Clinical Trial

. 2022 Jan;25(1):197-206.

doi: 10.1007/s10120-021-01227-z. Epub 2021 Sep 1.

Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial

Charles S Fuchs¹, Mustafa Özgüroğlu², Yung-Jue Bang³, Maria Di Bartolomeo⁴, Mario Mandala⁵, Min-Hee Ryu⁶, Lorenzo Fornaro⁷, Tomasz Olesinski⁸, Christian Caglevic⁹, Hyun C Chung¹⁰, Kei Muro¹¹, Eric Van Cutsem¹², Anneli Elme¹³, Peter Thuss-Patience¹⁴, Ian Chau¹⁵, Atsushi Ohtsu¹⁶, Pooja Bhagia¹⁷, Anran Wang¹⁸, Chie-Schin Shih¹⁷, Kohei Shitara¹⁶

Affiliations

¹ Yale Cancer Center and Smilow Cancer Hospital, 333 Cedar Street, New Haven, CT, 06510, USA. Charles.S.Fuchs@gmail.com.
² Department of Internal Medicine, Division of Medical Oncology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey.
³ Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁴ Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
⁵ Unit of Medical Oncology, University of Perugia, Perugia, Italy.
⁶ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁷ Unit of Medical Oncology, Department of Translational Research and New Technology in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
⁸ Department of Oncological Gastroenterology, Maria Skłodowska-Curie Memorial, Warsaw, Poland.
⁹ Department of Cancer Research, Instituto Oncologico Fundacion Arturo Lopez, Santiago, Chile.
¹⁰ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
¹¹ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
¹² Department of Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU, Leuven, Belgium.
¹³ Chemotherapy Centre and Oncology and Hematology Clinic, The North Estonia Medical Centre, Tallinn, Estonia.
¹⁴ Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.
¹⁵ Department of Medicine, Royal Marsden NHS Foundation Trust, London, UK.
¹⁶ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
¹⁷ Department of Medical Oncology, Merck & Co., Inc, Kenilworth, NJ, USA.
¹⁸ Department of Biostatistics and Research Decision Science, Merck & Co., Inc, Kenilworth, NJ, USA.

PMID: 34468869
PMCID: PMC8732941
DOI: 10.1007/s10120-021-01227-z

Clinical Trial

Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial

Charles S Fuchs et al. Gastric Cancer. 2022 Jan.

. 2022 Jan;25(1):197-206.

doi: 10.1007/s10120-021-01227-z. Epub 2021 Sep 1.

Authors

Affiliations

¹ Yale Cancer Center and Smilow Cancer Hospital, 333 Cedar Street, New Haven, CT, 06510, USA. Charles.S.Fuchs@gmail.com.
² Department of Internal Medicine, Division of Medical Oncology, Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey.
³ Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁴ Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
⁵ Unit of Medical Oncology, University of Perugia, Perugia, Italy.
⁶ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁷ Unit of Medical Oncology, Department of Translational Research and New Technology in Medicine and Surgery, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
⁸ Department of Oncological Gastroenterology, Maria Skłodowska-Curie Memorial, Warsaw, Poland.
⁹ Department of Cancer Research, Instituto Oncologico Fundacion Arturo Lopez, Santiago, Chile.
¹⁰ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
¹¹ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
¹² Department of Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU, Leuven, Belgium.
¹³ Chemotherapy Centre and Oncology and Hematology Clinic, The North Estonia Medical Centre, Tallinn, Estonia.
¹⁴ Medical Department, Division of Hematology, Oncology, and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.
¹⁵ Department of Medicine, Royal Marsden NHS Foundation Trust, London, UK.
¹⁶ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
¹⁷ Department of Medical Oncology, Merck & Co., Inc, Kenilworth, NJ, USA.
¹⁸ Department of Biostatistics and Research Decision Science, Merck & Co., Inc, Kenilworth, NJ, USA.

PMID: 34468869
PMCID: PMC8732941
DOI: 10.1007/s10120-021-01227-z

Abstract

Background: In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019).

Methods: Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models.

Results: 366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%).

Conclusion: In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel.

Trial registration: ClinicalTrials.gov, NCT02370498.

Keywords: Chemotherapy; Gastric cancer; Gastroesophageal junction cancer; Pembrolizumab.

PubMed Disclaimer

Conflict of interest statement

Charles S. Fuchs reports board membership (director of board) for CytomX; consultancy for Agios, Amylin Pharmaceuticals, AstraZeneca, Bain Capital, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, Genentech, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Taiho, and Unum Therapeutics; expert testimony for Amylin Therapeutics and Eli Lilly; unexercised stock options for CytomX and Entrinsic Health; and co-founder of EvolveImmune Therapeutics. Mustafa Özgüroğlu has nothing to disclose. Yung-Jue Bang reports consultancy for Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, Daiichi-Sankyo, Eli Lilly, Genentech/Roche, Genexine, GreenCross, Hanmi, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Novartis, Samyang Biopharm, and Taiho; and grants from Astellas Pharma, AstraZeneca, Bayer, BeiGene, Boehringer-Ingelheim, BMS, Boston Biomedical, CKD Pharma, Curis, Daiichi-Sankyo, Eli Lilly, FivePrime, Genentech/Roche, Genexine, GreenCross, GSK, Macrogenics, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Novartis, Ono, Pfizer, Taiho, and Takeda. Maria Di Bartolomeo has nothing to disclose. Mario Mandala reports board membership for Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche; and grants from BMS, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche. Min-Hee Ryu reports honoraria from and advisory boards for AstraZeneca, BMS, Daehwa Pharmaceutical, Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono, and Taiho; payment for lectures from BMS, Daehwa Pharmaceutical, Lilly, and Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Lorenzo Fornaro reports board membership for Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; payment for lectures, including service on speakers bureaus, from Eli Lilly; and travel/accommodations/meeting expenses from Celgene. Tomasz Olesinski has nothing to disclose. Christian Caglevic reports consultancy for Andes Biotechnologies, Boehringer Ingelheim, BMS, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche; payment for lectures, including service on speakers bureaus, from BMS, Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche; travel/accommodations/meeting expenses from Roche; and service as a clinical trial investigator for Astellas Pharma, AstraZeneca, BMS, GSK, Medivation, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche. Hyun C. Chung reports consultancy for Amgen, BeiGene, BMS, Celltrion, Gloria, Lilly, Merck-Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Taiho, Zymework; and grants from Amgen, BeiGene, BMS/Ono, GSK Incyte, Lilly, Merck-Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Taiho. Kei Muro reports grants from Astellas Pharma, Amgen Biopharma, Daiichi Sankyo, Merck-Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Parexel International, Ono, Pfizer, Sanofi, Solasia Pharma, and Taiho; and consulting fees or honoraria from Amgen, AstraZeneca, Bayer, BMS, Chugai, Eli Lilly, Ono Pharmaceutical, Sanofi, Taiho, and Takeda. Eric Van Cutsem reports consultancy for Array, Astellas Pharma, AstraZeneca, Bayer, Biocartis, BMS, Celgene, Daichi-Sankyo, GSK, Halozyme, Incyte, Ipsen, Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck KGaA, Novartis, Pierre-Fabre, Roche, Servier, Sirtex, and Taiho; and grants from Amgen, Bayer, Boehringer-Ingelheim, BSM, Celgene, Ipsen, Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier. Anneli Elme has nothing to disclose. Peter Thuss-Patience reports consulting fees or honoraria from AstraZeneca, BMS, Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Pfizer, Roche, and Servier. Ian Chau reports advisory boards for AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Eli Lilly, Five Prime Therapeutics, Merck-Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Oncologie International, Pierre Fabre, Roche; research funding from Eli Lilly, Janssen-Cilag, and Sanofi Oncology; and honorarium from Eli Lilly. Atsushi Ohtsu reports personal fees from BMS, Chugai, Ono, and Taiho. Pooja Bhagia is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Anran Wang is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Chie-Schin Shih is an employee and stockholder of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Kohei Shitara reports consultancy with AbbVie, Astellas Pharma, BMS, Eli Lilly, GSK, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical; grants from Astellas Pharma, Chugai Pharma, Dainippon Sumitomo Pharma, Daiichi Sanyko, Eli Lilly, Medi Science, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Ono Pharmaceutical, and Taiho Pharmaceutical; and honoraria (lecture fees) from AbbVie, Novartis, and Yakult.

Figures

**Fig. 1**
Patient disposition. AE adverse event, *CPS* combined positive score, CR complete response, PD progressive disease. ^aDefined as clinical progression or progressive disease. ^bThere was no maximum number of doses of paclitaxel

**Fig. 2**
Kaplan–Meier analysis of overall survival in the populations with (a) CPS ≥ 1, (b) CPS ≥ 5, and (c) CPS ≥ 10 tumors. *CPS* combined positive score, HR hazard ratio, *Pts* patients

**Fig. 3**
Overall survival analysis by (a) subgroups and Kaplan–Meier analysis in the population with CPS ≥ 1 tumors and ECOG PS (b) 0 or (c) 1. *CPS* combined positive score, *ECOG PS* Eastern Cooperative Oncology Group performance status, *GEJ* gastroesophageal junction, HR hazard ratio, *Pts* patients

**Fig. 4**
Kaplan–Meier analysis of progression-free survival in the populations with (a) CPS ≥ 1, (b) CPS ≥ 5, and (c) CPS ≥ 10 tumors. *CPS* combined positive score, HR hazard ratio, *Pts* patients

See this image and copyright information in PMC

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. doi: 10.3322/caac.21492. - DOI - PubMed
1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): gastric cancer (Version 4.2020). 2020. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.o.... Accessed 8 Feb 2021.
1. KEYTRUDA® (2021) (pembrolizumab) injection, for intravenous use. 03/2021. Merck Sharp & Dohme Corp.: Whitehouse Station, NJ, USA
1. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17:717–726. doi: 10.1016/S1470-2045(16)00175-3. - DOI - PubMed
1. Wainberg ZA, Jalal S, Muro K, Yoon HH, Grrido M, Golan T, et al. KEYNOTE-059 update: efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal (G/GEJ) cancer. Ann Oncol. 2017;28:616. doi: 10.1093/annonc/mdx440.020. - DOI

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
Medical
- ClinicalTrials.gov
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial

Affiliations

Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Research Materials