A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer

摘要: The mechanisms of resistance to anti-human epidermal growth factor receptor 2 (HER 2) therapies are unclear but may include the tyrosine-protein kinase Met (c-Met), vascular endothelial (VEGF) and AXL pathways. Foretinib is an inhibitor c-Met, VEGF (VEGFR-2), platelet-derived beta (PDGFRB), AXL, Fms-like tyrosine 3 (FLT3), angiopoiten (TIE-2), RET RON kinases. This phase Ib study sought establish associated toxicities, pharmacokinetics (PK) recommended II doses (RP2D) foretinib lapatinib in a cohort HER-2-positive patients with metastatic breast cancer (MBC). Women HER-2 positive MBC, Performance status (PS 0-2), no limit on number prior chemotherapies or lines anti-HER-2 were enrolled. A 3 + 3 dose escalation design was utilized. Four levels intended starting 30 mg 750 orally once day (OD) 4-weekly cycle. Assessment c-MET from primary archival tissue performed. We enrolled 19 patients, all evaluable for toxicity assessment response evaluation. Median age 60 years (34–86 years), 95% PS 0-1, 53% estrogen receptor-positive had at least one anti-HER-2-based regimen. fourth level reached (foretinib 45 mg/lapatinib 1250 mg) dose-limiting toxicities grade-3 diarrhea fatigue. There only grade-4 non-hematological across levels. PK interactions between agents. median two cycles delivered (range 1–20) progression-free survival 3.2 months (95% CI 1.61–4.34 months). By immunohistochemical specified cutoff, none 17 samples tested classified as c-Met. RP2D combined 1000 PO OD, respectively. Limited activity seen this combination predominantly unselected MBC.