Efficacy and safety of perioperative anlotinib combined with cisplatin and doxorubicin in treatment-naive stage IIB classic osteosarcoma of the extremity: Updated results from the ALTER-S002 trial.

11526 Background: Clinical studies show overexpression of multiple tyrosine kinase receptors in osteosarcoma, supporting targeted therapy as a promising direction. Anlotinib, a multi-targeted tyrosine kinase inhibitor, exerts anti-tumor angiogenesis effects. Combining anti-angiogenic agents with chemotherapy may yield synergistic tumor control, particularly as perioperative therapy. We present updated long-term efficacy and safety data, including key secondary endpoints, to validate this regimen’s clinical value. Methods: This was an open-label, single-arm, multicenter phase II trial. Eligible patients (12-40 years) had histologically confirmed primary localized stage IIB classic extremity osteosarcoma and were operable. Patients received anlotinib (10mg, po, d1-14, q3w), doxorubicin (A, 20-25 mg/m², iv, d1-3, q3w) and cisplatin (P, 70-90 mg/m², iv, d1, q3w) for 9 weeks. Radical surgery was performed at week 10 (no contraindications). Postoperatively, A+P was given at weeks 12-14, followed by anlotinib+A+P (same doses) at weeks 15-20. From week 21, anlotinib monotherapy (12mg, po, d1-14, q3w) continued until week 104 or an event-free survival (EFS) event. Primary endpoint: 24-month EFS rate. Secondary endpoints: 36-month EFS rate, local recurrence rate, lung metastasis rate, 3-year overall survival (OS) rate, and safety. Results: From May 2020 to April 2022, 52 patients were enrolled, treated, and included in full analysis set (FAS) and safety set (SS). Of these, 84.6% (44/52) were Han and 55.8% (29/52) male. Median follow-up was 42.7 months (IQR 30.4-52.7). The 24-month and 36-month EFS rates were 73.7% (95% CI 59.0-83.9) and 46.6% (95% CI 27.4-63.7), respectively. Median OS was not reached; 36-month and post-hoc 60-month OS rates were 74.6% (95% CI 59.6-84.7) and 71.4% (95% CI 55.5-82.4). Twenty-five percent (13/52) of patients died, mostly due to lung metastasis (13%). Among 51 surgical patients, local recurrence, lung metastasis, and other-site metastasis occurred in 23.5%, 17.6%, and 9.8%, respectively. Median recurrence-free survival (RFS) was 32.4 months (95% CI 25.7-not estimable). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 84.6% (44/52) of patients, with neutropenia most common (28/52 [53.8%]). No grade 5 TRAEs were observed. Serious TRAEs occurred in 40.4% (21/52), mainly myelosuppression (14/52 [26.9%]). None of the 13 on-study deaths were TRAE-related. Conclusions: Perioperative anlotinib plus cisplatin and doxorubicin shows promising efficacy in treatment-naïve stage IIB classic extremity osteosarcoma, with manageable safety. It achieves favorable long-term OS, and clinically acceptable local recurrence and lung metastasis rates, serving as a potential new perioperative option for this population. Clinical trial information: ChiCTR 2000033298.