Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) with Concurrent Immunotherapy

Summary: Stereotactic ablative radiotherapy (SAbR) has been investigated in clinical trials and largely failed to improve immunotherapy efficacy. Personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) is a novel technique where ablative "pulses" of radiation are given separated by a week or more. Pre-clinical studies have shown that combining PULSAR with immune check-point inhibitor (ICI) therapy improved tumor control compared to daily fractionated SAbR. Furthermore, PULSAR mimics a vaccination schedule, allowing adaptive immune cells to uptake tumor antigens from dying tumor cells and initiate antigen presentation prior to the next “booster” pulse. Thus, PULSAR offers the prospect of leveraging the synergy of ablative radiotherapy and immunotherapy. In this study, we characterize outcomes for patients receiving PULSAR with concurrent ICI. Clinical data was extracted from electronic medical records for patients treated with PULSAR and concurrent ICI prior to 1/1/2024. PULSAR was defined as at least 2 pulses of 5 Gy or more, with a minimum interval of 6 days. Toxicity was graded using CTCAEv5. Local control (LC) and disease progression were based on clinical and radiographic assessment. We identified 16 patients that received PULSAR with concurrent ICI. Primary tumor pathology varied, but the most prevalent tumors were of renal (n=7) and esophagogastric (n=3) origin. Treatment site included lungs/chest (n=8), abdomen (n=4), pelvis (n=3) and head/neck (n=1). Most patients received pembrolizumab or atezolizumab and 31% received combination of nivolumab with ipilimumab. Six patients were on ICI for a median of 219 days prior to starting PULSAR, with an initial clinical radiographic response reported in 67%. PULSAR treatment intent was mostly consolidative, with 25% being palliative. The median dose per pulse was 8.25 Gy (range: 6 to 15) and median number of pulses was 5 (range: 2 to 5). The median time between pulses was 15 days (range: 6 to 27). Plans were adapted over the course of treatment in 69% of patients; 31% of patients showed a reduction in PTV greater than 10 cm3. Radiotherapy related toxicity was rare, including grade 2 nausea and one report of grade 3 mucositis in a case of re-irradiation. For curative intent patients that completed a treatment course, LC was 91% and median time to progression at any site was 151 days (range: 18 to 434). Most patients (69%) ultimately discontinued or changed ICI therapy due to progression. Median follow-up was 364 days (range: 15 to 1157) and overall survival at one year was 62% (95% CI 42 to 91). PULSAR with concurrent immunotherapy provides excellent local control with minimal toxicity. We observed reasonable disease control in this heterogeneous patient cohort; but further study is needed to evaluate if PULSAR improves local and systemic synergy with ICI therapy, resulting in more durable disease control over traditionally fractionated SAbR Brett Tortelli (he/him/his), MD, PhD (Presenting Author) - University of Texas Southwestern; Casey Moore, MD, PhD (Co-Author) - University of Texas Southwestern; Robert Timmerman, MD (Co-Author) - UT Southwestern Medical Center; Raquibul Hannan, MD, PhD (Co-Author) - UT Southwestern Medical Center