Tucatinib Shows Promise in Phase I Study of HER2-Positive Breast Cancer

The combination of the HER2 tyrosine kinase inhibitor (TKI) tucatinib and capecitabine or trastuzumab was reasonably well tolerated and showed preliminary antitumor activity in a phase I trial of patients with HER2-positive breast cancer who had progressed on other currently available therapies.

“Treatment options for patients who progress following treatment with trastuzumab, pertuzumab, and trastuzumab emtansine are scarce,” wrote study authors led by Rashmi Murthy, MD, of the University of Texas MD Anderson Cancer Center in Houston. “Currently, no single regimen is considered standard of care in this setting, and treatment options with improved efficacy and safety profile are an unmet need.”

Tucatinib is an oral HER2-specific reversible TKI being developed as a new therapy for metastatic HER2-positive breast cancer. The new trial combined the agent with trastuzumab or capecitabine, or both, in patients with advanced metastatic disease, with or without brain metastases. The results were published in Lancet Oncology.

The trial included a total of 60 patients, 52 of whom received a tucatinib dose of 300 mg twice a day, and 8 of whom received a dose of 350 mg. Patients had received a median of three prior unique HER2-targeted agents.

There were no dose-limiting toxicities seen at the 300-mg dose level, and one-a case of grade 4 symptomatic cerebral edema in a patient with brain metastases-was reported in the 350-mg cohort. The investigators recommended 300 mg twice per day as the phase II dose for tucatinib.

The most common treatment-emergent adverse events at that recommended phase II dose included diarrhea (67% of patients), nausea (60%), palmar-plantar erythrodysesthesia (44%), fatigue (38%), and vomiting (38%). A total of 20 patients (33%) had a serious adverse event, including 17 patients at the 300-mg dose and 3 at the higher dose. More than half the patients (57%) required tucatinib dose interruption, and in 82% of those patients the agent was successfully re-initiated.

Among 6 patients receiving tucatinib 300 mg plus capecitabine, 5 had an objective response (83%); all were partial responses. The other patient had stable disease. In the group combining 300-mg tucatinib and trastuzumab (15 patients), there were 6 partial responses (40%), 6 had stable disease (40%), and 3 had progressive disease (20%). In the triplet group that received tucatinib, capecitabine, and trastuzumab (23 patients), there were 14 objective responses (61%), including 1 complete response (4%); 6 patients (26%) had stable disease, while 3 (13%) had progressive disease.

The median progression-free survival with the tucatinib 300-mg combinations was 7.8 months.

“Tucatinib represents a promising new therapy with potent and highly selective HER2 targeting that offers a favorable side-effect profile and demonstrates systemic and parenchymal brain activity when used in combination with standard-dose capecitabine and trastuzumab in patients with HER2-positive metastatic breast cancer,” the authors concluded. “Further studies with tucatinib and this drug combination are warranted.”