Neoadjuvant pegylated liposomal doxorubicin plus anlotinib in locally advanced soft tissue sarcoma: Clinical outcomes and multi-omics analysis from a phase II study.

11561 Background: Neoadjuvant therapy may improve the R0 resection and limb salvage rates in locally advanced soft tissue sarcomas (STS). This phase II trial was designed to evaluate the efficacy and safety of neoadjuvant pegylated liposomal doxorubicin (PLD) combined with anlotinib in the treatment of locally advanced STS. Methods: This single-center, single-arm phase II trial (NCT04765228) enrolled treatment-naïve patients with stage II/III. Patients received PLD (50 mg/m² intravenously on day 1) combined with anlotinib (12 mg orally daily on days 8-21) every 3 weeks for 2-4 cycles. Based on a one-proportion test, with α=0.05 (two-sided) and 80% power, to detect an increase in the objective response rate (ORR) from 10% to 26%, 45 patients were planned, accounting for a 20% dropout rate. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The exploratory endpoint was biomarker analyses. The corresponding two-sided 95% CIs were estimated using the Clopper-Pearson method. The PFS and OS were estimated using the Kaplan-Meier method. Results: A total of 40 eligible patients were treated between November 2020 and November 2022, of whom 34 (85.0%) underwent surgery. The median age was 46.5 years (range: 15-74 years), and 23 (57.5%) of the patients were male. Histologically, the 40 patients included 9 cases of liposarcoma (LPS), 6 cases of malignant peripheral nerve sheath tumor (MPNST), 6 cases of synovial sarcoma (SS), 3 cases of low-grade fibromyxoid sarcoma (LGFMS), 3 cases of myxofibrosarcoma (MFS), 3 cases of spindle cell sarcoma (SCS), 3 cases of undifferentiated pleomorphic sarcoma (UPS), 2 cases of leiomyosarcoma (LMS), and 5 cases of other STS. The most common sites of primary tumor were lower extremities (42.5%), waist/hip region (17.5%) and other regions. The ORR based on RECIST 1.1 was 15.0% (95% CI: 3.4%-26.6%), and the ORR of 36 patients based on Choi's criteria was 58.3%. The median PFS was 14 months (95% CI: 4.22 - 23.79 months), and the median OS was not reached. Pathological response was evaluable in 24 patients, with pathological complete response (pCR) and pathological partial response (pPR) observed in 4.2% (1/24) and 50.0% (12/24) of cases, respectively. Among 34 patients who underwent surgical resection, 30 (88.2%) achieved R0 resection, while 3 (8.8%) had R1 resection. Common treatment-related adverse events (TRAEs) of any grade included mucositis oral (52.5%), neutrophil count decreased (25.0%). Fifteen (37.5%) patients experienced at least one grade 3-4 AE. Conclusions: Neoadjuvant PLD combined with anlotinib exhibits promising efficacy and acceptable toxicity in patients with locally advanced STS. Results from multi-omics analyses will facilitate the screening of suitable patients in future clinical practice. Clinical trial information: NCT04765228 .