TReatment of ADC-Refractory Breast CancEr With Dato-DXd or T-DXd: TRADE DXd

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed invasive breastcancer with unresectable locally advanced or metastatic disease. Participantswithout pathologic or cytologic confirmation of metastatic disease should haveunequivocal evidence of metastasis from physical examination or radiologicevaluation; i.e., visible chest wall disease or metastases on imaging meetingstandard radiology criteria (i.e., lymph nodes larger than 1 cm in the short axisdiameter).

• The most recent pathology results will be considered for enrollment according tolocal testing of ER, PR and HER2 in a CLIA-certified environment. ER, PR and HER2status per local testing must be known prior to study registration.

• Participants must have history of HER2-low or HER2-0 breast cancer per localtesting, and no known history of HER2-positive breast cancer. All available priorHER2 pathology results must be HER2-low or HER2-0; no known HER2 IHC 3+ orISH-amplified breast cancer is allowed.

• HER2-low status is defined as IHC 1+ or 2+/ISH non-amplified breast cancer inany prior tumor sample (e.g., primary or metastatic tumor) collected prior tostudy enrollment: IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested (note: ISHmay be determined by either fluorescence in situ hybridization [FISH] or dualin situ hybridization [DISH])

• HER2-0 status is defined as IHC 0 (null or ultra-low) in all prior tumorsamples with available HER2 pathology results: IHC 0+/ISH- or IHC 0+/ISHuntested (IHC 0+: IHC 0 absent membrane staining [null] or IHC 0 with membranestaining >0 and <1+ [ultralow]). Note: Enrollment of patients with HER2-0breast cancer will be capped at 15% in each ADC1 and ADC2 cohort.

• Participants with any HR status will be allowed on study.

• HR-positive cohorts: ER and/or PR expression ≥1%

• HR-negative cohorts: ER and PR expression <1%

• All cohorts: The most recent HER2 pathology result must be HER2-0 or HER2-low (i.e., must not be HER2-positive).

• HER2-0: IHC 0+/ISH- or IHC 0+/ISH untested.

• HER2-low: IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested (note: ISH may bedetermined by either fluorescence in situ hybridization [FISH] or dual in situhybridization [DISH]).

• Participants must have measurable disease per RECIST 1.1.

• Participants must be willing to undergo research tissue biopsies (at baseline priorto ADC1, after 3 weeks of treatment with ADC1, at progression on ADC1 or baselineprior to ADC2, and at progression on ADC2), if tumor is safely accessible.

• Prior endocrine therapy: Participants with HR-positive breast cancer considered tobe candidates for endocrine therapy must have: a) progressed on or within 12 monthsof adjuvant endocrine therapy or received at least one line of endocrine therapy inthe metastatic setting, and b) received prior CDK4/6 inhibitor. Prior endocrinetherapy does not require washout.

• Prior chemotherapy: Prior lines of chemotherapy allowed in the metastatic settingare specified below. Prior topoisomerase I inhibitor therapy is not allowed in anysetting, except as specified below for ADC2 cohorts. Participants may havediscontinued all chemotherapy at least 14 days prior to study treatment initiation.All toxicities related to prior chemotherapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol, except alopecia (any gradeallowed) and neuropathy (grade 2 or lower allowed).

• ADC1 T-DXd cohorts: Participants must have progressed on 0-1 prior lines in themetastatic setting.

• ADC1 Dato-DXd cohorts: Participants must have progressed on 0-1 prior lines inthe metastatic setting.

• ADC2 T-DXd cohorts: Participants must have progressed on 1-2 prior lines in themetastatic setting, including Dato-DXd (single-agent) as the most recenttherapy. Confirmation of documented progressive disease on Dato-DXd (single-agent) as the most recent therapy is required prior to enrollment. Noother topoisomerase I inhibitor is allowed in the metastatic setting.

• ADC2 Dato-DXd cohorts: Participants must have progressed on 1-2 prior lines inthe metastatic setting, including T-DXd (single-agent) as the most recenttherapy. Confirmation of documented progressive disease on T-DXd (single-agent)as the most recent therapy is required prior to enrollment. No othertopoisomerase I inhibitor is allowed in the metastatic setting.

• Prior biologic or targeted therapy: Patients must have discontinued all biologic ortargeted therapy (e.g., CDK4/6 inhibitor) at least 14 days prior to study treatmentinitiation. All toxicities related to prior biologic or targeted therapy must haveresolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol.

• Prior investigational agents for treatment of cancer: Investigational agents musthave been discontinued at least 21 days prior to initiation of study therapy. Alltoxicities related to prior investigational agents must have resolved to CTCAE v5.0grade 1 or lower, unless otherwise specified per protocol.

• Prior radiation therapy: Patients may have received prior radiation therapy.Radiation therapy must be completed at least 14 days prior to the initiation ofstudy treatment (at least 7 days for SRS), and all toxicities related to priorradiation therapy must have resolved to CTCAE v5.0 grade 1 or lower, unlessotherwise specified per protocol. A 7-day washout is permitted for palliativeradiation (≤ 2 weeks of radiotherapy) to non-CNS disease.

• Patients with history of treated CNS metastases are eligible, provided the followingcriteria are met:

• Disease outside the CNS is present.

• Prior SRS/SRT or WBRT should be completed ≥ 7 days before study treatmentinitiation.

• Recovery from acute toxicity associated with the treatment to ≤ CTCAE v5.0grade 1 or baseline (with the exception of alopecia), with no requirement forescalating doses of corticosteroids over the past 7 days.

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy, there is no requirement for corticosteroids, andthe patient is asymptomatic.

• Participants on bisphosphonates or RANK ligand inhibitors may continue receivingtherapy during study treatment and also may initiate therapy with these agents onstudy if clinically indicated.

• The subject is ≥ 18 years old.

• ECOG performance status 0-1 (Karnofsky > 60%).

• Participants must have adequate organ and marrow function within 2 weeks prior tostudy treatment initiation as defined below:

• Absolute neutrophil count ≥1,500/mcL

• Platelets ≥ 100,000/mcL

• Hemoglobin ≥ 9.0 g/dl

• INR/PT/aPTT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapyand PT or aPTT is in therapeutic range of anticoagulant

• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (or ≤ 3.0 xULN in patients with documented Gilbert's Syndrome)

• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN or ≤ 5.0 × institutional ULN forparticipants with documented liver metastases

• Serum or plasma creatinine ≤ 1.5 × institutional ULN OR creatinine clearance (as calculated using the Cockcroft-Gault equation) ≥ 30 mL/min/ 1.73m2 forparticipants with creatinine levels above institutional ULN.

• Resolution of all toxicities related to prior anticancer therapy to Grade ≤ 1 orbaseline, including toxicities from ADC1 before enrolling to ADC2, unless otherwisespecified per protocol.

• For T-DXd cohorts, baseline LVEF ≥ 50% prior to registration, as measured byechocardiogram (or multiple-gated acquisition [MUGA] scan if an echocardiogramcannot be performed or is inconclusive).

• Female subjects of childbearing potential must have a negative serum or urinepregnancy test within 2 weeks prior to study treatment initiation. Childbearingpotential is defined as participants who have not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause)and have not undergone surgical sterilization (removal of ovaries and/or uterus).

• Women of childbearing potential (WOCBP) and the female partners of male participantsmust agree to use an adequate method of contraception. Contraception is requiredstarting with the first dose of study medication through 7 months after the lastdose of study medication.

• Males who are sexually active with WOCBP must agree to follow instructions formethod(s) of contraception for the duration of study treatment and 4 months afterthe last dose of study treatment.

• The participant must be capable of understanding and complying with the protocol andwilling to sign a written informed consent document.

Exclusion Criteria:

• Concurrent use of any other investigational or study agents that are being used totreat the underlying malignancy.

• Any prior treatment (including ADC) containing a chemotherapeutic agent targetingtopoisomerase I, except as specified per protocol for ADC2 cohorts.

• Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviralvaccines are not considered attenuated live vaccines) within 30 days prior to thefirst exposure to study intervention.

• Clinically significant corneal disease.

• History of severe hypersensitivity reactions to either trastuzumab deruxtecan ordatopotamab deruxtecan or their inactive ingredients.

• History of severe hypersensitivity reactions to other monoclonal antibodies.

• Major surgery within 2 weeks prior to study treatment initiation.

• Uncontrolled, significant intercurrent or recent illness including, but not limitedto, ongoing or active infection, uncontrolled non-malignant systemic disease,uncontrolled seizures, or psychiatric illness/social situation that would limitcompliance with study requirements in the opinion of the treating investigator.

• History of (non-infectious) pneumonitis/interstitial lung disease that requiredsteroids or current pneumonitis/interstitial lung disease, or where suspectedILD/pneumonitis cannot be ruled out by imaging at screening. For ADC2 cohorts, if aparticipant experienced G1 pneumonitis/ILD with ADC1 (e.g., treated with steroids)with complete resolution of radiographic findings and ability to resume ADC1 within 12 weeks of the scheduled interruption without recurrence of ILD, the participantmay enroll to ADC2.

• Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3months of the study enrollment, severe asthma, severe chronic obstructive pulmonarydisease (COPD), restrictive lung disease, pleural effusion etc.), and anyautoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), and priorcomplete pneumonectomy.

• Corrected QT interval (QTcF) prolongation to > 470 msec (females) or >450 msec (males).

• Any of the following procedures or conditions in 6 months prior to enrollment:coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction,angina pectoris, congestive heart failure (New York Heart Association FunctionalClassification Grade ≥2), and stroke.

• Individuals with a history of a second malignancy are ineligible except for thefollowing circumstances:

• Individuals with a history of other malignancies are eligible if they have beendisease-free for at least 3 years or are deemed by the investigator to be atlow risk for recurrence of that malignancy.

• Individuals with the following cancers that have been diagnosed and treatedwithin the past 3 years are eligible: cervical/prostate carcinoma in situ,superficial bladder cancer, non-melanoma cancer of the skin.

• Patients with other cancers diagnosed within the past 3 years and felt to be atlow risk of recurrence should be discussed with the study principalinvestigator to determine eligibility.

• Known human immunodeficiency virus (HIV) infection that is not well controlled.

• Known hepatitis B or C virus infection that is active or uncontrolled.

• Active infection, including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis testing inline with local practice).

• History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the subject'sparticipation for the full duration of the study, or is not in the best interest ofthe subject to participate, in the opinion of the treating investigator.

• Women who are pregnant or breastfeeding or planning to become pregnant.