Seattle Genetics’ Tucatinib Extends Survival Outcomes in Metastatic HER2-positive Breast Cancer Patients, Phase 2 Trial Shows

People with HER-positive advanced breast cancer who received multiple HER-targeted therapies have significantly better survival outcomes — including overall survival and survival without disease progression — when given a combination of Seattle Genetics‘ tucatinib plus standard trastuzumab and Xeloda (capecitabine), results from a Phase 2 trial show.

The triple combination was also significantly better than a trastuzumab-Xeloda combo at delaying death or disease progression in people with brain metastasis at baseline.

Seattle Genetics plans to submit these data to the U.S. Food and Drug Administration (FDA) to seek approval of the triple combo treatment for this patient population.

“The addition of tucatinib to the commonly used doublet of trastuzumab and capecitabine represents a potential significant clinical advance for patients with metastatic HER2-positive breast cancer, importantly, including those with brain metastases,” Roger Dansey, MD, chief medical officer at Seattle Genetics, said in a news release.

About a fifth of 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. For these patients, treatments such as trastuzumab and Perjeta (pertuzumab) — antibodies that target and inhibit HER2 — and Kadcyla (ado-trastuzumab emtansine) — trastuzumab bound to a toxic payload — can be life-saving. But their cancers can still progress after they undergo all these treatments.

“There is significant unmet medical need following treatment with trastuzumab, pertuzumab and T-DM1 in patients with metastatic HER2-positive breast cancer,” Dansey said.

A Phase 2 trial called HER2CLIMB (NCT02614794) investigated if adding tucatinib to a combination of trastuzumab and Xeloda, which is often used to treat this cancer, could improve the survival outcomes of these patients.

Tucatinib is an 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 FDA for treatment of breast cancer patients with brain metastases.

HER2CLIMB included 612 people with either metastatic (spread to other parts of the body) or inoperable locally advanced HER2-positive breast cancer who had received prior treatment with trastuzumab, Perjeta, and Kadcyla. Nearly half (47%) had brain metastasis at the time of enrollment.

During the trial, patients were randomly assigned to receive either tucatinib or placebo pills two times a day, given along with Xeloda pills two times a day during the first two weeks of each three-week cycle and trastuzumab injections on the first day of every cycle.

The study’s main goal was to determine if tucatinib was better than a placebo at extending progression-free survival (a measure of the time patients live without signs of disease progression). Secondary measures included overall survival and progression-free survival in the subpopulation of patients with brain metastasis. Response rates and duration of response were also assessed.

The recently announced results show that HER2CLIMB met its primary goal of progression-free survival — with tucatinib cutting the risk of disease worsening or death by 46% compared to the placebo — as well as two key secondary objectives.

In the overall population, tucatinib reduced the risk of death by 34%, and lowered the risk of disease progression or death by more than half (52%) in patients who had brain metastasis at the study’s start, reinforcing the treatment’s efficacy in HER2-positive brain tumors.

Regarding safety, the tucatinib triple combination was generally well-tolerated with a manageable safety profile. The most frequent adverse events included diarrhea, redness, swelling, pain on the palms of the hands or the soles of the feet, nausea, fatigue, and vomiting.

Adverse events leading to discontinuations were rare in both treatment groups — 5.7% for tucatinib and 3.0% for placebo.

Based on these findings, Seattle Genetics plans to offer tucatinib to patients in the control group.

“We also plan to submit a New Drug Application (NDA) to the FDA in the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients,” said Dansey.

Additional results will be presented at the San Antonio Breast Cancer Symposium on Dec. 11.