A Phase I/II Study of Ibrutinib Plus Trastuzumab in HER2‐Positive Metastatic Breast Cancer

ABSTRACT Ibrutinib has demonstrated inhibition of ErbB/HER tyrosine kinases in preclinical models. This Phase I/II study investigated the safety, efficacy, and immunomodulatory effects of ibrutinib in combination with trastuzumab in patients with HER2‐positive metastatic breast cancer (MBC) whose disease had progressed on ado‐trastuzumab emtansine therapy. In Phase I, cohorts of three patients received ibrutinib 560 mg or 420 mg by mouth once daily combined with standard dosing of trastuzumab. Phase II enrolled additional patients to assess the primary endpoint of clinical benefit rate (CBR) at 420 mg ibrutinib plus trastuzumab. Flow cytometry and NanoString analyses were performed on peripheral blood mononuclear cells. Overall, 26 patients were enrolled. Patients received a median of three prior regimens containing a HER2‐targeted therapy in any setting. The most common treatment‐related adverse events were bruising, rash, fatigue, and thrombocytopenia. Four patients (15%) experienced cardiac adverse events, including decreased left ventricular ejection fraction in two patients. The CBR of ibrutinib plus trastuzumab was 19.2% (95% confidence interval: 6.6–39.4). Flow cytometry of T‐ and natural killer (NK)‐cell and myeloid‐cell panels showed that treatment statistically significantly decreased T helper 17 (T H 17) and myeloid‐derived suppressor cells (MDSC) with no decrease in T helper 2 (T H 2) cells. Ibrutinib plus trastuzumab was well‐tolerated but had limited anti‐tumor activity in patients with heavily pretreated, HER2‐positive MBC (NCT03379428). Trial Registration: Clinicaltrials.gov , NCT03379428