Anlotinib Plus Epirubicin Elicits PFS Benefit in Advanced Soft Tissue Sarcoma

Anlotinib plus epirubicin demonstrated significant efficacy benefits vs epirubicin alone inpatients with advanced soft tissue sarcoma, according to data from a phase 3 study (NCT05121350) presented during the 2025 ASCO Annual Meeting.1

At a median follow-up of 7.16 months, the median progression-free survival (PFS) per blinded independent central review (BICR) was 8.6 months (95% CI, 7.8-10.1) in the anlotinib plus epirubicin arm (n =135) was 8.6 months (95% CI, 7.8-10.1) vs 3.0 months (95% CI, 2.3-4.3) among patients who received epirubicin alone (HR, 0.30; 95% CI, 0.21-0.44; P < .001). The median investigator-assessed PFS values were 8.6 months (95% CI, 7.8-10.5) and 3.5 months (95% CI, 2.7-4.5), respectively (HR, 0.38; 95% CI, 0.27-0.53; P < .001).

“An unprecedented median PFS was observed with [anlotinib plus epirubicin],” Yuhong Zhou, MD, of the Zhongshan Hospital at Fudan University in Shanghai, China, said during the presentation. “This phase 3 evidence support this anti-angiogenic TKI plus anthracycline [combination] as a new standard treatment for advanced soft tissue sarcoma.”

Phase 3 Study Design and Baseline Characteristics

The multicenter, randomized, double-blind phase 3 study enrolled patients 18 to 75 years of age with pathologically confirmed, unresectable locally advanced or metastatic soft tissue sarcoma.1,2 Patients were required to have an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and have not received systemic anticancer therapy or experienced disease progression at least 6 months following neoadjuvant or adjuvant therapy. Those with Ewing sarcoma, non-pleomorphic rhabdomyosarcoma, alveolar soft tissue sarcoma, or clear cell sarcoma were not eligible for the study.

Eligible patients were randomly assigned 1:1 to receive anlotinib at 12 mg once daily via a 2-week-on and 1-week-off dosing schedule or placebo, both in combination with epirubicin at 90 mg/m2 every 3 weeks.1 Patients who did not experience disease progression during the combination proceeded to the maintenance phase, where they received anlotinib or placebo via the same dosing schedule.

The primary end point was PFS by blinded independent review committee (BIRC) assessment per RECIST 1.1 criteria. Secondary end points included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety.

At baseline, the median ages in the combination and control arms were 53.0 years (range, 22-74) and 58.0 years (range, 18-76), respectively. Most patients in both arms were male (60.0% vs 50.4%), had an ECOG performance status of 1 (68.9% vs 66.4%), and had other target lesion sites beyond the lungs (93.3% vs 92.0%). Disease histology subtypes included leiomyosarcoma (28.1% vs 27.7%), synovial sarcoma (11.9% vs 13.1%), and others (60.0% vs 59.1%).

Additional Efficacy Findings and Safety Data

Although OS data were immature at the time of the presentation, a trend towards a reduction in the risk of death was reported in favor of the investigational arm (HR, 0.78; 95% CI, 0.49-1.25). The ORR per BICR in the investigational arm was 17.8% (95% CI, 11.7%-25.3%) compared with 2.9% (95% CI, 0.8%-7.3%) in the control arm (P < .001). The DCR was 79.3% (95% CI, 71.4%-85.8%) vs 54.7% (95% CI, 46.0%-63.3%), respectively (P < .001). Data from a subgroup analysis revealed that the BIRC-assessed PFS favored the investigational arm in every patient subgroup except for those with a target lesion site in the lungs only.

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred at respective rates of 97.0% and 99.3% in the investigational and control arms. Patients in both arms experienced drug-related TEAEs (97.0% vs 99.3%), grade 3 or higher TEAEs (69.6% vs 59.1%), and serious TEAEs (17.8% vs 16.8%), and TEAEs leading to death (3.7% vs 3.6%).

The most common any-grade TEAEs in the anlotinib arm included neutropenia (71.1%), leukopenia (70.3%), and hypertriglyceridemia (47.4%). In the control arm, common any-grade TEAEs consisted of leukopenia (61.3%), neutropenia (55.5%), and anemia (49.6%).

“The manageable toxicity confirmed the clinical feasibility of this combination therapy,” Zhou said.

Disclosures: Zhou reported no relevant disclosures.

References

1. Zhou Y, Niu X, Jiang T, et al. Anlotinib in combination with epirubicin followed by maintenance anlotinib versus placebo plus epirubicin as first-line treatment for advanced soft tissue sarcoma (STS): a randomized, double-blind, parallel-controlled, phase III study. J Clin Oncol. 2025;43(suppl 16):11501. doi:10.1200/JCO.2025.43.16_suppl.11501
2. A clinical trial to evaluate the efficacy and safety of anotinib hydrochloride capsule combined with epirubicin hydrochloride versus placebo combined with epirubicin hydrochloride in first-line treatment of advanced soft tissue sarcoma. ClinicalTrials.gov. Updated February 18, 2022. Accessed August 15, 2025. https://www.clinicaltrials.gov/study/NCT05121350