Seattle Genetics’ Tukysa (tucatinib) can now be used in combination with trastuzumab and Xeloda (capecitabine) to treat people with metastatic or inoperable HER2-positive breast cancer following its approval by the U.S. Food and Drug Administration (FDA). 

This will help patients with or without brain metastases who have received one or more prior treatments with HER2-targeted therapies, such as Kadcycla (ado-trastuzumab emtansine), Perjeta (pertuzumab), and trastuzumab (sold under the brand name Herceptin, among others).

“We’re pleased to have collaborated with the FDA on our second expedited real-time oncology review, enabling us to rapidly bring this new targeted medicine to patients,” Clay Siegall, PhD, CEO of Seattle Genetics, said in a company press release. “Tukysa has shown impressive results in people with HER2-positive metastatic breast cancer, including in patients with active brain metastases, and offers patients an effective medicine following previous treatment with other anti-HER2 agents in the metastatic setting.”

For Tukysa’s approval, which was granted priority review in February, the FDA conducted the review under the Real-Time Oncology Review Pilot Program and Project Orbis. 

The pilot program is aimed at bringing safe and effective treatments to patients as early as possible by making the review process more efficient. Project Orbis facilitates a collaborative process with international regulators allowing the simultaneous submission and review of cancer treatments, which may enable patients to receive earlier access in countries with regulatory submission delays. 

For this review, the FDA collaborated with Health Canada, the Australian Therapeutic Goods Administration, Switzerland’s Swissmedic, and Singapore’s Health Sciences Authority. 

“The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international collaborators. We are pleased to work with our Singapore and Switzerland colleagues for the first time, and to continue working alongside our Australian and Canadian colleagues as we facilitate new treatment options for patients — like today’s first new molecular entity under Project Orbis,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

Tukysa is an oral small molecule that blocks the HER2 receptor and helps prevent cancer cells from growing. It has the potential to fight brain metastases in people with HER2-positive cancers because it can cross the blood-brain barrier — the selective membrane that prevents large molecules in the blood from entering the brain. 

FDA approval was based on positive data from the Phase 2 HER2CLIMB trial (NCT02614794) recently published in the New England Journal of Medicine. 

HER2CLIMB tested Tukysa in 612 people with HER2-positive breast cancer that was inoperable or metastatic and had been previously treated with Kadcycla, Perjeta, or Herceptin. Those with stable or growing brain metastases were included as well, totaling 48% of enrolled patients. 

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

The Tukysa combination significantly extended the median PFS to 7.8 months, compared with 5.6 months for those on the placebo, reducing the risk of disease progression and death by 46%. 

Likewise, the median PFS in patients with brain metastases was 7.6 months, compared with 5.4 months in patients who received the placebo combination, resulting in a 52% decrease in the risk of disease progression and death in this subgroup of patients. 

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

“With highly significant and clinically important results for overall and progression-free survival, the addition of TUKYSA to trastuzumab and capecitabine has the potential to become a standard of care for people with HER2-positive metastatic breast cancer after having received one or more previous anti-HER2 therapies in the metastatic setting,” said Eric P. Winer, MD, chief of the Division of Breast Oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber.

The combination therapy was generally safe and well-tolerated. The serious to life-threatening adverse events in those taking Tukysa over the placebo were diarrhea and high levels of aminotransferase, a marker of liver damage. Deaths and treatment discontinuations related to adverse events were rare among both groups.

“We recognize that patients with cancer constitute a vulnerable population at risk of contracting the coronavirus disease,” Pazdur said. “In this critical time, we remain steadfast in our commitment to patients with cancer and doing everything we can to expedite oncology product development.”

“Tukysa was approved four months prior to the FDA goal date, providing an example of this commitment and showing how our regular work in reviewing treatments for patients with cancer is moving forward without delay,” he added. 

Seattle Genetics is also conducting the Phase 3 HER2CLIMB-02 trial (NCT03975647) to test the combination of Tukysa and Kadcycla in people with the same condition who failed to respond to taxane chemotherapy and trastuzumab. The trial is taking place in the U.S. only and is still recruiting patients. For more information on recruitment locations, go here.