FDA Approves Merck's Keytruda With Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma

The FDA has approved Merck’s pembrolizumab (Keytruda) plus fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic, human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

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The approval was based on data from the Phase 3 KEYNOTE-859 trial (NCT03675737). Findings from the trial demonstrated that adding Keytruda to chemotherapy produced statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).^1,2 At a median follow-up of 31.0 months, median OS was 12.9 months for those administered Keytruda plus chemotherapy compared with 11.5 months for chemotherapy alone.¹

The approval was based on data from the Phase 3 KEYNOTE-859 trial (NCT03675737). Findings from the trial demonstrated that adding Keytruda to chemotherapy produced statistically significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).^1,2 At a median follow-up of 31.0 months, median OS was 12.9 months for those administered Keytruda plus chemotherapy compared with 11.5 months for chemotherapy alone.¹

“The majority of patients with gastric cancer are diagnosed at an advanced stage, at which point they face a poor prognosis with a five-year survival rate of 6%,” Zev A. Wainberg, MD, professor of medicine at University of California, Los Angeles School of Medicine and co-director of the UCLA GI Oncology Program, said in a press release.¹ “This approval of pembrolizumab plus chemotherapy offers patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction cancer a new immunotherapy regimen that has demonstrated the potential to help these patients live longer.”

KEYNOTE-859, a multicenter, randomized, double-blind, placebo-controlled study, included patients with histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma of the stomach or GEJ who were not previously treated, had a known PD-L1 status, were HER2-negative, and had an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive 200 mg of Keytruda or placebo plus investigator's choice of chemotherapy of either 800 mg/m² of 5-flourouracil per day on days one through five and 80 mg/m² of cisplatin every three weeks, or 1000 mg/m² of oral capecitabine twice daily on days one through 14 plus 130 mg/m² of IV oxaliplatin every three weeks. Keytruda and placebo were administered for up to 35 cycles, which equaled approximately two years. The primary endpoint of KEYNOTE-859 was OS, with secondary end points of PFS, ORR, duration of response (DOR), and safety.

The combination produced a median PFS of 6.9 months compared with 5.6 months with chemotherapy alone. PFS rates at 12- and 24-months with the Keytruda combination were 28.9% and 17.8% compared with 19.3% and 9.4% with chemotherapy, respectively. The treatment combination produced an ORR of 51.3%, with a complete response (CR) rate of 9.5% and a partial response (PR) rate of 41.8% compared with an ORR of 42.0%, a CR rate of 6.2%, and a PR rate of 35.7% in the placebo cohort. Median DOR was 8.0 months in patients administered the Keytruda combination compared with 5.7 months chemotherapy alone.

In terms of safety, the most common any-grade treatment-related adverse effects (TRAEs) in patients administered Keytruda vs. chemotherapy alone, respectively, were nausea (41.4% vs. 41.4%), diarrhea (32.1% vs. 27.2%), anemia (31.0% vs. 26.9%), vomiting (27.4% vs. 22.2%), reduced platelet count 25.0% vs. 22.5%), reduced neutrophil count (24.6% vs. 21.6%), palmar-plantar erythrodysesthesia syndrome (24.1% vs. 21.1%), diminished appetite (21.4% vs. 21.3%), fatigue (20.0% vs. 20.8%), peripheral neuropathy (19.1% vs. 20.8%), neutropenia (18.1% vs. 17.2%), increased aspartate aminotransferase (17.7% vs. 13.0%), and peripheral sensory neuropathy (17.5% vs. 16.6%). Serious AEs occurred in 23.4% of patients administered Keytruda compared with 18.6% of patients in the placebo cohort.

“At Merck, we have a comprehensive development program across a broad range of gastrointestinal cancers with the goal of providing meaningful new options to patients and their healthcare providers,” said Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories, in a press release.¹ “This latest approval of a Keytruda-based treatment option is an important milestone for patients with advanced HER2-negative gastric or GEJ adenocarcinoma and reinforces Merck’s commitment to addressing the needs of these patients in the US.”

References

1. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) Plus Chemotherapy as First-Line Treatment for Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma. Merck. News release. November 16, 2023. Accessed November 17, 2023. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-as-first-line-treatment-for-locally-advanced-unresectable-or-metastatic-her2-negative-gastric-or-gastroesophageal-junction/

2. Rha SY, Wyrwicz LS, Weber Y, et al. Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: phase 3 KEYNOTE-859 study. Presented at: ESMO Virtual Plenary Series; February 16-17, 2023. doi:10.1016/j.annonc.2023.01.006.