Low-dose apatinib combination with first-line chemotherapy rechallenge in advanced osteosarcoma: A single-center ambispective cohort study.

11529 Background: First-line treatment for osteosarcoma includes various combinations of four agents: high-dose methotrexate (HD-MTX), doxorubicin (DOX), cisplatin (DDP), and ifosfamide (IFO), achieving overall efficacy rate of 41-77% and remaining the most effective systemic therapy to date. However, patients (pts) with progression after first-line therapy lack a defined second-line standard, available treatments yield objective response rate (ORR) <20% with 5-year survival <10%. Though anti-angiogenic tyrosine kinase inhibitors have limited monotherapy efficacy, preclinical studies show they enhance intratumoral drug delivery and reverse multidrug resistance, thereby synergizing with chemotherapy. Thus, apatinib, a highly selective VEGFR-2 inhibitor, was added to the previously failed first-line chemotherapy-the most effective systemic therapy-to investigate whether it could reverse chemoresistance and restore response to the original regimen. Methods: This ambispective cohort study enrolled pts with advanced osteosarcoma who had tumor progression after first-line chemotherapy with HD-MTX, DOX, DDP and IFO at our center. Subsequently, low-dose apatinib (250 mg/d) was administered in combination with the same four-drug chemotherapy regimen. The primary endpoint was the ORR. Secondary endpoints included disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS) and adverse events (AEs). Results: From Jan 2018 to Jul 2025, 37 pts were enrolled, with 9 in the retrospective cohort and 28 in the prospective cohort. Of these, 27 (73%) were male and 10 (27%) were female, with a median age of 21 years (range: 10–67). 36 pts were diagnosed as conventional osteosarcoma (96.9%). Primary tumors were located in the femur (21, 56.8%), tibia and humerus (8, 21.6%), pelvis (6, 16.2%), clavicle and rib (2, 5.4%). Metastatic disease was present in 29 pts (78.4%). The most common sites of metastasis were the lung (28, 78.1%) and bone (6, 18.8%). Partial remission was seen in 8 pts, and stable disease in 23 (ORR: 21.6%, DCR: 83.8%). After a median follow-up of 17 months (mos), PFS was 5.8 mos (2.5–9.1), OS was 14.5 mos (10.3–18.7). Pts with lactate dehydrogenase <245 U/L had superior PFS (7.2 vs 3.3 mos; HR=0.28, 0.1–0.8, P=0.01), with a trend of OS benefit (14.5 vs 11.6 mos, P=0.74). Pts with alkaline phosphatase <150 U/L had a trend of PFS benefit (6.3 vs 5.8 mos, P=0.7) and significant better OS (20.3 vs 11.7 mos; HR=0.41, 0.17–1.01, P=0.046). Prognosis was not associated with gender, age, primary site, stage or first-line therapy response. AEs were consistent with known safety profiles and manageable. Conclusions: Low-dose apatinib combined with previously resistant first-line chemotherapy showed promising efficacy, providing a feasible therapeutic strategy for osteosarcoma pts lacking effective second-line choices.