Patients with HER2+ metastatic breast cancer (MBC) are living longer, often with good performance status, allowing additional therapies to be considered.Ĭombinations involving targets downstream of the HER2 pathway, particularly cyclin D and cyclin-dependent kinases (CDK) 4/6, could potentially enhance therapeutic efficacy in HER2+ MBC. Approved anti-HER2 therapies in the metastatic setting include HER2 monoclonal antibodies (trastuzumab, pertuzumab), tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib), and antibody-drug conjugates (ado-trastuzumab emtansine/T-DM1, trastuzumab deruxtecan) 2, 3, 4, 5, 6, 7, 8, 9, 10. Despite the development of multiple effective therapies for HER2-positive breast cancer, nearly all patients with advanced/metastatic HER2-positive disease will eventually experience disease progression and subsequent death 1. However, anti-HER2-directed therapies have changed the landscape and prognosis of HER2-positive (HER2+) breast cancer. The presence of human epidermal growth factor receptor 2 (HER2), also known as ERBB2, amplification confers an aggressive breast cancer phenotype. Based on the pharmacokinetic analysis, adverse events, and dose reductions, 400 mg was determined to be the RP2D for ribociclib given on days 8–21 of a 21-day cycle with T-DM1. After a median follow-up of 12.4 months, the median PFS was 10.4 months (95% confidence interval, 2.7–19.3). The majority of toxicities were Grade 1 and 2, and the most common Grade 3 toxicities were neutropenia (33%), leukopenia (33%), and anemia (25%). No dose-limiting toxicities were observed. The primary objective was to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of ribociclib in combination with T-DM1. A standard 3 + 3 dose-escalation design was used to evaluate various doses of ribociclib in combination with T-DM1, starting at 300 mg. We conducted a phase 1b study of ribociclib and ado-trastuzumab emtansine (T-DM1) in patients with advanced/metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane in any setting, with four or fewer prior lines of therapy in the metastatic setting. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors and anti-HER2 therapies. Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed.
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