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

Updated: Feb 23, 2021
  • Author: Elwyn C Cabebe, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Pembrolizumab (Keytruda) was approved in 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 phase 2, single-arm KEYNOTE-059 study, in which 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. In 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. [57]

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. [58]

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