Tucatinib and Trastuzumab Deruxtecan Show Promise in HER2+ Breast Cancer

In 1998, the U.S. Food and Drug Administration (FDA) approved the drug trastuzumab (brand name Herceptin) for people with HER2-positive metastatic breast cancer. Overnight, HER2+ metastatic breast cancer became treatable (though not curable). Subsequent successful clinical studies led to use of trastuzumab earlier in the breast cancer journey—after surgery—to help prevent recurrence, as well as in earlier-stage HER2+ breast cancer. Meanwhile, the FDA approved additional HER2-targeted drugs: the monoclonal antibody pertuzumab (Perjeta), and the antibody-drug conjugate, ado-trastuzumab emtansine (Kadycla), both of which are used for early stage as well as metastatic breast cancer.

While use of these HER2-targeted agents in early stage breast cancer has resulted in better outcomes, it presents a challenge for advanced metastatic cancer patients. Using these therapies for early stage disease might mean they cannot be used later on if a patient progresses to metastatic disease. Even patients with metastatic disease as their primary diagnosis eventually progress beyond currently available HER2-targeted therapies.

So there is a real need for new therapies that are effective for people with HER2+ metastatic cancer who have already been heavily treated with existing options. For these patients, two drugs—tucatinib and trastuzumab deruxtecan—now hold promise.

Tucatinib is a type of drug known as a reversible HER2 inhibitor, and it is able to cross the blood-brain barrier. In the HER2CLIMB clinical trial, a combination of tucatinib, trastuzumab, and capecitabine was more efficacious in a group of heavily treated HER2+ patients than trastuzumab and capecitabine given to a control group of patients. Progression-free survival with the triple-drug combination was 33% compared to 12.3% in the control group, while overall survival was 21.9 months compared to 17.4 months.

Most impressively, tucatinib shows efficacy in patients with brain metastases, a patient population with poor prognosis; progression-free survival at 1 year was 24.9% for these patients as compared to 0% in the control group. Based on these data, the FDA granted priority review to tucatinib for HER2+ breast cancer, and it will most likely be approved in a few months. [Update 4/21/20: The FDA has now approved tucatinib (brand name Tukysa) for people who have already had at least one prior HER2-targeted treatment for their metastatic HER2+ breast cancer.]

Trastuzumab deruxtecan (also known as DS-8201, brand name Enhertu) also holds promise for treating HER2+ metastatic breast cancer.  It is an antibody-drug conjugate that comprises trastuzumab and a derivative of a drug called exatecan, a topoisomerase I inhibitor. It was granted accelerated approval by the FDA in December 2019 for the treatment of HER2+ metastatic breast cancer patients who have received at least 2 prior lines of anti–HER2-based treatment regimens for their metastatic cancer. The approval was based on findings from the phase II DESTINY-Breast01 clinical trial, in which trastuzumab deruxtecan induced a confirmed objective response rate (ORR) of 60.3%, a disease control rate (DCR) of 97.3%, and a progression-free survival of 16.4 months.

Interestingly, trastuzumab deruxtecan demonstrated efficacy in another patient population with high unmet need—those characterized as “HER2 low.” About 40% to 50% of patients with breast cancer have tumors with low HER2 expression (defined as IHC 1+ or IHC 2+). Current treatment guidelines consider such patients to be HER2-negative. None of the currently available HER2-targeted treatments have shown efficacy in HER2-negative cancer, and therefore are not recommended for use. However, in a study with 54 patients who were extensively pretreated (they had a median of 7.5 prior therapies), trastuzumab deruxtecan elicited an objective response rate of 37.0% and a median duration of response of 10.4 months.

In summary, it is a really exciting time for management of HER2+ breast cancer, with practice-changing clinical data emerging for two novel HER2-targeted agents, tucatinib and trastuzumab deruxtecan. Not only are these drugs highly efficacious in heavily treated metastatic breast cancer patients, but they have shown efficacy in “special” patient populations with high unmet need; namely, those with brain metastases and those with intermediate levels of HER2 expression. 

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