BACKGROUND: Tucatinib is a potent and selective oral HER2 tyrosine kinase 
inhibitor, with the potential to provide a well tolerated new treatment option 
for patients whose disease has progressed on currently available therapies. We 
aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and 
preliminary activity of tucatinib in combination with capecitabine or 
trastuzumab in patients with HER2-positive breast cancer with or without brain 
metastases.
METHODS: In this non-randomised, open-label, phase 1b trial done in five sites 
in the USA, we recruited patients aged 18 years or older with HER2-positive 
progressive breast cancer who had been previously treated with trastuzumab, 
pertuzumab, and trastuzumab emtansine. Eligible patients required 
HER2-positivity assessed locally, evaluable lesions as defined per Response 
Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative 
Oncology Group performance status of 0 or 1. Tucatinib was administered twice a 
day in conjunction with capecitabine 1000 mg/m2 orally twice a day for 14 days 
of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or 
both. A modified 3 + 3 dose-escalation design was used to determine the 
recommended phase 2 dose, starting with tucatinib in combination with 
capecitabine or trastuzumab, and subsequently evaluating the triplet 
combination. The primary endpoint was to establish the maximum tolerated dose 
and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. 
Efficacy was assessed in all patients by contrast CT of the body. Analyses 
included all patients who had received at least one dose of study treatment. The 
study is registered with ClinicalTrials.gov, number NCT02025192.
FINDINGS: Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and 
treated. The current report is from mature data as of June 30, 2017. The 
tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a 
day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis 
showed that there was no drug-drug interaction with capecitabine. Adverse events 
seen at the recommended phase 2 dose regardless of causality, grade, and 
treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] 
patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), 
fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, 
treatment-related toxicities of grade 3 and worse included fatigue (five [8%] 
patients), diarrhoea (four [7%] patients), and palmar-plantar 
erythrodysaesthesia (four [7%] patients). No treatment-related deaths were 
reported. The proportion of patients with measurable disease achieving objective 
response was 83% (five of six patients) in the combination of tucatinib with 
capecitabine, 40% (six of 15 patients) in the combination of tucatinib with 
trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with 
both capecitabine and trastuzumab.
INTERPRETATION: Tucatinib in combination with capecitabine and trastuzumab had 
acceptable toxicity and showed preliminary anti-tumour activity. Validation of 
the current study results will be determined in the double-blinded randomised 
study, HER2CLIMB (ONT-380-206; NCT02614794).
FUNDING: Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics.