a study of t-dxd in participants with or without brain metastasis who have previously treated advanced or metastatic her2 positive breast cancer

Conditions: Breast Cancer

Summary: this is open-label, multicenter, international study, assessing the efficacy and safety of trastuzumab deruxtecan (t-dxd) in participants with or without brain metastasis (bms), with previously-treated advanced/metastatic her2-positive breast cancer whose disease has progressed on prior anti-her2-based regimens and who received no more than 2 lines/regimens of therapy in the metastatic setting (excluding tucatinib).

approximately 500 eligible participants will be enrolled into 1 of 2 cohorts (250 participants in each cohort) according to the presence or absence of bms at baseline. cohort 1 will include participants without bm at baseline and cohort 2 will consist of participants with bm at baseline. after study intervention discontinuation, all participants will undergo an end-of-treatment visit (within 7 days of discontinuation) and will be followed up for safety assessments 40 (+ up to 7) days after the discontinuation of all study intervention. all participants will be followed up for survival status and duration of treatment on subsequent therapies after intervention discontinuation every 3 months (± 14 days) from the date of the safety follow-up until death, withdrawal of consent, or the end of the study, as per defined in the protocol.

Eligibility criteria:
inclusion: * 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 or after her2 targeted therapies 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 * 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 * antibody-based anticancer therapy: \< 4 weeks * any concurrent anticancer treatment. concurrent use of hormonal therapy for noncancer- related conditions is allowed * unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade ≤ 1 or baseline * 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

Keywords: trastuzumab deruxtecan human epidermal growth factor receptor 2 positive breast cancer brain metastasis