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