Apatinib Shows Potential in Advanced Sarcoma

Chinese researchers have concluded that the oral VEGFR2 inhibitor apatinib (YN968D1) demonstrated efficacy with tolerable toxicity in a small study of patients with stage IV sarcoma, according to results published in Oncotarget.

The overall response rate was 20.0% with a disease control rate of 80%. The most common grade 3/4 treatment-related adverse events (AEs) were hypertension (18.7%), hand-foot syndrome (12.5%), and proteinuria (6.3%). There were no drug-related severe AEs observed.

Prognosis is poor for patients with stage IV sarcoma. For patients with soft tissue sarcomas, the response rate with chemotherapy is only 20% to 35% and median survival is about 12 months. Several large-scale studies have found a 5-year survival rate of less than 10%. For patients with advanced osteosarcoma, the overall survival rate is 0% to approximately 50%.

Treatment with traditional chemotherapy agents—including ifosfamide, doxorubicin, methotrexate, cisplatin, dacarbazine, gemcitabine, and docetaxel—is not curative and combination therapy or dose-dense regimens have largely failed to improve the response rates. Furthermore, long-term use of cytotoxic drugs is associated with increased risk for AEs, including death.

“Therefore, there is an urgent need for a new therapy for the treatment of advanced sarcomas,” wrote the authors, led by Feng Li, Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Sixteen patients with a median age of 45 years (range, 16-83) were treated with apatinib at Tianjin Medical University Cancer Institute and Hospital in Tianjin, China from August 2015 to August 2016. The initial dose was 500 mg per day, which could be reduced to 375 mg daily or 250 mg daily due to toxicity.

Most patients had undergone wide resection (87.5%), and a significant percentage had undergone radiotherapy (37.5%). All patients had received prior chemotherapy per NCCN guidelines.

Six patients received less than 1 full cycle of treatment and were not evaluable for efficacy. Three patients discontinued for financial reasons, and 2 stopped treatment after 7 days due to sudden disease progression. One patient required hospitalization for cerebral hemorrhage.

Eight of 10 patients who received at least 1 full cycle of treatment responded to apatinib. Two patients were determined to have partial response. Six others had stable disease. Two patients had disease progression, 1 of whom subsequently died.

Median progression-free survival (PFS) was 8.84 months. PFS was 90% at month 2 and 80% at month 4. PFS dropped to 60% at month 6 before stabilizing. Patients with metastatic osteosarcoma appeared to benefit slightly more than patients with metastatic soft tissue sarcoma, but researchers said the difference was not statistically significant.

“These data suggest that sarcoma patients could acquire longer benefit from apatinib treatment,” the researchers wrote. “These results are encouraging for the efficacy and seem better than or at least comparable with what was reported in previous studies involving single-agent angiogenesis inhibitors.”

Gender and previous local treatment, such as radiotherapy or surgery types, had no significant effect on efficacy.

Li et al found that most AEs were mild and easily controlled. Grade 1 AEs accounted for 42.9% of total toxicity. Grade 2 AEs made up another 42.9%, and 14.2% of patients had grade 3 toxicity. There were no grade 4 AEs observed in the trial.

Overall, the most commonly reported treatment-related AEs included hand-foot syndrome (43.8%), proteinuria (43.8%), hypertension (31.3%), pain (25.0%), neutropenia (18.8%), and increased bilirubin (18.8%).

Three patients needed dose reduction due to nonhematologic toxicities. These adverse events, including hand-foot syndrome and proteinuria, were quickly reduced, and patients recovered following dose reduction.

“Our study provides supporting evidence that apatinib exhibits objective efficacy in stage IV sarcomas with manageable toxicity,” wrote Li et al. “Therefore, random controlled trials based on these data are warranted to further evaluate the apatinib activity in advanced sarcomas.

Li F, Lio Z, Zhao J, et al. Efficacy and safety of apatinib in stage IV sarcomas: experience of a major sarcoma center in China [published online March 16, 2017]. Oncotarget. doi:10.18632/oncotarget.16293.