ONT-380 Combinations Effective in HER2-positive Metastatic Breast Cancer

Erika P. Hamilton, MD, associate director, Breast Cancer and Gynecologic Cancer Research Program, principal investigator, Sarah Cannon Research Institute

Erika P. Hamilton, MD

The oral selective small molecule HER2 inhibitor ONT-380 in combination with other therapies demonstrated promising activity in previously treated patients with HER2-positive metastatic breast cancer, including those with central nervous system (CNS) metastases, according to findings from two phase Ib studies. Findings from the studies were presented at the 2015 ASCO Annual Meeting.

"The level of clinical activity seen in these trials, both systemically and in the CNS, in heavily pretreated patients is very encouraging," Stacy Moulder, MD, associate professor, Breast Medical Oncology, University of Texas MD Anderson Cancer Center, said in a statement. "Moreover, ONT-380 has been well-tolerated in these trials, an important consideration in patients who may need prolonged therapy."

The first study assessed ONT-380 in combination with capecitabine (Xeloda) and trastuzumab (Herceptin) in patients with HER2-positive breast cancer who had previously received trastuzumab and T-DM1. In this analysis, 4 patients had partial responses, two have had stable disease, and two had had progressive disease.

Toxicities were minimal with a dose-limiting toxicity of reversible cerebral edema with grade 3 dysarthria and visual field deficit seen in one patient with known brain metastases. Most other toxicities have been grade 1 or 2, including nausea, vomiting, and diarrhea.

"ONT-380 is only a HER2-specific inhibitor, unlike other oral HER2 inhibitors that are commercially available like lapatinib which block both HER2 and EGFR," lead investigator Erika P. Hamilton, MD, associate director, Breast Cancer and Gynecologic Cancer Research Program, principal investigator, Sarah Cannon Research Institute. "With lapatinib, we sometimes see rash and diarrhea as a problem for patients. Because ONT-380 is just specific against HER2, those side effects are not a problem for patients and the drug has been very well tolerated."

Additionally, a CNS analysis for ONT-380 examined patients from the first phase Ib study in addition to a separate phase Ib trial examining combination therapy with ONT-380 and T-DM1 in HER2-positive patients. According to Oncothyreon Inc, the manufacturer of ONT-380, there was one complete response, four patients had partial responses, and nine patients had stable disease. At the time of the analysis, no patients experienced progressive disease.

Across both phase Ib studies, the most common adverse events included diarrhea, nausea, constipation, fatigue, dyspepsia, headache and vomiting. Laboratory abnormalities included asymptomatic elevated liver function tests, which were more common in patients also receiving T-DM1.

No grade 3 diarrhea was seen in either trial at the recommended dose of ONT-380. Furthermore, antidiarrheal prophylaxis was not required in the study.

Based on the positive phase Ib data, Oncothyreon is planning a blinded, randomized, placebo-controlled phase II trial that will examine the triplet of ONT-380, trastuzumab, and capecitabine in patients who have progressed after both T-DM1 and pertuzumab (Perjeta).

"Oncothyreon is currently planning a blinded, randomized placebo-controlled phase II trial of ONT-380 in combination with Herceptin and Xeloda for the treatment of HER2-positive metastatic breast cancer in patients who have failed both Perjeta and Kadcyla, which we expect to initiate late this year," Diana Hausman, MD, chief medical officer of Oncothyreon. "The trial design includes endpoints focused on the prevention and treatment of CNS metastases. We have also now enrolled over 40 patients in our trial of ONT-380 in combination with Kadcyla and continue to evaluate this combination for the treatment of patients with CNS metastases."