What is the role of pembrolizumab (Keytruda) in the treatment of unresectable gastric cancer?

Updated: Feb 24, 2020
  • Author: Elwyn C Cabebe, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Pembrolizumab (Keytruda) was approved in September 2017 for gastric or GE junction carcinoma in patients expressing PD-L1 with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. Approval was based on the KEYNOTE-059 study. In the multinational trial, 259 heavily pretreated patients received single-agent pembrolizumab 200 mg IV every 3 weeks. Before enrolling, 51.7% of patients had received 2 prior lines of therapy, and 29% and 19.3% had received 3 or more than 4 prior lines of therapy, respectively. Median follow-up was 5.8 months. In the study, 143 of 259 patients had PD–L1-positive tumors (CPS ≥1) and microsatellite stable tumor status or undetermined microsatellite instability or mismatch repair status. The objective response rate (ORR) in these patients was 13.3%, comprising 1.4% complete responses and 11.9% partial responses. Among the 19 patients who were responders, the duration of response ranged from 2.8+ to 19.4+ months, with 58% having responses 6 months or longer and 26% having responses 12 months or longer. [55]

Rapid progression of cancer (ie, hyperprogression) occurs in a fraction of patients treated with PD-1/PD-L1 inhibitors such as pembrolizumab, including approximately 10% of those with advanced gastric cancer.  Kamada et al propose that hyperprogression may occur when when PD-1 blockade activates and expands the population of tumor-infiltrating PD-1+ regulatory T (Treg) cells, which then overwhelm tumor-reactive PD-1+ effector T cells. These authors report that the presence of actively proliferating PD-1+ effector Treg cells in tumors is a reliable marker for hyperprogression, and suggest that inhibiting Treg cell proliferation (eg, with nivolumab plus ipilimumab) could be an important strategy for prevention and treatment of hyperprogression in high-risk patients receiving PD-1 inhibitor therapy. [56]

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