Safety and Biomarker Analysis of NRG-LU004: Phase I Trial of Accelerated or Conventionally Fractionated Radiotherapy...

Patients with advanced non-small cell lung cancer (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) without concurrent chemotherapy would be safe and feasible in patients with locally advanced NSCLC (LA-NSCLC).

Stage II-III LA-NSCLC patients with PD-L1 >50% received durvalumab (1500 mg Q4 weeks x 13 cycles) with either accelerated fractionated RT (ACRT, 60 Gy/15 fractions) or standard fractionated RT (SDRT, 60 Gy/30 fractions), as 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.

Among 24 evaluable patients (n=12 each), one DLT occurred (SDRT arm). Both initial cohorts advanced to expansion. Most patients received RT per protocol (83%). 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. RT was completed per protocol in all 12 ACRT, and 10 of 12 for SDRT. Soluble proteomic analysis revealed significant immune changes particularly in the SDRT arm and potential biomarkers of immune-related adverse events.

Chemotherapy-free thoracic RT with either standard fractionated or accelerated courses with concurrent durvalumab is safe in PD-L1 high LA-NSCLC.