The addition of tucatinib to capecitabine and trastuzumab significantly improved progression-free survival and overall survival in patients with advanced HER2-positive breast cancer, with or without brain metastasis. These findings—from the HER2CLIMB study—were presented by Murthy et al at the 2019 San Antonio Breast Cancer Symposium (Abstract GS1-01) and simultaneously published in The New England Journal of Medicine.
Tucatinib is a tyrosine kinase inhibitor that is highly selective for HER2.
“This is a uniquely designed trial in that it allowed patients to enroll if they had untreated, treated stable, or previously treated but progressive brain metastasis,” said first author Rashmi K. Murthy, MD. “Brain metastasis is a common clinical problem developing in up to half of patients during the disease course, but there are limited systemic treatment options as most drugs have difficulty crossing the blood brain barrier.”
The international randomized trial enrolled 612 patients with locally advanced or metastatic HER2-positive breast cancer who received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine. Researchers randomly assigned patients 2:1 to trastuzumab and capecitabine with or without tucatinib. Nearly half (47.5%) of patients had brain metastasis at baseline.
“Tucatinib in combination with trastuzumab and capecitabine should be the new standard of care for patients pretreated with multiple anti-HER2 agents, including patients with brain metastasis.”— Rashmi K. Murthy, MD
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The trial met its primary endpoint and showed that the treatment combination reduced the risk of death by 46% compared with trastuzumab and capecitabine alone. The trial also met its secondary endpoints at interim analysis, showing tucatinib prolonged overall survival, reduced the risk of death by 34%, and extended progression-free survival by 52% among patients with brain metastasis. The overall response rate was higher in the tucatinib group at 41% compared with 23% in the standard-of-care treatment group.
The triplet combination was generally well tolerated, with no unexpected toxicities. The most frequent adverse events in the tucatinib arm included diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting—all mostly low-grade. There was a low drug discontinuation rate—5.7% in the triplet arm compared with 3% in the control arm.
“This trial verified that tucatinib is both a safe and effective treatment,” said Dr. Murthy. “These results are unprecedented for late-line therapy in advanced breast cancer and are a major advance for patients who have significant unmet medical need. Tucatinib in combination with trastuzumab and capecitabine should be the new standard of care for patients pretreated with multiple anti-HER2 agents, including patients with brain metastasis.”
These positive trial results led to the decision to unblind the study so that all patients can benefit from the combination. There are plans to submit a new drug application to the Food and Drug Administration in the first quarter of 2020.
The HER2CLIMB trial is ongoing but is no longer recruiting patients. Completion of the trial is expected in September 2020.
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