Addition of Tucatinib with First-Line HER2-Positive Therapy Shows Improved Progression-Free, Overall Survival Rates

Treatment with tucatinib, trastuzumab (Herceptin), and capecitabine (Xeloda) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer resulted in 33.1% progression-free survival (PFS) at 1 year, compared with 12.3% in the placebo-combination arm, according to a study presented in the opening general session of the 2019 San Antonio Breast Cancer Symposium.¹

The pivotal data from the HER2CLIMB study were also published in The New England Journal of Medicine simultaneously.

Rashmi Murthy, MD, MBE, presented the results of the study, and noted that patients with HER2-positive metastatic breast cancer often have limited treatment options. Current standard-of-care treatment for patients with HER2-positive metastatic breast cancer is first-line trastuzumab plus pertuzumab (Perjeta) and a taxane, followed by second-line trastuzumab emtansine for patients who have disease progression.²

According to the study authors, approximately 15% to 20% of breast cancers overexpress HER2, and most patients with HER2-positive metastatic breast cancer ultimately die from the disease. The incidence of brain metastases has also increased in recent years, now seen in up to half of patients.¹

Treatment for brain metastases in this patient population includes local therapies, such as neurosurgical resection and stereotactic radiation therapy.¹ The authors noted that randomized trial data showing better treatment outcomes in these patients are lacking.¹

Tucatinib is an investigational, oral, high-selective inhibitor of the HER2 tyrosine kinase.¹ HER2-positive patients who experience disease progression have typically already been treated with multiple HER2-negative targeted agents, Murthy said, so a new drug could be an exciting development.²

The HER2CLIMB study included patients with HER2-positive metastatic breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who did or did not have brain metastases. They were randomly assigned to receive either tucatinib or a placebo, both in combination with trastuzumab and capecitabine.²

The primary endpoint was PFS among the first 480 patients who underwent randomization.¹ Secondary endpoints were assessed in the total 612 patients, and included overall survival (OS), PFS among patients with brain metastases, confirmed objective response rate, and safety.¹

“At 1 year, the estimated progression-free survival was 33% in the tucatinib arm, compared with 12% in the control arm,” Murthy said. “In addition, there was a 4-and-a-half-month improvement favoring overall survival in the tucatinib arm.”

At 2 years, OS was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group, and the median OS was 21.9 months and 17.4 months, respectively.¹

Among patients with brain metastases, PFS at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group. The median PFS was 7.6 months and 5.4 months, respectively.¹

Safety data for tucatinib showed a safe and tolerable profile, consistent with previous studies.² Murthy noted that adverse events leading to discontinuation were extremely low, at just 6% in the tucatinib arm and 3% in the placebo arm. This tolerability profile and low discontinuation rate are encouraging, she added, as they allow for continued HER2 inhibition until progression in heavily pre-treated patients.²

Although these results are encouraging, Murthy said, more studies are needed to assess whether continuation of tucatinib is recommended after relapse.

“This result represents an important advance toward improving outcomes for patients with HER2-positive breast cancer,” she concluded.

REFERENCES

• Murthy R, Loi S, Okines A, Paplomata E, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa1914609?query=featured_home. Accessed December 11, 2019.
• Murthy R. Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2019 San Antonio Breast Cancer Symposium; San Antonio, TX: December 11, 2019.