Durvalumab Plus Concurrent CRT Does Not Add Benefit in Stage III NSCLC

Regarding responses, a difference of 0.2% was observed between the 2 arms, with a confirmed objective response rate of 60.7% with durvalumab vs 60.6% with placebo.

The addition of durvalumab (Imfinzi) to concurrent chemoradiation therapy (CRT) did not confer additional clinical benefit vs placebo among patients with unresectable stage III non–small cell lung cancer (NSCLC), according to findings from the phase 3 PACIFIC-2 trial (NCT03519971) published in the Journal of Clinical Oncology.1

An efficacy analysis comparing durvalumab administered concurrently vs placebo showed no statistically significant improvement in progression-free survival (PFS) between the 2 regimens (HR, 0.85; 95% CI, 0.65-1.12; P = .247). Additionally, the median PFS was 13.8 months (95% CI, 9.5-16.9) with durvalumab vs 9.4 months (95% CI, 7.5-16.6) with placebo.

The Kaplan Meier curves for PFS overlapped during the first 6 months of treatment, and following 9 months of treatment, a sustained and stable separation favored durvalumab. Additionally, HRs for PFS across prespecified subgroups were consistent with the overall analysis.

Overall survival (OS) outcomes also did not show a significant improvement with durvalumab vs placebo (HR, 1.03; 95% CI, 0.78-1.39; P = .823). The median OS in the durvalumab arm was 36.4 months (95% CI, 26.2-45.6) vs 29.5 months (95% CI, 23.2-45.1) with placebo.

The Kaplan Meier curves for OS crossed at 24 months, initially favoring placebo before crossing. At 27 months, a separation favoring durvalumab was observed, and was sustained until 54 months. The OS rate at 24 months was 58.4% (95% CI, 51.6%-64.7%) with durvalumab vs 59.5% (95% CI, 49.6%-68.2%) with placebo (HR, 1.04; 95% CI, 0.72-1.50]; P = .847). Subgroup analyses for OS were mostly consistent with the overall OS analysis.

“In PACIFIC-2, simultaneous durvalumab plus definitive [concurrent] CRT followed by consolidation durvalumab did not significantly improve PFS or OS [vs concurrent] CRT plus placebo for patients with unresectable stage III NSCLC,” Jeffrey D. Bradley, MD, FACR, FASTRO, professor of Radiation Oncology and vice chair of Proton Therapy and Technical Development at the Hospital of the University of Pennsylvania, wrote in the publication with study coinvestigators.1 “The PACIFIC [NCT02125461] regimen, comprising 12 months of consolidation durvalumab after definitive [concurrent] CRT among patients without progression after [concurrent] CRT, has demonstrated robust efficacy with 5 years of follow-up, with replicable safety and efficacy, and remains the [standard of care] in this setting.”

Regarding responses, a difference of 0.2% (95% CI, –15.2% to 16.3%; P = .976) was observed between the 2 arms, with a confirmed objective response rate (ORR) of 60.7% with durvalumab vs 60.6% with placebo. The median duration of response (DOR) was 30.7 months vs 18.6 months in the respective arms.

The phase 3 trial enrolled patients 18 years and older with newly diagnosed, histologically or cytologically confirmed, unresectable stage III NSCLC and randomly assigned them 2:1 to receive durvalumab at 1500 mg (n = 219) or matching placebo (n = 109) once every 4 weeks from the onset of concurrent CRT. In the absence of disease progression after completion of CRT, patients received consolidation durvalumab at 1500 mg or matching placebo once every 4 weeks until disease progression, withdrawal of consent, or other discontinuation criteria were met.

In the durvalumab and placebo arms, the median age was 63 years (range, 36-84) and 63 years (range, 38-84), respectively. Most patients in the respective arms were younger than 65 years (57.1% vs 56.9%), male (75.8% vs 73.4%), and White (64.4% vs 56.9%). A total of 49.3% vs 42.2% of the respective arms were from Europe, 85.4% vs 81.7% had a smoking history, 55.3% vs 51.4% had a World Health Organization (WHO) or ECOG performance status of 1, and 51.6% vs 55.0% had positive PD-L1 status.

The primary end point of the trial was PFS per RECIST v1.1 criteria by blinded independent central review (BICR). Secondary end points included ORR per RECIST v1.1 by BICR, OS, DOR, disease control rate, and safety.

Treatment-emergent adverse effects (TEAEs) occurred in 98.6% vs 100% in the durvalumab and placebo arms. Treatment-related AEs (TRAEs) occurred in 94.1% vs 91.7% of the respective arms, 59.4% vs 44.4% of which were related to durvalumab or placebo.

Grade 3 or 4 TEAEs occurred in 53.4% vs 59.3% of each arm; grade 5 AEs occurred in 13.7% and 10.2% of patients. AEs deemed serious occurred in 47.0% vs 51.9% of each arm.

The most common any-grade TEAEs in the durvalumab and placebo arms included anemia (42.0% vs 38.0%), pneumonitis or radiation pneumonitis (28.8% vs 28.7%), neutropenia (27.4% vs 25.9%), and nausea (25.6% vs 24.1%). The most common grade 3 or higher TEAEs included neutropenia (13.7% vs 7.4%), pneumonia (11.0% vs 12.0%), lymphopenia (9.6% vs 13.9%), leukopenia (9.1% vs 7.4%), and anemia (7.3% vs 10.2%).

Reference

Bradley JD, Sugawara S, Lee KH, et al. Simultaneous durvalumab and platinum-based chemoradiotherapy in unresectable stage III non–small cell lung cancer: the phase III PACIFIC-2 study. J Clin Oncol. Published online October 13, 2025. doi:10.1200/JCO-25-00036