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

Stephen K Chia, Susan L Ellard, Mihaela Mates, Stephen Welch, Catalin Mihalcioiu, Wilson H Miller Jr, Karen Gelmon, Caroline Lohrisch, Vikaash Kumar, Sara Taylor, Linda Hagerman, Rachel Goodwin, Tao Wang, Shingo Sakashita, Ming S Tsao, Elizabeth Eisenhauer, Penelope Bradbury, Stephen K Chia, Susan L Ellard, Mihaela Mates, Stephen Welch, Catalin Mihalcioiu, Wilson H Miller Jr, Karen Gelmon, Caroline Lohrisch, Vikaash Kumar, Sara Taylor, Linda Hagerman, Rachel Goodwin, Tao Wang, Shingo Sakashita, Ming S Tsao, Elizabeth Eisenhauer, Penelope Bradbury

Abstract

Background: 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 growth factor (VEGF) and AXL pathways. Foretinib is an inhibitor of c-Met, VEGF receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFRB), AXL, Fms-like tyrosine kinase 3 (FLT3), angiopoiten receptor (TIE-2), RET and RON kinases. This phase Ib study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of foretinib and lapatinib in a cohort of HER-2-positive patients with metastatic breast cancer (MBC).

Methods: Women with HER-2 positive MBC, Performance status (PS 0-2), and no limit on number of prior chemotherapies or lines of anti-HER-2 therapies were enrolled. A 3 + 3 dose escalation design was utilized. Four dose levels were intended with starting doses of foretinib 30 mg and lapatinib 750 mg orally once a day (OD) on a 4-weekly cycle. Assessment of c-MET status from the primary archival tissue was performed.

Results: We enrolled 19 patients, all evaluable for toxicity assessment and for response evaluation. Median age was 60 years (34-86 years), 95% were PS 0-1, 53% were estrogen receptor-positive and 95% had at least one prior anti-HER-2-based regimen. The fourth dose level was reached (foretinib 45 mg/lapatinib 1250 mg) with dose-limiting toxicities of grade-3 diarrhea and fatigue. There was only one grade-4 non-hematological toxicity across all dose levels. There were no PK interactions between the agents. A median of two cycles was delivered across the dose levels (range 1-20) with associated progression-free survival of 3.2 months (95% CI 1.61-4.34 months). By immunohistochemical assessment with a specified cutoff, none of the 17 samples tested were classified as positive for c-Met.

Conclusions: The RP2D of the combined foretinib and lapatinib is 45 mg and 1000 mg PO OD, respectively. Limited activity was seen with this combination in a predominantly unselected cohort of HER-2-positive patients with MBC.

Keywords: Breast cancer; HER-2; Lapatinib; Pharmacokinetics; c-Met inhibitor.

Figures

Fig. 1
Fig. 1
Progression-free survival (PFS). trt treatment
Fig. 2
Fig. 2
Best tumor shrinkage based on tyrosine-protein kinase Met expression. IHC immunohistochemial analysis

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