CheckMate 577 Final Results: Adjuvant Nivolumab Sustains Disease-Free Survival Benefit in Resected Esophageal and Gastroesophageal Junction Cancer

Esophageal cancer (EC) and gastroesophageal junction cancer (GEJC) remain aggressive malignancies with poor prognosis, even after curative-intent surgery and neoadjuvant chemoradiotherapy (CRT). A significant subset of patients harbor residual pathologic disease post-treatment, placing them at high risk for recurrence and metastasis. The CheckMate 577 trial (NCT02743494), a global, randomized phase 3 study, initially demonstrated that adjuvant nivolumab, an immune checkpoint inhibitor targeting PD-1, significantly improved disease-free survival (DFS) compared with placebo in patients with resected EC/GEJC with residual disease following neoadjuvant CRT and surgery.

At ASCO 2025, investigators reported the final overall survival (OS) analysis, along with updated longer-term follow-up for DFS, distant metastasis-free survival (DMFS), and progression-free survival on subsequent systemic therapy (PFS2), providing a more comprehensive understanding of the clinical benefit and safety of adjuvant nivolumab in this patient population.

Study Design and Methods

This double-blind, placebo-controlled trial enrolled adults with resected (R0) stage II/III EC or GEJC who had undergone neoadjuvant CRT and had residual pathologic disease confirmed at surgery. Patients were randomized in a 2:1 ratio to receive adjuvant nivolumab (240 mg intravenously every 2 weeks for 16 weeks, followed by 480 mg every 4 weeks) or placebo for up to one year.

The primary endpoint was DFS, while OS served as a hierarchically tested secondary endpoint. Exploratory endpoints included DMFS and PFS2. Safety and treatment-related adverse events (TRAEs) were also assessed throughout the study.

Patient Population

A total of 794 patients were randomized: 532 received nivolumab, and 262 received placebo. Patients had a median follow-up of 78.3 months (range 60.1–96.6), representing one of the longest follow-ups for adjuvant immunotherapy in this setting.

Efficacy Outcomes

Disease-Free Survival: Adjuvant nivolumab continued to demonstrate a sustained and statistically significant DFS benefit compared to placebo. Median DFS was 21.8 months (95% CI, 16.6–29.7) in the nivolumab arm versus 10.8 months (95% CI, 8.3–14.3) in the placebo arm, with a hazard ratio (HR) of 0.76 (95% CI, 0.63–0.91), reaffirming earlier findings.

Overall Survival: Although the difference in median OS did not reach statistical significance at the final analysis, nivolumab showed a meaningful numerical improvement. Median OS was 51.7 months (95% CI, 41.0–61.6) for patients receiving nivolumab, compared with 35.3 months (95% CI, 30.7–48.8) in the placebo group (HR 0.85; 95.87% CI, 0.70–1.04; P = 0.1064). OS rates at 3 and 5 years were 57% and 46% with nivolumab versus 50% and 41% with placebo, respectively, suggesting a durable survival benefit.

Distant Metastasis-Free Survival: Nivolumab also conferred a significant improvement in DMFS, with median values of 27.3 months (95% CI, 21.4–36.0) versus 14.6 months (95% CI, 10.9–20.3) in the placebo arm (HR 0.75; 95% CI, 0.62–0.90). This indicates a substantial delay in distant recurrence among treated patients.

Progression-Free Survival 2 (PFS2): PFS2, measuring time to progression after subsequent systemic therapy, favored nivolumab with an HR of 0.81 (95% CI, 0.67–0.98), suggesting lasting benefits beyond initial adjuvant treatment.

Safety Profile

Treatment-related adverse events (TRAEs) were more common in the nivolumab arm but remained manageable. Any-grade TRAEs occurred in 71% of nivolumab-treated patients compared to 48% in placebo recipients. Grade 3–4 TRAEs were reported in 14% and 7%, respectively. Discontinuations due to TRAEs were slightly higher with nivolumab (9% any-grade, 5% grade 3–4) compared to placebo (3% and 3%). No new safety signals or unexpected toxicities emerged during the extended follow-up.

Clinical Significance

These findings from CheckMate 577 trial reinforce the role of adjuvant nivolumab as a new standard of care for patients with resected EC/GEJC with residual disease following neoadjuvant CRT. The durable DFS and improved DMFS suggest a meaningful impact on disease control, while the trend toward prolonged OS is encouraging.

With a favorable safety profile and manageable toxicity, nivolumab offers a significant therapeutic advance in this high-risk population, where recurrence rates remain historically high.

What They’re Saying: Reactions to CheckMate 577 Trial at ASCO 2025

Richard Dunne, MD, Leader, GI Oncologist from wilmotcancer center shared on X

Checkmate 577 data final OS analysis. Key Subgroups reported: HR of 0.92 for OS in patients with esophageal adenocarcinoma with adjuvant nivolumab and tumors that are PDL1+ driving small benefit

Key Takeaway Messages from CheckMate 577 Trial

Adjuvant nivolumab significantly improved disease-free survival (DFS) compared to placebo in patients with resected stage II/III esophageal or gastroesophageal junction cancer with residual pathologic disease following neoadjuvant chemoradiotherapy. Median DFS was 21.8 months with nivolumab versus 10.8 months with placebo (HR 0.76, 95% CI 0.63–0.91).

Long-term data show a persistent DFS benefit with nivolumab after a median follow-up of over 78 months. The 3- and 5-year DFS rates remained higher for patients treated with nivolumab compared to placebo.

Overall survival (OS) showed a numerical improvement with nivolumab (median OS 51.7 vs 35.3 months for placebo), although the difference was not statistically significant at this final analysis (HR 0.85, 95% CI 0.70–1.04; P = 0.1064).

Distant metastasis-free survival (DMFS) and progression-free survival on subsequent therapy (PFS2) also favored nivolumab over placebo, further supporting its long-term benefit.

The safety profile of adjuvant nivolumab was manageable and consistent with previous reports, with no new safety signals observed over extended follow-up.

Fewer patients receiving nivolumab required subsequent therapy compared to placebo, and the need for subsequent immunotherapy was markedly lower in the nivolumab group.

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Written by Armen Gevorgyan, MD