The FDA's Oncologic Drugs Advisory Committee (ODAC) recently convened to discuss the role of PD-L1 expression as a predictive biomarker for immunotherapy response in esophageal squamous cell carcinoma (ESCC). The central question was whether the level of PD-L1 expression could reliably identify patients likely to benefit from anti-PD-1 therapies.
ODAC's Vote and Clinical Trial Data
On September 26, 2024, ODAC voted 11 to 1, with 1 abstention, against the favorable risk-benefit profile of anti-PD-1 therapies for the frontline treatment of metastatic or unresectable ESCC in patients with a PD-L1 combined positive score (CPS) of less than 1%. This decision followed presentations of data from the phase 3 KEYNOTE-590, CheckMate 648, and RATIONALE-306 trials, which evaluated pembrolizumab (Keytruda), nivolumab (Opdivo), and tislelizumab-jsgr (Tevimbra) based regimens, respectively. While all three trials demonstrated a statistically significant overall survival (OS) benefit with the anti-PD-1 containing regimens compared to chemotherapy, subgroup analyses revealed that OS outcomes were not significantly different between arms among patients with a PD-L1 CPS of less than 1%.
Challenges in PD-L1 Testing and Interpretation
According to Nataliya Uboha, MD, PhD, an associate professor and researcher at the University of Wisconsin School of Medicine and Public Health, a key challenge lies in the reliable measurement of PD-L1 expression. "There’s a lot of heterogeneity in expression," Uboha noted, highlighting concerns about variations between primary and metastatic sites, as well as the potential impact of treatments like radiation on PD-L1 expression. The committee also discussed the difficulty in reliably identifying the exact PD-L1 score, especially in the 1% to 10% range.
Potential Restrictions on Immunotherapy Approvals
The ODAC's discussion raised the possibility of restricting the approval of nivolumab and pembrolizumab to PD-L1–positive populations in esophageal cancer. This would mirror the FDA's decision to narrow pembrolizumab’s approval in HER2-positive tumors based on PD-L1 expression. Initially, pembrolizumab had a broad approval in HER2-positive tumors, regardless of PD-L1 expression. However, accumulating data led the FDA to limit the approval to patients with both HER2-positive and PD-L1–positive tumors with a PD-L1 CPS cutoff of 1%.
The Need for Simplified Guidelines and Testing
Experts emphasize the need for simpler testing, recommendations, and guidelines for community oncologists. Currently, there is discordance between the label, FDA approval, and ASCO/NCCN guidelines. A push for uniform cutoffs for PD-L1 expression could facilitate the interchangeable use of these agents and ease adoption in clinical practice.
Implications for Tislelizumab and Chemotherapy Combinations
The ODAC meeting also touched on the potential implications of tislelizumab's approval in combination with different chemotherapy backbones for ESCC management. The phase 3 study of tislelizumab used both 5-FU–based and paclitaxel–based chemotherapy. If tislelizumab is approved in combination with chemotherapy, clinicians will have the opportunity to offer a different chemotherapy backbone to patients with ESCC.
