In June 2025, the US Food and Drug Administration (FDA) revised the labels for Merck’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s Opdivo (nivolumab), limiting their use in advanced gastric, gastroesophageal junction (GEJ) and esophageal cancers to patients whose tumors express programmed cell death ligand 1 (PD-L1) with combined positive score ≥ 1 as determined by an FDA approved test. This decision followed a September 2024 vote by the FDA’s Oncologic Drugs Advisory Committee, which found that the benefits of these drugs did not outweigh the risks for patients with PD-L1–negative tumors.

This action underscores the complexities surrounding off-label use, clinical compendia, and payer coverage when an FDA-approved indication is rescinded. Despite regulatory withdrawal, patients and providers navigate intricate pathways to maintain access based on existing evidence and payer policies.

FDA’s Decision and Its Rationale

The FDA’s decision to limit the market Immuno Oncology (IO) therapies to PD-L1–positive tumors was based on post-market data indicating minimal benefit for patients with PD-L1–negative tumors. In trials such as KEYNOTE-859 and CheckMate-649, PD-L1–negative subgroups showed only an 8% reduction in death risk with Keytruda and Opdivo, respectively. These findings led the FDA to conclude that the overall survival benefits observed were primarily attributable to patients with PD-L1–positive tumors.

This action also reflects the FDA’s ongoing scrutiny of the accelerated approval pathway, emphasizing the need for confirmatory trials to validate clinical benefits.

Role of Clinical Compendia and Guidelines

An FDA label withdrawal does not automatically remove a drug from clinical compendia or guidelines. Clinical compendia or guidelines may maintain recommendations based on supporting evidence, reclassify the use as off-label, or remove it if evidence is insufficient. For instance, in previous cases, certain breast cancer indications were withdrawn by the FDA, yet compendia continued to recommend use for specific subpopulations. This underscores the importance of clinical judgment and flexibility in evidence-based care, allowing providers to consider individual patient circumstances even when regulatory approvals change.

Payer Coverage Dynamics

Medicare may continue to cover treatments as off-label use, if they are supported by clinical compendia and literature, even after FDA label withdrawal. Commercial insurance plans vary in their responses; some may deny coverage for off-label use, while others may allow continued access based on medical necessity.

A critical concern is whether payers will terminate coverage for patients already undergoing treatment Generally, payers avoid disrupting ongoing therapy unless significant safety issues arise. In such cases, medical necessity reviews or transition plans may be implemented to ensure patient safety and continuity of care.

Patient Impact and Ethical Dilemmas

For the approximately 7% of patients with PD-L1-negative tumors who respond to treatment with Keytruda or Opdivo, the FDA’s decision introduces uncertainty regarding the continuation of therapy. Loss of access due to payer decisions can have negative effects on patient outcomes.

Providers must find the right balance of evidence-based practice with individual patient needs, balancing evidence-based practice with individual patient needs. They must navigate the tension between adhering to updated guidelines and advocating for continued treatment in patients who are benefiting from therapy.

Policy and Market Implications

The FDA’s action highlights the need for greater transparency in how clinical compendia and payers respond to label withdrawals. Manufacturers have an opportunity to proactively support off-label access by providing real-world data and engaging with stakeholders to demonstrate clinical benefits.

This development also prompts consideration of reforms to the accelerated approval lifecycle management to ensure that approvals are based on robust evidence and that withdrawals are communicated effectively to all stakeholders.

The FDA’s decision to limit Keytruda and Opdivo to PD-L1-positive gastric, GEJ, and esophageal cancers underscores the evolving complexity of oncology drug approvals and access. While off-label use remains a critical pathway for patient care, it is unevenly supported across healthcare systems. Ongoing dialogue among the FDA, clinical compendia, payers, and providers is essential to ensure patient-centered care amidst changing evidence landscapes.

How Avalere Health Can Help

Avalere Health continues to monitor the adoption of this FDA decision by compendia and other key stakeholders. Our expertise in compendia, coverage, and access strategy can help manufacturers, payers, and other stakeholders analyze clinical coverage policies and access implications to off-label treatments and help develop strategies to mitigate delays in patient access to treatment. To learn more, connect with us.