The CheckMate 577 trial—reported in The New England Journal of Medicine by Kelly et al1 and reviewed in this issue of The ASCO Post—is the first global randomized controlled trial for patients with resectable esophageal cancer that showed a significant disease-free survival benefit for adjuvant immunotherapy vs observation. There is no doubt that CheckMate 577 will change clinical practice. The question is for which patients with esophageal cancer?
Neoadjuvant radiochemotherapy followed by surgery has become one, but not the only, standard of care for patients with esophageal cancer, following the results of the randomized controlled CROSS trial. This study compared trimodality therapy with surgery alone. Patients with an incomplete response to preoperative neoadjuvant radiochemotherapy are at high risk of relapse and death from esophageal cancer.
“The disease-free survival results from CheckMate 577 will change practice for patients who underwent trimodality therapy for locally advanced esophageal cancer without achieving a histopathologic complete response in the resection specimen.”— FLORIAN LORDICK, MD, PhD
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In CheckMate 577, 1 year of adjuvant nivolumab dramatically improved outcomes for patients with high-risk esophageal cancer following trimodality therapy. Disease-free survival doubled from 11 months to 22 months in nivolumab-treated patients, suggesting that longer follow-up may also show a difference in overall survival. The short disease-free survival in the control arm underpins the selection of a poor prognostic group of patients for this trial.
Histologic Subtype May Guide Treatment Selection
Centers that recommend neoadjuvant radiochemotherapy for both histologic subtypes of locally advanced esophageal cancer may now feel prompted to use nivolumab for all patients with residual tumor in the resection specimen. However, many centers worldwide have adopted different treatment strategies for esophageal squamous cell cancer and esophageal adenocarcinoma. Although trimodality treatment is a widely accepted standard of care for patients with esophageal squamous cell cancer, at least in the Western world, esophageal adenocarcinoma is treated either with neoadjuvant radiochemotherapy or perioperative chemotherapy. Following European Society for Medical Oncology guidelines, the latter approach is particularly common in Europe but also in parts of North America, Latin America, the United Kingdom, and Australia-New Zealand. Results from randomized controlled trials comparing both approaches -(ESOPEC and Neo-AEGIS) are awaited.
It is currently unknown whether adjuvant immunotherapy improves outcomes following neoadjuvant chemotherapy and surgery in patients with esophagogastric junction adenocarcinoma (types I–III) or gastric cancer. This important question is currently being investigated in the European Organisation of Research and Treatment of Cancer VESTIGE study.
Different Histologies, Different Responses
Both patients with esophageal squamous cell cancer and esophageal adenocarcinoma were enrolled in CheckMate 577. This approach must be questioned, given that these two histologic subtypes have a totally different genomic background and tumor biology, according to The Cancer Genome Atlas investigators, and respond differently to neoadjuvant radiochemotherapy and immune checkpoint inhibitors. As expected, patients with esophageal squamous cell cancer had a much larger disease-free survival benefit from adjuvant nivolumab (hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.42–0.88) compared with patients who had esophageal adenocarcinoma (HR = 0.78, 95% CI = 0.59–0.96). Another criticism of the study design might be that tumor location was not a stratification criterion at randomization. Finally, no significant benefit for adjuvant nivolumab was shown for patients with cancers located at the esophagogastric junction (HR = 0.87, 95% CI = 0.63–1.21).
In advanced esophageal cancer, PD-L1 expression on tumor and infiltrating immune cells (combined positive score) predicts benefit from anti–PD-1 therapy. In CheckMate 577, tumor cell PD-L1 expression (tumor proportion score [TPS] ≥ 1% or < 1%) was used as a stratification factor. In 12% of patients, the PD-L1 TPS was indeterminate or could not be evaluated. No difference in nivolumab efficacy was observed between PD-L1–positive and PD-L1–negative cancers, supporting the conclusion that PD-L1 TPS is not predictive in this disease setting. Meaningful biomarkers for the selection of patients for adjuvant immunotherapy still need to be established. In addition, the presence of persistent circulating tumor DNA after surgery should be explored to monitor patients receiving adjuvant immunotherapy.
It is reassuring that no geographic or ethnic differences in adjuvant immunotherapy efficacy were observed in CheckMate 577. This is important to note since some discussions at regulatory agencies circled around that point. Thus far, European patients have not been granted the same access to immunotherapy for upper gastrointestinal cancers compared with East Asian and U.S. patients.
Finally, longer-term follow-up will be required to demonstrate an improvement in overall survival. However, the disease-free survival results from CheckMate 577 are meaningful and will change practice for patients who underwent trimodality therapy for locally advanced esophageal cancer without achieving a histopathologic complete response in the resection specimen.
Dr. Lordick is Director and Professor of Oncology at the University Cancer Center, Leipzig.
DISCLOSURE: Dr. Lordick has received honoraria from AstraZeneca, BioNTech AG, Bristol Myers Squibb, Elsevier, Infomedica, Lilly, Medscape, Merck KGaA, Merck Sharp & Dohme, Roche, and Servier; has served as a consultant or advisor to Amgen, Astellas Pharma, BeiGene, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Servier, and Zymeworks; has received institutional research funding from Bristol Myers Squibb; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and Lilly.
REFERENCE
1. Kelly RJ, Ajani JA, Kuzdzal J, et al: Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384:1191-1203, 2021.
