A Phase 2 Single-Arm Trial of High-Dose Precision Targeted Radiation Therapy Added to Immunotherapy for Patients With Metastatic Non-Small Cell Lung Cancer

Purpose: For metastatic non-small cell lung cancer, the addition of radiation therapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS). Methods and Materials: In this single-arm phase 2 trial, 45 patients with metastatic non-small cell lung cancer who had received an anti-PD-1/anti-PD-L1 ICI for 4+ weeks were enrolled from July 2017 to May 2021. Patients received high-dose RT to 1 to 4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing with a historical control rate of 35%. Results: Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1–positive. Median number of treated tumors was 2 and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI, 44%-75%), higher than the historical control rate (P <.001). Median PFS was 6.9 months (95% CI, 4.0-13.5 months) and median overall survival was 27.4 months (95% CI, 20.4-not reached). Several patients with prestudy disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at 1, 2, and 3 years. Two dose-limiting toxicities were observed (5%), including 1 grade 5 pneumonitis. Conclusions: The strategy improved 24-week PFS compared with historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.