Safety and Biomarker Analysis of Nrg-Lu004: Phase I Trial of Radiotherapy With Durvalumab in PD-L1 High LA-NSCLC

Document Type

Conference Proceeding

Publication Date

9-8-2025

Publication Title

J Thorac Oncol

Keywords

biological marker, CD5 antigen, durvalumab, Fas ligand, granzyme, immune checkpoint inhibitor, interleukin 15, programmed death 1 ligand 1, adult, aged, antineoplastic activity, cancer inhibition, cell count, conference abstract, controlled study, drug therapy, female, human, lung infection, lymphocytopenia, male, non small cell lung cancer, phase 1 clinical trial, radiotherapy, respiratory failure, T lymphocyte activation

Abstract

Introduction: Patients with locally advanced non-small cell lung cancer (LA-NSCLC) and high PD-L1 (>50%) expression show improved outcomes with immune checkpoint inhibitors compared to chemotherapy. We hypothesized that concurrent durvalumab and radiotherapy (RT) would be safe and feasible in this population. Methods: In the phase I study, NRG-LU004 (NCT03801902), stage IIIII unresectable LA-NSCLC patients with PD-L1 >50% received durvalumab (1500 mg Q4 weeks) with either accelerated fractionated RT (ACRT, 60 Gy/15 fractions) or standard fractionated RT (SDRT, 60 Gy/30 fractions) for initial and expansion cohorts. Primary objective was safety assessed through dose-limiting toxicities (DLTs). Feasibility was defined as >80% of patients receiving >80% of planned durvalumab in the first eight weeks. Peripheral blood specimens were collected at baseline and throughout treatment for exploratory immune profiling analyses to evaluate biomarkers related to treatment and/or adverse events. Results: Among 24 evaluable patients (enrolled 2019-2021), no DLTs occurred in ACRT. One DLT (bronchopulmonary hemorrhage, unrelated) occurred in SDRT. Both initial cohorts advanced to expansion. Most patients received RT per protocol (82.6%). At time of analysis, 24% had completed all durvalumab cycles. In ACRT, adverse events included four grade 3, one grade 4 (lymphopenia), and one grade 5 (lung infection, unrelated). In SDRT, there were eight grade 3 and one grade 5 (respiratory failure, unrelated) events reported. Durvalumab feasibility was 85% in ACRT and 75% in SDRT. Soluble proteomic analysis revealed significant immune changes, with increased Th1 signatures and homing markers in both arms (IFN-Y, IL15, CXCL11). The most extensive changes in circulating immune markers occurred in the durva+SDRT arm, while they were relatively limited in the durva+ACRT arm. Inflammatory and cytotoxicity soluble markers were consistently increased with the prolonged SDRT regimen, up to Day 90 (D90). Soluble markers associated with T-cell activation and cytotoxicity peaking at D90 in plasma were corrobo rated by CyTOF data where a rebound in T effector memory and T E M R A cell numbers was observed at D90 following an initial decrease. Finally, we also found immune biomarkers differentially associated with the occurrence of AEs, particularly presenting as decreased sol uble protein measures at d15 upon durva+SDRT, but not upon durva +ACRT. Several of these markers appear related to tumor or endothelial cell expression (EGF, CAIX, ADA) and to cell death (CASP-8, granzymes A and H, FAS ligand), which implies that SDRT toxicity may reduce the capacity to mobilize effective anti-tumor responses. The most consistent biomarker significantly associated with AE occurrence regardless of arms, when measured either at baseline or early upon treatment (D15), was soluble CD5. Conclusions: Chemotherapy-free thoracic RT (SDRT or ACRT) with concurrent durvalumab is safe in PD-L1 high LA-NSCLC. In addition, our work establishes the mecha nistic basis for combination immunotherapy and radiation on circu lating immune biomarkers.

Volume

20

Issue

10

First Page

S350

Last Page

S351

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