TOPAZ: Tucatinib in COmbination With Pembrolizumab And TrastuZumab in Patients With HER2-Positive Breast Cancer Brain Metastases

TOPAZ: Single Arm, Open Label Phase 1b/2 Study of Tucatinib in COmbination With Pembrolizumab And TrastuZumab in Patients With HER2-Positive Breast Cancer Brain Metastases

This is a single arm, open label trial to assess the safety and efficacy of tucatinib in combination with pembrolizumab and trastuzumab for the treatment of HER2+ breast cancer brain metastases (BCBM). A total of 33 patients with untreated or previously treated and progressing HER2+ BCBM not requiring urgent central nervous system (CNS)-directed therapy will be enrolled. The study will determine the recommended dose of tucatinib in this combination and assess the efficacy of this combination in controlling CNS disease in patients with HER2+ BCBM.

Inclusion Criteria:

1. Age ≥18 years.
2. ECOG performance status of 0-2.
3. HER2+ (as defined by ASCO/CAP clinical practice guideline) metastatic breast cancer.
4. Untreated or previously treated and progressing CNS disease.
5. Measurable CNS metastases.
6. Must be able to undergo MRI of the brain.
7. Adequate organ function.

Exclusion Criteria:

1. Any indication for immediate CNS-directed therapy.
2. History of generalized or complex partial seizures.
3. Any other manifestation of neurologic progression that in the opinion of the treating physician is due to brain metastases.
4. Leptomeningeal disease.
5. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.
6. Prior therapy with tucatinib.
7. Active autoimmune disease that has required systemic treatment in excess of prednisone 10mg daily or equivalent in the past 2 years.

Complete inclusion/exclusion criteria are detailed in the protocol.