The U.S. Food and Drug Administration (FDA) faces a pivotal decision regarding the use of immune checkpoint inhibitors in gastric and esophageal cancers, as recent advisory committee votes recommend restricting their use based on biomarker expression levels.
In September 2024, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 10-2 against the use of Merck's Keytruda (pembrolizumab) and Bristol Myers Squibb's Opdivo (nivolumab) as first-line treatments for advanced HER2-negative stomach cancer in patients with PD-L1 expression scores less than 1. The committee also voted 11-1 against their use in first-line unresectable or metastatic esophageal squamous cell carcinoma with low or no PD-L1 expression.
Biomarker-Based Decision Making Gains Momentum
This potential label restriction represents a significant shift in the FDA's approach to cancer therapeutics. Initially approved with broad indications, these PD-1 inhibitors are now under scrutiny as more comprehensive biomarker data becomes available.
"When [PD-1 inhibitors] first came out, we were like 'everyone gets pembro,' no matter the PD-L1 expression level because there was literally nothing else," explained Harpreet Singh, former FDA division director of oncology and current chief medical officer at Precision for Medicine.
The evolving regulatory landscape reflects the FDA's data-driven approach. As the only regulatory body with access to comprehensive clinical trial data across multiple drugs and sponsors, the agency can identify trends that individual companies cannot detect independently.
Risk-Benefit Analysis Drives Potential Restrictions
At the heart of the ODAC votes is the risk-benefit profile of PD-1 inhibitors in patients with low biomarker expression. Data presented at the ODAC meeting demonstrated that patients with high PD-L1 expression are more likely to benefit from these therapies, while those with low expression received limited therapeutic benefits and faced increased risks of toxicity.
Elad Sharon, a medical oncologist at the Dana-Farber Cancer Institute, explained the scientific rationale: "PD-L1 is a measure of how involved the immune system is in a cancer. If an immune response is evident by the presence of PD-L1 on the cell surfaces, then PD-1 inhibition has a chance to work and benefit the patient."
He added, "If you're not providing benefit to a patient, then you probably are only providing harm," noting that immuno-oncology agents disrupt normal regulatory pathways of the immune system, potentially leading to inflammation and other adverse effects.
Balancing Safety and Access
The FDA now faces the challenging task of balancing patient safety with access to treatments in areas of high unmet need. For gastric and esophageal cancers, where treatment options are limited, even therapies with modest benefits might provide meaningful outcomes for some patients.
"It's a balance between leading with the data and patient access," Singh noted, indicating her preference to publish the data and allow practitioners to ultimately make the call for their patients. However, she clarified that if the label is restricted, relatively few patients would be affected as gastroesophageal junction tumors rarely lack PD-L1 expression.
Manufacturers have advocated for preserving physician discretion, arguing that clinical judgment should determine treatment decisions for individual patients, particularly in diseases with few alternatives.
Precedent for Biomarker-Based Restrictions
This is not the first time the FDA has narrowed indications based on biomarker data. In 2022, the agency limited the use of PARP inhibitors from Clovis Oncology and GSK to ovarian cancer patient populations with certain BRCA mutations. In 2018, the FDA incorporated PD-L1 status into the labels of Keytruda and Tecentriq for existing frontline approvals in urothelial cancers after studies showed decreased overall survival in PD-L1 low patients.
A Merck spokesperson stated that the company "cannot speculate on the future actions of the FDA" and is "committed to continuing discussions" with the agency.
Implications for Drug Development
The increased scrutiny of biomarkers after approval carries significant implications for drug developers. Sharon recommended that the FDA require pre-specified analyses of relevant biomarkers in early-stage clinical trials.
"Identifying appropriate patient populations and developing statistically valid conclusions from clinical trials is an essential role that sponsors have to play," he emphasized.
Early biomarker tracking without excluding patients can help target drugs to populations expected to benefit most while developing accompanying diagnostic tests for patient selection.
"We have the technology to lead us to the right patient with the right therapy at the right time more now than ever," Sharon concluded. "We just have to make sure that when we're developing new agents, we rigorously test and co-develop these biomarkers so that we can achieve that significant level of precision and benefit for our patients."
Future of Precision Medicine Regulation
The regulatory shift highlights a pressing need for innovation in clinical trial design. Biomarker-driven trials allow for more precise patient selection and may mitigate the need for restrictive post-approval label changes.
Traditional approaches that test drugs on "all-comers" regardless of biomarker status maximize inclusivity but can later complicate regulatory decisions when discrepancies in outcomes emerge. Incorporating robust dose exploration studies and biomarker analyses earlier in development can streamline approvals and preserve both trial integrity and patient access.
As precision medicine continues to evolve, the FDA's approach to biomarker-based regulation will likely set important precedents for balancing scientific rigor, patient safety, and treatment access in oncology and beyond.
