A Phase 1 Study of Neoadjuvant Cabozantinib in Combination With Radiation Therapy for Sarcomas of the Extremities

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

Adults with newly diagnosed localized extremity STS planned for neoadjuvant RT and surgical resection were eligible. Participants received radiation with 5000 to 5040 cGy with conventional fractionation and cabozantinib 40 mg or 60 mg daily. Patients were observed for dose-limiting toxicity (DLT) up to 28 days after completion of concurrent cabozantinib/RT. The primary objective was to identify a recommended phase 2 dose (RP2D) of cabozantinib for combination with RT, and secondary objectives included estimating rates of treatment-related adverse event (TRAE), margin positivity, and objective response.

Six patients were enrolled with histologic subtypes of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, and myxoid liposarcoma. No DLT due to the combination of cabozantinib and radiation was observed, but 3/6 (50%) patients required dose-reduction due to TRAE of cabozantinib alone. No grade ≥3 toxicities were attributed to RT. The RP2D was cabozantinib 60 mg. Six (100%) patients demonstrated stable disease at 12 weeks, and 5 (83%) underwent R0 resection. Two (33%) patients experienced metastatic relapse, and 1 (17%) died without relapse; 3 (50%) patients survived without relapse by last contact. No local recurrences occurred.

In this phase 1 trial, concurrent cabozantinib/RT was feasible and demonstrated an acceptable safety profile for patients with extremity STS.