At the 2025 ASCO Annual Meeting, updated survival data from the CheckMate 577 trial reignited discussion within the global oncology community. The study focused on patients with esophageal or gastroesophageal junction (GEJ) cancer who had received neoadjuvant chemoradiotherapy (nCRT) followed by surgery but did not achieve a pathologic complete response (non-pCR). In this high-risk subgroup, adjuvant treatment with nivolumab demonstrated sustained disease-free survival (DFS) benefits and a numerical improvement in overall survival (OS) compared with placebo. Oncology Frontier invited Dr. Wentao Fang and Dr. Xuan Hong from Shanghai East Hospital to offer insights into the efficacy and safety data of CheckMate 577.

1. Current Global Debate on Neoadjuvant Strategies: Chemoradiotherapy vs. Chemotherapy (DCF) vs. Immunotherapy Combinations

Neoadjuvant chemoradiotherapy followed by surgery remains the guideline-recommended standard of care for patients with resectable, locally advanced esophageal cancer. Landmark trials such as CROSS and China’s NEOCRTEC5010 have demonstrated significant survival benefits in patients with resectable esophageal or GEJ tumors. In Japan, the JCOG1109 study reported a 3-year survival rate of 78.8% using neoadjuvant chemotherapy with DCF (docetaxel, cisplatin, 5-FU), whereas Western countries continue to favor concurrent chemoradiotherapy. Recently, several phase II trials suggest that combining immunotherapy with chemotherapy in the neoadjuvant setting significantly increases pCR rates, and multiple phase III trials are currently underway to validate this approach.

2. CheckMate 577: A New Era for Adjuvant Immunotherapy in Esophageal Cancer

CheckMate 577 is the first global phase III trial to evaluate adjuvant immunotherapy following nCRT and R0 resection in esophageal cancer. It has been included in the NCCN Guidelines as a category 1 recommendation and remains the only globally recognized standard for adjuvant treatment in this setting. The trial specifically targeted high-risk non-pCR patients—representing 70–75% of those receiving nCRT. Multiple research centers in China, led by Prof. Fang Wentao, contributed to this international effort.

Key updated findings (NCT02743494):

• Significant DFS benefit: Median DFS was 21.8 months in the nivolumab group vs. 10.8 months in the placebo group (HR 0.76 [95% CI 0.63–0.91]).
• Improved distant metastasis-free survival (DMFS): HR 0.75, suggesting enhanced control of distant spread.
• Positive OS trend: 5-year OS rate improved by 5% (46% vs. 41%), though not statistically significant (HR 0.85, P=0.1064). The high crossover rate (60% of patients in the placebo arm received immunotherapy upon relapse) likely diluted the observable OS difference.

In non-pCR patients, CheckMate 577 strongly confirmed that adjuvant nivolumab significantly prolongs DFS—median DFS reached 22.4 months, effectively doubling that of the control group. To date, it remains the only approved immunotherapy for adjuvant treatment in esophageal cancer.

In pCR patients, who generally have a lower recurrence risk, the necessity of adjuvant therapy remains controversial. Patients with high-risk features—such as lymph node involvement—may derive greater benefit from adjuvant strategies.

3. Safety Profile and Quality of Life

• Excellent tolerability: Grade 3–4 treatment-related adverse events (TRAEs) occurred in only 13% of patients (vs. 6% in the placebo group). No treatment-related deaths were reported.
• Stable quality of life: Patient-reported outcomes (FACT-E and EQ-5D-3L scores) showed no significant decline during treatment, with over 90% of patients completing the assessments.

The combination of low toxicity and meaningful survival gain makes this a safe and effective option, particularly suitable for Asian populations, where squamous cell carcinoma predominates (90%), and managing toxicity is a clinical priority.

4. Unanswered Questions and Future Directions

• Why was OS improvement not statistically significant? The high rate of crossover treatment in the placebo arm (60%) may have masked a true OS benefit. Real-world data are needed to confirm long-term survival outcomes.
• What about patients who received neoadjuvant chemotherapy (not CRT)? CheckMate 577 only included patients treated with nCRT. The value of adjuvant immunotherapy following neoadjuvant chemotherapy (e.g., DCF) or chemoimmunotherapy remains unproven and requires dedicated trials.
• Can immunotherapy be integrated earlier? There is strong interest in incorporating agents like nivolumab into neoadjuvant regimens or using them as postoperative maintenance strategies after various neoadjuvant approaches. Esophageal squamous cell carcinoma may eventually adopt a perioperative immunotherapy model, similar to what has been seen in lung cancer.

Conclusion

The latest data from CheckMate 577 (NCT02743494) provide robust evidence supporting adjuvant nivolumab for patients with non-pCR esophageal cancer following nCRT. The trial demonstrated a doubling of median DFS and clinically meaningful improvements in DMFS. While the 5-year OS rates (46% vs. 41%, HR 0.85, P=0.1064) did not reach statistical significance, the results remain clinically important.

However, three key contradictions need resolution:

1. OS not statistically significant: Likely influenced by the 60% crossover rate in the placebo arm; real-world validation of survival benefit is crucial.
2. Limited scope of the study population: The trial only evaluated nCRT-treated patients; it’s unclear whether patients treated with chemotherapy or investigational immunotherapy combinations would derive similar benefits.
3. Lack of biomarkers for patient selection: Without precise predictive markers, there is a risk of overtreating low-risk patients while undertreating high-risk individuals. Incorporating minimal residual disease (MRD) detection technologies may help assess recurrence risk and guide personalized treatment decisions, shifting from population-based standards toward precision oncology.