Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial


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Shitara K., Di Bartolomeo M., Mandala M., Ryu M., Caglevic C., Olesinski T., ...More

JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol.11, no.6, 2023 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 11 Issue: 6
  • Publication Date: 2023
  • Doi Number: 10.1136/jitc-2023-006920
  • Journal Name: JOURNAL FOR IMMUNOTHERAPY OF CANCER
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, MEDLINE, Directory of Open Access Journals
  • Istanbul University Affiliated: No

Abstract

Background In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1- positive (combined positive score >= 1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial. Methods Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (Tcell(inf)GEP) and 10 non-Tcell infGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/ transforming growth factor-ss, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for Tcell(inf)GEP (prespecified alpha=0.05) and the 10 non-Tcell(inf)GEP signatures (multiplicity-adjusted; prespecified alpha=0.10). Results RNA sequencing data were available for 137 patients in each treatment group. Tcell(inf)GEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The Tcell(inf)GEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the Tcell(inf)GEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel. Conclusions This exploratory analysis of tumor Tcell(inf)GEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. Tcell(inf)GEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis.