Tukysa Combo Approved in EU for Advanced HER2-Positive Breast Cancer

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Tukysa, EU approval

Seagen’s Tukysa (tucatinib) has been approved by the European Commission (EC) as part of a triple-combination therapy for people with previously treated advanced or metastatic HER2-positive breast cancer.

The EC approved Tukysa, when given alongside trastuzumab and the chemotherapy medication Xeloda (capecitabine), for patients who have received at least two anti-HER2-based treatments for metastatic disease.

With this decision, Seagen — previously known as Seattle Genetics — will be able to market the Tukysa combo in all European Union (EU) member states, plus Norway, Liechtenstein, Iceland, and Northern Ireland.

“We are pleased Tukysa is now approved in Europe, and we look forward to further collaborating with individual countries to ensure it is available to patients,” Clay Siegall, PhD, CEO at Seagen, said in a press release.

The U.S. Food and Drug Administration (FDA) approved Tukysa for the same indication in May 2020. In December 2020, the Committee for Medicinal Products for Human Use (CHMP), an arm of the European Medicines Agency, also had supported Tukysa’s approval in the EU.

“This approval is a significant advancement for patients in Europe, who will for the first time have an approved medicine demonstrating a survival benefit for HER2-positive metastatic breast cancer after disease progression following two standard anti-HER2 treatment regimens,” said Volkmar Mueller, MD, deputy director at the University Medical Center Hamburg-Eppendorf, in Germany, a trial investigator.

Tukysa is an oral small molecule that blocks the activity of HER2, a protein receptor that is known to promote the growth of certain types of breast cancer. The medication also can be used to treat patients with brain metastases, due to its ability to cross the blood-brain barrier — a semi-permeable barrier that protects the brain and spinal cord from the surrounding environment.

A pivotal Phase 2 trial, named HER2CLIMB (NCT02614794), tested Tukysa in 612 people with HER2-positive breast cancer that was inoperable or metastatic. All of the participants had been previously treated with Kadcycla (ado-trastuzumab emtansine), Perjeta (pertuzumab), or trastuzumab (Herceptin). Those with stable or growing brain metastases were included as well, totaling 48% of enrolled patients.

The participants were randomly assigned to receive either Tukysa or a placebo, in combination with trastuzumab and Xeloda. The goal was to prolong the time patients lived without disease progression or death, known as progression-free survival, or PFS, among the first 480 dosed participants.

Compared with a placebo, Tukysa significantly extended patients’ PFS (median 5.6 vs. 7.8 months), representing a 46% reduced risk of disease progression or death with the therapy.

The therapy was generally safe and well-tolerated, with side effects (adverse events) reported by at least 20% of patients. The most common adverse events were diarrhea, high levels of the liver damage marker aminotransferase, nausea, vomiting, stomatitis — an inflammation of the mouth and lips — and rash.

Among participants who had brain metastases, the median PFS was significantly longer for those given Tukysa compared with those given a placebo, at 7.6 vs. 5.4 months. That represented a 52% reduced risk of disease progression or death with Tukysa.

The Tukysa combo extended overall survival to 21.9 months, compared with 17.4 months on the placebo. It also lowered the risk of death by 34% and demonstrated a significantly higher overall response rate (41%) compared with the placebo (23%).

“In the HER2CLIMB pivotal trial, the tucatinib combination regimen improved overall and progression-free survival compared to trastuzumab and capecitabine alone, including in patients with active, untreated or progressing brain metastases, a population with significant unmet need,” Mueller said.

Siegall noted that the patients all had undergone two prior anti-HER2 treatment regimens.

“The TUKYSA combination is a landmark therapy for patients with HER2-positive metastatic breast cancer with or without brain metastases, extending overall survival in these patients,”  Siegall said.

Phase 3 trial, named HER2CLIMB-02 (NCT03975647), is testing the combination of Tukysa and Kadcycla in people with advanced or metastatic HER2-positive breast cancer who failed to respond to taxane chemotherapy and trastuzumab.

That trial is recruiting patients at 115 locations worldwide, including study sites in the U.S., Australia, Belgium, Canada, France, Israel, Japan, Korea, Spain, and Switzerland. More information and contacts can be found here.

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