Novel HER2 Inhibitor Offers Manageable Toxicity, Anti-Tumor Activity in Metastatic Breast Cancer

A phase I trial found that the HER2 inhibitor ONT-380 had a lower incidence of certain adverse events associated with this class of agent and notable anti-tumor activity in heavily pretreated patients with HER2-positive metastatic breast cancer (MBC).

“Though existing targeted therapies are improving outcomes in patients with HER2-positive MBC, disease resistance does eventually develop in most patients,” wrote study authors led by Stacy Moulder, MD, of the MD Anderson Cancer Center in Houston. Also, some agents preclude combination with other regimens due to off-target effects such as skin rash and diarrhea.

ONT-380 is a potent, selective, oral HER2 inhibitor. The new study was a modified 3+3 dose escalation trial of patients with HER2-positive solid tumors, followed by a dose expansion only in those with HER2-positive MBC. A total of 50 patients were treated (33 in the escalation phase, 17 in the expansion phase), 43 of whom had MBC. The results were published online ahead of print last month in Clinical Cancer Research.

Patients in the trial were heavily pretreated, with a median of five prior anti-cancer regimens; all MBC patients had received prior trastuzumab, and 81% had received prior lapatinib. The escalation phase found a maximum tolerated dose of 600 mg BID, with dose-limiting toxicities including grade 3 increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) at the 800 mg BID dose.

The most common treatment-related adverse events included nausea in 34% of patients, diarrhea in 22%, and fatigue in 20%. Grade 3 treatment-related adverse events included hypokalemia, increased ALT and AST, rash, night sweats, and others were reported only in the 600 mg BID and higher cohorts.

Five patients discontinued ONT-380 due to an adverse event, but none were considered drug-related. Fifteen patients (30%) required a dose interruption, and four patients (8%) needed a dose reduction.

Thirty-five patients were evaluable for a tumor response at any dose level. Of those, three patients (9%) had a partial response, and 20 (57%) had stable disease (two of which were unconfirmed partial responses).

Only among the 22 HER2-positive MBC patients with measurable disease at baseline treated at the maximum tolerated dose or above, the clinical benefit rate combining partial responses and stable disease was 27%. In the three of these patients with a confirmed partial response, the response duration was 12.3 weeks in one patient and 28 weeks in the other two.

“This study demonstrated that ONT-380 appears to have a more favorable and manageable toxicity profile compared to either current dual EGFR/HER2 or pan-HER tyrosine kinase inhibitors, with clinical activity in a heavily pretreated HER2-positive MBC cohort,” the authors concluded. A phase II trial combining the agent with trastuzumab and capecitabine is now ongoing.