Low-Dose Stereotactic Body Radiation Therapy–Based Radiation Therapy Followed by Pembrolizumab and Chemotherapy for Potentially Resectable Non-Small Cell Lung Cancer: A Phase 1b Study

PURPOSE: Chemoradiation therapy is standard for unresectable stage III non-small cell lung cancer (NSCLC). This phase 1b study assessed the safety and surgical conversion of neoadjuvant low-dose stereotactic body radiation therapy (SBRT)-based radiation therapy followed by pembrolizumab and chemotherapy in patients with potentially resectable stage III NSCLC. METHODS AND MATERIALS: Patients deemed potentially resectable by the multidisciplinary team received neoadjuvant low-dose SBRT-based radiation therapy to the primary tumor (24 Gy for peripheral lesions and 12 Gy for central lesions) delivered in 3 fractions. Selective planning target volumes were applied to spare critical structures and optimize surgical safety. Two cycles of 100-mg pembrolizumab plus platinum-based chemotherapy followed. Surgical feasibility was evaluated by the second multidisciplinary team 4 to 6 weeks after neoadjuvant therapy. The primary endpoint was safety; secondary endpoints included pathological complete response, progression-free survival, and overall survival. RESULTS: Seventeen patients received neoadjuvant therapy, with no dose-limiting toxicities observed. Across the overall treatment course, grade 3 to 5 treatment-related adverse events were reported in 5 patients (29.4%), most commonly grade 3 leukopenia (2 patients, 11.8%), and included 1 grade 5 surgical event due to fatal pulmonary artery hemorrhage. Objective responses were noted in 16 patients (94.1%). Surgery was successfully conducted in 11 patients (64.7%), with 10 (90.9%) achieving R0 resection. Six patients (54.5%) achieved pathological complete response. At a median follow-up of 22.8 months (95% CI, 18.9-26.7), the median progression-free survival was 29.0 months (95% CI, 18.1-39.9), and median overall survival was 37.9 months (95%CI, 21.9-53.9). CONCLUSIONS: Neoadjuvant low-dose SBRT-based radiation therapy followed by pembrolizumab and chemotherapy is tolerable and demonstrates promising rates of surgical conversion and pathological response in patients with potentially resectable stage III NSCLC.