FDA considers restricting PD-1 drugs for stomach cancer, seeks expert input on Merck, BMS, and BeiGene medications

The FDA is convening an Oncologic Drugs Advisory Committee (ODAC) to evaluate the use of PD-1 inhibitors for stomach and esophageal cancers. The meeting, scheduled for September 26, will specifically consider whether the approvals for these treatments should be limited based on the expression of PD-L1 in tumors. This scrutiny extends to currently approved drugs like Bristol Myers Squibb's Opdivo and Yervoy, Merck's Keytruda, and two open applications for BeiGene’s Tevimbra.

According to an FDA filing, cumulative data suggest that PD-L1 expression may predict the efficacy of these treatments in patients. However, clinical trials have varied in how they measure and define PD-L1 positivity. PD-1 inhibitors are generally more effective in tumors expressing PD-L1, but their performance in stomach cancer has been modest, typically reducing the risk of death by about 20% compared to chemotherapy.

The focus of the upcoming ODAC meeting will be on HER2-negative stomach cancer. Last year, Merck voluntarily requested the FDA to narrow Keytruda’s approval in first-line HER2-positive gastric and gastroesophageal junction (GEJ) cancer to PD-L1-positive tumors only. The FDA complied and revised the label in November. In the phase 3 KEYNOTE-811 trial, Keytruda combined with Roche’s Herceptin and chemotherapy reduced the risk of progression or death by about 30% compared to Herceptin and chemotherapy alone in HER2-positive, PD-L1-positive cases. However, in a subset of patients with PD-L1-negative disease, the combination showed no progression advantage and even posed a greater risk to patient survival.

Despite achieving overall statistical significance in the trial population, the poor performance in PD-L1-negative patients raised concerns. Following this, the FDA approved Keytruda for use with chemotherapy in HER2-negative disease without PD-L1 constraints based on the KEYNOTE-859 trial. In this study, the combination reduced the risk of death by 22% and extended median overall survival by 1.4 months compared to chemotherapy alone. However, the benefit was minimal in PD-L1-negative patients, with only an 8% reduction in death risk.

Given these mixed results, the FDA is reconsidering the broad approval for Keytruda. Merck asserts that Keytruda plays an essential role in treating certain advanced gastric and esophageal cancers and looks forward to discussions with the ODAC about PD-L1 as a predictive biomarker of treatment efficacy.

Similar issues have been observed with Bristol Myers Squibb's Opdivo and BeiGene’s Tevimbra. In the phase 3 RATIONALE-305 trial for Tevimbra in first-line gastric and GEJ cancer, the addition of the drug to chemotherapy reduced the risk of death by 29% in PD-L1-positive patients, but only by 8% in PD-L1-negative patients. The CheckMate-649 trial for Opdivo showed a 25% reduction in death risk for PD-L1-positive patients, but just 5% for PD-L1-negative patients.

Merck, BMS, and BeiGene have also conducted trials for their respective drugs in esophageal squamous cell carcinoma (ESCC). Recently, BeiGene announced a delay in the FDA's decision for its first-line ESCC application due to postponed clinical site inspections. The company aims to secure FDA approvals for broad patient populations and remains committed to collaborating with the agency.

Bristol Myers Squibb's Opdivo, in combination with chemotherapy or Yervoy, received full FDA approval in 2022 for first-line ESCC based on overall survival results from the CheckMate-648 trial. BMS emphasizes the survival benefits of Opdivo-based treatments across various gastric and esophageal cancers, regardless of PD-L1 status, and anticipates discussing this further with the ODAC. This meeting follows a similar 2021 FDA review, which led to the withdrawal or narrowing of some PD-1/L1 accelerated approvals due to unmet trial commitments.