The role of PD-1 inhibitors in treating gastric, gastroesophageal junction (GEJ), and esophageal squamous cell carcinoma (ESCC) cancers is under scrutiny, particularly concerning the appropriate PD-L1 expression thresholds for treatment decisions. Recent discussions have centered on whether to restrict the use of these inhibitors based on PD-L1 expression levels, especially in light of varying efficacy and potential toxicities.
ODAC's Deliberations on PD-L1 Cutoffs
Oncologic Drugs Advisory Committee (ODAC) meetings have highlighted concerns regarding the risk-benefit profile of PD-1 inhibitors in patients with PD-L1-negative gastrointestinal tumors. Nataliya Uboha, MD, PhD, from the University of Wisconsin School of Medicine and Public Health, noted the ongoing debate about the optimal PD-L1 cutoff, particularly for patients with expression levels between 1% and 10%.
Uboha stated, "In my practice, I offer immunotherapy to those with a PD-L1 combined positive score [CPS] of 1% or greater." However, she acknowledged variability in PD-L1 expression between primary and metastatic sites, emphasizing the need for better treatments in patients with serious illnesses. She also highlighted the uncertainty in biomarker testing reliability.
Tislelizumab and PD-L1 Expression
The pending approval of tislelizumab-jsgr (Tevimbra) in combination with platinum-containing chemotherapy for ESCC is adding another layer to the discussion. Data from the phase 3 RATIONALE-306 trial indicated a significant improvement in overall survival (OS) compared to placebo and chemotherapy. However, 3-year survival data presented at the 2024 ASCO Annual Meeting revealed a greater survival benefit in patients with a PD-L1 tumor area positivity (TAP) score of 10% or higher.
Specifically, among patients with a PD-L1 TAP score of 10% or greater, the median OS was 16.6 months in the tislelizumab plus chemotherapy arm versus 10.0 months in the placebo plus chemotherapy arm (HR, 0.70; 95% CI, 0.52-0.95). In contrast, for those with a PD-L1 TAP score less than 10%, the median OS was 16.0 months in the tislelizumab arm versus 10.4 months in the placebo arm (HR, 0.77; 95% CI, 0.60-0.99).
Challenges in PD-L1 Testing
The accuracy and reliability of PD-L1 testing are central to the debate. Robert Albert Anders, MD, PhD, a pathologist at Johns Hopkins Kimmel Cancer Center, emphasized the caveats in PD-L1 testing, including specimen type, staining methods, and test interpretation. He argued that PD-L1 should be an additional piece of evidence, not the sole determinant for PD-1 inhibitor treatment.
Anders noted, "There are a lot of very detailed portions of PD-L1 testing, [and] the thresholds are presented as all or none... I find these things are often overlooked in the discussion of clinical biomarkers."
Uboha also pointed out the discordance between drug prescribing information, FDA approval, and ASCO/NCCN guidelines, advocating for simpler and more uniform PD-L1 cutoffs to facilitate clinical practice and trial designs.
Data from Gastric/GEJ Adenocarcinoma Trials
Data from the phase 3 CheckMate 649, KEYNOTE-859, and RATIONALE-305 trials in gastric/GEJ adenocarcinoma showed statistically significant OS benefits for patients treated with PD-L1 agent-containing arms versus control arms. However, exploratory results highlighted by the FDA indicated that benefits were greatest in patients with a PD-L1 score of 10% or higher.
For instance, patients with a PD-L1 score of 10% or higher treated with nivolumab plus chemotherapy had an HR of 0.65 (95% CI, 0.55-0.78), while those with PD-L1 expression less than 1% had an HR of 0.92 (95% CI, 0.70-1.23).
Implications for ESCC Treatment
In ESCC, trials like KEYNOTE-590, CheckMate 648, and RATIONALE-306 showed statistically significant OS data favoring anti–PD-L1-containing arms versus chemotherapy alone. However, the treatment effect estimates were not favorable in patients with PD-L1 expression less than 1% and appeared intermediate in those with PD-L1 expression less than 10%.
Uboha noted that most ESCCs express PD-L1, suggesting broader use of anti–PD-1 agents in these patients. However, the data indicate that the extent of PD-L1 expression still influences treatment outcomes.
Future Directions and the Approval of Zolbetuximab
The treatment landscape is evolving with the recent FDA approval of zolbetuximab-clzb (Vyloy) plus fluoropyrimidine- and platinum-containing chemotherapy for HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive. This development adds complexity to treatment paradigms, requiring reflexive CLDN18.2 testing.
As targeted agents like zolbetuximab enter the market and the approval of tislelizumab plus chemotherapy for ESCC and gastric cancer indications is pending, clarity is emerging regarding the optimal approach for patients with low PD-L1 expression.
Uboha concluded, "The ODAC committee voted to recommend restricting the use of these [anti–PD-1 antibody] agents to patients whose tumors have PD-L1 expression, and I’m hoping that the FDA will further refine the label going forward."
