First Patient Dosed in Phase 3 Trial of Tucatinib-Kadcyla Combo for Advanced HER2-Positive Breast Cancer

A Phase 3 trial exploring a combination of Seattle Genetics‘ tucatinib plus standard Kadcyla (ado-trastuzumab emtansine) in people with advanced HER2-positive breast cancer has dosed its first participant, the company announced.

The trial — called HER2CLIMB-02 (NCT03975647) — is enrolling up to 460 adult patients with metastatic or inoperable, locally advanced disease who received prior treatment with a taxane chemotherapy and trastuzumab. The trial’s results are expected to be included in Seattle Genetics’ application seeking approval for tucatinib in the U.S. for this indication.

“We are building a comprehensive strategy for tucatinib in combination with other medicines across a range of HER2-positive cancers,” Roger Dansey, MD, chief medical officer at Seattle Genetics, said in a news release.

“We are pleased to advance this tucatinib clinical trial with the vision of improving combination outcomes for patients with HER2-positive metastatic breast cancer who receive T-DM1,” he said. “This trial has the potential to support tucatinib use in earlier lines of therapy.”

When breast cancers are driven by the protein HER2, which acts to send signals that drive excessive cell growth and is associated with more aggressive cancers, the standard approach is targeted therapy against this protein.

Many HER2-targeted treatments exist for breast cancer patients, including trastuzumab and Perjeta (pertuzumab) — antibodies that target and inhibit HER2 — and Kadcyla (ado-trastuzumab emtansine), which is trastuzumab bound to a toxic payload. However, patients may still see their disease progress after all these treatments.

Tucatinib is an oral investigational small molecule inhibitor of the HER2 receptor with the ability to cross the blood-brain barrier, and holds promise in fighting brain metastasis in people with HER2-positive cancers. It has received orphan drug status by the U.S. Food and Drug Administration for the treatment of breast cancer patients with brain metastases.

HER2CLIMB-02 was designed to determine if adding tucatinib to Kadcyla could delay cancer progression and death in people who had failed prior taxane chemotherapy and trastuzumab. Patients are eligible regardless of brain metastasis or prior Perjeta treatment.

The study will randomly assign participants to receive either oral tucatinib or a placebo, twice a day, plus intravenous injections of Kadcyla once every three weeks.

In addition to progression-free survival — the trial’s main goal — the researchers will also measure overall survival, the time without disease worsening, or death in people with brain metastasis at the study’s start, and the proportion of patients who respond to treatment, as well as duration of responses. Safety will also be assessed.

The study is ongoing and recruiting participants at three U.S. sites: the Center for Cancer and Blood Disorders/RCCA in Bethesda, Maryland, the Nebraska Cancer Specialists in Omaha, Nebraska, and the Summit Medical Group in Florham Park, New Jersey.

In addition to HER2CLIMB-02, Seattle Genetics is sponsoring a Phase 2 clinical trial called HER2CLIMB (NCT02614794), which is studying a combination of tucatinib plus standard Xeloda (capecitabine) and trastuzumab in advanced HER2-positive breast cancer patients who received prior treatment with trastuzumab, Perjeta, and Kadcyla.

That trial recently met its primary endpoint of progression-free survival as well as two key secondary measures: the tucatinib combo reduced the risk of disease progression or death by 46% compared to standard Xeloda plus trastuzumab, and cut the risk of death by 34%. In people with brain metastasis, the risk of disease progression or death was lowered by more than half (52%).