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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 elici...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314681/
https://www.ncbi.nlm.nih.gov/pubmed/37399357
http://dx.doi.org/10.1136/jitc-2023-006920
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author 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
author_facet 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
author_sort Shitara, Kohei
collection PubMed
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 (Tcell(inf)GEP) and 10 non-Tcell(inf)GEP 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 Tcell(inf)GEP (prespecified α=0.05) and the 10 non-Tcell(inf)GEP signatures (multiplicity-adjusted; prespecified α=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. TRIAL REGISTRATION NUMBER: NCT02370498.
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spelling pubmed-103146812023-07-02 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 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 J Immunother Cancer Clinical/Translational Cancer Immunotherapy 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(inf)GEP 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 Tcell(inf)GEP (prespecified α=0.05) and the 10 non-Tcell(inf)GEP signatures (multiplicity-adjusted; prespecified α=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. TRIAL REGISTRATION NUMBER: NCT02370498. BMJ Publishing Group 2023-06-30 /pmc/articles/PMC10314681/ /pubmed/37399357 http://dx.doi.org/10.1136/jitc-2023-006920 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Clinical/Translational Cancer Immunotherapy
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
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 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
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10314681/
https://www.ncbi.nlm.nih.gov/pubmed/37399357
http://dx.doi.org/10.1136/jitc-2023-006920
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