FDA Grants Breakthrough Therapy Status to Tucatinib for Advanced HER2-Positive Breast Cancer

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to Seattle Genetics’ tucatinib, in combination with trastuzumab and Xeloda (capecitabine), for the treatment of patients with locally advanced inoperable or metastatic HER2-positive breast cancer.

The designation, which also includes those with brain metastases, is for patients who previously received treatment with three other HER2-targeted therapies: trastuzumab (sold under the brand name Herceptin, among others), Perjeta (pertuzumab) and Kadcycla (ado-trastuzumab emtansine).

Breakthrough designation is given to medications that have the potential to provide significant advantages over currently available options. It is intended to accelerate the development, review, and approval of treatments for serious or life-threatening conditions.

Tucatinib is a potent oral inhibitor of the HER2 receptor that has the ability to cross the blood-brain barrier — a highly selective, semipermeable membrane that isolates the brain from the blood circulating in the body — and shows promise in fighting brain metastases in people with HER2-positive cancers. It previously received orphan drug designation from the FDA for the treatment of breast cancer patients with brain metastases.

The breakthrough designation for the treatment of advanced HER2-positive breast cancer was granted based on top-line data from the pivotal Phase 2 HER2CLIMB trial (NCT02614794).

Additional findings from the trial were also recently presented at the 2019 San Antonio Breast Cancer Symposium and published in The New England Journal of Medicine.

HER2CLIMB investigated if adding tucatinib to a combination of trastuzumab and Xeloda, which is often used to treat patients with this particular type of cancer, could improve the survival of patients with advanced HER2-positive breast cancer.

It enrolled a total of 612 patients with either metastatic (cancer spread to other parts of the body) or inoperable locally advanced cancer who had received prior treatment with trastuzumab, Perjeta, and Kadcyla. Nearly half (47%) had brain metastasis at the time of enrollment.

Once enrolled, patients were randomly assigned to receive either tucatinib or a placebo, in combination with Xeloda and trastuzumab. The study’s main goal was to determine if the addition of tucatinib to Xeloda and trastuzumab could prolong the time patients lived without disease progression, or death — called progression-free survival, or PFS.

Additional goals included overall survival and PFS in the subgroup of patients with brain metastases. Treatment safety, response rates, and duration of response were also assessed.

Data presented at the symposium included that of the first 480 patients treated in HER2CLIMB, 320 of whom were on tucatinib and 160 on placebo.

Findings revealed that adding tucatinib to Xeloda and trastuzumab reduced the risk of disease progression or death by 46% over placebo, meaning the trial reached its primary goal. At one year, 33% of patients on tucatinib were alive and without signs of disease progression, a status only seen in 12% of those on placebo.

Moreover, the triple combination therapy reduced the risk of death by 34% in the overall population, and the risk of disease progression or death by 52% among those who had brain metastases at the beginning of the study.

The triple-combo therapy was also found to be safe and generally well tolerated by patients. The most common adverse events reported during the trial included diarrhea, redness, swelling, and pain on the palms of the hands or the soles of the feet, nausea, fatigue, and vomiting.

Severe (grade 3), life-threatening (grade 4), or fatal (grade 5) adverse events were reported in 55.2% of the patients receiving tucatinib and on 48.7% of those receiving the placebo.

Treatment discontinuations due to adverse events were rare among participants from both treatment groups (5.7% on tucatinib and 3% on placebo). Six patients receiving tucatinib (1.5%) and five treated with the placebo (2.5%) died during the study due to treatment adverse events.

“The addition of tucatinib to the commonly used combination of trastuzumab and capecitabine demonstrated superior activity compared to trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with and without brain metastases,” Roger Dansey, MD, chief medical officer of Seattle Genetics, said in a press release.

“The decision by the FDA to grant breakthrough therapy designation to tucatinib recognizes the urgent need for new medicines that can impact the lives of those with HER2-positive metastatic breast cancer. We intend to submit a new drug application to the FDA and a [marketing authorization application] to the [European Medicines Agency] by the first quarter 2020, with the goal of making tucatinib available to patients in this setting as soon as possible,” Dansey added.