Chemotherapy-Free Durvalumab Plus Radiation Meets PFS End Point in Locally Advanced Non-Small Cell Lung Cancer

Clinical Summary:

• Design/Population: DART was a multicenter, single-arm, phase 2 trial evaluating definitive thoracic radiation therapy with concurrent and consolidative durvalumab in patients with inoperable locally advanced non-small cell lung cancer who were ineligible for concurrent chemoradiotherapy.
• Key Outcomes: The trial met its 2-year progression-free survival end point and showed encouraging overall survival and response rates. Toxicity was clinically relevant, with pneumonitis and immune-related adverse events requiring careful monitoring.
• Clinical Relevance: Concurrent and consolidative durvalumab with definitive radiation provides  a potential chemotherapy-free strategy for frail and elderly patients with locally advanced non-small cell lung cancer who cannot tolerate standard concurrent chemoradiotherapy, a population without an established standard of care. However, the single-arm design, historical comparison, and risks of severe pneumonitis and treatment discontinuation warrant prospective randomized confirmation.

Results from the phase 2 DART trial showed that definitive thoracic radiation therapy with concurrent and consolidative durvalumab met the prespecified progression-free survival (PFS) end point in elderly and frail patients with locally advanced non-small cell lung cancer (NSCLC) who are ineligible for concurrent platinum-based chemoradiotherapy. 

“No [standard of care] exists for patients who are [concurrent platinum-based chemoradiotherapy]-ineligible because of age, comorbidities, or frailty,” stated Andreas Rimner, MD, Memorial Sloan Kettering Cancer Center, New York, New York, and coauthors. “Here, we investigated the efficacy and adverse events of concurrent and consolidative durvalumab with definitive radiation therapy without chemotherapy.”

In this multicenter, single-arm trial, 58 patients with surgically unresectable or medically inoperable locally NSCLC received 1500 mg of intravenous durvalumab once every 4 weeks for up to 13 cycles with definitive thoracic radiotherapy at 54 to 66 Gy in 2-Gy. Radiation therapy was initiated within 7 days of durvalumab. The primary end point was 2-year PFS, with the trial designed to demonstrate an improvement from a historical rate of 20% rate for sequential chemoradiotherapy to 36%. Secondary end points included overall survival (OS), objective response rate (ORR), and safety.

At a median follow-up of 19.3 months, the 2-year PFS rate was 39%. Median PFS was 14 months, with PFS rates of 78% at 6 months, 55% at 12 months, and 39% at 24 months. Median OS was 25 months, with OS rates of 83% at 6 months, 78% at 12 months, and 54% at 24 months. Among evaluable patients, the ORR was 72%, and the disease control rate was 87%. 

Performance status and PD-L1 expression were also associated with outcomes. Better ECOG/Karnofsky performance status was significantly associated with improved PFS and OS. Patients with PD-L1-positive tumors has a median PFS of 15 months compared with 9.2 months in patients with PD-L1-negative tumors (P = .12). Median OS not reached in patients with PD-L1-positive tumors and 15 months in patients with PD-L1-negative tumors (P = .049). PD-L1 positivity was also associated with a lower cumulative incidence of cancer-specific death (P = .018). 

Treatment was associated with clinically meaningful toxicity in this elderly and frail population. Grade 3/4 adverse events occurred in 21% of patients, with 4 deaths due to pneumonitis (n = 2) and cardiac arrest (n = 2). Grade 3/4 pneumonitis occurred in 7% of patients. Adverse events led 18 patients (31%) to discontinue durvalumab after a median of 8 doses, primarily because of pneumonitis or hypoxia. Grade ≥2 radiation pneumonitis occurred in 24% of patients and resulted in durvalumab discontinuation in 14%.

This study “demonstrates the best PFS and acceptable safety profile thus far for particularly high-risk, elderly, frail chemotherapy-ineligible patients with [locally advanced] NSCLC,” concluded Dr Rimner et al. “These results serve as a benchmark for future trials in this underserved but growing patient population.”

“Clinical trials addressing this population of frail and elderly patients can provide informative evidence for treatment selection that addresses the unique balances of treatment efficacy and safety,” added Journal of Clinical Oncology associate editor Caroline Chung, MD, MD Anderson Cancer Center, Houston, Texas. 

Source:

Rimner A, Lebow ES, Fitzgerald KJ, et al. Durvalumab with radiation therapy in patients with inoperable locally advanced non–small cell lung cancer ineligible for concurrent chemoradiotherapy (DART). J Clin Oncol. Published online: July 16, 2026. doi: 10.1200/jco-25-02517