Apatinib for Advanced Osteosarcoma after Failure of Standard Multimodal Therapy: An Open Label Phase II Clinical Trial

Abstract

Background Antiangiogenesis tyrosine kinase inhibitors (TKIs) have been shown to prolong progression‐free survival (PFS) in advanced osteosarcoma. Methylsulfonic apatinib is a TKI that specifically inhibits vascular endothelial growth factor receptor‐2. We aim to assess apatinib in patients with advanced high‐grade osteosarcoma progressing upon chemotherapy. Materials and Methods This phase II trial was conducted at Peking University People's Hospital. We enrolled participants (≥16 years of age) with progressive relapsed or unresectable osteosarcoma. Participants received 750 mg or 500 mg of apatinib according to body surface area once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate and PFS at 4 months. Results A total of 37 participants were finally included into the analysis. Until final follow‐up, the objective response rate (complete response + partial response) was 43.24% (16/37). The 4‐month PFS rate was 56.76% (95% confidence interval [CI], 39.43%–70.84%). Median PFS and overall survival were 4.50 (95% CI, 3.47–6.27) and 9.87 (95% CI 7.97–18.93) months, respectively. Toxic effects led to dose reductions or interruptions in a total of 25 of 37 (67.57%) patients. The most common grade 3–4 adverse events were pneumothorax in six (16.22%) patients, wound dehiscence in four (10.81%), proteinuria in three (8.11%), diarrhea in three (8.11%), and palmar‐plantar erythrodysesthesia syndrome in three (8.11%). No other serious adverse events were reported during the trial. There were no treatment‐related deaths. Conclusion Apatinib is a sensitive drug for advanced osteosarcoma with a high response rate after failure of chemotherapy, with similar duration of response compared to other TKIs. Implications for Practice For advanced osteosarcoma progressing upon chemotherapy, antiangiogenesis tyrosine kinase inhibitors (TKIs) have been proved to be effective in prolonging the progression‐free survival in previous multicenter trials and have been included into new National Comprehensive Cancer Network guidelines as second‐line therapy. Apatinib is a TKI that specifically inhibits vascular endothelial growth factor receptor‐2, which is domestically made in China. This phase II trial supports the use of apatinib in patients with advanced osteosarcoma progressing after chemotherapy.

TAS‐115 inhibits PDGFRα/AXL/FLT‐3 signaling and suppresses lung metastasis of osteosarcoma

“…However, several clinical studies of selective inhibitors, such as imatinib, demonstrated little or no activity as a single agent in OS [23,24]. On the other hand, several clinical trials of multiple TK inhibitors, such as regorafenib [25], cabozantinib [26], and apatinib [27], in OS indicated a marked effect for OS and the potential to be developed as new therapeutic agents. TAS‐115 is also a novel multiple RTK inhibitor that demonstrates much less toxicity in various normal cell lines than other VEGFR‐targeted kinase inhibitors.…”

<p>Anorexia, Hypertension, Pneumothorax, and Hypothyroidism: Potential Signs of Improved Clinical Outcome Following Apatinib in Advanced Osteosarcoma</p>

“…Baseline characteristics have been reported. 27 The overall incidence of apatinib-related AEs was 89.2%. In general, drug-related AEs were limited to grade one or two.…”

“…With a median follow-up time of 7.37 months (interquartile range [IQR], 6.33-11.07) for the safety analysis, 22/37 (59.5%) patients had dose-reduced treatment, and 11/37 (29.7%) patients had temporary treatment interruption. 27 The frequency of apatinib administration was 40.5% of the planned administration dose. Due to the small sample size, we did not observe some rarely seen AEs (overall incidence ≤5% of patients) and merged some of the AEs into one bigger group for more appropriate statistical analyses.…”

“…AEs correlation analysis showed that fatigue was also correlated with hypothyroidism and weight loss (P = 0.07 and 0.00, respectively). When included in the multivariate analysis together with other clinicopathological factors that affected PFS, 27 only anorexia was found to be an independent factor for prognosis (P = 0.04). Although it did not appear to greatly impact the PFS, the HR was reduced for myalgia/arthralgia, bilirubin increase, hypothyroidism, pneumothorax, and bleeding (HR = 0.59, 0.60, 0.58, 0.56, 0.46, respectively), which suggests that the occurrence of these toxicities might benefit prognosis.…”

Apatinib in treating clinical and biochemical recurrent ovarian cancer

“…In China, apatinib has been approved for the thirdline treatment of advanced gastric adenocarcinoma and adenocarcinoma in the gastric-esophageal junction (7)(8)(9). Moreover, multiple studies have demonstrated its use in patients with other advanced malignancies, such as breast cancer (10,11), hepatic carcinoma (12), lung cancer (13,14), colorectal cancer (15), and soft tissue tumors (16,17). Case reports and clinical studies have also illustrated the e cacy and safety of apatinib in recurrent OC (18)(19)(20)(21)(22); however, to our knowledge, its e cacy in biochemical recurrent patients is not yet known.…”