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?
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.
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.
Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability–high (MSI-H) tumors.
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.
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.
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.
ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583
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Chao J, Fuchs CS, Shitara K, et al. 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. JAMA Oncol. 2021;7(6):895–902. doi:10.1001/jamaoncol.2021.0275
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