The FDA is evaluating whether to narrow the approved use of PD-1 inhibitors, specifically Keytruda (pembrolizumab) and Opdivo (nivolumab), in the first-line treatment of gastric adenocarcinoma. This re-evaluation stems from concerns that patients with low PD-L1 expression may not derive significant benefit from these drugs, potentially exposing them to unnecessary immune-related adverse events.
The debate centers on the current broad approval of these agents for gastric adenocarcinoma patients with unresectable or metastatic disease who are negative for HER2 expression, irrespective of their PD-L1 levels. FDA internal reviewers analyzed subgroup data from Phase III studies of Keytruda, Opdivo, and BeiGene's Tevimbra (tislelizumab), suggesting PD-L1 as a predictive biomarker for treatment efficacy.
Concerns Over Broad Approval
The FDA staff expressed concerns that the broad approval of PD-1 blockers "may not be in the best interest of patients with tumors with low PD-L1 expression." Their analysis indicated a lack of substantial benefit in patients with PD-L1 scores below 1, and unclear benefit for those with scores less than 10. The potential harm from anti-PD1 therapy in these patients, including serious immune-related adverse events, raises questions about the current treatment paradigm.
Pharmaceutical Companies' Positions
Bristol Myers Squibb (BMS) and Merck are advocating for the status quo. BMS argues that the existing Opdivo label adequately informs prescribers about the potential benefits and risks based on PD-L1 expression levels, leaving treatment decisions to physicians. Merck asserts that retaining the current Keytruda indications ensures appropriate access for patients who may benefit.
BeiGene takes a more nuanced stance, supporting efforts to standardize labeling and testing across anti-PD-1 agents. The company believes Tevimbra, when combined with platinum and fluoropyrimidine chemotherapy, offers a favorable benefit/risk profile, particularly for patients with PD-L1 levels of at least 5%.
Advisory Committee Meeting
An FDA advisory committee meeting is scheduled to discuss these issues. The committee will consider the available data and arguments from the FDA and the pharmaceutical companies to determine whether the current broad label for PD-1 inhibitors in gastric cancer should be narrowed based on PD-L1 expression.
