ARRY-380 + trastuzumab

## Drug Information ARRY-380 + trastuzumab is a combination therapy being investigated for HER2-positive breast cancer, particularly in patients with brain metastases. This combination targets the HER2 receptor through two different mechanisms, potentially providing enhanced efficacy compared to single-agent therapy. ### Key Details ARRY-380 (also known as ONT-380 and later developed as tucatinib) is an orally active, reversible and selective small-molecule HER2 inhibitor that was discovered by Array BioPharma and developed in collaboration with Oncothereon[5][7]. It specifically targets the HER2 receptor without inhibiting EGFR, which results in fewer side effects like diarrhea, rash, and fatigue compared to other HER2 inhibitors such as lapatinib[5]. Trastuzumab is an FDA-approved monoclonal antibody for the treatment of HER2-positive metastatic breast cancer[1][2]. When combined with ARRY-380, the two agents work synergistically by attaching to different parts of the HER2 receptor, preventing it from functioning[1][2]. The combination is particularly promising for patients with brain metastases, as ARRY-380 has demonstrated some penetration into the brain in laboratory studies[1][2]. This is significant because approximately one-third of women with metastatic HER2+ breast cancer develop brain metastases[5]. ### Clinical Development A Phase I dose-escalation trial was conducted to test the safety of different doses of ARRY-380 in combination with trastuzumab in patients with brain metastases from HER2+ breast cancer[1]. The trial aimed to determine the maximum tolerated dose and evaluate the combination's efficacy and safety profile. In previous studies, ARRY-380 as a single agent demonstrated an acceptable safety profile with primarily Grade 1 adverse events and no treatment-related cardiac events or Grade 4 treatment-related adverse events[5]. The maximum tolerated dose established in a Phase 1 trial was 600 mg twice daily[5]. The strategy of combining two agents targeting HER2 has previously proven useful in HER2+ breast cancer, making the combination of ARRY-380 and trastuzumab a logical approach to evaluate as treatment options for metastatic HER2+ breast cancer continue to evolve[7].