FDA Limits Use of PD-1 Inhibitors in Stomach Cancer

The U.S. Food and Drug Administration (FDA) has taken decisive action to restrict the use of prominent PD-1 inhibitors in certain stomach cancer patients, marking a significant shift in the treatment landscape for gastric and esophageal cancers.

Revised Indications for Keytruda and Opdivo

Merck's Keytruda (pembrolizumab) and Bristol Myers Squibb's Opdivo (nivolumab) have both seen their indications narrowed for the treatment of advanced or metastatic gastric, gastroesophageal junction (GEJ), and esophageal cancers. The FDA now limits the use of these immunotherapies to patients whose tumors express PD-L1, a protein that helps cancer cells evade the immune system.

For Opdivo, the restriction applies to its use in combination with chemotherapy. Additionally, the approval for the combination of Opdivo and Yervoy (ipilimumab) in first-line esophageal squamous cell carcinoma has been limited to PD-L1-positive disease.

Keytruda's label has been similarly amended, with its use in gastric, GEJ, and esophageal cancers now confined to PD-L1-positive tumors. This change primarily affects HER2-negative disease, as Keytruda's approvals for HER2-positive cases in these settings had already been narrowed to PD-L1-positive patients in March.

FDA's Decision Based on Risk-Benefit Analysis

The FDA's decision stems from a comprehensive review of PD-L1 subgroup data from multiple phase 3 trials. The agency found that the risk-benefit profiles of these drugs appeared unfavorable in PD-L1-negative patients. This conclusion was supported by an external advisory committee, which voted overwhelmingly in favor of the FDA's updated perspective in September.

The Keynote-859 trial for Keytruda illustrates the rationale behind this decision. While the study showed a statistically significant improvement in overall survival for Keytruda plus chemotherapy versus chemotherapy alone in a broad population of patients with HER2-negative gastric or GEJ adenocarcinoma, an exploratory analysis of the PD-L1-negative subgroup revealed only an 8% death-risk reduction. This suggests that the overall improvement was primarily driven by results observed in PD-L1-positive patients.

Implications for the Pharmaceutical Industry

This regulatory action represents a broader trend of refining the use of immunotherapies based on biomarker data. It follows a similar move in 2018 when the FDA restricted the use of Keytruda and Roche's Tecentriq as monotherapies in certain bladder cancer patients.

The decision also highlights the evolving landscape of precision medicine in oncology, where treatments are increasingly tailored to specific patient subgroups based on biomarker expression. This approach aims to optimize treatment efficacy while minimizing unnecessary exposure to potential side effects in patients less likely to benefit.

For pharmaceutical companies, this development underscores the importance of comprehensive biomarker analysis in clinical trials and the potential for post-approval label revisions based on accumulated data. It also emphasizes the need for ongoing dialogue with regulatory agencies to ensure that drug indications accurately reflect the most current understanding of their efficacy and safety profiles.