Aim: Apatinib, a specific tyrosine kinase inhibitor (TKI) that targets mainly vascular endothelial growth factor receptor-2 (VEGFR-2) as well as Ret, c-Kit and c-Src, has been assessed in patients with advanced osteosarcoma (phase II), the primary report of which has been published in PMID 30559126. This sub-study explored the potential signs of Adverse Events (AEs) for apatinib-treated osteosarcoma.
Methods: Participants with advanced osteosarcoma progressing upon chemotherapy received apatinib until disease progression or unacceptable toxicity. Toxicities, progression-free survival (PFS), and clinical benefit rate (CBR) following treatment were evaluated.
Results: Of the 41 patients recruited to the study, 37 received treatment and constituted the safety population. At data cut-off (December 30, 2017), median follow-up for safety was 7.37 (IQR, 6.33–11.07) months. The most common grade 3–4 AEs were pneumothorax (16.22%), wound dehiscence (10.81%), proteinuria (8.11%), diarrhea (8.11%), and skin reaction (8.11%). Only hypertension was an independent predictive factor for both PFS (hazard ratio [HR], 0.44; P = 0.07) and CBR (P = 0.07). Anorexia was also significantly related to a longer PFS in a Cox regression model (HR, 0.35; P =0.01). For CBR, pneumothorax and hypothyroidism showed more clinical benefit (P = 0.07 and 0.00, respectively).
Conclusion: The results of this study suggest that anorexia, hypertension, pneumothorax, and hypothyroidism might be markers for a favorable clinical outcome following apatinib-treated refractory osteosarcoma.

Keywords: apatinib, osteosarcoma, prognosis


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The process of angiogenesis is crucial for osteosarcoma growth, invasiveness, and metastasis.1 Anti-angiogenesis tyrosine kinase inhibitors (TKIs) are effective in prolonging progression-free survival (PFS) for advanced osteosarcoma that has progressed upon first- or second-line chemotherapy.2,3 In a prospective study on apatinib for advanced osteosarcoma after the failure of traditional multimodal therapy (NCT02711007), apatinib reached 4-month PFS rate of 56.8% for advanced osteosarcoma4–7 with a tolerable and manageable safety profile.5,8–10 The administration of apatinib induced tumor shrinkage and showed a high objective response (43.2%), but the toxic effects were severe with high rates of dose reduction (59.5%). Anti-angiogenesis TKIs have some common toxicities such as hypertension, hand-foot skin reactions, hypothyroidism, fatigue, and anorexia.11–14 However, previous trials15–17 on other tumors have indicated that some of these toxicities correspond to a favorable outcome with these drugs.

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The goals of this study were to determine the types of adverse events (AEs) most commonly seen in apatinib-treated osteosarcoma patients; whether the development of these AEs may be potential signs for drug efficacy; if these toxicities are related to the activity of apatinib; and when and how the management of these AEs would lead to optimal drug efficacy. To this end, we describe the clinical course, management, and resolution of key AEs in patients treated with apatinib in this phase two study to evaluate potential apatinib-induced toxicities for efficacy prediction.

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