Findings from a Phase 1 clinical trial show that women with heavily treated breast cancer could benefit from the investigational HER2 small molecule inhibitor tucatinib. Despite a median of five prior treatment regimens, more than a quarter of the women saw clinical benefit from the treatment.
Based on the findings, the study, which was only meant to assess tucatinib’s safety, will now expand into a more elaborate Phase 1b trial. The U.S. Food and Drug Administration (FDA) also granted the treatment fast-track status in June.
The study, “Phase 1 Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+ Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC),” was published in the journal Clinical Cancer Research.
“Usually we expect the results of a phase 1 clinical trial to give us data that we can use to guide the results of future treatments. This is a great case in which, for many of these patients, the results were immediate. There are women who are alive today because of this drug,” Virginia Borges, MD, MMSc, director of the Breast Cancer Research Program and Young Women’s Breast Cancer Translational Program at the University of Colorado Cancer Center, said in a press release.
Tucatinib is a small molecule inhibitor of the HER2 receptor that stops cancers with activating mutations in the HER2 gene from sending abnormal growth signals to cells. HER2-positive breast cancers are more likely to metastazise to the brain, and because tucatinib is a small molecule that crosses the blood-brain barrier, it holds promise in fighting brain metastasis in such patients.
The Phase 1 clinical trial was designed to assess tucatinib’s safety in 50 patients with HER2-positive solid tumors, 43 of whom had metastatic breast cancer. The patients had received, on average, five prior anti-cancer treatments.
They received tucatinib twice daily in continuous, 28-day cycles.
Among the 35 evaluable patients, three (9%) had partial response and 20 (57%) had stable disease. For metastatic breast cancer patients, the clinical benefit rate 24 weeks after treatment was 27%, which included three confirmed partial responses and three stable diseases.
This suggests tucatinib may be an effective treatment for HER2-positive metastatic breast cancer, with or without brain metastasis.
Elena Shagisultanova, MD, PhD, has been working with the Young Women’s Breast Cancer Translational Program, and has earned a $1.4 million ASPIRE grant to evaluate tucatinib in patients with triple-positive breast cancer.
Because these cancers express all three growth factor receptors, they can be driven by estrogen, progesterone, and overactivated HER2 signaling. Blocking any of the receptors in such cancers has little impact because the other pathways can counteract the effects and allow the cancer to survive.
Shagisultanova’s trial will assess the efficacy of a combination therapy of tucatinib, Femara (letrozole), and Ibrance (palbociclib) against HER2-positive, estrogen receptor-positive breast cancers.
“I think this drug has an extremely high likelihood of being approved for women with HER2+ breast cancer for use after previous treatments,” Borges said. “And it’s going to be an especially important drug due to its ability to control brain metastases. The opportunity to study it as a front-line drug for recurrent triple positive breast cancer could even someday help us prevent or delay these brain metastases.”
Tucatinib’s developer, Cascadian Therapeutics, also is recruiting for a Phase 2 trial (NCT02614794) evaluating the drug in combination with trastuzumab and capecitabine for HER2-positive patients. As many as 180 people with and without brain metastases are expected to be enrolled in about 100 clinical sites in the United States, Canada, and Western Europe.