ONT-380 Active Against CNS Mets in HER2-Positive Breast Cancer

Two studies of the new HER2 selective tyrosine kinase inhibitor ONT-380 showed the drug has promising activity in HER2-positive breast cancer, especially in patients with central nervous system metastases. Both studies were presented at the 2015 San Antonio Breast Cancer Symposium.

The first study was a phase Ib trial of ONT-380 in combination with trastuzumab emtansine (T-DM1) in patients with metastatic breast cancer with and without CNS metastases. The study used a 3 + 3 dose escalation design with expansion cohorts, and included a total of 57 total patients; all patients had been previously treated with trastuzumab and a taxane.

The study found the maximum tolerated dose of ONT-380 to be 300 mg administered twice daily. Among 34 patients with measurable disease, a confirmed partial response was observed in 14 (41%); 15 patients (44%) had stable disease, and 5 patients (15%) had progressive disease.

The clinical benefit rate (59%), was defined as patients with a complete response, a confirmed partial response, or either stable disease or non-complete response/non-progressive disease for at least 6 months.

Of the full cohort, 60% had CNS metastases, and 20 patients had response assessable CNS metastases. The overall response rate among these was 33%, and the CNS clinical benefit rate was 64%. Progression-free survival could not yet be evaluated in this trial, as half the patients enrolled at the maximum tolerated dose remained active on the study.

The most common adverse events in the trial were nausea, vomiting, and diarrhea, and most of these were grade 1 in severity. There were some grade 3 or greater elevated ALT/AST tests, but all were reversible with dose interruption.

The second study combined patients from both that phase Ib trial and another phase Ib study of ONT-380 in combination with trastuzumab and capecitabine. This included a total of 34 patients with response-assessable CNS metastases.

Among 14 patients with previously untreated lesions, 8 had measurable disease; among these, the best CNS response was 1 complete response, 2 confirmed partial responses, and 4 with stable disease (the other patient did not have a follow-up scan). The CNS clinical benefit rate for those with previously untreated CNS metastases was 44%.

Among 20 patients with new or progressive lesions following prior therapy, 17 of them had measurable disease. In these patients, the CNS clinical benefit rate was 59%.

“CNS metastases occur in up to 50% of women with HER2-positive metastatic breast cancer, and these patients have limited options for systemic treatment,” said Stacy Moulder, MD, of the MD Anderson Cancer Center in Houston, in a press release from Oncothyreon, the developer of ONT-380. “The level of clinical activity seen in the expanded data set for ONT-380 in these advanced-stage patients is encouraging and worthy of urgent further development.”