If approved, the potential restrictions would impact Merck’s Keytruda and Bristol Myers Squibb’s Opdivo, which are marketed for the first-line treatment of several types of stomach cancer regardless of PD-L1 expression.
Ahead of a Thursday advisory committee meeting, the FDA has raised questions about the broad use of PD-1 inhibitors in gastric adenocarcinoma, pointing to the potential need to limit treatment-eligible patients based on specific biomarkers.
The issue potentially impacts Merck and Bristol Myers Squibb, which market Keytruda (pembrolizumab) and Opdivo (nivolumab) for the first-line treatment of gastric adenocarcinoma patients with unresectable or metastatic disease who are negative for HER2 expression. Keytruda and Opdivo can be used in these patients regardless of their PD-L1 levels.
BeiGene, which is also developing its own PD-1 blocker Tevimbra (tislelizumab) for this indication, will participate in Thursday’s meeting.
In a briefing document, the regulator’s internal reviewers dug into subgroup data from the separate Phase III studies for Keytruda, Opdivo and Tevimbra. Their analysis—which they concede is “exploratory”—shows that PD-L1 is likely a “predictive biomarker of treatment efficacy” in first-line gastric adenocarcinoma.
The broad approval of these PD-1 blockers “may not be in the best interest of patients with tumors with low PD-L1 expression,” the FDA staffers wrote, pointing out that treatment does not appear to shave substantial benefit in patients with PD-L1 scores lower than 1, and “unclear” benefit in those with scores less than 10.
“If patients with low or no PD-L1 expression are not expected to benefit based on the available data, then administering anti-PD1 therapy has the potential for harm including serious immune related adverse events on top of a malignancy that can markedly affect a patient’s quality of life,” according to FDA staffers.
BMS and Merck are arguing for maintaining the status quo. In its briefing document, BMS noted that the current label for Opdivo “adequately informs prescribers on the potential benefits and risks” of its use in stomach cancer, including “the clinical efficacy by PD-L1 expression level.”
“The existing labelling leaves the decision-making in the hands of the treating physician and increases the chance for patients who may potentially benefit … to be considered for treatment,” BMS wrote.
Merck was more direct in its argument, asserting that the currently approved indications for Keytruda “should be retained.” According to the company, this will help ensure that patients who may benefit from treatment will continue to have “appropriate access in the U.S.”
For its part, BeiGene was more measured in its position, though it maintains that Tislelizumab—when used with platinum and fluoropyrimidine chemotherapy—has a “favorable benefit/risk” profile for the frontline treatment in unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, particularly for patients with PD-L1 levels at least 5%.
“BeiGene supports efforts in gaining consistency in labeling and testing across the class of anti-PD-1 agents as it would help provide clarity among the medical community and would better support treatment decisions in clinical practice,” the company wrote in its briefing document.
