FDA Approves Pembrolizumab, Trastuzumab and Chemotherapy as First-Line Treatment for Certain Adenocarcinomas

The FDA has approved pembrolizumab (Keytruda, Merck), an anti-programmed cell death protein 1 therapy, in combination with trastuzumab, 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)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication has received accelerated approval based on tumor response rate and durability of response, though the results of confirmatory trials may change the approval status.

According to a press release from Merck, the approval for this indication is based on data from the ongoing phase 3 KEYNOTE-811 trial, in which pembrolizumab was combined with trastuzumab and either 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin. KEYNOTE-811 is a multicenter, randomized, double-blind, placebo-controlled trial that was designed to enroll 692 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients were randomized into treatment arms containing either pembrolizumab or placebo alongside trastuzumab and investigator’s choice of chemotherapy regimen.

The pembrolizumab combinations demonstrated a statistically significant objective response rate of 74% for patients who received the regimen with pembrolizumab versus 52% for those who received trastuzumab and chemotherapy alone (P <.0001). For patients on the regimen containing pembrolizumab, the complete response rate was 11% and the partial response rate was 63%, whereas the patients receiving trastuzumab and chemotherapy alone had a complete response rate of 3.1% and a partial response rate of 49%.

“Today’s approval marks an important milestone, as this is the first time an anti-PD-1 therapy has been approved in combination with anti-HER2 therapy and chemotherapy as a first-line treatment for these patients,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development at Merck, in the release.

According to the trial, pembrolizumab and placebo were discontinued due to adverse effects (AEs) in 6% of patients in each arm, with pneumonitis being the most common AE leading to discontinuation in the pembrolizumab arm. AEs led to temporary interruption of pembrolizumab in 58% of patients, with the most common AEs being neutropenia, thrombocytopenia, diarrhea, anemia, hypokalemia, fatigue/asthenia, decreased appetite, increased aspartate aminotransferase, increased blood bilirubin, pneumonia, increased alanine aminotransferase, and vomiting. There were no clinically meaningful differences in the incidence of grade 3-4 toxicity between the 2 arms.

REFERENCE

FDA Approves Merck’s KEYTRUDA® (pembrolizumab) Combined With Trastuzumab and Chemotherapy as First-line Treatment in Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma [news release]. Merck; May 5, 2021. Accessed May 5, 2021. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-combined-with-trastuzumab-and-chemotherapy-as-first-line-treatment-in-locally-advanced-unresectable-or-metastatic-her2-positive-gastric-or-g/