• Tucatinib has been granted orphan drug status for the treatment of breast cancer patients with brain metastases.
• Overall response rate (ORR) was 61% for Ph Ib triplet study
• Tucatinib was well tolerated both trials

Seattle Genetics, Inc.  (Nasdaq:SGEN) announced on 7/11/2018 that results of a phase 1b clinical trial of tucatinib in combination with standard of care agents for the treatment of patients with advanced HER2-positive (HER2+) metastatic breast cancer were recently published in the journal  The Lancet Oncology. Results demonstrated that tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) was generally well-tolerated and had encouraging clinical activity in heavily pre-treated patients with advanced HER2+ breast cancer, including those with brain metastases (ONT-380-005/triplet study). A separate phase 1b clinical trial of tucatinib in combination with ado-trastuzumab emtansine (T-DM1, Kadcyla) was published in  JAMA Oncology. Results showed an acceptable safety profile and preliminary antitumor activity among heavily pretreated patients with HER2+ metastatic breast cancer, with and without brain metastases (ONT-380-004). Tucatinib is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2.

“There remains a need for a well-tolerated, oral targeted therapy to treat patients with HER2+ metastatic breast cancer whose disease progresses on conventional anti-HER2 treatments, particularly for those whose cancer has metastasized to the brain, which occurs in up to 50 percent of these patients,” said Rashmi Murthy, M.D., MBE, Assistant Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “In the ONT-380-005 triplet study, durable responses were seen in heavily pretreated patients with metastatic HER2+ breast cancer, including those with brain metastases, after treatment with tucatinib. Importantly, in the trial, tucatinib treatment was associated with few clinically significant side effects, such as diarrhea or skin rash, commonly seen with other tyrosine kinase inhibitors targeting this disease, which may allow for prolonged use and as a result potentially improve outcomes for patients.”

The phase 1b triplet study was an open-label dose-escalation and expansion cohort study of tucatinib in combination with capecitabine and/or trastuzumab in patients with HER2+ metastatic breast cancer, including those with or without brain metastases. The objective of the study was to assess the safety, tolerability, pharmacokinetics and antitumor activity, and to determine the recommended phase 2 dose of tucatinib in combination with these agents.  Once a recommended phase 2 dose of 300 mg BID was established in the triplet combination, an expansion cohort using that regimen was opened. The trial enrolled 60 patients with HER2+ metastatic breast cancer who had previously received a median of three HER2-targeted agents, such as trastuzumab, pertuzumab (Perjeta), lapatinib (Tykerb) or T-DM1.

Data from patients treated with the triplet combination at 300 mg BID (n=27) included:

•  Median progression-free survival (PFS) was 7.8 months.
• Objective response rate (ORR) was 61 percent (n=14/23) with a median duration of response of 11.0 months.
• Median PFS for patients with brain metastases (n=11) was 6.7 months.
• ORR was 42 percent (n=5/12) in patients with measurable brain metastases that had received the 300mg BID tucatinib dose in any combination.

    The triplet combination was well-tolerated and the majority of adverse events were grade 1, with most patients being able to continue on the full dose of tucatinib. Grade 3 diarrhea was infrequent without a requirement for prophylactic anti-diarrheal medicine.

This phase 1b, open-label dose escalation and expansion cohort study of tucatinib in combination with T-DM1 enrolled 57 patients with HER2+ breast cancer. The objective of the study was to assess the safety, tolerability, pharmacokinetics and antitumor activity, and to determine the recommended phase 2 dose of tucatinib in combination with T-DM1.  Participants in the study previously received a median of two prior HER2-directed therapies.
Data from the phase 1b study of tucatinib and T-DM1 (n=57) included:

•     Median PFS was 8.2 months.
• ORR was 47 percent (n=34/50).

    The combination of tucatinib and T-DM1 was well-tolerated and the majority of adverse events were grade 1.


Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab. Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 are more aggressive and historically have been associated with poor overall survival, compared with HER2-negative cancers. Tucatinib has been granted orphan drug designation by the U.S. Food and Drug Administration (“FDA”) for the treatment of breast cancer patients with brain metastases.