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 (DESTINY - Breast12)

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).

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