Approximately 15 to 20 percent of breast cancers require a protein called HER2 for growth. While HER2-positive breast cancer was once a very difficult disease to treat, there are now several targeted therapies available for this type of breast cancer.
However, many HER2-positive tumors will become resistant to these drugs, and if the cancer spreads to other tissues it is considered incurable. However, strides are being made to extend the lives of patients with advanced (metastatic) HER2-positive breast cancer. The HER2-targeted drugs under investigation—tucatinib and trastuzumab deruxtecan—bring new hope to patients:
HER2CLIMB (NCT02614794)
This is a phase II clinical trial testing tucatinib, an oral HER2-targeting drug, in combination with capecitabine (a chemotherapy drug) and trastuzumab (another HER2-targeting drug) versus the chemotherapy agents alone. The trial investigators reported that the addition of tucatinib resulted in improved overall survival with a 34 percent reduction in risk of death compared to chemotherapy. Importantly, 47 percent of participants in the trial had brain metastases—a group of patients often excluded from clinical trials. Even in this difficult-to-treat population, progression-free survival was increased by 2 months.
Based on these results, the FDA announced Breakthrough Therapy designation for tucatinib with trastuzumab and capecitabine. The results were published in the New England Journal of Medicine.
DESTINY-Breast01 (NCT03248492)
This is a phase II clinical trial testing a HER2-targeting drug, trastuzumab deruxtecan (T-DXd). Like ado-trastuzumab emtansine (T-DM1, trade name Kadcyla), T-DXd is an antibody drug conjugate. This class of drugs combines a HER2-targeting portion that directs the drug to the HER2 on breast cancer cells with a chemotherapy payload.
Presenting at SABCS for the study investigators, BCRF researcher Ian Krop, MD, PhD, reported an objective response rate of 61 percent with T-DXd and a durable benefit in patients with advanced HER2-positive disease who had progressed on multiple prior treatments. Commenting on the findings, Dr. Krop said: “The high rate of durable responses observed with trastuzumab deruxtecan in patients whose cancers had progressed on T-DM1 and other therapies suggests this agent could provide a new treatment option for this patient population.”
More than 50 percent of patients reported adverse events of grade 3 or higher, however, and there were four fatal cases of lung toxicity while on the study. These events will need to be closely evaluated and monitored as studies continue. The results were published in the New England Journal of Medicine.
Based on these results, the FDA subsequently approved T-Dxd (ENHERTU®) for patients with advanced HER2-positive breast cancer whose cancer advanced on other HER2-targeting drugs.
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