Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple‐negative breast cancer

• Published in: International journal of cancer 2014-10, Vol.135 (8), p.1961-1969
• Main Authors: Hu, Xichun, Zhang, Jian, Xu, Binghe, Jiang, Zefei, Ragaz, Joseph, Tong, Zhongsheng, Zhang, Qingyuan, Wang, Xiaojia, Feng, Jifeng, Pang, Danmei, Fan, Minhao, Li, Jin, Wang, Biyun, Wang, Zhonghua, Zhang, Qunling, Sun, Si, Liao, Chunmei
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; apatinib; Biological and medical sciences; Breast cancer; Cancer; Chemotherapy; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Gynecology. Andrology. Obstetrics; Humans; Kaplan-Meier Estimate; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - mortality; Lung Neoplasms - secondary; Lymphatic Metastasis; Mammary gland diseases; Medical research; Medical sciences; Medical treatment; Metastasis; metastatic breast cancer; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Ovarian cancer; Pyridines - pharmacology; Pyridines - therapeutic use; triple negative; Triple Negative Breast Neoplasms - blood; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - mortality; Triple Negative Breast Neoplasms - pathology; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - blood; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - blood; VEGFR2
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28829

Apatinib is an oral, highly potent tyrosine‐kinase inhibitor targeting VEGFR2. Phase I study showed the recommended dose of 750 mg/day with substantial antitumor activity. This phase II study aims to evaluate the optimum dose level for the efficacy and safety of apatinib monotherapy in heavily pretreated patients with metastatic triple negative breast cancer (mTNBC) in China. Phase IIa was first performed among 25 patients previously treated with anthracycline and/or taxane. All patients received apatinib 750 mg/day p.o. in a 4‐week cycle. Subsequently, a phase IIb study of 59 patients was activated, with the endpoint progression‐free survival (PFS). The dosage of drug for the Phase IIb was determined according to safety, tolerability and efficacy from the phase IIa study. As a result of toxicity associated with the 750 mg dose in phase IIa, the recommended initial dose of apatinib in the phase IIb was 500 mg/day. In phase IIb, grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%) and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand–foot syndrome, proteinuria, hypertension, and increased ALT. In the 56 evaluable patients, overall response rate and clinical benefit rate (CBR) were 10.7 and 25.0%, respectively. Median PFS and overall survival were 3.3 (95% CI 1.7–5.0) and 10.6 (95% CI 5.6–15.7) months, respectively. Our results indicate that apatinib dose of 500 mg rather than 750 mg is the recommended starting dose for the heavily pretreated mTNBC patients with measurable rate of partial response and PFS. What's new? While metastatic breast cancer remains incurable, metastatic triple‐negative breast cancer (mTNBC) is proving particularly challenging because tumors lack recognized therapeutic molecular biology targets. This report is the first clinical phase II study of a highly potent inhibitor of VEGFR2 (apatinib) in mTNBC, evaluating its activity and safety. The results indicate that apatinib daily dose of 500mg rather than 750mg is the recommended starting dose for heavily pretreated mTNBC patients in China, with measurable and encouraging rates of partial response and progression‐free survival. In addition, tumor pVEGFR2 expression shows promise as an apatinib efficacy predictor of mTNBC, which warrants further validation.