The addition of durvalumab during concurrent chemoradiotherapy failed to provide survival benefits compared to the current standard of consolidation durvalumab alone in patients with unresectable stage III non-small cell lung cancer (NSCLC), according to results from the phase 3 EA5181 trial presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.
The study enrolled 662 patients with previously untreated, unresectable stage IIIA to IIIC NSCLC, randomizing them 1:1 to receive either concurrent durvalumab at 750 mg every 2 weeks with platinum doublet chemotherapy and radiotherapy at 60 Gy, or standard chemoradiotherapy alone. Both arms could transition to consolidation durvalumab at 1500 mg every 4 weeks for one year following chemoradiotherapy completion.
Primary Efficacy Outcomes
The trial's primary endpoint of overall survival showed no significant difference between treatment arms. Median overall survival was 41.5 months (95% CI, 34.4-not reached) in the concurrent durvalumab arm versus 39.4 months (95% CI, 33.4-not reached) in the chemoradiotherapy alone arm (HR, 1.03; 95% CI, 0.80-1.32; P = 0.83).
Similarly, progression-free survival showed no improvement with concurrent durvalumab. The median progression-free survival was 15.5 months (95% CI, 13.9-22.1) in the durvalumab arm compared to 16.4 months (95% CI, 12.0-20.2) in the chemoradiotherapy arm (HR, 1.05; 95% CI, 0.86-1.29; P = 0.65).
"In patients with unresectable, stage III [NSCLC], the addition of concomitant durvalumab during the course of chemotherapy/radiation did not improve OS, did not improve PFS, did not change the recurrence patterns or ORRs [overall response rates], and did not increase toxicity," stated John M. Varlotto, MD, professor and chief of Radiation Oncology at Marshall Health, during the presentation.
Patient Characteristics and Treatment Completion
The median follow-up was 29.9 months (95% CI, 28.4-33.1). In the concurrent durvalumab arm, 335 patients were enrolled, with 305 completing treatment and 277 proceeding to consolidation therapy. In the chemoradiotherapy alone arm, 327 patients were enrolled, 300 completed treatment, and 277 moved to consolidation.
Patient demographics were well-balanced across both arms, with 60.6% male patients, median age of 67.1 years (range, 37.6-89.4), and 50.6% having stage IIIA disease. Adenocarcinoma histology was present in 48.7% of patients, 53.3% were former smokers, and 82.5% received carboplatin/paclitaxel chemotherapy.
Response Rates and Recurrence Patterns
Objective response rates were comparable between arms. Prior to consolidation, the overall response rate was 51.3% in the durvalumab arm and 47.1% in the chemoradiotherapy alone arm (P = 0.28). During consolidation, response rates were 71.5% versus 67.1% (P = 0.31), respectively.
Disease progression occurred in 45.4% of patients in the durvalumab arm and 44.0% in the chemoradiotherapy arm. Local recurrence patterns showed no significant differences, with rates of 55.9% versus 49.6% (P = 0.34), and radiation in-field recurrences observed in 28.6% versus 28.4% (P = 0.98).
Safety Profile
The safety analysis revealed comparable toxicity profiles between treatment arms. Adverse events of any grade occurred in 99.1% of patients in the durvalumab arm versus 98.7% in the chemoradiotherapy alone arm. Grade 3/4 adverse events were noted in 67.7% versus 62.2% of patients, respectively.
Serious adverse events were observed in 3.6% versus 3.5% of patients, and adverse events leading to treatment discontinuation occurred in 19.0% versus 16.5% of patients in the durvalumab and chemoradiotherapy alone arms, respectively.
The most common grade 3 to 5 treatment-related adverse events included lymphocyte count decrease (50% vs 45%), white blood cell count decrease (22% vs 27%), esophagitis (21% vs 27%), neutrophil count decrease (16% vs 14%), and pneumonitis (12% vs 5%).
Clinical Implications
The EA5181 trial results support maintaining the current standard of care using durvalumab as consolidation therapy after chemoradiotherapy completion rather than concurrent administration. Despite theoretical rationale that concurrent chemoradiotherapy might enhance immunogenic cell death and improve checkpoint inhibitor efficacy, the clinical data demonstrate no survival advantage.
John Varlotto emphasized the significance of these findings: "Our data demonstrate that adding durvalumab concurrently with chemoradiotherapy does not improve overall survival compared to the current approach of initiating durvalumab as consolidation therapy. These results support maintaining the present standard in treating unresectable stage III NSCLC."
The study had 82% power to detect a 25% reduction in the overall survival hazard ratio and used a one-sided alpha level of 0.025, providing robust statistical framework for the negative results. These findings reinforce evidence-based treatment guidelines and support continued use of durvalumab consolidation post-chemoradiotherapy as the standard of care for unresectable stage III NSCLC.
