Anlotinib versus placebo as adjuvant therapy for localized high-grade soft tissue sarcomas: a phase 2, double-blinded, randomized controlled trial

Abstract Purpose: We aimed to investigate the efficacy and safety of anlotinib as adjuvant targeted therapy for completely resected localized high-grade soft tissue sarcomas (STS). Patients and Methods: Patients with localized high-grade STS after complete resection were randomly assigned in a 1:1 ratio to receive either oral 12 mg anlotinib or placebo once daily on days 1-14 every 21 days as a cycle, with up to 6 cycles until disease relapse, unmanageable toxicity or death. The efficacy and safety were analyzed. This trial was the first trial exploring adjuvant targeted therapy for STS (NCT03951571). Results: Between June 2019 and November 2023, 88 patients were randomly assigned to receive anlotinib (n=44) or placebo (n=44). With a median follow-up of 30.95 months, the 1-year and 2-year disease-free survival (DFS) rates were 88% and 77% in the anlotinib group, compared to 64% and 58% in the placebo group. Compared to patients treated with surgery alone, patients receiving adjuvant anlotinib combined with surgery had a reduced risk of disease recurrence (HR 0.47 [95% CI 0.22~1.00, P=0.0445]). Based on the tumor histology, the reduced risk of disease recurrence with anlotinib versus placebo was observed in patients with myxofibrosarcoma (HR 0.54 [95% CI 0.17~1.65], P=0.2698) and undifferentiated pleomorphic sarcoma (HR 0.58 [95% CI 0.12~2.87], P=0.4971). Four patients discontinued anlotinib, including two for proteinuria/hematuria (2/44, 5%) and two for poor healing of surgical wound (2/44, 5%). Conclusions: Compared to surgery alone, adjuvant anlotinib following surgery reduces the incidence of disease relapse in localized high-grade STS, with acceptable toxicity.