Clinical benefit of INCB7839, a potent and selective ADAM inhibitor, in combination with trastuzumab in patients with metastatic HER2+ breast cancer.

3025 Background: In HER2+ breast cancer, the HER2 protein is cleaved by the metalloproteinase ADAM10 resulting in release of the HER2 extracellular domain (ECD) into the serum while the truncated HER2 receptor (p95) remains in the membrane as a constitutively active kinase. Studies have shown that the presence of p95 is associated with poor clinical outcome, including resistance to trastuzumab-based therapy. Therefore, inhibition of HER2 cleavage by the ADAM inhibitor INCB7839 may enhance the clinical efficacy of trastuzumab in HER2+ breast cancer patients. Methods: This study was initiated as a single arm modified dose escalation open label trial of INCB7839 + trastuzumab in women with HER2+ metastatic breast cancer, naive to chemotherapy. Three doses of INCB7839 were studied (100 mg, 200 mg, 300 mg BID) with an expansion arm at the 300 mg dose. Trastuzumab was administered on a Q3 week schedule. Pharmacokinetics, plasma HER2 ECD levels and p95 expression in tumor tissue were assessed in addition to clin...