Clinical Benefit of INCB7839, a Potent and Selective Inhibitor of ADAM10 and ADAM17, in Combination with Trastuzumab in Metastatic HER2 Positive Breast Cancer Patients.
Authors: Friedman S. , Levy R. , Garrett W. , Doval D. , Bondarde S. , Sahoo T. , Lokanatha D. , Julka P. , Shenoy K. , Nagarkar R. , Bhattacharyya G. , Kumar K. , Nag S. , Mohan P. , Narang N. , Raghunadharao D. , Walia M. , Yao W. , Li J. , Emm T. , Yeleswaram S. , Scherle P. , Newton R. 
Published: December 2010

Abstract
Background: In HER2 over-expressing breast cancer cells, the HER2 protein can be cleaved by a metalloproteinase, ADAM10. While the extracellular domain (ECD) of HER2 is released into the serum, the truncated HER2 receptor fragment, termed p95, remains in the tumor cell membrane as a constitutively active receptor tyrosine kinase. Previous studies have shown that the presence of p95 in tumor cells is associated with poor clinical outcomes in patients with metastatic HER2 positive breast cancer and it was recently shown that patients with p95+ HER2 positive breast cancer are resistant to trastuzumab-based therapy. Therefore, inhibition of HER2 cleavage by the ADAM10/ADAM17 inhibitor, INCB7839, which reduces the formation of soluble HER2 ECD as well as p95 levels in the tumor, may enhance the clinical efficacy of trastuzumab in HER2+ breast cancer patients. Materials and Methods: This study is a single arm modified dose escalation open label trial of INCB7839 + trastuzumab in women with HER2+ metastatic breast cancer, naïve to chemotherapy. Three doses of INCB7839 were studied (100 mg, 200 mg, 300 mg BID) with 6 patients/cohort and an expansion arm at the 300mg BID dose. Herceptin was administered on a Q3 week schedule. Pharmacokinetics, plasma HER2 ECD levels and p95 expression in tumor tissue were assessed in addition to clinical response and safety. Results: 39 patients have been enrolled in the study and assessment of HER2 ECD levels, p95 status and best clinical response completed on 30 patients. INCB7839 administration results in a dose-dependent reduction in the elevated levels of circulating HER2 ECD with a mean of ∼80% inhibition achieved at the highest dose tested (300 mg BID). At the 300mg BID dose, the current overall response rate is 40% (6/15 evaluable patients) with a higher response rate (6/11 or 55%) observed in patients with average plasma concentrations of INCB7839 above the IC50 for reduction of ECD levels, 320nM. Importantly, INCB7839 increases the clinical response rate in p95+ patients, with equivalent responses observed in the p95+ and p95- patients treated with INCB7839 + trastuzumab. The combination has been generally safe and well tolerated. Discussion: Proteolytic cleavage of the HER2 receptor by ADAM proteases results in the formation of a cytoplasmic fragment (p95) that possesses constitutive kinase activity with the release of ECD. Importantly, elevated levels of ECD and/or p95 have been associated with poor prognosis and clinical data suggest that p95 affords resistance to trastuzumab. Biomarker and clinical data from this trial demonstrate that INCB7839 can markedly reduce HER2 cleavage in patients with HER2+ breast cancer, and suggests that INCB7839, by inhibiting the HER2 shedding process, can render a subpopulation of HER2+ patients (as defined by the presence of p95) that would be predicted to be trastuzumab resistant clinically responsive to trastuzumab therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5056.