Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma

K. Shitara; M. Özgüroğlu; Y. J. Bang; M. Di Bartolomeo; M. Mandalà; M. H. Ryu; C. Caglevic; H. C. Chung; K. Muro; E. Van Cutsem; J. Kobie; R. Cristescu; D. Aurora-Garg; J. Lu; C. S. Shih; D. Adelberg; Z. A. Cao; C. S. Fuchs

doi:10.1016/j.annonc.2021.05.803

Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma

K. Shitara, M. Özgüroğlu, Y. J. Bang, M. Di Bartolomeo, M. Mandalà, M. H. Ryu, C. Caglevic, H. C. Chung, K. Muro, E. Van Cutsem, J. Kobie, R. Cristescu, D. Aurora-Garg, J. Lu, C. S. Shih, D. Adelberg, Z. A. Cao, C. S. Fuchs

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

Background: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. Patients and methods: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. Results: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). Conclusion: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

Original language	English
Pages (from-to)	1127-1136
Number of pages	10
Journal	Annals of Oncology
Volume	32
Issue number	9
DOIs	https://doi.org/10.1016/j.annonc.2021.05.803
Publication status	Published - 2021 Sept

Bibliographical note

Funding Information:
Funding for this study was provided by Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. , Kenilworth, NJ, USA. The authors thank the patients and their families and caregivers as well as the primary investigators and site personnel for participating in the study. The authors also thank David Fabrizio from Foundation Medicine, Cambridge, MA, USA, for his contribution to the data using the FoundationOne®CDx assay. In addition, the authors thank Jared Lunceford and Cinthia Umemoto of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding Information:
Funding for this study was provided by Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors thank the patients and their families and caregivers as well as the primary investigators and site personnel for participating in the study. The authors also thank David Fabrizio from Foundation Medicine, Cambridge, MA, USA, for his contribution to the data using the FoundationOne?CDx assay. In addition, the authors thank Jared Lunceford and Cinthia Umemoto of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Funding for this study was provided by Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA (no grant number). The funder participated in study design, data analysis and interpretation, and manuscript writing and maintained the study database. All authors had full access to the data and had final responsibility for the decision to submit for publication. KS reports honoraria for AbbVie, Novartis, and Yakult; consulting or advisory role for AbbVie, Astellas Pharma, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; researching funding for Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Medi Science, Ono Pharmaceutical, and Taiho Pharmaceutical. M? reports honoraria for Astellas Pharma, Janssen, and Roche; consulting or advisory role for Janssen; and travel, accommodations, expenses for AstraZeneca. Y-JB reports consulting/advisory for Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi Sankyo, Eli Lilly, Genentech/Roche, Genexine, Green Cross, Hammi, Merck Serono, MSD, Novartis, Samyang Biopharm, and Taiho; grants (to the institution for clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bostin Biomedical, BMS, CKD Pharma, Curis, Daiichi-Sankyo, Eli Lilly, Five Prime, Genentech/Roche, Genexine Green Cross, GSK, MacroGenics, Merck Serono, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda. MDB reports honoraria for Eli Lilly, Merck Serono, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Servier; consulting or advisory role for Eli Lilly; speakers? bureau for Eli Lilly and Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA; researching funding for Eli Lilly; and travel, accommodations, expenses for Roche. MM reports honoraria for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; consulting or advisory role for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; speakers? bureau for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; and research funding for Novartis and Roche. M-HR reports honoraria for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho; and consulting or advisory role for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho. CC reports honoraria for Andes Biotechnologies; consulting or advisory role for Boehringer Ingelheim Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Roche; speakers? bureau for Bristol Myers Squibb, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Roche; research funding for AstraZeneca, Astella Pharma, Bristol Myers Squibb, Medivation, and Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA; and travel, accommodations, expenses for Bristol Myers Squibb and Roche. HCC reports honoraria for Eli Lilly and Merck Serono; consulting or advisory role for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Eli Lilly, Gloria, Merck Serono, Quintiles, Taiho, and Zymeworks; and research funding for Amgen, BeiGene, Bristol Myers Squibb/Ono Pharmaceutical, Eli Lilly, Glaxo Smith Kline, Merch Serono, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Taiho. KM reports research funding (to his institution) from Daiichi Sankyo, MEDISCIENCE PLANNING, MSD, Parexel International, Pfizer, Sanofi, Solasia Pharma, and Sumitomo Dainippon Pharma; honoraria for speaking from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical Co. Ltd. Taiho Pharmaceutical, Takeda Pharmaceutical, and Sanofi; and advisory/consultancy for Amgen, AstraZeneca, and Ono Pharmaceutical Co. Ltd. EVC reports consulting or advisory role for Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly, Halozyme, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier; and research funding (to his institution) for Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier. JK is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. RC is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. DA-G is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA and received travel, accommodations, or expenses from Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. JL is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. C-SS is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc, and received researching funding and travel, accommodations, or expenses for Exelixis. DA is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. ZAC is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and has stock ownership interests in Merck & Co. Inc. Kenilworth, NJ, USA, and in Bristol Myers Squibb. CSF served in an advisory/consultancy role for Agios, Amylin Pharmaceuticals, AstraZeneca, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Taiho, and Unum Therapeutics. He also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; is a cofounder of EvolveImmune Therapeutics and has equity in this private company; and has provided expert testimony for Amylin Pharmaceuticals and Eli Lilly. Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data-sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

Publisher Copyright:
© 2021 European Society for Medical Oncology

All Science Journal Classification (ASJC) codes

Hematology
Oncology

Access to Document

10.1016/j.annonc.2021.05.803

Cite this

Shitara, K., Özgüroğlu, M., Bang, Y. J., Di Bartolomeo, M., Mandalà, M., Ryu, M. H., Caglevic, C., Chung, H. C., Muro, K., Van Cutsem, E., Kobie, J., Cristescu, R., Aurora-Garg, D., Lu, J., Shih, C. S., Adelberg, D., Cao, Z. A., & Fuchs, C. S. (2021). Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma. Annals of Oncology, 32(9), 1127-1136. https://doi.org/10.1016/j.annonc.2021.05.803

@article{38f4555b9ba24984a949f4e2790e990b,

title = "Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma",

abstract = "Background: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. Patients and methods: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne{\textregistered}CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne{\textregistered}CDx were used. Results: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne{\textregistered}CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). Conclusion: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.",

author = "K. Shitara and M. {\"O}zg{\"u}roğlu and Bang, {Y. J.} and {Di Bartolomeo}, M. and M. Mandal{\`a} and Ryu, {M. H.} and C. Caglevic and Chung, {H. C.} and K. Muro and {Van Cutsem}, E. and J. Kobie and R. Cristescu and D. Aurora-Garg and J. Lu and Shih, {C. S.} and D. Adelberg and Cao, {Z. A.} and Fuchs, {C. S.}",

note = "Funding Information: Funding for this study was provided by Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. , Kenilworth, NJ, USA. The authors thank the patients and their families and caregivers as well as the primary investigators and site personnel for participating in the study. The authors also thank David Fabrizio from Foundation Medicine, Cambridge, MA, USA, for his contribution to the data using the FoundationOne{\textregistered}CDx assay. In addition, the authors thank Jared Lunceford and Cinthia Umemoto of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Information: Funding for this study was provided by Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors thank the patients and their families and caregivers as well as the primary investigators and site personnel for participating in the study. The authors also thank David Fabrizio from Foundation Medicine, Cambridge, MA, USA, for his contribution to the data using the FoundationOne?CDx assay. In addition, the authors thank Jared Lunceford and Cinthia Umemoto of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Funding for this study was provided by Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA (no grant number). The funder participated in study design, data analysis and interpretation, and manuscript writing and maintained the study database. All authors had full access to the data and had final responsibility for the decision to submit for publication. KS reports honoraria for AbbVie, Novartis, and Yakult; consulting or advisory role for AbbVie, Astellas Pharma, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; researching funding for Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Medi Science, Ono Pharmaceutical, and Taiho Pharmaceutical. M? reports honoraria for Astellas Pharma, Janssen, and Roche; consulting or advisory role for Janssen; and travel, accommodations, expenses for AstraZeneca. Y-JB reports consulting/advisory for Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi Sankyo, Eli Lilly, Genentech/Roche, Genexine, Green Cross, Hammi, Merck Serono, MSD, Novartis, Samyang Biopharm, and Taiho; grants (to the institution for clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bostin Biomedical, BMS, CKD Pharma, Curis, Daiichi-Sankyo, Eli Lilly, Five Prime, Genentech/Roche, Genexine Green Cross, GSK, MacroGenics, Merck Serono, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda. MDB reports honoraria for Eli Lilly, Merck Serono, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Servier; consulting or advisory role for Eli Lilly; speakers? bureau for Eli Lilly and Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA; researching funding for Eli Lilly; and travel, accommodations, expenses for Roche. MM reports honoraria for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; consulting or advisory role for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; speakers? bureau for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; and research funding for Novartis and Roche. M-HR reports honoraria for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho; and consulting or advisory role for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho. CC reports honoraria for Andes Biotechnologies; consulting or advisory role for Boehringer Ingelheim Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Roche; speakers? bureau for Bristol Myers Squibb, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Roche; research funding for AstraZeneca, Astella Pharma, Bristol Myers Squibb, Medivation, and Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA; and travel, accommodations, expenses for Bristol Myers Squibb and Roche. HCC reports honoraria for Eli Lilly and Merck Serono; consulting or advisory role for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Eli Lilly, Gloria, Merck Serono, Quintiles, Taiho, and Zymeworks; and research funding for Amgen, BeiGene, Bristol Myers Squibb/Ono Pharmaceutical, Eli Lilly, Glaxo Smith Kline, Merch Serono, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Taiho. KM reports research funding (to his institution) from Daiichi Sankyo, MEDISCIENCE PLANNING, MSD, Parexel International, Pfizer, Sanofi, Solasia Pharma, and Sumitomo Dainippon Pharma; honoraria for speaking from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical Co. Ltd. Taiho Pharmaceutical, Takeda Pharmaceutical, and Sanofi; and advisory/consultancy for Amgen, AstraZeneca, and Ono Pharmaceutical Co. Ltd. EVC reports consulting or advisory role for Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly, Halozyme, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier; and research funding (to his institution) for Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier. JK is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. RC is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. DA-G is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA and received travel, accommodations, or expenses from Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. JL is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. C-SS is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc, and received researching funding and travel, accommodations, or expenses for Exelixis. DA is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. ZAC is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and has stock ownership interests in Merck & Co. Inc. Kenilworth, NJ, USA, and in Bristol Myers Squibb. CSF served in an advisory/consultancy role for Agios, Amylin Pharmaceuticals, AstraZeneca, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Taiho, and Unum Therapeutics. He also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; is a cofounder of EvolveImmune Therapeutics and has equity in this private company; and has provided expert testimony for Amylin Pharmaceuticals and Eli Lilly. Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data-sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses. Publisher Copyright: {\textcopyright} 2021 European Society for Medical Oncology",

year = "2021",

month = sep,

doi = "10.1016/j.annonc.2021.05.803",

language = "English",

volume = "32",

pages = "1127--1136",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "9",

}

Shitara, K, Özgüroğlu, M, Bang, YJ, Di Bartolomeo, M, Mandalà, M, Ryu, MH, Caglevic, C, Chung, HC, Muro, K, Van Cutsem, E, Kobie, J, Cristescu, R, Aurora-Garg, D, Lu, J, Shih, CS, Adelberg, D, Cao, ZA & Fuchs, CS 2021, 'Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma', Annals of Oncology, vol. 32, no. 9, pp. 1127-1136. https://doi.org/10.1016/j.annonc.2021.05.803

TY - JOUR

T1 - Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma

AU - Shitara, K.

AU - Özgüroğlu, M.

AU - Bang, Y. J.

AU - Di Bartolomeo, M.

AU - Mandalà, M.

AU - Ryu, M. H.

AU - Caglevic, C.

AU - Chung, H. C.

AU - Muro, K.

AU - Van Cutsem, E.

AU - Kobie, J.

AU - Cristescu, R.

AU - Aurora-Garg, D.

AU - Lu, J.

AU - Shih, C. S.

AU - Adelberg, D.

AU - Cao, Z. A.

AU - Fuchs, C. S.

N1 - Funding Information: Funding for this study was provided by Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. , Kenilworth, NJ, USA. The authors thank the patients and their families and caregivers as well as the primary investigators and site personnel for participating in the study. The authors also thank David Fabrizio from Foundation Medicine, Cambridge, MA, USA, for his contribution to the data using the FoundationOne®CDx assay. In addition, the authors thank Jared Lunceford and Cinthia Umemoto of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Information: Funding for this study was provided by Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors thank the patients and their families and caregivers as well as the primary investigators and site personnel for participating in the study. The authors also thank David Fabrizio from Foundation Medicine, Cambridge, MA, USA, for his contribution to the data using the FoundationOne?CDx assay. In addition, the authors thank Jared Lunceford and Cinthia Umemoto of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Funding for this study was provided by Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA (no grant number). The funder participated in study design, data analysis and interpretation, and manuscript writing and maintained the study database. All authors had full access to the data and had final responsibility for the decision to submit for publication. KS reports honoraria for AbbVie, Novartis, and Yakult; consulting or advisory role for AbbVie, Astellas Pharma, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; researching funding for Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Medi Science, Ono Pharmaceutical, and Taiho Pharmaceutical. M? reports honoraria for Astellas Pharma, Janssen, and Roche; consulting or advisory role for Janssen; and travel, accommodations, expenses for AstraZeneca. Y-JB reports consulting/advisory for Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi Sankyo, Eli Lilly, Genentech/Roche, Genexine, Green Cross, Hammi, Merck Serono, MSD, Novartis, Samyang Biopharm, and Taiho; grants (to the institution for clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bostin Biomedical, BMS, CKD Pharma, Curis, Daiichi-Sankyo, Eli Lilly, Five Prime, Genentech/Roche, Genexine Green Cross, GSK, MacroGenics, Merck Serono, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda. MDB reports honoraria for Eli Lilly, Merck Serono, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Servier; consulting or advisory role for Eli Lilly; speakers? bureau for Eli Lilly and Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA; researching funding for Eli Lilly; and travel, accommodations, expenses for Roche. MM reports honoraria for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; consulting or advisory role for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; speakers? bureau for Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, and Pierre Fabre; and research funding for Novartis and Roche. M-HR reports honoraria for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho; and consulting or advisory role for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho. CC reports honoraria for Andes Biotechnologies; consulting or advisory role for Boehringer Ingelheim Bristol Myers Squibb, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Roche; speakers? bureau for Bristol Myers Squibb, Eli Lilly, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Roche; research funding for AstraZeneca, Astella Pharma, Bristol Myers Squibb, Medivation, and Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA; and travel, accommodations, expenses for Bristol Myers Squibb and Roche. HCC reports honoraria for Eli Lilly and Merck Serono; consulting or advisory role for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Eli Lilly, Gloria, Merck Serono, Quintiles, Taiho, and Zymeworks; and research funding for Amgen, BeiGene, Bristol Myers Squibb/Ono Pharmaceutical, Eli Lilly, Glaxo Smith Kline, Merch Serono, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and Taiho. KM reports research funding (to his institution) from Daiichi Sankyo, MEDISCIENCE PLANNING, MSD, Parexel International, Pfizer, Sanofi, Solasia Pharma, and Sumitomo Dainippon Pharma; honoraria for speaking from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical Co. Ltd. Taiho Pharmaceutical, Takeda Pharmaceutical, and Sanofi; and advisory/consultancy for Amgen, AstraZeneca, and Ono Pharmaceutical Co. Ltd. EVC reports consulting or advisory role for Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly, Halozyme, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier; and research funding (to his institution) for Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck Sharp and Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier. JK is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. RC is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. DA-G is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA and received travel, accommodations, or expenses from Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. JL is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. C-SS is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc, and received researching funding and travel, accommodations, or expenses for Exelixis. DA is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and stockholder of Merck & Co. Inc. Kenilworth, NJ, USA. ZAC is an employee of Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, and has stock ownership interests in Merck & Co. Inc. Kenilworth, NJ, USA, and in Bristol Myers Squibb. CSF served in an advisory/consultancy role for Agios, Amylin Pharmaceuticals, AstraZeneca, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA, Taiho, and Unum Therapeutics. He also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; is a cofounder of EvolveImmune Therapeutics and has equity in this private company; and has provided expert testimony for Amylin Pharmaceuticals and Eli Lilly. Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data-sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses. Publisher Copyright: © 2021 European Society for Medical Oncology

PY - 2021/9

Y1 - 2021/9

N2 - Background: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. Patients and methods: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. Results: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). Conclusion: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

AB - Background: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. Patients and methods: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. Results: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). Conclusion: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

UR - http://www.scopus.com/inward/record.url?scp=85109047875&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85109047875&partnerID=8YFLogxK

U2 - 10.1016/j.annonc.2021.05.803

DO - 10.1016/j.annonc.2021.05.803

M3 - Article

C2 - 34082019

AN - SCOPUS:85109047875

SN - 0923-7534

VL - 32

SP - 1127

EP - 1136

JO - Annals of Oncology

JF - Annals of Oncology

IS - 9

ER -

Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma

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