Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown potential activity in this subset of patients in small clinical series.KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer (MBC) with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post-hoc, exploratory analysis. The main outcome measures were best overall response rate (BOR; complete response + partial response) and clinical benefit rate (CBR; complete response + partial response + stable disease lasting ≥6 months) by RECIST v1.1 criteria, progression-free survival (PFS), overall survival (OS), and safety.Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the BOR and CBR were 21.4% (95% CI 14.6-29.6) and 42.9% (95% CI 34.1-52.0), respectively. A reduction in the sum of the major diameters of BM ≥30% occurred in 42.9% (95% CI 34.1-52.0), including 49.3% (95% CI 36.9-61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median PFS and OS were 5.5 (95% CI 5.3-5.6) months and 18.9 (95% CI 17.1-21.3) months, respectively. Adverse event (AE) profile was broadly similar in patients with and without baseline BM, although nervous system AEs were more common in patients with (208 [52.3%]) versus without (701 [43.7%]) baseline BM.This exploratory analysis of patients with HER2-positive MBC and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting.