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Figure.  Kaplan-Meier Estimates of Overall Survival Among Patients With Advanced Gastric or Gastroesophageal Junction Cancer by Line of Therapy
Kaplan-Meier Estimates of Overall Survival Among Patients With Advanced Gastric or Gastroesophageal Junction Cancer by Line of Therapy

Combination indicates pembrolizumab plus chemotherapy; MSI-H, microsatellite instability–high. A, All patients in KEYNOTE-061 clinical trial. B, Patients with MSI-H tumors in KEYNOTE-061 clinical trial. C, All patients in KEYNOTE-062 clinical trial. D, Patients with MSI-H tumors in KEYNOTE-062 clinical trial. The tick marks on each survival curve indicate censored patients.

Table 1.  Baseline Characteristics of Patients With Microsatellite Instability–High Advanced Gastric or Gastroesophageal Junction Cancer by Line of Therapy
Baseline Characteristics of Patients With Microsatellite Instability–High Advanced Gastric or Gastroesophageal Junction Cancer by Line of Therapy
Table 2.  Outcomes in Patients With Advanced Gastric or Gastroesophageal Junction Cancer by Line of Therapy
Outcomes in Patients With Advanced Gastric or Gastroesophageal Junction Cancer by Line of Therapy
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Yoshino  T, Pentheroudakis  G, Mishima  S,  et al.  JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions.   Ann Oncol. 2020;31(7):861-872. doi:10.1016/j.annonc.2020.03.299 PubMedGoogle ScholarCrossref
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Fuchs  CS, Doi  T, Jang  RW,  et al.  Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.   JAMA Oncol. 2018;4(5):e180013. doi:10.1001/jamaoncol.2018.0013 PubMedGoogle Scholar
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Tabernero  J, Van Cutsem  E, Bang  YJ,  et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study. J Clin Oncol. 2019;37(18 suppl):LBA4007.
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Le  DT, Kim  TW, Van Cutsem  E,  et al.  Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164.   J Clin Oncol. 2020;38(1):11-19. doi:10.1200/JCO.19.02107 PubMedGoogle ScholarCrossref
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Kim  SY, Choi  YY, An  JY,  et al.  The benefit of microsatellite instability is attenuated by chemotherapy in stage II and stage III gastric cancer: results from a large cohort with subgroup analyses.   Int J Cancer. 2015;137(4):819-825. doi:10.1002/ijc.29449 PubMedGoogle ScholarCrossref
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Andre  T, Shiu  KK, Kim  TW,  et al. Pembrolizumab versus chemotherapy for microsatellite instability–high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;38(18 suppl):LBA4. doi:10.1200/JCO.2020.38.18_supple.LBA4
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    2 Comments for this article
    EXPAND ALL
    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?
    CONFLICT OF INTEREST: None Reported
    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.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    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.

    Abstract

    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

    Introduction

    The phenotype for microsatellite instability–high (MSI-H) is a distinct tumor subclass that is highly susceptible to immunotherapy.1 These tumors typically have high tumor mutational burden and high levels of programmed cell death 1 ligand 1 (PD-L1) expression, leading to improved response to anti–programmed cell death 1 protein (anti–PD-1) therapy.1 Approximately 5% to 20% of gastric tumors are MSI-H,2 warranting further understanding of the benefits of anti–PD-1 therapy across treatment lines in this subgroup. The anti–PD-1 monoclonal antibody pembrolizumab has provided durable antitumor immunity in patients with advanced gastric or gastroesophageal junction cancer in the phase 2 KEYNOTE-059 clinical trial (1 arm; third-line treatment or higher),3 the phase 3 KEYNOTE-061 randomized clinical trial (2 arms; second-line treatment),4 and the phase 3 KEYNOTE-062 randomized clinical trial (3 arms; first-line treatment).5 In this post hoc analysis, we examined the antitumor activity of pembrolizumab therapy among patients with MSI-H advanced gastric or gastroesophageal junction cancer who were enrolled in these studies.

    Methods
    Study Design, Treatment, and Participants

    This post hoc analysis of the phase 2 KEYNOTE-059 and phase 3 KEYNOTE-061 and KEYNOTE-062 clinical trials included patients with advanced gastric or gastroesophageal junction 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. Institutional review board approval was obtained from all study centers, and all patients provided written informed consent.

    Eligibility criteria and study treatment for the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials were previously reported.3-5 In brief, patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 studies had received 2 or more previous lines of therapy, 1 previous line of therapy, or no previous therapy, respectively. With regard to study treatment, patients in the KEYNOTE-059 study (third-line treatment or higher) received pembrolizumab monotherapy (200 mg every 3 weeks for up to 2 years), patients in the KEYNOTE-061 study (second-line treatment) received pembrolizumab monotherapy or chemotherapy (paclitaxel) alone, and patients in the KEYNOTE-062 study (first-line treatment) received pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone. Patients received treatment until disease progression or unacceptable toxic effects. Evaluations of study objectives, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response, were previously reported.3-5

    Biomarker Analysis

    Tumor PD-L1 expression was evaluated in pretreatment tissue samples through the PD-L1 IHC 22C3 pharmDx assay (Agilent) using the combined positive score. Tumors that were PD-L1 positive had combined positive scores of 1 or higher. Microsatellite instability–high status was determined centrally through polymerase chain reaction testing using the MSI analysis system, version 1.2 (Promega).

    Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. Patients with evaluable tumors had available matching tissue and blood samples that met the sufficiency requirements of the MSI analysis. Tumors were considered to be MSI-H if 2 or more markers were changed compared with normal controls.

    Statistical Analysis

    All patients who received 1 or more doses of the study treatment (KEYNOTE-059) and all randomized patients (KEYNOTE-061 and KEYNOTE-062) were included in the analysis. 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. Data cutoff dates were August 8, 2018, for KEYNOTE-059; October 26, 2017, for KEYNOTE-061; and March 26, 2019, for KEYNOTE-062. Kaplan-Meier estimates were provided for OS, PFS, and duration of response. For ORR, point estimates and 95% CIs were provided using the exact binomial Clopper-Pearson method. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute), and full descriptions of analytic methods were previously published.3-5

    Results

    A total of 259 patients (median age, 62 years [range, 24-89 years]; 198 men [76.4%]) were enrolled in KEYNOTE-059, 592 patients (median age, 61 years [range, 20-87 years]; 410 men [69.3%]) were enrolled in KEYNOTE-061, and 763 patients (median age, 62 years [range, 20-87 years]; 554 men [72.6%]) were enrolled in KEYNOTE-062 (eTable 1 in the Supplement). Overall, 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 with evaluable tumors had MSI-H gastric or gastroesophageal junction cancer (Table 1). At data cutoff, the median follow-up period was 5.6 months (range, 0.5-37.6 months) for KEYNOTE-059, 7.9 months (range, 0.2-27.7 months) for KEYNOTE-061, and 11.3 months (range, 0.2-41.2 months) for KEYNOTE-062.

    Among patients in KEYNOTE-059 (with updated data cutoff date from the original publication), no patients were receiving ongoing therapy, and 3 of 7 patients (42.9%) had completed 2 years of pembrolizumab monotherapy (eTable 2 in the Supplement). Among those in KEYNOTE-061, a larger proportion of patients who received pembrolizumab monotherapy had completed therapy (3 of 15 patients [20%]) or were receiving ongoing therapy (4 of 15 patients [26.7%]) compared with patients who received chemotherapy alone (0 patients in both categories). In KEYNOTE-062, a larger proportion of patients who received pembrolizumab monotherapy or pembrolizumab plus chemotherapy had completed therapy (6 of 14 patients [42.9%] and 6 of 17 patients [35.3%], respectively) or were receiving ongoing therapy (1 of 14 patients [7.1%] and 2 of 17 patients [11.8%], respectively) compared with patients who received chemotherapy alone (1 of 19 patients [5.3%] completed therapy, and 1 of 19 patients [5.3%] were receiving ongoing therapy) (eTable 2 in the Supplement).

    Data from the period after discontinuation of clinical trial anticancer therapy among patients with MSI-H tumors are summarized in eTable 3 in the Supplement. A small proportion of patients were receiving post–clinical trial immunotherapy after disease progression.

    Among patients with MSI-H tumors, the median OS for pembrolizumab monotherapy was not reached (ie, >50% of patients were still alive at data cutoff) in KEYNOTE-059 (95% CI, 1.1 months to not reached) or KEYNOTE-061 (95% CI, 5.6 months to not reached) compared with a median OS of 8.1 months (95% CI, 2.0-16.7 months) for chemotherapy alone in KEYNOTE-061. In KEYNOTE-062, the median OS was not reached for both pembrolizumab monotherapy (95% CI, 10.7 months to not reached) and pembrolizumab plus chemotherapy (95% CI, 3.6 months to not reached) compared with a median OS of 8.5 months (95% CI, 5.3-20.8 months) for chemotherapy alone (Table 2; Figure; eFigure 1 in the Supplement).

    The estimated 12-month OS rates for pembrolizumab monotherapy among patients with MSI-H tumors were 71% (95% CI, not available) for KEYNOTE-059 and 73% (95% CI, 44%-89%) for KEYNOTE-061 (compared with 25% [95% CI, 6%-50%] for chemotherapy alone in KEYNOTE-061). In KEYNOTE-062, the estimated 12-month OS rates were 79% (95% CI, 47%-92%) for pembrolizumab monotherapy, 71% (95% CI, 43%-87%) for pembrolizumab plus chemotherapy, and 47% (95% CI, 24%-67%) for chemotherapy alone. In KEYNOTE-059 and KEYNOTE-061, the estimated 24-month OS rates for pembrolizumab monotherapy were 57% (95% CI, not available) and 59% (95% CI, 31%-79%), respectively (24-month OS rate not available for chemotherapy alone in KEYNOTE-061). In KEYNOTE-062, the estimated 24-month OS rates were 71% (95% CI, 41%-88%) for pembrolizumab monotherapy, 65% (95% CI, 38%-82%) for pembrolizumab plus chemotherapy, and 26% (95% CI, 10%-57%) for chemotherapy alone.

    The median PFS among patients with MSI-H tumors was not reached (95% CI, 1.1 months to not reached) for pembrolizumab monotherapy in KEYNOTE-059 compared with 17.8 months (95% CI, 2.7 months to not reached) for pembrolizumab monotherapy and 3.5 months (95% CI, 2.0-9.8 months) for chemotherapy alone in KEYNOTE-061. In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to not reached) for pembrolizumab monotherapy, not reached (95% CI, 3.6 months to not reached) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy alone (Table 2; eFigure 1 and eFigure 2 in the Supplement).

    Among patients with MSI-H gastric or gastroesophageal junction cancer, the ORR for pembrolizumab monotherapy in KEYNOTE-059 was 57.1% (95% CI, 18.4%-90.1%) (Table 2). In KEYNOTE-061, the ORR was 46.7% (95% CI, 21.3%-73.4%) for pembrolizumab monotherapy vs 16.7% (95% CI, 2.1%-48.4%) for chemotherapy alone. In KEYNOTE-062, the ORR was 57.1% (95% CI, 28.9%-82.3%) for pembrolizumab monotherapy, 64.7% (95% CI, 38.3%-85.8%) for pembrolizumab plus chemotherapy, and 36.8% (95% CI, 16.3%-61.6%) for chemotherapy alone. The median duration of response was not reached for pembrolizumab monotherapy in both KEYNOTE-059 (range, 20.0-26.8 months) and KEYNOTE-061 (range, 5.5-26.0 months) and not reached for chemotherapy alone (range, 2.2-12.2 months) in KEYNOTE-061. In KEYNOTE-062, the median duration of response was 21.2 months (range, 1.4+ to 33.6 months, with + indicating no progressive disease at last assessment) for pembrolizumab monotherapy, not reached (range, 1.6+ to 34.5+ months) for pembrolizumab plus chemotherapy, and 7.0 months (range, 2.0-30.4+ months) for chemotherapy alone.

    Outcomes in patients with non–MSI-H tumors or nonevaluable MSI-H tumors (ie, the confirmed cases with MSI-H tumors were removed) are summarized in eTable 4 in the Supplement. The distribution of baseline characteristics was similar across these patients (eTable 5 in the Supplement), patients with MSI-H tumors (Table 1), and patients with nonevaluable MSI-H tumors (eTable 6 in the Supplement).

    Discussion

    The results of this post hoc analysis indicate that pembrolizumab or pembrolizumab plus chemotherapy provided durable antitumor activity vs chemotherapy alone among patients with MSI-H gastric or gastroesophageal junction cancer regardless of the line of therapy in which it was received. This finding is exemplified by the greater number of patients with MSI-H cancer who were receiving ongoing therapy or had completed 2 years of pembrolizumab therapy. These data are consistent with those reported in previous studies of patients with MSI-H tumors,6-8 and they illustrate the benefits of pembrolizumab therapy in patients with MSI-H gastric or gastroesophageal junction cancer across all lines of therapy. To our knowledge, the 31 patients with MSI-H tumors in the KEYNOTE-062 clinical trial who received pembrolizumab monotherapy or pembrolizumab plus chemotherapy represent the largest international gastric cancer cohort receiving first-line immune checkpoint inhibitor therapy reported to date.

    The worse OS outcomes observed in the first-line setting among patients with MSI-H gastric or gastroesophageal junction cancer who received chemotherapy are consistent with other case series suggesting that patients with MSI-H gastric cancer respond worse to chemotherapy alone.9-12 The early divergence of the survival curves between patients with MSI-H tumors who received first-line pembrolizumab therapy vs chemotherapy suggests that earlier introduction of pembrolizumab is beneficial in patients with this molecular subtype of gastric or gastroesophageal junction cancer. Primary resistance to immune checkpoint inhibitors in patients with MSI-H advanced gastric or gastroesophageal junction cancer remains an active area of investigation, and data have suggested that intratumoral heterogeneous loss of mismatch repair enzymes may account for reduced response to pembrolizumab monotherapy.13 In the KEYNOTE-062 study, 12- and 24-month OS rates were favorable for both the pembrolizumab and pembrolizumab plus chemotherapy arms among patients with MSI-H tumors, and PFS numerically favored the combination of therapies; however, this conclusion remains hypothesis generating. The recent phase 3 KEYNOTE-177 study of patients with MSI-H metastatic colorectal cancer reported significant improvements in PFS with first-line pembrolizumab therapy vs chemotherapy alone.14 In addition, the phase 3 CheckMate 649 study, which included a subgroup of patients with MSI-H gastric or gastroesophageal adenocarcinoma, reported improved OS with first-line nivolumab therapy plus chemotherapy vs chemotherapy alone, further supporting the robustness of MSI-H status to estimate benefits for immune checkpoint blockade.15 These data support routine testing for MSI-H status in patients with advanced gastric cancer. The addition of pembrolizumab to first-line chemotherapy in patients with MSI-H gastric or gastroesophageal junction cancer is being validated in the ongoing phase 3 KEYNOTE-859 clinical trial (NCT03675737).

    Limitations

    This study has limitations. The small numbers of patients with MSI-H tumors limited statistical interpretation, such as the performance of multivariable analysis. In addition, MSI-H status was not available for all patients, which may have introduced selection bias. However, the distribution of baseline characteristics among patients with nonevaluable tumors was similar to that of the overall study population.

    Conclusions

    The findings of this analysis support MSI-H status as a biomarker for pembrolizumab therapy among patients with advanced gastric or gastroesophageal junction cancer and warrant its prospective validation in ongoing first-line studies.

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    Article Information

    Accepted for Publication: December 23, 2020.

    Published Online: April 1, 2021. doi:10.1001/jamaoncol.2021.0275

    Corresponding Author: Joseph Chao, MD, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010 (jchao@coh.org).

    Author Contributions: Dr Chao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Chao, Fuchs, Shitara, Tabernero, Shah, Wainberg.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Chao, Shitara, Lee, Özgüroğlu, Wainberg.

    Critical revision of the manuscript for important intellectual content: Chao, Fuchs, Shitara, Tabernero, Muro, Van Cutsem, Bang, De Vita, Landers, Yen, Chau, Elme, Özgüroğlu, Catenacci, Yoon, Chen, Adelberg, Shih, Shah, Bhagia, Wainberg.

    Statistical analysis: Chen, Adelberg.

    Administrative, technical, or material support: Tabernero, Muro, Van Cutsem, Bang, Chau, Shih, Wainberg.

    Supervision: Chao, Fuchs, Tabernero, De Vita, Yen, Catenacci, Chen, Shih, Shah, Bhagia, Wainberg.

    Other—patient recruitment: Van Cutsem.

    Conflict of Interest Disclosures: Dr Chao reported receiving manuscript-writing assistance from Merck Sharp & Dohme during the conduct of the study and receiving grants from Brooklyn ImmunoTherapeutics and Merck and personal fees from Amgen, AstraZeneca, Boston Biomedical, Daiichi Sankyo, Foundation Medicine, MacroGenics, Merck, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Fuchs reported receiving personal fees from Agios Pharmaceuticals, Amylin Pharmaceuticals, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck, Taiho Pharmaceutical, and Unum Therapeutics; owning stock in CytomX Therapeutics and Entrinsic Health; cofounding EvolveImmune Therapeutics; serving as the director of CytomX Therapeutics and EvolveImmune Therapeutics; and providing expert testimony for Amylin Pharmaceuticals and Eli Lilly outside the submitted work. Dr Shitara reported receiving grants from Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck, Medi Science, Ono Pharmaceutical, Sumitomo Dainippon Pharma, and Taiho Pharmaceutical and personal fees from AbbVie, Astellas Pharma, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Takeda Pharmaceutical, and Yakult Honsha outside the submitted work. Dr Tabernero reported receiving personal fees from Array BioPharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Genentech, Genmab, HalioDx, Halozyme Therapeutics, Imugene, Inflection Biosciences, Ipsen Biopharmaceuticals, Kura Oncology, Menarini, Merck Serono, Merck Sharp & Dohme, Merrimack Pharmaceuticals, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, SeaGen (formerly Seattle Genetics), Servier Laboratories, Symphogen, Taiho Pharmaceutical, and VCN Biosciences outside the submitted work. Dr Muro reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving grants from Amgen, Astellas Pharma, Daiichi Sankyo, Merck Sharp & Dohme, Merck Serono, Ono Pharmaceutical, Parexel, Pfizer, Sanofi, Solasia Pharma, and Taiho Pharmaceutical and personal fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Sanofi, Takeda Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Van Cutsem reported receiving grants from Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Ipsen Biopharmaceuticals, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche, and Servier Laboratories and serving on the advisory boards of Array BioPharma, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Halozyme Therapeutics, Incyte, Ipsen Biopharmaceuticals, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Servier Laboratories, Sirtex Medical, and Taiho Pharmaceutical outside the submitted work. Dr Bang reported receiving grants from Astellas Pharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Boston Biomedical, Bristol Myers Squibb, CKD Pharmaceuticals, Curis, Daiichi Sankyo, Eli Lilly, Five Prime Therapeutics, Genentech, Genexine, GlaxoSmithKline, GC Pharma, MacroGenics, Merck Serono, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical and serving as a consultant or advisor for Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Genentech, Genexine, GC Pharma, Hanmi Pharmaceutical, Merck Serono, Merck Sharp & Dohme, Novartis, Samyang Biopharm, and Taiho Pharmaceutical outside the submitted work. Dr De Vita reported serving as a consultant or advisor for Celgene and Eli Lilly outside the submitted work. Dr Chau reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving grants from Eli Lilly, Janssen-Cilag, and Sanofi Oncology and personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Five Prime Therapeutics, Merck Serono, Merck Sharp & Dohme, Oncologie, Pierre Fabre, and Roche outside the submitted work. Dr Elme reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving grants from Roche and personal fees from Amgen, Astra Zeneca, Ipsen Biopharmaceuticals, Merck Sharp & Dohme, and Roche outside the submitted work. Dr Özgüroğlu reported receiving grants from Merck Sharp & Dohme during the conduct of the study and receiving personal fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen Pharmaceuticals, Novartis, Roche, and Sanofi outside the submitted work. Dr Catenacci reported receiving grants from Merck Sharp & Dohme and personal fees from Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Five Prime Therapeutics, Foundation Medicine, Genentech, Gritstone Oncology, Guardant Health, Merck, Pieris Pharmaceuticals, Taiho Pharmaceutical, and Tempus Labs during the conduct of the study. Dr Yoon reported receiving grants from Merck and personal fees from BeiGene, Bristol Myers Squibb, and MacroGenics outside the submitted work. Dr Wainberg reported receiving grants from Bristol Myers Squibb, Five Prime Therapeutics, Merck Serono, Novartis, and Ipsen Biopharmaceuticals and personal fees from AstraZeneca, Bayer, Daiichi Sankyo, Eli Lilly, MacroGenics, and Merck outside the submitted work. No other disclosures were reported.

    Funding/Support: This study and assistance with medical writing were funded by Merck Sharp & Dohme, a subsidiary of Merck, and supported by grant 5K12CA001727-23 from the National Institutes of Health (Dr Chao).

    Role of the Funder/Sponsor: Employees of Merck Sharp & Dohme were involved in the design and conduct of the study and in the collection, management, analysis, and interpretation of the data. Drs Chen, Adelberg, Shih, Shah, and Bhagia, employees of Merck, were involved in the review and approval of the manuscript and the decision to submit the manuscript for publication.

    Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Additional Contributions: Jonathan Cheng, MD, an employee of Merck Sharp & Dohme, provided critical review. Luana Atherly-Henderson, PhD, CMPP, an employee of Merck Sharp & Dohme, provided medical writing assistance. We thank the patients and their families and caregivers along with all of the primary investigators and their site personnel.

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