WCLC 2025 - Posters & ePosters-P2.08 .23 Safety and Biomarker Analysis of Nrg-Lu004: Phase I Trial of Radiotherapy With Durvalumab in PD-L1 High LA-NSCLC

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This phase I trial (NRG-LU004) investigated the safety, feasibility, and immune biomarker changes of concurrent durvalumab (an anti-PD-L1 immunotherapy) with radiotherapy (RT) in patients with unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) exhibiting high PD-L1 expression (≥50%). Twenty-five patients received durvalumab with either accelerated fractionated RT (ACRT, 60 Gy/15 fractions) or standard fractionated RT (SDRT, 60 Gy/30 fractions). The primary goal was to assess safety via dose-limiting toxicities (DLTs), with feasibility defined as ≥80% patients receiving ≥80% of planned durvalumab doses in the first 8 weeks.<br /><br />No DLTs occurred in the ACRT arm, and a single DLT (bronchopulmonary hemorrhage, unrelated) occurred in the SDRT arm. Most patients tolerated treatment per protocol, with durvalumab feasibility at 85% (ACRT) and 75% (SDRT). Grade 3 or higher adverse events included lymphopenia, lung infections, and respiratory failure; however, some severe events were unrelated to treatment. These results indicate that concurrent durvalumab with RT without chemotherapy is safe and tolerable.<br /><br />Exploratory immune profiling of peripheral blood revealed that both regimens induced immune activation, but SDRT generated broader and sustained inflammatory and cytotoxic changes including elevated Th1 cytokines (IFN-γ, IL-15) and chemokines (CXCL11). CyTOF analysis showed a rebound of T effector memory cells at day 90 post-treatment, especially in SDRT. Importantly, soluble immune biomarkers correlated with adverse events; lower early levels of markers related to tumor and endothelial cell activity (e.g., EGF, CAIX, CASP-8) were associated with toxicity in SDRT, while soluble CD5 levels were consistently linked to lower adverse event occurrence regardless of treatment arm.<br /><br />This study supports chemotherapy-free thoracic RT concurrent with durvalumab as a safe strategy for PD-L1 high LA-NSCLC, demonstrating distinct immunologic effects depending on RT fractionation. The findings provide a mechanistic basis for combining immunotherapy with radiotherapy and identify potential biomarkers predictive of toxicity, informing future trials aiming to optimize treatment while minimizing side effects.

Asset Subtitle

Steven Lin

Meta Tag

Speaker Steven Lin

Topic Local-Regional Non-small Cell Lung Cancer

Keywords

NRG-LU004

durvalumab

radiotherapy

non-small cell lung cancer

PD-L1 high expression

phase I trial

dose-limiting toxicities

immune biomarkers

Th1 cytokines

CyTOF analysis