A Study of T-DXd in AI-Assessed HER2-Ultralow Metastatic Breast Cancer

• For inclusion in the study subjects should fulfil the following criteria based on local regulations:

  1. Provision of ICF prior to any study-specific qualification procedures.
  2. Adults ≥ 18 years of age at the time the ICF is signed.
  3. Must have an adequate tumor tissue sample available for assessment of HER2 status obtained most recently at the time of metastatic disease or later. If a suitable archival sample is not available, a fresh biopsy sample may be used to determine eligibility.

  4. Pathologically documented BC that:

     1. Is unresectable and/or metastatic.
     2. Is documented as HR+ (either estrogen receptor [ER] and/or progesterone receptor [PR] positive [ER or PR ≥1%]) per ASCO CAP guidelines32 in the metastatic setting. If a patient has had multiple ER/PR results after metastatic disease, the most recent test result will be used to confirm eligibility.
     3. Has a history of HER2 IHC 0 (with/without membrane staining).
     4. Was never previously reported as HER2+ (IHC 3+ or ISH+) as per ASCO CAP guidelines.
     5. Is scored as HER2-null (IHC 0; no membrane staining) by a local laboratory using the PATHWAY/VENTANA® HER2 (4B5) assay, and subsequently re-scored as HER2-ultralow (IHC 0; with membrane staining) under AI assistance by the central laboratory based on the stained slides sent by local laboratory.
  5. Must have progressed on at least one and up to two prior lines of ET ± targeted therapy in the metastatic setting.
  6. Have received no more than one chemotherapy in the metastatic setting but chemotherapy must not be the most recent treatment for patients at disease progression.
  7. Presence of at least one measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) as assessed by the Investigator, per RECIST version 1.1.
  8. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
  9. Has a minimum life expectancy of 12 weeks at Screening.
  10. Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before enrollment.

  11. Adequate organ and bone marrow function within 14 days before enrolment.. All parameters must be the most recent results available.

      Note: Transfusion (red blood cell or platelet) or granulocyte colony-stimulating factor (G-CSF) administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to Cycle 1 Day 1 (C1D1).

  12. Adequate treatment washout period before enrollment,
  13. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the Screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of study treatment.Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
  14. Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 4 from the time of Screening and must agree to continue using such precautions for 7 months after the last dose of study treatment. Not all methods of contraception are highly effective. It is strongly recommended that non-sterilized male partners of female subjects of childbearing potential use a male condom plus spermicide while on study and for 7 months after the last dose of study treatment (note: male condoms are not reliable as a sole contraception method). Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the subject's usual lifestyle (consideration must be made to the duration of the clinical study); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.
  15. Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use a condom with spermicide from Screening to 4 months after the final dose of study treatment. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the subject's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male subject to also use at least one highly effective method of contraception throughout this period, as described in Table 4. In addition, male subjects should refrain from fathering a child throughout the study Treatment Period and for 4 months after the last dose of study treatment. Male subjects should refrain from freezing or donating sperm from the time of first exposure until 4 months after the final dose of the study treatment. Preservation of sperm should be considered prior to enrollment in this study.
  16. Female subjects must not donate, or retrieve for their own use, ova from the time of enrollment and throughout the study Treatment Period, and for at least 7 months after the final study treatment administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study.

Exclusion Criteria:

• Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

  1. Subjects with contraindications to T-DXd per the local prescribing information and T-DXd IB cannot be enrolled to the study.
  2. Previous treatment with anti-HER2 therapy.
  3. Prior treatment with an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor.
  4. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
  5. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.
  6. Subjects with a medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Subjects with troponin levels above upper limit of normal (ULN) at Screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI.
  7. Corrected QT interval by Fredericia's method (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG).
  8. 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.

  9. Lung criteria:

     1. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disorder [COPD], restrictive lung disease, pleural effusion, etc.).
     2. Any autoimmune, connective tissue or inflammatory disorders (including Rheumatoid arthritis, Sjogren's and sarcoidosis) where there is documented, or a suspicion of pulmonary involvement at the time of Screening.
     3. Prior pneumonectomy (complete).
  10. Uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals.

  11. Active primary immunodeficiency, known uncontrolled active human immunodeficiency virus (HIV) infection, or active hepatitis B (hepatitis B virus surface antigen [HBsAg] or hepatitis B virus core antibody [HBcAb] positive, at Screening) or C virus infection. Subjects should be tested for HIV prior to enrollment if required by local regulations or institutional review board (IRB)/ethics committee (EC). Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). Subjects with past or resolved hepatitis B virus (HBV) infection are eligible only if they meet all of the following criteria:

      1. HBsAg (-) (for > 6 months off anti-viral treatment).
      2. Anti-hepatitis B core antibody (HBc) (+) (IgG or total Ig).
      3. HBV DNA undetectable.
      4. Absence of cirrhosis or fibrosis on prior imaging or biopsy.
      5. Absence of HCV co-infection or history of HCV co-infection.
      6. Access to a local hepatitis B expert during and after the study. Such subjects should be closely monitored for HBV reactivation. Further instructions for monitoring and management of subjects at risk of HBV reactivation are provided in Appendix C.

  12. Receipt of live, attenuated vaccine (messenger RNA [mRNA] and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study treatment.

      Note: Subjects, if enrolled, should not receive live vaccine during the study and up to 90 days after the last dose of study treatment.

  13. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to >Grade 2 for at least 3 months prior to enrollment and managed with standard-of-care treatment) that the Investigator deems related to previous anticancer therapy, such as:

      1. Chemotherapy-induced neuropathy.
      2. Fatigue.
      3. Residual toxicities from prior immuno-oncology (IO) treatment: Grade 2 endocrinopathies which may include:

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      1. Hypothyroidism/hyperthyroidism.
      2. Type 1 diabetes.
      3. Hyperglycemia.
      4. Adrenal insufficiency.
      5. Adrenalitis.
      6. Skin hypopigmentation (vitiligo).
  14. Known allergy or hypersensitivity to study treatment or any of the study drug excipients.
  15. History of severe hypersensitivity reactions to other monoclonal antibodies.
  16. Pregnant or breastfeeding female subjects, or subjects who are planning to become pregnant.

  17. Multiple primary malignancies within 3 years, with the exception of:

      1. Adequately resected non-melanoma skin cancer.
      2. Curatively treated in-situ disease.
      3. Other solid tumors curatively treated.
      4. Contralateral BC.
  18. Any other clinically significant medical conditions, that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.

Social, familial, or geographical factors that would interfere with study participation or follow-up.