Concurrent Durvalumab and Chemoradiotherapy Fails to Provide Survival Advantage in Unresectable, Stage III NSCLC

The concurrent use of durvalumab (Imfinzi) and chemoradiation followed by consolidation durvalumab did not lead to survival benefits compared with chemoradiation alone followed by consolidation durvalumab in patients with unresectable stage III non–small cell lung cancer (NSCLC), according to findings from the phase 3 EA5181 trial (NCT04092283) that were shared at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.¹

In the durvalumab arm, the median overall survival (OS) was 41.5 months (95% CI, 34.4-not reached [NR]) vs 39.4 months (95% CI, 33.4-NR) for patients in the chemoradiation arm (HR, 1.03; 95% CI, 0.80-1.32; P = .83). The median progression-free survival (PFS) was 15.5 months in the durvalumab arm (95% CI, 13.9-22.1) vs 16.4 months (95% CI, 12.0-20.2) in the chemoradiation arm (HR, 1.05; 95% CI, 0.86-1.29; P = .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,” John M. Varlotto, MD, professor and chief of Radiation Oncology at Marshall Health, stated during the presentation.

What Was the Design of the EA5181 Trial?

Patients were randomly assigned 1:1 to receive either platinum doublet durvalumab at 750 mg every 2 weeks plus 3 concurrent rounds of radiotherapy at 60 Gy or platinum doublet chemotherapy with concurrent radiotherapy at 60 Gy. Patients could then transition to consolidation durvalumab at 1500 mg every 4 weeks for 1 year from the end of chemoradiation. This transition could occur within 2 weeks, but may be delayed up to 45 days, depending on whether patients’ toxicities are not grade 2 or less.

Patients were stratified by planned chemotherapy, age, sex, and disease stage. Patients were eligible for treatment if they had unresectable stage IIIA to C NSCLC and had an ECOG performance status of 0 to 1. The primary end point was OS, with secondary end points being PFS, toxicity, ORRs, and recurrence patterns.

A total of 662 patients were randomly assigned to either arm. Varlotto noted the study had an 82% power to detect a 25% reduction in the OS HR rate of 0.01631 to 0.01223, and a 1-sided alpha level of 0.025.

What Baseline Characteristics Were Observed Among Patients in the EA5181 Trial?

The median follow-up was 29.9 months (95% CI, 28.4-33.1). In the durvalumab arm, 335 patients were enrolled, with 305 completing treatment, and 277 moving on to consolidation. In the chemoradiation alone arm, 327 patients were enrolled, 300 completed treatment, and 277 moved on to consolidation.

Across both arms, 60.6% of patients were male, the median age was 67.1 years (range, 37.6-89.4), and 50.6% of patients had stage IIIA disease. Additionally, 48.7% of patients had adenocarcinoma, 53.3% were former smokers, and 82.5% were given carboplatin/paclitaxel.

What Additional Efficacy Findings Were Seen in the EA5181 Trial?

A total of 45.4% of patients experienced disease progression in the durvalumab arm, and 44.0% had it in the chemoradiation arm. Local recurrence was noted in 55.9% vs 49.6% (P = .34), and radiation in-field recurrences were observed in 28.6% vs 28.4% (P = .98).

Prior to consolidation, the ORR was 51.3% in the durvalumab arm and 47.1% in the chemoradiation alone arm (P = .28), while in consolidation, the ORR was 71.5% vs 67.1% (P = .31). In both arms, the median number of consolidative cycles of durvalumab was 10.

What Were the Safety Findings From the EA5181 Trial?

In the durvalumab arm, adverse effects (AEs) of any grade occurred in 99.1% of patients vs 98.7% of those in the chemoradiation alone arm, whereas grade 3/4 AEs were noted in 67.7% of patients in the durvalumab arm vs 62.2% of those in the chemoradiation alone arm. Serious AEs were observed in 3.6% vs 3.5% of patients, respectively, and AEs leading to treatment discontinuation occurred in 19.0% vs 16.5% of patients, respectively.

The most common grade 3 to 5 treatment-related AEs in the durvalumab and chemoradiation alone arms were 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%).

Reference

Varlotto JM, Xie Y, Pennell N, et al. ECOG-ACRIN EA5181: phase 3 trial of concurrent and consolidative durvalumab vs consolidation durvalumab alone for unresectable stage III NSCLC. Presented at the 2025 World Conference on Lung Cancer; Barcelona, Spain; September 6-9, 2025. Abstract PL-3.04.