Top Line: Does high dose trastuzumab better penetrate the blood-brain-barrier?
The Study: Antibody-based HER2 targeted therapies are assumed to have poor CNS penetration owing to their large molecular size. Tucatinib, a small molecule HER2 TKI, has recently shown significant intracranial efficacy for patients with HER2+ brain metastases when added to trastuzumab and capecitabine. The phase 2 PATRICIA trial asks whether the limited CNS penetration of trastuzumab can be overcome by increasing the dose. Thirty-nine patients with CNS progression despite prior brain radiation and stable extracranial disease received pertuzumab and 6 mg/kg weekly trastuzumab in addition to ongoing systemic therapy (except they had to stop T-DM1 or lapatanib). The overall response rate was only 11%, and all responses were partial with a median response duration of 3-6 months. However, 68% of patients maintained at least stable disease at 4 months and 51% at 6 months. While this isn’t a direct comparison, overall response rate was 47% with tucatinib in HER2CLIMB, with 72% maintaining response at 6 months. Another question is whether high dose trastuzumab increased toxicity, particularly cardiac toxicity. There were no congestive heart failure events and one grade 3 cardiac event in a patient with prior cardiac disease.
TBL: Despite a relatively low intracranial response rate (11%), most patients with CNS progression after prior radiation maintain stable intracranial disease for 6 months with pertuzumab and high dose trastuzumab. | Lin, J Clin Oncol 2021