April 17, 2020
On April 17, 2020, the Food and Drug Administration 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. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The U.S. FDA, the Australian Therapeutic Goods Administration, Health Canada, Health Sciences Authority (Singapore), and Swissmedic (Switzerland) collaborated on this review.
While the FDA approved tucatinib today, the application is still under review at the
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 randomized patients. The median PFS in patients receiving tucatinib was 7.8 months (95% CI: 7.5, 9.6) compared to 5.6 months (95% CI: 4.2, 7.1) for patients enrolled on the control arm (HR 0.54; 95% CI: 0.42, 0.71; p<0.00001).
Additional efficacy outcome measures were evaluated in all randomized 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 diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Tucatinib can also cause severe diarrhea 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.
This review used the Real-Time Oncology Review (RTOR) pilot program 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. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
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 or by calling 1-800-FDA-1088.
For information on the COVID-19 pandemic, see the following resources:
- FDA: Coronavirus Disease 2019 (COVID-19)
- NCI: Coronavirus: What People With Cancer Should Know
- CDC: Coronavirus (COVID-19)