BACKGROUND: Esophageal cancer is a leading cause of cancer-related morbidity and mortality worldwide. Chemoradiotherapy followed by surgery is the standard of care for patients with resectable, locally advanced esophageal cancer. However, the risk for recurrence after this treatment remains high, especially among the majority of patients who do not have a pathologic complete response. Commenting on the recent publication of the CheckMate-557 study in an accompanying editorial published in the New England Journal of Medicine, David H. Ilson, MD, PhD, discussed the benefits and limitations of current treatments for esophageal cancer, noting that the current debate is whether chemotherapy alone or chemoradiotherapy is the preferred strategy for esophageal cancer before surgery.
“Improvement in survival among patients with esophageal cancer has been long awaited in those undergoing the arduous journey of chemotherapy, radiation, and surgery,” Dr Ilson emphasized, while discussing the findings from the CheckMate-557 clinical trial, which were published in the same issue. The study evaluated the use of the checkpoint inhibitor nivolumab as adjuvant treatment after chemoradiotherapy and surgery for esophageal cancer or gastroesophageal junction (GEJ) cancer. “CheckMate 577 is a practice-changing trial in the treatment of esophageal cancer,” Dr Ilson suggested.
METHODS: CheckMate-557 was a global, randomized, double-blind, placebo-controlled, phase 3 clinical trial of 532 patients with resected stage II or III esophageal cancer or GEJ cancer who had received neoadjuvant chemoradiotherapy and had residual pathologic disease. Patients were randomized in a 2:1 ratio to nivolumab or to placebo. The maximum duration of the study intervention was 1 year. The primary end point was disease-free survival.
RESULTS: Nivolumab significantly prolonged disease-free survival with a median of 22.4 months compared with a median of 11 months for placebo (hazard ratio [HR], 0.69; 96.4% confidence interval, 0.56-0.86; P <.001). Both distant and locoregional recurrence occurred less often with nivolumab than with placebo (29% and 12% vs 39% and 17%, respectively). “Although overall survival data are not mature, the doubling of median disease-free survival will almost certainly translate into an overall survival benefit,” Dr Ilson noted. The benefit of nivolumab compared with placebo in patients with esophageal cancer or GEJ cancer was seen across all subgroups, including patients with squamous-cell carcinoma (HR, 0.61), adenocarcinoma (HR, 0.75), node-negative disease (HR, 0.74), and node-positive disease (HR, 0.67). No new safety signals with nivolumab were observed, and only 9% of patients discontinued nivolumab therapy because of adverse events. Grade 3 or 4 adverse events occurred in 13% of patients who received nivolumab versus 6% of patients receiving placebo. Health-related quality of life was maintained during the treatment period.
“The trial shows the first true advance in the adjuvant therapy of esophageal cancer in recent years and will become a new standard of care,” noted Dr Ilson. However, he added, “despite the improvement observed, most patients will not gain benefit from adjuvant therapy with nivolumab. More contemporary biomarkers, including the presence of persistent circulating tumor DNA after surgery, should be explored to better define high-risk populations.” Dr Ilson concluded that the study provides a “welcome new therapeutic option for patients undergoing combined chemoradiotherapy before surgery.”
Sources: Kelly RJ, Ajani JA, Kuzdzal J, et al; for the CheckMate 577 investigators. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384:1191-1203; Ilson DH. Adjuvant nivolumab in esophageal cancer—a new standard of care. N Engl J Med. 2021;384:1269-1271.
Commentary by Robert J. Ignoffo
The study by Kelly and colleagues demonstrates a very welcome result for a cancer with poor prognosis and a devastating impact on survival. As has been shown previously, recurrence occurs in 70% to 75% of patients with esophageal cancer or GEJ cancer who do not have a pathologic complete response after neoadjuvant chemoradiotherapy.1 In the current trial by Kelly and colleagues, nivolumab was associated with a dramatic, 2-fold improvement in disease-free survival in patients with esophageal cancer or GEJ cancer compared with placebo and with a 31% decreased rate in recurrence or death. Moreover, the sustained separation of the Kaplan–Meier curves indicates a durable beneficial outcome. Of note, the greatest benefit occurred in patients who initiated nivolumab therapy ≥10 weeks after surgery compared with patients who initiated nivolumab therapy <10 weeks after surgery. However, in the 2 patient subgroups, which were stratified according to time from complete resection to randomization, the median disease-free survival was approximately 10 months longer with nivolumab than with placebo.
I fully agree with Dr Ilson’s editorial that accompanied this article. This study provided enough evidence to include adjuvant nivolumab therapy in the setting of locally advanced esophageal cancer or GEJ cancer.
- Blum Murphy M, Xiao L, Patel VR, et al. Pathological complete response in patients with esophageal cancer after the trimodality approach: the association with baseline variables and survival—the University of Texas MD Anderson Cancer Center experience. Cancer. 2017;123:4106-4113.