Heterogeneous Radioimmunotherapy for Bulky Tumors: A Phase 1 Trial for Advanced Non-Small Cell Lung Cancer

PURPOSE: Inoperable bulky tumors remain challenging to treat with chemotherapy, radiation therapy (RT), or immune checkpoint inhibitors. We developed a novel heterogeneous RT technique with an eclipse-shaped dose distribution (EclipseRT, ERT) by embedding partial-tumor stereotactic body RT (immunogenic) within a low-dose RT (immunomodulatory) field targeting the gross tumor volume. In our previous study, we demonstrated that ERT plus anti-programmed cell death protein 1 (αPD-1) (iERT) activated the natural killer/DC/CD8⁺ T-cell axis, triggering potent antitumor immunity against bulky tumors in mouse tumor models. Here, we report a phase 1 trial to evaluate the safety and feasibility of iERT for advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: This phase 1 trial (NCT05615142, iERT-01) employed a 3 + 3 dose-escalation design. Patients with stage IV NSCLC and bulky tumors (>5 cm) who had failed standard therapy, were ineligible for standard therapy, or declined standard therapy were enrolled. iERT was delivered in 1 to 3 fractions of 10 Gy stereotactic body RT plus 2 Gy low-dose RT with anti-programmed cell death protein 1 (αPD-1). The primary endpoint of the iERT-01 trial was safety and tolerability. Key secondary endpoints included objective response rate, progression-free survival, and overall survival. RESULTS: A total of 9 patients with bulky NSCLC were included. The median follow-up was 22.3 months. iERT was well tolerated, with no dose-limiting toxicities observed. Overall, 7 of 9 patients (77.8%) experienced at least 1 adverse event, and 7 of 9 (77.8%) experienced treatment-related adverse events, all of which were grade 1 or 2. Moreover, it demonstrated encouraging antitumor activity, achieving an objective response rate of 55.6% (5 of 9), with a median progression-free survival of 12.6 months and a median overall survival of 26.4 months. CONCLUSIONS: iERT demonstrated favorable safety and feasibility in this phase 1 trial for advanced bulky NSCLC. Larger-cohort studies with optimized dose regimens are still warranted to further validate the novel strategy.