FDA Restricts Keytruda and Opdivo for Stomach Cancer

In a significant development for cancer treatment, the U.S. Food and Drug Administration (FDA) has revised its approval guidelines concerning the use of PD-1 inhibitors for patients with certain types of cancer. The changes specifically affect the use of Merck & Co.’s Keytruda and Bristol Myers Squibb’s Opdivo in the treatment of advanced or metastatic gastric, gastroesophageal junction (GEJ), and esophageal cancers. This adjustment highlights the FDA's commitment to ensuring that cancer therapies have favorable risk-benefit profiles for patients.

The revisions primarily target the use of these immunotherapies in patients whose tumors do not express PD-L1, a protein that can impact the effectiveness of checkpoint inhibitors. Opdivo, when used in combination with chemotherapy, is now approved only for patients with tumors that express PD-L1. Additionally, the use of Opdivo in combination with Bristol Myers Squibb’s Yervoy has been narrowed to first-line treatment for esophageal squamous cell carcinoma in PD-L1-positive patients.

Similarly, Merck’s Keytruda has seen its usage in gastric, GEJ, and esophageal cancers restricted to PD-L1-positive tumors. This update specifically addresses Keytruda's use in HER2-negative gastric or GEJ adenocarcinoma, as its application in HER2-positive cases had already been restricted to PD-L1-positive patients earlier in the year. These modifications reflect the FDA's reassessment of the patient populations that could benefit the most from these treatments.

The decision follows findings from the phase 3 Keynote-859 trial, where Keytruda combined with chemotherapy showed a significant improvement in overall survival compared to chemotherapy alone in HER2-negative gastric or GEJ adenocarcinoma patients. However, further analysis revealed that the overall survival benefit was mainly observed in patients with PD-L1-positive tumors, with only an 8% reduction in death risk for the PD-L1-negative subgroup. This pivotal insight prompted the FDA to refine its approval criteria, limiting the use of these therapies to patients likely to experience the most benefit.

The FDA's action was anticipated, following previous expressions of concern regarding the use of PD-1 inhibitors in PD-L1-negative upper gastrointestinal cancers. Initially, these therapies were approved broadly without specifying PD-L1 biomarker requirements. The reassessment was reinforced by data from phase 3 trials of three different PD-1 inhibitors, which indicated an unfavorable risk-benefit profile for PD-L1-negative patients.

An external advisory committee overwhelmingly supported the FDA's revised perspective during a meeting in September. Subsequently, BeOne (then known as BeiGene) became the first company to adapt to these changes, receiving approval in December for its Tevimbra when used with chemotherapy in first-line, PD-L1-positive HER2-negative gastric or GEJ cancers.

Despite advocating for broader labels during the advisory committee meeting, both Merck and Bristol Myers Squibb submitted revisions to their drug indications in February, aligning with the FDA’s updated guidelines. This strategic move underscores the FDA's ongoing efforts to ensure that cancer treatments are appropriately targeted to benefit specific patient groups while minimizing potential risks.

This is not the first instance of the FDA refining its approvals for PD-1/L1 inhibitors. In 2018, the agency restricted the use of Keytruda and Roche’s Tecentriq as single agents for certain bladder cancer patients not eligible for cisplatin-containing chemotherapy. By 2021, the FDA further specified that Keytruda monotherapy in newly diagnosed bladder cancer should only be used for patients ineligible for any platinum-based chemotherapy. These historical precedents reflect a consistent approach by the FDA to refine and enhance treatment protocols based on emerging clinical evidence and patient safety considerations.