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

BackgroundIn 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...

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Published in:Journal for ImmunoTherapy of Cancer Vol. 11; no. 6; p. e006920
Main Authors: Shitara, Kohei, Di Bartolomeo, Maria, Mandala, Mario, Ryu, Min-Hee, Caglevic, Christian, Olesinski, Tomasz, Chung, Hyun Cheol, 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
Format: Journal Article
Language:English
Published: England BMJ Publishing Group Ltd 01.06.2023
BMJ
BMJ Publishing Group LTD
BMJ Publishing Group
Series:Original research
Subjects:
Angiogenesis
Antibodies
Antibodies, Monoclonal, Humanized
Antibodies, Monoclonal, Humanized - therapeutic use
Cancer
Cancer therapies
Cell death
Clinical outcomes
Clinical/Translational Cancer Immunotherapy
Gastric cancer
Gastrointestinal Neoplasms
Gene expression
Gene Expression Profiling
Genetic Markers
Growth factors
Humanized
Humans
Hypoxia
Immunotherapy
Medical prognosis
Metastasis
Monoclonal
Monoclonal antibodies
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Paclitaxel
Paclitaxel - pharmacology
Paclitaxel - therapeutic use
Patients
Programmed Cell Death 1 Receptor
RC254-282
Response rates
Review boards
Stomach Neoplasms
Stomach Neoplasms - drug therapy
Stomach Neoplasms - genetics
Stomach Neoplasms - pathology
Targeted cancer therapy
Transcriptome
Tumors
United States > US
Programmed Cell Death 1 Receptor
Gene Expression Profiling
Gastrointestinal Neoplasms
Genetic Markers
Immunotherapy
ISSN:2051-1426, 2051-1426
Online Access:Get full text
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Summary:BackgroundIn 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.MethodsUsing RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 non-TcellinfGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, 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 TcellinfGEP (prespecified α=0.05) and the 10 non-TcellinfGEP signatures (multiplicity-adjusted; prespecified α=0.10).ResultsRNA sequencing data were available for 137 patients in each treatment group. TcellinfGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the TcellinfGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel.ConclusionsThis exploratory analysis of tumor TcellinfGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. TcellinfGEP-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.Trial registration number NCT02370498.
Bibliography:Original research
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ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2023-006920