New Standard Likely for Some Metastatic HER2 Breast Cancer

Tucatinib Improves Overall Survival

Nick Mulcahy

December 11, 2019

SAN ANTONIO, TEXAS — Patients with HER2-positive metastatic breast cancer — with and without brain metastases — whose disease is progressing after multiple targeted therapies now likely have a new treatment option, according to research presented here at the San Antonio Breast Cancer Symposium 2019.

The investigational oral therapy tucatinib (Seattle Genetics), when added to standard trastuzumab and capecitabine, resulted in a "clinically meaningful" lower risk of disease progression or death compared with placebo, which was also added to standard therapy, reported lead author Rashmi Murthy, MD, University of Texas MD Anderson Cancer Center, Houston.

And, even better, the secondary endpoint of overall survival was longer by 4.5 months with tucatinib (median of 21.9 vs 17.4 months) in the study, known as HER2CLIMB.

The results of the study, which was funded by Seattle Genetics, were simultaneously published in the New England Journal of Medicine.

"This is the most exciting study presented today at San Antonio," said Amy Tiersten, MD, Icahn School of Medicine at Mount Sinai, New York City, who was not involved in the trial, when asked for comment.

"I think this regimen may be considered a new standard of care for pretreated HER2-positive metastatic disease," she said.

Much of the excitement stemmed from tucatinib's activity among patients with brain metastases in the 612-patient trial.

As the investigators observe, they enrolled a large percentage of patients with untreated or previously treated progressing brain metastases (about 50% of the total study group), which is "a population typically excluded from clinical trials despite this condition being a common clinical problem."

Among trial patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio [HR], 0.48; 95% CI, 0.34 - 0.69; P < .001). Median progression-free survival was 7.6 and 5.4 months, respectively.

In general, the incidence of brain metastases among patients with HER2+ disease has increased as targeted therapies have extended survival in recent decades; these mets may develop in up to 50% of patients, say the authors.

Treatment for brain metastases in this population includes surgery, radiation therapy, and some systemic HER2-targeted agents, including tyrosine kinase inhibitors lapatinib and neratinib and chemotherapy. But the drug treatments have not been proven very effective.

"Outcomes in the field have been pretty dismal," summarized Jawad Fares, MD, Northwestern University, Chicago, Illinois, who was lead author of a 2018 review of systemic drug treatments for breast cancer brain metastases and was asked for comment (Neurooncol Pract  2019;5:392-401).

Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2, explain the authors.

Notably, there are currently no systemic therapies specifically approved by the US Food and Drug Administration for patients with metastatic breast cancer and brain metastases.

Study Details

Patients were randomly assigned in a 2:1 ratio to receive either tucatinib (300 mg orally twice daily throughout the treatment period) or placebo (orally twice daily), in combination with trastuzumab (once every 21 days) and capecitabine (orally twice daily on days 1 to 14 of each 21-day cycle).

Among the first 480 patients randomized in the trial, progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (HR for disease progression or death, 0.54; 95% CI, 0.42 - 0.71; P < .001); median duration of progression-free survival was 7.8 and 5.6 months, respectively.

Among the total population of 620 patients (who were added to bolster statistical strength), overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (HR for death, 0.66; 95% CI, 0.50 - 0.88; P = .005); median overall survival was 21.9 and 17.4 months, respectively.

Common adverse events in the tucatinib group included diarrhea, palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting, reported the authors. Diarrhea and elevated aminotransferase levels of grade ≥ 3 were more common in the tucatinib- than in the placebo-combination group.

The study authors point out that most events of diarrhea were grade 1 (in 43.3% and 32.0% of patients, respectively) or grade 2 (24.8% and 12.7%, respectively); grade ≥ 3 diarrhea occurred in 12.9% and 8.6%, respectively.

Some study patients used antidiarrheal agents; the median duration of use was 3 days per cycle in both treatment groups, reported the authors.

N Engl J Med. Published December 11, 2019. Abstract

San Antonio Breast Cancer Symposium 2019: Abstract GS1-01. Presented December 11, 2019.

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