Murthy R, et al. - Researchers investigated 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. With acceptable toxicity profile, preliminary anti-tumour activity was shown by tucatinib in combination with capecitabine and trastuzumab.

Methods

• This non-randomised, open-label, phase 1b trial was conducted at five sites in the USA.
• Patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine were recruited.
• Patients with 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 were considered eligible.
• Patients received tucatinib 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.
• Researchers used a modified 3 + 3 dose-escalation design to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently assessing the triplet combination.
• The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, assessed by toxicity assessments.
• Contrast CT of the body was used to assess the efficacy in all patients and all patients who had received at least one dose of study treatment were analyzed.

Results

• A total of 60 patients were enrolled and treated between Jan 15, 2014, and Dec 15, 2015 and the current report is from mature data as of June 30, 2017.
• Data showed that the determined tucatinib recommended phase 2 dose was 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose.
• No drug–drug interaction with capecitabine was demonstrated in pharmacokinetic analysis.
• Regardless of causality, grade, and treatment group, the following adverse events were noted at the recommended phase 2 dose: 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).
• Fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients) were reported as treatment-related toxicities of grade 3 and worse in all patients.
• Findings showed no treatment-related deaths.
• Researchers found that 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.