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This Phase I\/II study investigated the safety, efficacy, and immunomodulatory effects of ibrutinib in combination with trastuzumab in patients with HER2\u2010positive metastatic breast cancer (MBC) whose disease had progressed on ado\u2010trastuzumab emtansine therapy. In Phase I, cohorts of three patients received ibrutinib 560\u2009mg or 420\u2009mg 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\u2009mg 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\u2010targeted therapy in any setting. The most common treatment\u2010related 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\u201339.4). Flow cytometry of T\u2010 and natural killer (NK)\u2010cell and myeloid\u2010cell panels showed that treatment statistically significantly decreased T helper 17 (T\n                    <jats:sub>H<\/jats:sub>\n                    17) and myeloid\u2010derived suppressor cells (MDSC) with no decrease in T helper 2 (T\n                    <jats:sub>H<\/jats:sub>\n                    2) cells. Ibrutinib plus trastuzumab was well\u2010tolerated but had limited anti\u2010tumor activity in patients with heavily pretreated, HER2\u2010positive MBC (NCT03379428).\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">Clinicaltrials.gov<\/jats:ext-link>\n                    , NCT03379428\n                  <\/jats:p>","DOI":"10.1002\/cam4.72085","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:03:36Z","timestamp":1785143016000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Phase I\/II Study of Ibrutinib Plus Trastuzumab in HER2\u2010Positive Metastatic Breast 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