Ronan J. Kelly, MB BCh, MBA

As reported in The New England Journal of Medicine by Ronan J. Kelly, MB BCh, MBA, of The Charles A. -Sammons Cancer Center at Baylor University Medical Center, and colleagues, an interim analysis of the phase III CheckMate 577 trial has shown a significant improvement in disease-free survival with adjuvant nivolumab vs placebo in patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy.¹

As noted by the investigators: “No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer.”

Study Details

In the double-blind trial, 794 patients from sites in 29 countries with resected (R0) stage II or III esophageal or gastroesophageal junction cancer. (All patients had received neoadjuvant chemoradiotherapy, after which they had residual pathologic disease and then proceeded to complete resection.) They were randomly assigned 2:1 between July 2016 and August 2019 to receive nivolumab at 240 mg every 2 weeks for 16 weeks followed by 480 mg every 4 weeks (n = 532) or placebo (n = 262). Randomization was stratified according to tumor cell PD-L1 expression (≥ 1% or < 1%, indeterminate/could not be evaluated), pathologic lymph node status (≥ ypN1 or ypN0), and histologic type. Nivolumab and placebo were continued until disease recurrence, unacceptable toxic effects, or withdrawal of consent. The maximum duration of the trial intervention period was 1 year. The primary endpoint was investigator-assessed disease-free survival.

For the nivolumab vs placebo groups: median age was 62 years (range = 26–82 years) vs 61 years (range = 26–86 years); 84% vs 85% were male; 81% vs 82% were White and 16% vs 13% Asian; geographic region was Europe for 38% vs 39%, United States or Canada for 31% vs 34%, Asia for 14% vs 11%, and the rest of the world for 16% vs 17%; Eastern Cooperative Oncology Group performance status was 0 (58% vs 60%) or 1 in all patients; stage at diagnosis was II in 34% vs 38% and III in 66% vs 62%; tumor location was esophagus in 60% vs 59% and gastroesophageal junction in 40% vs 41%; histology was adenocarcinoma in 71% vs 71% and squamous cell carcinoma in 29% vs 29%; tumor cell PD-L1 expression was < 1% in 70% vs 75%, ≥ 1% in 17% vs 15%, and indeterminate/could not be evaluated in 13% vs 10%; pathologic lymph node status at entry was ≥ ypN1 in 57% vs 58% and ypN0 in 43% vs 42%; and pathologic tumor status at entry was ypT0 in 6% vs 6%, ypT1–2 in 38% vs 40%, and ypT3–4 in 56% vs 53%.

Disease-Free Survival

At the time of interim analysis (clinical data cutoff in May 2020), median follow-up was 24.4 months (range = 6.2–44.9 months). Median disease-free survival was 22.4 months (95% confidence interval [CI] = 16.6–34.0 months) in the nivolumab group vs 11.0 months (95% CI = 8.3–14.3 months) in the placebo group (hazard ratio [HR] = 0.69, 96.4% CI = 0.56–0.86, P < .001).

Disease-free survival favored nivolumab across all prespecified subgroups examined. For example, this benefit was seen among 129 patients with PD-L1 expression ≥ 1% (89 received nivolumab, 40 received placebo; median disease-free survival = 19.7 vs 14.1 months, HR = 0.75, 95% CI = 0.45–1.24), among 374 vs 196 patients with expression < 1% (median = 21.3 vs 11.1 months, HR = 0.73, 95% CI = 0.57–0.92), and among 69 vs 26 patients with indeterminate/could not be evaluated status (median = not reached vs 9.5 months, HR = 0.54, 95% CI = 0.27–1.05). Median disease-free survival was not reached vs 27.0 months among 227 vs 109 patients with pathologic lymph node status of ypN0 (HR = 0.74, 95% CI = 0.51–1.06) and 14.8 vs 7.6 months among 305 vs 152 patients with ≥ ypN1 (HR = 0.67, 95% CI = 0.53–0.86).

Nivolumab treatment was associated with a disease-free survival benefit among 376 vs 187 patients with adenocarcinoma (median = 19.4 vs 11.1 months, HR = 0.75, 95% CI = 0.59–0.96) and among 155 vs 75 with squamous cell carcinoma (median = 29.7 vs 11.0 months, HR = 0.61, 95% CI = 0.42–0.88).

Distant recurrence occurred in 29% vs 39% of patients and locoregional recurrence in 12% vs 17%. Median distant metastasis–free survival was 28.3 months (95% CI = 21.3 months to not estimable) in the nivolumab group vs 17.6 months (95% CI = 12.5–25.4 months) in the placebo group (HR = 0.74, 95% CI = 0.60–0.92).

Subsequent anticancer therapy was received by 30% vs 42% of patients, including radiotherapy in 8% vs 16%, surgery in 5% vs 8%, and systemic therapy in 23% vs 34%, including immunotherapy in < 1% vs 7%.

Adverse Events

Grade 3 or 4 adverse events of any cause occurred in 34% of the nivolumab group vs 32% of the placebo group. Serious adverse events of any cause occurred in 30% of patients in each group. Treatment was discontinued due to adverse events of any cause in 13% vs 8%. Among adverse events considered related to study treatment, grade 3 or 4 adverse events occurred in 13% vs 6% of patients, serious adverse events occurred in 8% vs 3%, and adverse events led to discontinuation of treatment in 9% vs 3%. The most common adverse events of any grade considered related to treatment were fatigue (17%), diarrhea (17%), pruritus (10%), and rash (10%) in the nivolumab group and diarrhea (15%) and fatigue (11%) in the placebo group.

The most common any-grade potential immune-related adverse events in the nivolumab group were skin events (24%), endocrine events (17%), and gastrointestinal events (17%). The most common of grades 3 or 4 were hepatic, pulmonary, and skin events (1% each).

The investigators concluded: “Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo.” 

DISCLOSURE: The study was funded by Bristol Myers Squibb and Ono Pharmaceutical. Dr. Kelly has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, EMD Serono, Lilly, Medscape, Merck, Novartis, Onc Live, Peerview, Pieris Pharmaceuticals, and Takeda; and has received institutional research funding from 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.