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

Abstract

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.Despite significant improvements in the treatment of breast cancer during the last decade, the metastatic breast cancer (MBC) remains incurable, with a median life expectancy of 2-3 years.1 Metastatic triple-negative breast cancer (TNBC)is particularly challenging because tumors lack recognized therapeutic molecular biology targets. Molecular profiling has identified TNBC as a disease that encompasses a number of intrinsic molecular subtypes, such as the basal-like,

Tetrandrine suppresses lung cancer growth and induces apoptosis, potentially via the VEGF/HIF-1α/ICAM-1 signaling pathway

“…Lung cancer is typically a malignant cancer with sufficient blood supply that can secrete lots of VEGF during tumor growth (16). Expression of VEGF mRNA and protein in lung cancer samples are 3-7 higher than normal renal tissues (16). In the present study, tetrandrine significantly induced the protein expression of PARP and Bax, suppressed p-Akt protein levels and increased VEGF expression in A549 cells.…”

“…VEGF is the most effective vasculogenesis-associated factor (16). VEGF is highly expressed in ovarian cancer, breast carcinoma, gastric carcinoma and urinary bladder carcinoma (17).…”

“…In addition, VEGF stimulates the proliferation of tumor-derived vascular endothelial cells and facilitates the generation of new capillaries, allowing the nutritional requirements of tumors to be met. Lung cancer is typically a malignant cancer with sufficient blood supply that can secrete lots of VEGF during tumor growth (16). Expression of VEGF mRNA and protein in lung cancer samples are 3-7 higher than normal renal tissues (16).…”

Targeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets

“…Phase II trials in different settings with motesanib, pazopanib, axitinib, cediranib and vandetanib in breast cancer patients showed no clinical efficacy while toxicity was present in most of the studies Rugo et al, 2011;Boer et al, 2012;Hyams et al, 2013;Johnston et al, 2013). Two other phase I trials and one phase II trial with nintedanib, tivozanib and apatinib respectively showed partial response or pathological response up to 50% of the patients (Mayer et al, 2013;Hu et al, 2014;Quintela-Fandino et al, 2014). Further studies with TKIs targeting VEGFR are ongoing (Table 1).…”

The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts

“…Additionally, levels of VEGF in plasma may be a biomarker of response to anti-angiogenic therapy20. Despite recent setbacks in the use of anti-angiogenic therapy in breast cancer, the importance of VEGF in tumor progression, and its potential targeting for treatment remains undeniable21222324.…”