A Phase I Trial of Concurrent Or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients with Stage IV Non-Small Cell Lung Cancer (COSINR Study)

ABSTRACT INTRODUCTION Prior studies have examined stereotactic body radiotherapy (SBRT) in oligometastatic NSCLC patients, including multimodality treatment with anti-PD1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT (mSBRT) in stage IV NSCLC patients to evaluate safety and obtain preliminary activity data. METHODS Treatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab/ipilimumab continued until clinically significant progression, development of toxicity, or two years. Dose-limiting toxicity (DLT) was defined as grade ≥ 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy within 3 months. RESULTS A total of 37 patients were evaluable. No dose limiting toxicity occurred in the concurrent cohort (n=18). The sequential cohort required a dose reduction in the central lung group due to two grade 4 pneumonitis events (2/19). Overall best response was: 5.4%(2/37) complete response, 40.5%(15/37) partial response, 16.2%(6/37) stable disease, and 37.8%(14/37) progressive disease. Median progression-free survival was 5.8 months (95% CI: 3.6 to 11.4 mos), with median follow up of 17.0 months. Median overall survival was not reached. CONCLUSIONS Concurrent nivolumab/ipilimumab and SBRT was not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastases control and encouraging early OS.