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
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/6/e006920.full |
| _version_ | 1827207907485155328 |
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| author | Kohei Shitara Kei Muro Razvan Cristescu Michael Nebozhyn Andrey Loboda Hyun Cheol Chung Wasat Mansoor Mustafa Ozguroglu Mario Mandala Maria Di Bartolomeo Christian Caglevic Julie Kobie Min-Hee Ryu Z Alexander Cao Tomasz Olesinski Eray Goekkurt Raymond S McDermott Zev A Wainberg Chie-Schin Shih |
| author_facet | Kohei Shitara Kei Muro Razvan Cristescu Michael Nebozhyn Andrey Loboda Hyun Cheol Chung Wasat Mansoor Mustafa Ozguroglu Mario Mandala Maria Di Bartolomeo Christian Caglevic Julie Kobie Min-Hee Ryu Z Alexander Cao Tomasz Olesinski Eray Goekkurt Raymond S McDermott Zev A Wainberg Chie-Schin Shih |
| author_sort | Kohei Shitara |
| collection | DOAJ |
| description | 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 (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).Results RNA 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.Conclusions This 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. |
| first_indexed | 2024-03-12T14:24:12Z |
| format | Article |
| id | doaj.art-47cdd46fe09d4f619548677a08c6eb63 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2025-03-21T12:47:31Z |
| publishDate | 2023-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-47cdd46fe09d4f619548677a08c6eb632024-06-27T04:35:13ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-06-0111610.1136/jitc-2023-006920Association 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 trialKohei Shitara0Kei Muro1Razvan Cristescu2Michael Nebozhyn3Andrey Loboda4Hyun Cheol Chung5Wasat Mansoor6Mustafa Ozguroglu7Mario Mandala8Maria Di Bartolomeo9Christian Caglevic10Julie Kobie11Min-Hee Ryu12Z Alexander Cao13Tomasz Olesinski14Eray Goekkurt15Raymond S McDermott16Zev A Wainberg17Chie-Schin Shih18Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan9 Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, JapanMerck & Co., Inc, Rahway, New Jersey, USA14 Merck & Co Inc, Rahway, New Jersey, USAMerck & Co., Inc, Rahway, New Jersey, USA8 Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)12 Christie Hospital NHS Foundation Trust, University of Manchester, Manchester, UK15 Division of Medical Oncology, Clinical Trial Unit, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Istanbul, Turkey1 Unit of Medical Oncology, University of Perugia, Perugia, ItalyDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy6 Cancer Research Department, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago, Chile14 Merck & Co Inc, Rahway, New Jersey, USA5 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (the Republic of)3 Merck, Kenilworth, New Jersey, USA7 Department of Gastrointestinal Cancers and Neuroendocrine Tumors Surgery, Maria Sklodowska–Curie National Research Institute of Oncology, Warsaw, Poland10 Hematology-Oncology Practice Eppendorf (HOPE) and University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany11 St Vincent’s University Hospital & Cancer Trials, Dublin, Ireland1University of California, Los Angeles, CA, USA14 Merck & Co Inc, Rahway, New Jersey, USABackground 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 (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).Results RNA 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.Conclusions This 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.https://jitc.bmj.com/content/11/6/e006920.full |
| spellingShingle | Kohei Shitara Kei Muro Razvan Cristescu Michael Nebozhyn Andrey Loboda Hyun Cheol Chung Wasat Mansoor Mustafa Ozguroglu Mario Mandala Maria Di Bartolomeo Christian Caglevic Julie Kobie Min-Hee Ryu Z Alexander Cao Tomasz Olesinski Eray Goekkurt Raymond S McDermott Zev A Wainberg Chie-Schin Shih 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 Journal for ImmunoTherapy of Cancer |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/11/6/e006920.full |
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