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Brief Report
April 1, 2021

Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability–High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials

Author Affiliations
  • 1Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
  • 2Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut
  • 3National Cancer Center Hospital East, Kashiwa, Japan
  • 4Vall d’Hebron University Hospital and Institute of Oncology, Baselga Oncological Institute–Quiron, University of Vic–Central University of Catalonia, Barcelona, Spain
  • 5Aichi Cancer Center Hospital, Nagoya, Japan
  • 6University Hospital Leuven and KU Leuven, Leuven, Belgium
  • 7Seoul National University College of Medicine, Seoul, Republic of Korea
  • 8University of Study of Campania Luigi Vanvitelli, Naples, Italy
  • 9The Oncology Centre, Durban, South Africa
  • 10National Cheng Kung University Hospital, Taiwan, People’s Republic of China
  • 11Royal Marsden Hospital, Sutton, Surrey, United Kingdom
  • 12North Estonia Medical Center Foundation, Tallinn, Estonia
  • 13Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
  • 14Cerrahpaşa Medical Faculty, Cerrahpaşa School of Medicine, Istanbul University–Cerrahpaşa, Istanbul, Turkey
  • 15Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
  • 16Mayo Clinic, Rochester, Minnesota
  • 17Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, New Jersey
  • 18David Geffen School of Medicine, University of California, Los Angeles
JAMA Oncol. 2021;7(6):895-902. doi:10.1001/jamaoncol.2021.0275
Key Points

Question  Is treatment with pembrolizumab therapy vs chemotherapy associated with improvements in antitumor activity among patients who have advanced microsatellite instability–high gastric or gastroesophageal junction cancer regardless of the line of therapy in which it was received?

Findings  In this post hoc cohort study of 1614 patients in which 84 had confirmed microsatellite instability–high advanced gastric or gastroesophageal junction cancer, each of whom was enrolled in one of the KEYNOTE-059, KEYNOTE-061, or KEYNOTE-062 clinical trials, treatment with pembrolizumab therapy alone or in combination with chemotherapy was associated with prolonged overall and progression-free survival and provided durable responses vs chemotherapy alone among patients who had received 2 or more previous lines of therapy in KEYNOTE-059, 1 previous line of therapy in KEYNOTE-061, or no previous therapy in KEYNOTE-062.

Meaning  The study’s findings indicate that incorporation of pembrolizumab with or without chemotherapy may be more beneficial than chemotherapy alone for the treatment of patients who have microsatellite instability–high advanced or metastatic gastric or gastroesophageal junction cancer across all lines of therapy.


Importance  Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability–high (MSI-H) tumors.

Objective  To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received.

Design, Setting, and Participants  This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively.

Interventions  Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062.

Main Outcomes and Measures  Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing.

Results  At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy.

Conclusions and Relevance  Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received.

Trial Registration  ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583

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    2 Comments for this article
    Assessment of Pembrolizumab Therapy for the Treatment of MSI-H gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059
    Jose L Gonzalez | Medical Oncology, Hospital Ángeles, Leon, Guanajuato, Mexico.
    And what was results to patient had completed 2 years of pembrolizumab? Somebody relapso?
    Low prevalence of MSI-High cancer in Japanese patients
    takuma hayashi, MBBS, DMSci, GMRC, PhD | National Hospital Organization Kyoto Medical Center
    According to materials published by Merck & Co., which manufactures and sells Pembrolizumab, In the classification of MSI-High cancers in various cancer types, MSI-High gastric cancer accounts for about 8.5% of all gastric cancers, and MSI-High esophageal gastric junction cancer accounts for about 4% of all esophageal cancers.

    In cancer genomic medicine conducted at a national university in Japan during one year from April 2020 to March 2021, medical treatment was examined for 587 cases of all cancer types, and MSI-High cancer accounted for about 6.6% (39/587) of all cancer types. There was only one case of MSI-High gastric
    cancer. Currently, patients with MSI-High gastric cancer are being treated with Pembrolizumab. The antitumor effect of Pembrolizumab to this patients with MSI-High gastric cancer has not yet been clarified.

    The incidence and characteristics of each cancer type in Japanese patients are different compared to other races. From clinical practice, the prevalence of MSI-High cancer is clearly lower in all Japanese cancer types than in other races.