Phase 2 Trial of GDC-0084 in Combination with Trastuzumab for Patients with HER2+ Breast Cancer Brain Metastases

The PI3K/Akt/mTOR is an important pathway in patients with breast cancer with brain metastases (BCBM). Moreover, mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenograft (PDX) models of BCBM.1

At SABCS 2019, the clinical trial design was presented of a single-center, phase 2 study of GDC-0084, a brain-penetrant inhibitor of class I PI3K and mTOR.2 The study will evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2+ breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8-mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, 2-stage, phase 2 cohort; and Cohort B: a presurgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2+ CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), and clinical indication for CNS metastasis resection (Cohort B).

The primary end point for Cohort A is objective response rate in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary end point is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary end points include overall survival, safety, and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment, and at progression. In Cohort A, 37 patients will be enrolled in a Simon 2-stage design. If ≥4 responses are seen, the regimen will be considered successful. Cohort B will enroll 10 patients. The trial opened in February 2019 under number NCT03765983.


  1. Ippen FM, et al. Clin Cancer Research. Published online February 22, 2019. doi: 10.1158/1078-0432.CCR-18-3049.
  2. Leone JP, et al. SABCS 2019. Abstract OT-1-08.

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