A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer

Key Inclusion Criteria:

* Patients must be at least 18 years of age
* Pathologically documented breast cancer that:

  1. Is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic
  2. HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local assessment. The local HER2 result must be from a tumour sample obtained in the metastatic setting.
  3. Is documented as hormone receptor-positive (estrogen or progesterone receptor) or negative in the metastatic setting
* Patient must have adequate tumor sample from the metastatic setting for biomarker assessment
* ECOG Performance Status of 0 or 1
* Part 1

  1. Disease progression on or after the last systemic therapy prior to starting study treatment
  2. At least 1 prior treatment line in metastatic setting required.
* Part 2 (Modules 0 - 5)

  a) No prior lines of therapy for advanced/MBC allowed
* Part 2 (Module 6 and 7) a) Zero or one prior lines of therapy for advanced/MBC allowed

CNS Inclusion

* Modules 0 - 5 Patients must have no brain metastases or stable brain metastases.
* Module 6 and 7 Patients must have untreated brain metastases not needing local therapy or previously treated brain metastases that have progressed since prior local therapy

Key Exclusion Criteria:

* Uncontrolled or significant cardiovascular disease
* Active or prior documented (non-infectious) ILD/pneumonitis that required steroids, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
* Lung-specific intercurrent clinically significant illnesses
* Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
* Spinal cord compression or a history of leptomeningeal carcinomatosis
* Prior treatment with immune checkpoint inhibitors
* Prior treatment with an ADC containing a topoisomerase I inhibitor
* Prior treatment with tucatinib

CNS Exclusion

* Modules 0 - 5: Has untreated brain metastasis
* Module 6 and 7: Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \> 2 mg dexamethasone or any brain lesion thought to require immediate local therapy