P values (1-sided for pembrolizumab with hypothesized negative association except for proliferation and 2-sided for paclitaxel with no hypothesized association) indicate multiplicity-adjusted statistical significance (α = 0.10); model includes additional covariates of ECOG PS and TcellinfGEP.
Citation Format: Kohei Shitara, Maria Di Bartolomeo, Mario Mandala, Min-Hee Ryu, Christian Caglevic, Tomasz Olesinski, Hyun C. Chung, Kei Muro, Eray Goekkurt, Raymond S. McDermott, Wasat Mansoor, Zev A. Wainberg, Chie-Schin Shih, Julie Kobie, Michael Nebozhyn, Razvan Cristescu, Z. Alexander Cao, Andrey Loboda, Mustafa Özgüroğlu. Association between gene expression signatures and outcomes of pembrolizumab (pembro) and paclitaxel (pac) in advanced gastric cancer (GC): Exploratory analysis from KEYNOTE-061 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2140.