Neratinib and Ado-Trastuzumab-Emtansine for Pre-treated and Untreated HER2-positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022.

PURPOSE: Treatment options for HER2-positive breast cancer brain metastases (BCBM) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab-emtansine (T-DM1) when given in combination. In TBCRC 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts (cohort 4A-previously untreated BCBM, cohorts 4B and 4C- BCBM progressing after local CNS-directed therapy without [4B] and with [4C] prior exposure to T-DM1). Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. Overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018-2021, 6, 17, and 21 patients enrolled to cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% (95% confidence interval [CI]: 4.3-77.7%), 35.3% (95% CI: 14.2-61.7%), and 28.6% (95% CI: 11.3-52.2%), respectively; 38.1-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). Median OS was 30.2 months (cohort 4A; 95% CI: 21.9, not reached [NR]), 23.3 months (cohort 4B; 95% CI: 17.6, NR), and 20.9 months (cohort 4C; 95% CI: 14.9, NR). CONCLUSION: We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

Intravenous versus subcutaneous dosing of epoetin: a review of the literature.

Recombinant human erythropoietin (epoetin) is approved to be administered by the intravenous (i.v.) or subcutaneous (SC) route. Several studies have been conducted and published that compare the relative pharmacokinetics and efficacy of the IV and SC routes. An analysis of the methodology and results of these studies reveals that the data have been somewhat contradictory and highly variable. However, most investigations have concluded that the SC route is associated with a decreased dose requirement in the correction and/or maintenance phase. To justify a switch from the i.v. to the SC route, it is important to consider the practical implications, including patient and staff acceptance, as well as the financial aspects. Regardless of the route of administration, dose titration must be individualized based on the patient's response to epoetin therapy, red blood cell turnover rate, and iron status. More studies are needed to develop a standardized cost-effective method for epoetin dosing in patients on dialysis.