Abstract Background: Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase that has demonstrated potent inhibition of ErbB/HER family receptor tyrosine kinases in preclinical models. Ibrutinib also displays immunomodulatory effects, shifting the profile of the immune response from Th2-type to Th1-type cytokines (Dubovsky et al. 2013), resulting in enhanced antitumor immunity. As there is a need for novel HER2-targeted therapies following progression on established anti-HER2–directed therapies, and as combining multiple HER2-directed agents is more effective than single-agent therapy (Blackwell et al. 2012), this study explored the safety and efficacy of ibrutinib in combination with trastuzumab in patients (pts) with HER2-positive metastatic breast cancer (MBC) (NCT03379428). Trial design: Phase I was a dose-escalation study to define the recommended Phase II dose (RP2D) of ibrutinib plus trastuzumab. The primary objective of Phase II was to define the clinical benefit rate (CBR = complete response CR + partial response PR + stable disease SD ≥ 6 months) of ibrutinib plus trastuzumab; secondary objectives were to determine objective response rate (ORR = CR + PR), overall survival (OS), progression-free survival (PFS), and safety/tolerability. Pts had HER2-positive MBC with measurable disease per RECIST v1.1, disease progression on or within 6 months of completing ado-trastuzumab emtansine (T-DM1) therapy, and ≤4 (Phase I) or ≤5 (Phase II) prior chemotherapy regimens for MBC, with no limit on prior endocrine therapies. Results: 26 pts were treated in Phases I and II: median age, 65.1 y; 15.4% Asian, 15.4% Black, 46.2% Caucasian, 19.2% Hispanic, and 3.8% Other; 46.2% with ECOG performance status (PS) of 0, 42.3% with PS of 1, and 7.7% with PS of 2. Median prior lines of therapy for MBC was 2 (range: 0, 6); median prior lines of therapy in any setting was 4 (range: 1, 9). In any setting, 88.5% of pts had prior treatment (Tx) with trastuzumab, 80.8% had prior Tx with pertuzumab, and 100% had prior Tx with T-DM1. 0% of pts had brain, 38.5% had bone, 23.1% had liver, and 42.3% had lung metastases. All pts were HER2+ by local pathology, 61.5% positive by IHC and 42.3% by FISH; 12 pts had ER+ and/or PR+ and 14 pts had ER-/PR- cancers. The starting dose of ibrutinib for Phase I was 560 mg. Of the 3 pts enrolled at this dose level, all experienced grade 3 or higher adverse events (AEs), with 2 of the pts experiencing serious AEs (grade 4 alanine aminotransferase ALT increased and grade 5 respiratory failure). As such, 420 mg of ibrutinib was selected as the RP2D. At the time of data extraction, across Phase I/II, 16 pts (61.5%) experienced a Tx-related adverse event (TRAE). The most common (≥5%) TRAEs of any grade were bruising and rash (each 19.2%); fatigue and thrombocytopenia (each 15.4%); anemia, diarrhea, and edema (each 11.5%); and ALT increased, aspartate aminotransferase increased, blurred vision, ecchymoses, mucositis, nausea, pruritus, and vomiting (each 7.7%). A total of 5 pts (19.2%) experienced grade 3 or 4 TRAEs; no grade 5 TRAEs were reported. 26 pts were treated with ibrutinib and trastuzumab, and 26 pts were in the evaluable population. 1 pt had CR for an ORR of 3.8% (95% CIs: 0.1, 19.6); 9 pts had SD, and 4 pts had SD for ≥6 months for a CBR of 19.2% (95% CIs: 6.6, 39.4). Median OS was 27.1 months (range: 0.30, 27.1), and median PFS was 2.0 months (range: 0.03, 27.1). The PFS rate at 12 months was 34.6% (95% CIs: 15.6, 54.6). Conclusion: Ibrutinib plus trastuzumab had a manageable safety profile; however, the CBR did not reach the protocol-specified goal of 28%, and these results do not support further clinical investigation. An in-depth evaluation of the immune effects of ibrutinib in these pts is ongoing. Citation Format: Joyce O'Shaughnessy, Andrea Glidden, Tracy Locke, Amy Scales. Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-03.
O’Shaughnessy et al. (Thu,) studied this question.
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