A Pilot Trial of Proton-Based Cardiac Sparing Accelerated Fractionated Radiation Therapy in Unresectable Non-small Cell Lung Cancer With Extended Durvalumab Therapy (PARTICLE-D)

Purpose: Concurrent chemoradiation therapy is the current nonsurgical standard of care for locally advanced non-small cell lung cancer. However, this is a difficult regimen to tolerate, especially for those who are elderly, have multiple comorbidities, or have poor performance status. Alternative treatment regimens are needed for this vulnerable population. We report initial results of concurrent durvalumab, an immune checkpoint inhibitor, and hypofractionated, dose-escalating, proton external beam radiation therapy (EBRT). Methods and Materials: This phase 1, pilot dose escalation trial enrolled 7 patients with newly diagnosed stage IIIA to IIIC non-small cell lung cancer and who were unable or unwilling to undergo concurrent chemoradiation therapy. Patients previously treated with immunotherapy were excluded. Five patients in this 3 + 3 study design received a fixed dose of durvalumab on day 1 of each 28-day cycle plus hypofractionated proton EBRT with initial dose of 60 Gy (Arm 1) in 20 fractions while 2 patients received the escalation dose of 69 Gy in 23 fractions (Arm 2). The primary objective was to assess safety and the secondary objective was to assess feasibility and adverse events. Results: All patients experienced treatment-related adverse events, primarily grades 1 and 2. Pneumonitis and anemia were the most common. Only 1 dose-limiting toxicity occurred in arm 1, which was a grade 3 pneumonitis leading to grade 5 pneumonia. Additionally, 2 delayed-onset grade 5 tracheal necrosis events occurred >13 months after treatment initiation. Conclusions: Concurrent durvalumab plus hypofractionated proton EBRT was well tolerated in the short term. However, 3 treatment-related deaths, including 2 delayed-onset grade 5 tracheal necroses negatively impacted overall safety. A dose de-escalation protocol of proton-based radiation therapy plus durvalumab is warranted.