Pembrolizumab has been voluntarily withdrawn from the North American market as a treatment option for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.
Pembrolizumab (Keytruda) has been voluntarily withdrawn from the North American market as a treatment option for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [combined positive score ≥1], as determined by an FDA-approved test, and who have disease progression on 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.1
According to a press release from the drug developer, Merck, the withdrawal of pembrolizumab for this indication follows the April 29 meeting of the Oncologic Drugs Advisory Committee (ODAC) during which time the ODAC members voted 6 to 2 against the continued FDA approval of the agent for this indication.2 The decision was the result of a consultation with the FDA after ODAC made its vote. Merck agreed to initiate withdrawal within 6 months.1
Merck recommends that oncologists have conversations with patients receiving pembrolizumab for this disease about other treatment options. The company also noted that other indications for pembrolizumab are not impacted by this withdrawal.
“While there remains an unmet need for heavily pretreated patients with advanced gastric cancer, we recognize that the treatment landscape has evolved and we respect the FDA’s efforts to continually evaluate accelerated approvals,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories. “Our research with Keytruda has contributed to recent advances in the treatment of gastric cancer, and we are continuing to advance studies to help more patients with this disease.”
Accelerated approval was originally granted to pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ in September of 2017 based on findings from the phase 2 KEYNOTE-059 trial (NCT02335411). The study showed activity in this patient group who were being treated in the third-line setting and beyond.
The objective response rate was 13.3% (95% CI, 8.2%-20.0%) among patients with microsatellite stable disease or undetermined status.The median duration of response ranged from 2.8+ to 19.4+ months.
Adverse events observed in the study and were reported in at least 20% of patients were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, and others.
The accelerated approval has a post-marketing requirement of a confirmatory study to verify and describe the clinical benefit of pembrolizumab compared with standard therapy. It was required that this confirmatory study show a clinically meaningful improvement in overall survival in patients with PD-L1 positive, microsatellite stable/mismatch repair (MMR)-proficient metastatic gastric or GEJ adenocarcinoma. The 6 members of ODAC who voted against continued approval did not feel that the benefit was verified.
Despite this withdrawal, pembrolizumab is still FDA approved for the treatment of 3 subtypes of gastric cancer. One indication is in combination with trastuzumab (Herceptin), fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive disease. The second indication is to treat adult and pediatric patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. The final indication for pembrolizumab in gastric cancer is for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
All current indications for pembrolizumab in gastric cancer are a result of accelerated approvals based on tumor response as well as durability of response. To continue FDA approval, verification of clinical benefit in confirmatory trials is a requirement.
1. Merck provides update on KEYTRUDA® (pembrolizumab) indication in third-line gastric cancer in the US. News release. Merck. July 1, 2021. Accessed July 6, 2021. https://bit.ly/3jO1kGM
2. April 27-29, 2021: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. FDA website. Accessed April 29, 2021.