Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study

Abstract

Background The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. Methods Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m 2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m 2 on days 1–5 of each 3-week cycle (or capecitabine 1000 mg/m 2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). Results In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8–24.1) and 17.5 months (range 1.7–20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3–5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7–78.9] (combination therapy) and 25.8% (95% CI 11.9–44.6) (monotherapy). Conclusions Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma. Clinical Trial ClinicalTrials.gov NCT02335411 Electronic supplementary material The online version of this article (10.1007/s10120-018-00909-5) contains supplementary material, which is available to authorized users.

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Treatment includes gastric resection, radiation, chemotherapy, and targeted therapy, including antibodies against (VEGF)/VEGF receptor 2 (VEGFR2), and HER2 (131). Recently, ICI therapy was approved for GC (Table 1) (6). However, most patients do not benefit.…”

“…Gastrointestinal (GI) cancers are some of the most common cancers worldwide and a major cause of cancer-related deaths (1)(2)(3)(4)(5). Immune checkpoint inhibitors (ICIs), including pembrolizumab (Keytruda) and nivolumab (Opdivo), antibodies against programmed death-1 (PD-1), recently gained Food and Drug Administration (FDA) approval for use in GI cancers (Table 1) (6)(7)(8)(9)(10)(11). While their approval has been a significant step forward in advancing clinical care, currently, few patients benefit (12).…”

Noncoding RNAs in gastric cancer: implications for drug resistance

“…Multiple targeted therapy drugs have been developed to treat cancers including gastric cancer, such as cetuximab and panitumumab (anti-EGFR monoclonal antibodies [MoAbs]), trastuzumab and pertuzumab (anti-HER2 MoAbs), lapatinib (anti-HER2 and EGFR tyrosine kinase dual inhibitor), bevacizumab (anti-VEGF-A MoAb) and ramucirumab (anti-VEGFR-2 MoAb). Among these drugs, trastuzumab and ramucirumab have been found to improve prognosis of advanced gastric cancer patients [34,[150][151][152][153]. Emerging evidences have demonstrated that several miRNAs have been involved in resistance to targeted therapy drugs in gastric cancer, such as trastuzumab and lapatinib (Table 6).…”

“…Immunotherapy with immune checkpoint inhibitors for gastric cancer has emerged [31][32][33][34][35][36][37]. In gastric cancer, the relatively identified and useful population for immunotherapy is patients receiving third-line treatment.…”

New Treatment Options for Advanced Gastroesophageal Tumours: Mature for the Current Practice?

“…A recent phase II KEYNOTE-059 study (cohort II and III) demonstrated the anti-tumour activity and moderate toxicity profiles of pembrolizumab as monotherapy and in combination with chemotherapy in a first line setting (objective response rate: 25.8% (95% CI 11.9-44.6) and 60.0% (95% CI, 38.7-78.9), respectively) [16]. Until then, there had been no evaluation of a potential benefit upon a combination strategy of immunotherapy plus chemotherapy when compared to chemotherapy alone.…”