Background: Overexpression of the HER2 protein is an important prognostic and predictive biomarker in about 20% of breast cancers, and while trastuzumab-based regimens are still considered standard of care in the early and metastatic settings, these regimens require chemotherapy co-administration. Pre-clinical mouse models suggest that a tucatinib/CDK 4/6 inhibitor combination regimen may be equally effective as standard regimens. Thus, finding more effective/tolerable therapies for this disease remains an area of unmet need. This randomized, open label, phase II clinical trial will explore the safety and efficacy of two novel, chemotherapy free combination drug regimens, given neoadjuvantly, in patients with anatomic stage I-III, HER2+ breast cancer. Methods: Phase 1b dose escalation trial: To establish the safety profile of the combination of ribociclib and tucatinib, an initial dose-finding phase 1b trial will be performed in patients with metastatic HER2+ breast cancer before moving into the larger phase 2 trial. 3-6 patients will be assigned sequentially to groups of increasing doses of ribociclib (200mg-600 mg) with fixed doses of tucatinib (300mg) and trastuzumab (SOC dosing) for a total of four 28-day cycles. The recommended phase 2 dose will be established when 6 patients have been treated at the highest dose level cohort. As of January 2023, 1 participant has been enrolled in dose level 1. Phase 2 neoadjuvant trial: Following MTD determination and approval from regulatory boards and funding partners, a total of 100 patients will be enrolled in the phase 2 portion of the study. Enrollment will be stratified by hormone receptor status. Patients will be randomized 1:1 (25 in each group) to receive six cycles of one of the following regimens: ribociclib/trastuzumab/tucatinib/+/- fulvestrant (28 day cycles) or docetaxel/carboplatin/trastuzumab/pertuzumab (SOC, 21 day cycles), preceded by one run-in cycle of trastuzumab/pertuzumab. To assess for changes in predictive molecular biomarkers, biopsies pre-and-post cycle 1 will be planned in all arms. Early imaging response assessments in the experimental arms will be planned after 2 cycles. Other endpoints include safety, changes in Ki67 expression, RCBi, biomarker analysis, and health-related quality of life. Clinical trial information: NCT05319873.