(P 287) A PHASE 1 STUDY OF NEOADJUVANT CABOZANTINIB IN COMBINATION WITH RADIATION THERAPY FOR SARCOMAS OF THE EXTREMITIES

Objective: Cabozantinib demonstrates promising activity in multiple soft tissue sarcoma (STS) subtypes, but use with concurrent radiation therapy (RT) has previously been limited by concern for risk of fistula or perforation. This phase 1 nonrandomized trial evaluated safety of concurrent cabozantinib and RT as neoadjuvant therapy in patients with extremity STS.

Methods: Adults with new diagnosis of localized extremity STS who were planned for neoadjuvant RT and surgical resection were eligible. Subjects received radiation per standard clinical care with 5000-5040 cGy with conventional fractionation. A 3+3 dose-finding design was used with starting doses of cabozantinib 40mg and 60mg daily. Patients were observed for dose-limiting toxicity (DLT) up to 28 days after completion of concurrent RT with cabozantinib. The primary endpoint was recommended phase 2 dose (RP2D) of cabozantinib for combination with RT, and secondary endpoints were treatment related adverse event (TRAE) rates, margin status, and objective response rates.

Results: Six patients were enrolled from 2020-2024, with histologic subtypes of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, and myxoid liposarcoma. No DLT due to the combination of cabozantinib and radiation were observed, but 3/6 (50%) patients required dose-reduction due to TRAE of cabozantinib alone. No grade ≥3 toxicities were attributed to RT, with most common grade 1-2 RT-related TRAE of fatigue and dry skin. The maximum tolerated dose (MTD) was not reached, and RP2D for the combination was cabozantinib 60mg. 6/6 (100%) of patients demonstrated stable disease 12 weeks after initiating therapy, and 5/6 (83%) underwent R0 resection. Relapse-free survival at a median follow up of 24.1 months was 50% (3/6). 2/6 (33%) of patients developed metastatic recurrence and 1/6 (17%) of patients died of unrelated causes, with no local recurrences.

Conclusion: In this phase 1 trial, concurrent cabozantinib and RT was safe and feasible for patients with extremity STS.

Table 1. Patient Demographics and Baseline Characteristics for All Patients (n=6)