Evaluation of dose distribution to organs-at-risk in a prospective phase 1 trial of pembrolizumab and multi-site stereotactic body radiotherapy (SBRT).

Abstract Purpose To characterize the radiation doses to organs-at-risk (OARs) in the phase 1 trial (NCTXXX) that established safety/efficacy of SBRT using NRG-BR001 dose constraints combined with PD1 blockade for metastatic disease. Materials/Methods Between January 2016 and May 2018, 73 patients with advanced solid tumors were treated with SBRT followed by pembrolizumab. Tumor volumes (GTV/ITV) were delineated for each metastasis, with planning target volume (PTV) contraction to limit OAR dose per protocol (n=54) or when GTV/ITV >65cc (n=19). For 20 OARs, doses were compared to NRG-BR001 constraints. Protocol constraints were considered challenged when the minimum of the highest dose received by ≥6 patients without DLTs ( D m a x 6 t h ) was ≥70% of the protocol constraint. Results A total of 151 metastases were irradiated including 32 peripheral lung, 23 central lung, 13 mediastinal/cervical, 24 liver, 28 abdominal-pelvic, 16 osseous, and 15 spinal metastases. A median of 2 metastases (range 2-4) with mean volumes of 33.5cc (range 0.4cc-391cc) were treated using average PTVs of 50.7cc (range 3.2cc-161cc). At least one NRG-BR001 dose constraint was exceeded in 38 of 73 (52%) of patients. OAR constraints were challenged in 10 serial organs (gastrointestinal, cardio-pulmonary, musculoskeletal and nervous systems) and 1 parallel OAR (lung). Grade 3 dose-limiting toxicities (DLTs) occurred in 6 patients including pneumonitis (n=3), colitis (n=2), and hepatic failure (n=1). In 4 patients, the toxicity could be directly attributed to the planned dose to OAR (i.e., pneumonitis due to high lung dose or colitis due to high bowel dose). Conclusion Multi-site SBRT in combination with PD1 blockade was safely tolerated when treating critical central, abdominal-pelvic, and peripheral OARs nearing NRG-BR001 constraints with clinically acceptable toxicity in the corresponding organ systems. The observed relationship between dose and DLTs in 4 of 6 patients indicates that NRG-BR001 dose constraints should be respected in subsequent trials to maintain clinical safety.