Adjuvant Anlotinib Displays Efficacy in High-Grade Soft Tissue Sarcoma

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Adjuvant treatment with anlotinib decreased the risk of disease recurrence compared with surgery alone for the treatment of patients with completely resected localized, high-grade soft tissue sarcoma, according to data from a phase 2 trial (NCT03951571) published in Clinical Cancer Research.

At the January 15, 2024, data cutoff, with a median follow-up of 30.95 months, the 1-year disease-free survival (DFS) rate among patients in the intention-to-treat population who received anlotinib (n = 44) was 88% (95% CI, 74%-95%) vs 64% (95% CI, 47%-77%) in the placebo am (n = 44; HR, 0.47; 95% CI, 0.22-1.00; P = .0445). The 2-year DFS rates were 77% (95% CI, 61%-88%) and 58% (95% CI, 40%-72%), respectively. Data from a subgroup analysis showed that the benefit with anlotinib over placebo was present across subgroups.

“This randomized clinical trial is the first to investigate adjuvant targeted therapy for localized, resectable soft tissue sarcoma,” the study authors wrote. “[In a population of] 88 patients, superior DFS and acceptable safety were found among the adjuvant anlotinib group compared with the placebo group. Evaluation of overall survival [OS] was not mature at the time of manuscript preparation; the results will be provided in the future report, with an update of safety results based on more extended follow-up periods.”

The double-blinded study enrolled adult patients with localized, high-grade soft tissue sarcoma who had not received adjuvant chemotherapy following a complete resection. Patients were also required to have an ECOG performance status of 2 or less. High-grade disease was defined as grade 2 or 3 according to the French Federation of Cancer Centers Sarcoma Group systems. Those who received adjuvant VEGF inhibitor therapy and patients with rhabdomyosarcoma, gastrointestinal stromal tumors, dermatofibrosarcoma protuberans, Ewing sarcoma or primary neuroectodermal tumors, inflammatory myofibroblastoma, or malignant mesothelioma were not eligible for the study.

Eligible patients were randomly assigned 1:1 to receive 12 mg of oral anlotinib or placebo once daily. Treatment in both arms continued for 2 weeks then stopped for 1 week during each 3-week treatment cycle.

The primary end point was DFS. Secondary end points included local relapse-free survival (RFS), distant metastasis-free survival (DMFS), OS, and safety.

The baseline characteristics were well-balanced between the anlotinib and placebo arms; the median age was 56.5 years (range, 19-74) vs 57.5 years (range, 28-85) in the respective groups. Most patients in both arms were males (59% vs 57%), had an ECOG performance status of 0 (61% vs 57%), and had a primary disease site in the extremities (52% vs 59%). Common disease histologies in both arms included myxofibrosarcoma (27% vs 34%), fibrosarcoma not otherwise specified (7% vs 11%), undifferentiated pleomorphic sarcoma (32% vs 20%), dedifferentiated liposarcoma (11.4% vs 9%), leiomyosarcoma (5% vs 11%), and synovial sarcoma (5% vs 5%).

Additional findings from the study demonstrated that patients in the anlotinib arm experienced a local RFS benefit compared with those in the placebo arm (HR, 0.40; 95% CI, 0.13-1.20; P = .0918). The 1- and 2-year local RFS rates in the anlotinib arm were both 90% vs 79% and 71%, respectively, in the placebo arm.

The 1-year DMFS rates in the anlotinib and placebo arms were 98% and 81%, respectively (HR, 0.54; 95% CI, 0.19-1.56; P = .2482). The 2-year DMFS rates were 86% and 81%, respectively.

In terms of safety, any-grade adverse effects (AEs) occurred at a rate of 68.18% in the anlotinib arm vs 22.73% in the placebo arm. The most common any-grade AEs in the anlotinib arm included hypertension (29.55%), voice hoarseness or pharyngitis (18.18%), proteinuria (15.91%), hypothyroidism (15.91%), oral mucositis (15.91%), and liver dysfunction (15.91%). Common any-grade AEs in the placebo arm included hypertension (13.64%), hematuria (6.82%), and hypertriglyceridemia (6.82%).

Four patients discontinued treatment with anlotinib due to AEs. No patients were forced to discontinue treatment in the placebo arm and no treatment-related deaths were reported in either arm.

“In the future, the efficacy of adjuvant anlotinib should be further validated in an international phase 3 trial with a larger sample size and more soft tissue sarcomas subtypes,” the study authors wrote in their conclusion. “This study did not include analyses investigating potential biomarkers for adjuvant anlotinib. Our next step is to explore biomarkers to predict anlotinib efficacy and guide precise anlotinib treatment using immunohistochemistry staining or next-generation sequencing based on the paraffin-embedded and frozen tumor tissues, which have been well preserved for the future study.”

Reference

Wang C, Hu X, Yang L, et al. Anlotinib versus placebo as adjuvant therapy for localized high-grade soft-tissue sarcomas: a phase II, double-blinded, randomized controlled trial. Clin Cancer Res. 2025;31(7):1194-1203. doi:10.1158/1078-0432.CCR-24-2531