The FDA's Oncologic Drugs Advisory Committee (ODAC) convened on September 26, 2024, to discuss the role of PD-L1 expression in guiding the use of checkpoint inhibitors for advanced gastroesophageal cancers. The committee reviewed data from multiple clinical trials and ultimately voted against the use of PD-1 inhibitors in specific patient subgroups with low PD-L1 expression.
Gastric/Gastroesophageal Junction Adenocarcinoma
The ODAC voted 10 to 2, with 1 abstention, against the risk-benefit profile of PD-1 inhibitors for first-line treatment of patients with advanced HER2-negative, microsatellite stable (MSS) gastric/gastroesophageal junction (GEJ) adenocarcinoma with a PD-L1 expression of less than 1. This decision impacts the use of drugs like nivolumab (Opdivo), pembrolizumab (Keytruda), and potentially tislelizumab-jsgr (Tevimbra) in this patient population.
Representatives from Bristol Myers Squibb, Merck Sharp & Dohme, and BeiGene presented data from the phase 3 CheckMate 649, KEYNOTE-859, and RATIONALE-305 trials, respectively. While these trials initially led to approvals for PD-1 inhibitors in the first-line setting for gastric and GEJ cancers, subgroup analyses revealed limited benefit in patients with low PD-L1 expression.
"My vote was no based upon the preponderance of evidence at this time. I think the risk:benefit ratio is not favorable," said Katherine Van Loon, MD, MPH, of the University of California, San Francisco, following the vote.
Supporting Data
- CheckMate 649: A subgroup analysis showed that among patients with a PD-L1 CPS of less than 1, those treated with nivolumab plus chemotherapy (n = 140) experienced a median OS of 13.08 months vs 12.48 months for those given chemotherapy alone (n = 125; HR, 0.92; 95% CI 0.70-1.23).
- KEYNOTE-859: Efficacy trends favoring pembrolizumab plus chemotherapy were seen in the PD-L1 CPS of less than 1 population for OS (HR, 0.92; 95% CI, 0.73-1.17) and PFS (HR, 0.90; 95% CI, 0.70-1.15).
- RATIONALE-305: Although an OS benefit was observed across PD-L1 subgroups for the tislelizumab regimen, the benefit was smallest in the population of patients with a PD-L1 expression of less than 1% (HR, 0.98; 95% CI, 0.64-1.50).
Esophageal Squamous Cell Carcinoma
In a separate session, the ODAC voted 11 to 1 against the risk-benefit assessment for the use of checkpoint inhibitors in patients with metastatic or unresectable esophageal squamous cell carcinoma with PD-L1 expression less than 1. This recommendation impacts the use of pembrolizumab, nivolumab, and tislelizumab in this specific cancer type and PD-L1 expression subgroup.
"Given the completely overlapping survival curves and even some suggestion of no benefit at all, even potential harm, I did not see enough evidence," said ODAC member Hanna Sanoff, MD, MPH, University of North Carolina at Chapel Hill.
Supporting Data
- KEYNOTE-590: The OS HR in patients with a CPS less than 1 was 1.00 (95% CI, 0.54-1.85), while it was 0.57 (95% CI, 0.44-0.75) with a CPS greater than 10.
- CheckMate 648: Showed an OS HR of 0.93 in patients with a CPS less than 1 and 0.62 for patients with a CPS greater than 10.
- Rationale-306: The HR for a tumor area positivity (TAP) score less than 1 was 1.34 and 0.66 with a TAP greater than 10.
Implications and Considerations
The FDA staff emphasized that the efficacy data suggests that PD-L1 expression is a predictive biomarker in identifying patients most likely to benefit from ICIs. They also highlighted the potential for harm, including serious immune-related adverse events, in patients with low or no PD-L1 expression who are unlikely to benefit from these therapies.
Several committee members raised concerns about the variability and standardization of PD-L1 testing, as well as the challenges of interpreting PD-L1 expression levels in clinical practice. The decisions reflect a growing emphasis on personalized medicine and the importance of carefully selecting patients for immunotherapy based on predictive biomarkers.
