On 17 April 2020, the US Food and Drug Administration (FDA) approved (TUKYSA, Seattle Genetics, Inc.) in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The US FDA, the Australian Therapeutic Goods Administration, Health Canada, Health Sciences Authority (Singapore), and Swissmedic (Switzerland) collaborated on this review.
While the FDA approved tucatinib on 17 April 2020, the application is still under review at the other agencies.
Efficacy was demonstrated in the HER2CLIMB trial (NCT02614794) enrolling 612 patients with HER2-positive metastatic breast cancer who had prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine. Patients received either tucatinib 300 mg twice daily plus trastuzumab and capecitabine (tucatinib arm, n=410) or placebo plus trastuzumab and capecitabine (control arm, n=202).
The primary endpoint was progression-free survival (PFS), assessed by a blinded independent central review, evaluated in the initial 480 randomised patients. The median PFS in patients receiving tucatinib was 7.8 months (95% confidence interval [CI] 7.5, 9.6) compared to 5.6 months (95% CI 4.2, 7.1) for patients enrolled on the control arm (hazard ratio [HR] 0.54; 95% CI 0.42, 0.71; p < 0.00001).
Additional efficacy outcome measures were evaluated in all randomised patients and included overall survival (OS), PFS among patients with a history or presence of brain metastases, and confirmed objective response rate (ORR).
The median OS in patients on the tucatinib arm was 21.9 months (95% CI 18.3, 31.0) compared to 17.4 months (95% CI 13.6, 19.9) for patients on the control arm (HR 0.66; 95% CI 0.50, 0.87; p = 0.00480).
The median PFS for patients with baseline brain metastases on the tucatinib arm was 7.6 months (95% CI 6.2, 9.5) compared to 5.4 months (95% CI 4.1, 5.7) for those on the control arm (HR 0.48; 0.34, 0.69; p < 0.00001).
The confirmed ORR for patients with measurable disease was 40.6% (95% CI 35.3, 46.0) and 22.8% (95% CI 16.7, 29.8) for patients in the tucatinib and control arms, respectively (p = 0.00008).
The most common adverse reactions (≥ 20% of patients) were diarrhoea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anaemia, and rash. Tucatinib can also cause severe diarrhoea and hepatotoxicity.
The recommended tucatinib dose is 300 mg taken orally twice a day in combination with trastuzumab (at standard dosage) and capecitabine (1000 mg/m2 given orally twice daily on days 1-14 of a 21-day cycle) until disease progression or unacceptable toxicity.
Full prescribing information for TUKYSA is available here.
This review used the Real-Time Oncology Review pilot programme and Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. The FDA approved this application 4 months ahead of the FDA goal date.
FDA granted tucatinib orphan drug, fast track, and breakthrough therapy designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA OCE’s Project Facilitate.