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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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.

in: J IMMUNOTHER CANCER, Jahrgang 11, Nr. 6, e006920, 06.2023.

Publikationen: SCORING: Beitrag in Fachzeitschrift/ZeitungSCORING: ZeitschriftenaufsatzForschungBegutachtung

Harvard

Shitara, K, Di Bartolomeo, M, Mandala, M, Ryu, M-H, Caglevic, C, Olesinski, T, Chung, HC, Muro, K, Goekkurt, E, McDermott, RS, Mansoor, W, Wainberg, ZA, Shih, C-S, Kobie, J, Nebozhyn, M, Cristescu, R, Cao, ZA, Loboda, A & Özgüroğlu, M 2023, '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', J IMMUNOTHER CANCER, Jg. 11, Nr. 6, e006920. https://doi.org/10.1136/jitc-2023-006920

APA

Shitara, K., Di Bartolomeo, M., Mandala, M., Ryu, M-H., Caglevic, C., Olesinski, T., Chung, H. C., Muro, K., Goekkurt, E., McDermott, R. S., Mansoor, W., Wainberg, Z. A., Shih, C-S., Kobie, J., Nebozhyn, M., Cristescu, R., Cao, Z. A., Loboda, A., & Özgüroğlu, M. (2023). 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. J IMMUNOTHER CANCER, 11(6), [e006920]. https://doi.org/10.1136/jitc-2023-006920

Vancouver

Bibtex

@article{9554fe252d4c4190b69ef8a845f52e7b,
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",
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 (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.",
keywords = "Humans, Paclitaxel/pharmacology, Stomach Neoplasms/drug therapy, Transcriptome, Antibodies, Monoclonal, Humanized/therapeutic use",
author = "Kohei Shitara and {Di Bartolomeo}, Maria and Mario Mandala and Min-Hee Ryu and Christian Caglevic and Tomasz Olesinski and Chung, {Hyun Cheol} and Kei Muro and Eray Goekkurt and McDermott, {Raymond S} and Wasat Mansoor and Wainberg, {Zev A} and Chie-Schin Shih and Julie Kobie and Michael Nebozhyn and Razvan Cristescu and Cao, {Z Alexander} and Andrey Loboda and Mustafa {\"O}zg{\"u}roğlu",
note = "{\textcopyright} 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.",
year = "2023",
month = jun,
doi = "10.1136/jitc-2023-006920",
language = "English",
volume = "11",
journal = "J IMMUNOTHER CANCER",
issn = "2051-1426",
publisher = "BioMed Central Ltd.",
number = "6",

}

RIS

TY - JOUR

T1 - 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

AU - Shitara, Kohei

AU - Di Bartolomeo, Maria

AU - Mandala, Mario

AU - Ryu, Min-Hee

AU - Caglevic, Christian

AU - Olesinski, Tomasz

AU - Chung, Hyun Cheol

AU - Muro, Kei

AU - Goekkurt, Eray

AU - McDermott, Raymond S

AU - Mansoor, Wasat

AU - Wainberg, Zev A

AU - Shih, Chie-Schin

AU - Kobie, Julie

AU - Nebozhyn, Michael

AU - Cristescu, Razvan

AU - Cao, Z Alexander

AU - Loboda, Andrey

AU - Özgüroğlu, Mustafa

N1 - © 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.

PY - 2023/6

Y1 - 2023/6

N2 - 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.

AB - 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.

KW - Humans

KW - Paclitaxel/pharmacology

KW - Stomach Neoplasms/drug therapy

KW - Transcriptome

KW - Antibodies, Monoclonal, Humanized/therapeutic use

U2 - 10.1136/jitc-2023-006920

DO - 10.1136/jitc-2023-006920

M3 - SCORING: Journal article

C2 - 37399357

VL - 11

JO - J IMMUNOTHER CANCER

JF - J IMMUNOTHER CANCER

SN - 2051-1426

IS - 6

M1 - e006920

ER -