Summary:
Up to 20% of breast cancers are HER2+. Over the past two decades, there has been a tremendous advancement in the treatment of HER2+ breast cancer. It has transformed from the historically most aggressive breast cancer into one of the most treatable. With HER2 targeted therapies, a clinically meaningful subset of HER2+ metastatic Breast Cancer (mBC) patients achieve outstanding, long-term responses. Despite remarkable systemic control, brain metastases (mets) remain the major hurdle in HER2+ mBC. Roughly 50% of patients develop brain mets and survival remains poor for these patients. Importantly, current treatment focuses on disease control rather than
curative intent, and patients remain on effective therapy indefinitely. Thus, novel treatment strategies are needed to prevent brain mets and to induce long-term remissions and potential cures.
Newer therapies including trastuzumab deruxtecan (T-DXd) and tucatinib, the latter of which is known to penetrate the blood brain barrier, have shown remarkable activity against brain mets. The investigators hypothesize combining sequential HER2+ targeted induction therapies, followed by surgery, then six months of consolidation therapy (treatment given after initial therapy to kill any residual cancer cells to improve the chances of a complete cure) with the tucatinib-based HER2CLIMB regimen, six months of maintenance with HER2+ targeted therapies, and subsequent active surveillance will induce long-term responses and prevent brain mets. Those who do not respond to initial induction therapy will receive T-DXd. Responders to T-DXd will proceed to surgery and continue with the planned treatment sequence. While receiving the above treatment schema, patients will be proactively monitored for brain mets, and liquid biopsies via circulating tumor DNA (ctDNA) will be obtained to assess for molecular complete responses. This phase II study will assess if this treatment strategy can induce and maintain both radiographic and molecular complete responses for one year after the initiation of maintenance therapy in de novo (newly diagnosed) HER2+ mBC patients without brain mets. This is the first study to test if this structured, response-adaptive strategy can shift the current paradigm and transform current outcomes into cures.
ClinicalTrials.gov Identifier: NCT07459673