Phase I Study of Stereotactic Body Radiotherapy Plus Nivolumab and Urelumab or Cabiralizumab in Patients with Advanced Solid Tumors.

Foster, Corey C; Fleming, Gini F; Karrison, Theodore G; Liao, Chih-Yi; Desai, Ami V; Moroney, John W; Ratain, Mark J; Nanda, Rita; Polite, Blase N; Hahn, Olwen M; O'Donnell, Peter H; Vokes, Everett E; Kindler, Hedy L; Hseu, Robyn; Janisch, Linda A; Dai, Julia; Hoffman, Mark D; Weichselbaum, Ralph R; Pitroda, Sean P; Chmura, Steven J; Luke, Jason J

BACKGROUND CD137 agonism and CSF-1R blockade augment stereotactic body radiotherapy (SBRT) and anti-PD1 in pre-clinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF-1R inhibitor). PATIENTS AND METHODS This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1-4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if {less than or equal to}33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies. RESULTS Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n=3 grade 3, n=4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months (95% CI 2.9-4.8) and 17.0 months (95% CI 6.8-undetermined), respectively. No patients with elevated pre-SBRT serum interleukin-8 experienced a response. CONCLUSIONS SBRT to {less than or equal to}4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest anti-tumor activity.