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A new first-line therapy treating patients with soft tissue sarcoma (STS)—combining anlotinib maintenance with chemotherapy—demonstrated favorable safety and efficacy in a single-arm, phase 2 trial, supporting further evaluation in randomized clinical trials, according to a recent study published in Clinical Cancer Research.¹

Targeted Therapy Meets Chemotherapy in Advanced STS

Patients with advanced STS have a considerably low 5-year survival rate. Doxorubicin, an anthracycline-based chemotherapy, is the current first-line therapy standard, but it has not improved prognoses for those with advanced STS. ¹ Prior research has investigated the combination of therapies combining chemotherapy with targeted or immune-based inhibitors with some success.² Angiogenesis inhibitors plus chemotherapy, specifically the human monoclonal antibody onartuzumab plus doxorubicin, showed negative results in early trials. However, this trial found that anlotinib, an oral multitarget tyrosine kinase inhibitor, plus an anthracycline and ifosfamide demonstrated an objective response rate (ORR) of 30.8% and a disease control rate (DCR) of 82.7%.¹

Comparatively, previous trials like phase 2 of the SAINT study (NCT03138161) assessing trabectedin, a DNA-binding chemotherapy, plus ipilimumab and nivolumab, immune checkpoint inhibitors, demonstrated encouraging safety and efficacy with an ORR of 24.7% and a DCR of 82.5%.² These findings suggest that targeted or immune-based inhibitors combined with chemotherapy may benefit and improve progression-free survival (PFS) and overall prognoses in patients with advanced STS.

This study enrolled 52 patients with histologically confirmed, unresectable, locally advanced, or metastatic high-grade STS and a mean age of 49.1 years. Patients received 4 to 6 cycles of combination therapy to be repeated every 21 days. Twelve mg of anlotinib was administered orally once daily on days 1 through 14, followed by anthracyclines: either 40 mg of epirubicin on days 1 and 2 or 30 mg of liposomal doxorubicin on day 1, administered intravenously. Lastly, patients would receive 2 mg of ifosfamide intravenously on days 1 through 3.

Patients were monitored between December 2021 and June 2024 and assessed for ORR, DCR, PFS, overall survival (OS), and treatment-related adverse events (TRAEs).

Of the patients included in the study, 45 (86.5%) had stage IV metastatic disease, and 7 (13.5%) had locally advanced disease. There were 29 (55.8%) patients who received liposomal doxorubicin and 23 (44.2%) who received epirubicin, both combined with ifosfamide. Thirteen patients did not reach the maintenance stage of the study due to progressive disease, intolerable toxicities, and switching to other therapies.

Strong Response and Disease Control Rates Observed

The ORR was 30.8% (95% CI, 18.7%-45.1%), the DCR was 82.7% (95% CI, 69.7%-91.8%), and the median PFS was 6.2 months (95% CI, 2.62-11.17). Across the different subtypes of STS, there were 13 cases (25%) with synovial sarcoma (SS). The ORR was 46.2% (95% CI, 23.2%-70.9%), and the DCR was 100% (95% CI, 77.2%-100.0%).

There were 11 cases (21.2%) with undifferentiated sarcoma (UDS). The ORR was 45.5% (95% CI, 16.8%-76.6%), and the DCR was 72.7% (95% CI, 39.0%-94.0%). Cases with SS and UDS had a median PFS of 7.3 months (95% CI, 4.4-NE and 95% CI, 0.8-11.2, respectively).

Safety Profile and Treatment Tolerability

The most frequently reported TRAEs were nausea, fatigue, hypoalbuminemia, anemia, lymphocytopenia, and leukopenia. Only 2 severe AEs were recorded: reduction in left ventricular ejection fraction and intestinal obstruction. Both patients recovered.

This study was limited by its single-arm design and small sample size, which may have restricted comparisons with standard therapy and may have limited generalizability. Although follow-up was sufficient for short- to intermediate-term outcomes, longer observation is needed to assess long-term toxicity and survival.

“First-line therapy combining anlotinib with anthracyclines and ifosfamide, followed by anlotinib maintenance, demonstrates promising efficacy and acceptable tolerability in patients with advanced STS,” the study authors concluded. “Our data provide preliminary evidence. Further studies with larger sample sizes, or even randomized controlled trials, are needed to evaluate the efficacy and safety of this combination therapy.”

References

1. Zhao J, Liu Z, Wang R, et al. First-line anlotinib plus anthracyclines and ifosfamide followed by anlotinib maintenance in advanced soft tissue sarcoma: a phase II single-arm trial. Clin Cancer Res. 2026;32(1):76-82. doi:10.1158/1078-0432.CCR-25-2487

2. Shaw ML. First-line combo yields strong results in advanced sarcoma. AJMC^®. September 20, 2024. Accessed January 23, 2026. https://www.ajmc.com/view/first-line-combo-yields-strong-results-in-advanced-sarcoma