ONT-380 (previously known as ARRY-380) is a small molecule selective inhibitor of HER2, a growth factor receptor that is over-expressed in multiple cancers, including breast, ovarian, and stomach cancer. HER2 mediates cell growth, differentiation and survival, and tumors that overexpress HER2 are more aggressive and historically have been associated with poorer overall survival compared with HER2-negative cancers. For additional information on the role of HER signaling in cancer, please click the About HER2 tab above.
ONT-380 is the only HER2-selective small molecule in clinical development. Other small molecule inhibitors of HER2 that are currently either approved or in development for treatment of HER2+ breast cancer are dual inhibitors of both HER1 (also known as epidermal growth factor receptor or EGFR) and HER2, including Tykerb® (lapatinib), neratinib and Gilotrif® (afatinib). ONT-380 selectively inhibits HER2 without significant inhibition of EGFR, resulting in highly potent inhibition of HER2 while avoiding the side effects associated with dual inhibitors, including skin rash and GI toxicities. Cascadian Therapeutics is currently conducting a Phase 2 trial of ONT-380 in women with HER2+ breast cancer.
ONT-380 is highly active as a single agent and in combination with both chemotherapy and Herceptin® (trastuzumab) in preclinical mouse tumor models of HER2+ breast cancer, including models of brain metastases that were refractory to Tykerb (lapatinib) or neratinib treatment. In a Phase 1 single agent clinical study, ONT-380 administered orally twice a day demonstrated anti-tumor activity in heavily pre-treated HER2+ breast cancer patients with metastatic disease without treatment-related Grade 3 diarrhea and only minimal Grade 3 rash. This safety and tolerability profile is important given that HER2 inhibitors are typically used in combination with other agents that may be associated with significant side effects. Addition of ONT-380 to these regimens has the potential to increase efficacy without adding significantly to the side effect burden. Based on these properties, Cascadian Therapeutics believes that ONT- 380 is well positioned to address the unmet needs in HER2+ breast cancer.
Cascadian Therapeutics has an exclusive license from Array BioPharma Inc. to manufacture, develop and commercialize ONT-380.