An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients With or Without Baseline Brain Metastasis With Previously Treated Advanced/Metastatic HER2 Positive Breast Cancer (PI: Olav Engebråten)

Inclusion Criteria:

  • Participants should have pathologically documented breast cancer that is: unresectable/advanced or metastatic; confirmed HER2-positive status expression as determined according to American Society of Clinical Oncology/College of American Pathologists guidelines
  • Participant must have either: no evidence of BM, or untreated BM on screening contrast brain magnetic resonance imaging/ computed tomography (MRI/CT) scan, not needing immediate local therapy or previously-treated stable or progressing BM
  • Participants with BMs must be neurologically stable
  • For participants requiring radiotherapy due to BMs, there should be an adequate washout period before day of first dosing:
  • ≥ 7 days since stereotactic radiosurgery or gamma knife
  • ≥ 21 days since whole brain radiotherapy
  • Eastern Cooperative Oncology Group performance status 0-1
  • Previous breast cancer treatment: radiologic or objective evidence of disease progression on trastuzumab, pertuzumab, or trastuzumab emtansine and no more than 2 lines/regimens of therapy in the metastatic setting
  • Participant with the following measurable: at least 1 lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with CT or MRI and is suitable for accurate repeated measurements; or following Non-measurable diseases: Non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-ray in the absence of measurable disease as defined above is acceptable; Participants with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible; and Non-measurable CNS disease (Cohort 2 only)
  • Adequate organ and bone marrow function within 14 days before the day of first dosing as defined in the protocol
  • Left ventricular ejection fraction ≥ 50% within 28 days before enrollment
  • Negative pregnancy test (serum) for women of childbearing potential

Exclusion Criteria:

  • Known or suspected leptomeningeal disease
  • Prior exposure to tucatinib treatment
  • Refractory nausea and vomiting, chronic gastrointestinal disease, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of T-DXd
  • History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence
  • Persistent toxicities (Common Terminology Criteria for Adverse Events Grade >1) caused by previous anticancer therapy, excluding alopecia
  • Based on screening contrast brain MRI/CT scan, participants must not have any of the following: any untreated brain lesions > 2.0 cm in size; ongoing use of systemic corticosteroids for control of symptoms of BMs; any brain lesion thought to require immediate local therapy; have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to BMs not withstanding CNS-directed therapy
  • Has spinal cord compression
  • Known active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Participants with past or resolved hepatitis B virus infection are eligible, if negative for hepatitis B surface antigen and positive for anti-hepatitis B core antigen
  • Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
  • Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
  • Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd
  • Participants with a medical history of myocardial infarction within 6 months before screening, symptomatic congestive heart failure (New York Heart Association Class II to IV)
  • History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
  • Lung-specific intercurrent clinically significant illnesses and any autoimmune, connective tissue or inflammatory disorders
  • Prior exposure, without adequate treatment washout period before the day of first dosing, to chloroquine/hydroxychloroquine: < 14 days
  • Anticancer chemotherapy: immunotherapy (non-antibody-based therapy), retinoid therapy, hormonal therapy: < 3 weeks
  • < 6 weeks for nitrosoureas or mitomycin
  • < 1 week for tyrosine kinase inhibitor (TKIs) approved for the treatment of non-small cell lung cancer – baseline CT scan must be completed after discontinuation of TKI
  • Antibody-based anticancer therapy: < 4 weeks
  • Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer- related conditions is allowed
  • Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation, radiation to the chest, or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention
  • Participants with prior exposure to immunosuppressive medication within 14 days prior to first study dose
  • Participants with a known hypersensitivity to study intervention or any of the excipients of the product or other monoclonal antibodies

Contact information: Olav Engebråten,