Tucatinib plus ado-trastuzumab emtansine (T-DM1) may be a well-tolerated and effective therapeutic option among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer, according to the results of a phase 1b study published in JAMA Oncology.1

Treatment options for disease progression after trastuzumab, pertuzumab, and T-DM1 are limited. Although newer therapies that target cancers characterized by overexpression of ERBB2/HER2 (eg, lapatinib, neratinib) have improved outcomes, they have been associated with epidermal growth factor receptor (EGFR) off-target and EGFR-related toxicities. Tucatinib is a potent, selective, and reversible novel therapy for this patient population, according to researchers.

For this phase 1b (ClinicalTrials.gov Identifier: NCT01983501) study, researchers enrolled 57 patients with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Patients received tucatinib 300 mg or 350 mg twice daily plus T-DM1 3.6 mg/kg intravenously. A modified 3+3 dose-escalation design was utilized, which allowed for at least 6 patients to be assigned to each tucatinib dose group, and an expansion cohort was implemented once the maximum tolerated dose was determined.

Continue Reading

Related Articles

Analyses showed that 1 patient in the 300 mg dose group, and 3 patients in the 350 mg dose group 32 patients (69%) experienced dose-limiting toxicities, leading researchers to establish 300-mg twice daily as the maximal tolerated dose. No drug-drug interactions were observed with T-DM1.

In sum, 32 of 57 patients (56%) required interruption of tucatinib treatment, though therapy was successfully restarted for 22 of 32 patients (69%). Frequently observed tucatinib-associated adverse events (AE) — the majority of which were grade 1 or 2 — included nausea, diarrhea, fatigue, increased AST/ALT levels, vomiting, decreased appetite, and hypokalemia.

Efficacy assessments showed that 50 patients treated with tucatinib plus T-DM1 had a median progression-free survival (PFS) of 8.2 months; patients previously treated with trastuzumab and pertuzumab had a median PFS of 6.5 months.

The objective response rate was 47%, with 1 and 15 patients achieving complete and partial responses, respectively. Fourteen patients had stable disease, and 4 experienced disease progression. The median duration of response was 6.9 months. Of the 14 patients who had brain metastases, the brain-specific objective response rate was 36%.

The authors concluded that “tucatinib represents a promising new therapy with highly selective ERBB2/HER2 targeting that offers a favorable adverse event profile and demonstrates preliminary systemic and brain metastases activity when used in combination with standard-dosage T-DM1 for the treatment of ERBB2/HER2-positive metastatic breast cancer.”


  1. Borges VF, Ferrario C, Aucoin N, et al. Tucatinib combined with ado-trastuzumab emtansine in advanced ERBB2/HER2-positive metastatic breast cancer [published online June 28, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.1812