Results from the phase II ARION trial, reported at ESMO 2026, showed that adding durvalumab to definitive chemoradiotherapy did not significantly improve progression-free survival in patients with locally advanced or unresectable esophageal cancer.
Although immunotherapy has demonstrated survival benefits in metastatic esophageal cancer, the ARION findings suggest that adding PD-L1 blockade to definitive chemoradiotherapy does not necessarily translate into improved outcomes in the non-metastatic setting.
Background
Definitive chemoradiotherapy is the standard treatment approach for patients with locally advanced or unresectable esophageal cancer who are not candidates for curative surgery.
However, long-term disease control remains challenging, with historical two-year disease-free survival rates of approximately 25%.
Given the benefits of immune checkpoint inhibitors in metastatic disease, the ARION trial investigated whether adding durvalumab, an anti-PD-L1 antibody, to standard chemoradiotherapy could improve outcomes in patients with non-metastatic esophageal cancer.
Study Design and Patient Population
ARION was a multicenter, open-label, randomized phase II trial conducted across 13 centers in France.
Between May 2019 and May 2024, 112 patients with locally advanced esophageal squamous cell carcinoma or unresectable adenocarcinoma were randomized to receive:
- Arm A: Standard chemoradiotherapy plus durvalumab (58 patients).
- Arm B: Standard chemoradiotherapy alone (54 patients).
Eligible patients were aged 18 years or older, had a WHO performance status of 0–1, and had non-metastatic disease.
Standard chemoradiotherapy consisted of intensity-modulated radiotherapy (IMRT) delivering 50 Gy in 25 fractions over five weeks, combined with six cycles of FOLFOX chemotherapy.
Patients in the experimental arm additionally received durvalumab at 1,500 mg every four weeks for 12 doses.
The primary endpoint was centrally reviewed progression-free survival (cPFS), while secondary endpoints included investigator-assessed PFS, overall survival (OS), and safety. The median patient age was 67 years, 68% were male, 77% had squamous cell carcinoma, and 70% had lymph node involvement.
Progression-Free Survival Results
At the analysis performed after 24 months of follow-up, durvalumab did not significantly improve centrally reviewed progression-free survival compared with chemoradiotherapy alone.
The 12-month cPFS rates were:
- Durvalumab plus chemoradiotherapy: 48.6% (95% CI, 34.6–61.3).
- Chemoradiotherapy alone: 48.9% (95% CI, 34.7–61.7).
The adjusted hazard ratio was 0.91 (95% CI, 0.55–1.49; one-sided P=0.351).
Similar findings were observed for investigator-assessed PFS, with 12-month rates of 50.1% in the durvalumab group versus 48.1% in the control group (HR 0.92; 95% CI, 0.56–1.50; one-sided P=0.369).
These results indicate that adding durvalumab did not provide a statistically significant improvement in disease control.
Overall Survival Outcomes
Although numerical differences were observed in 12-month overall survival, these did not translate into a statistically significant benefit.
The 12-month OS rates were:
- Durvalumab plus chemoradiotherapy: 75.1% (95% CI, 61.6–84.4).
- Chemoradiotherapy alone: 67.9% (95% CI, 53.6–78.7).
- The adjusted hazard ratio was 0.99 (95% CI, 0.59–1.68; one-sided P=0.489).
The findings therefore did not demonstrate an overall survival advantage with the addition of durvalumab. Longer-term survival analyses and investigations of potential predictive factors for treatment benefit are anticipated.
Safety Findings
Treatment-related adverse events were more frequent among patients receiving durvalumab in addition to chemoradiotherapy. However, the incidence of grade 3 or higher adverse events was similar between treatment groups. Investigators reported no new safety signals associated with the addition of durvalumab.
The results suggest that although the combination had a manageable safety profile within the trial, the additional treatment burden was not accompanied by a demonstrated improvement in progression-free survival.
Clinical Implications
The ARION findings add to the evidence questioning the benefit of routinely incorporating immune checkpoint inhibitors into definitive chemoradiotherapy for unresectable esophageal cancer.
Despite the established activity of immunotherapy in advanced disease, combining durvalumab with FOLFOX-based chemoradiotherapy did not significantly improve centrally reviewed PFS or overall survival in this randomized phase II study.
The results highlight the importance of evaluating immunotherapy combinations in specific treatment settings rather than extrapolating their benefits from metastatic disease.
However, the relatively small sample size and phase II design limit definitive conclusions regarding potential benefits in selected patient subgroups. Further investigation of molecular and clinical predictors of immunotherapy response may help identify patients most likely to benefit from combined treatment approaches.
Conclusion
The phase II ARION trial did not demonstrate a significant progression-free survival benefit from adding durvalumab to definitive FOLFOX-based chemoradiotherapy in patients with locally advanced or unresectable esophageal cancer.
At 12 months, centrally reviewed PFS was 48.6% with durvalumab versus 48.9% with chemoradiotherapy alone, while overall survival differences were not statistically significant.
Although no new safety concerns emerged, treatment-related adverse events were more frequent with durvalumab.
These findings do not support routine addition of durvalumab to this definitive chemoradiotherapy regimen based on the reported results, while longer follow-up and biomarker analyses may further clarify its potential role.
