A randomized study of tucatinib (ONT-380) vs. placebo in combination with capecitabine and trastuzumab in patients with pretreated HER2-pos. metastatic breast cancer: HER2CLIMB

Purpose:

Treatment for HER2-pos. breast cancer patients after trastuzumab/pertuzumab and T-DM 1 isnot well examined, especially for those patients with brain metastases. Tucatinib (ONT-380) is a small molecule inhibitor of HER2 kinase. In a Phase 1b study, tucatinib was combined with capecitabine (C) and trastuzumab (Tz) in pts with HER2+ MBC previously treated with T-DM 1 and Tz. Objective responses were seen, including in pts with brain mets. The combination was well tolerated, with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID). Therfore, tucatinib is now being evaluated in a study in combination with C and Tz (HER2CLIMB).

Methods:

Primary study objective is to assess the effect of tucatinib vs. placebo given with C + Tz on progression-free survival (PFS) based on independent central review. Additional objectives include PFS in patients with brain mets, overall survival, ORR, duration of response, clinical benefit rate, and safety. The study population includes adult patients with progressive HER2+ locally advanced or MBC who have had prior treatment with Tz, pertuzumab and T-DM 1. Patients with brain mets, including untreated or progressive brain mets, may be enrolled. 480 patients will be enrolled. Patients are receiving C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and Tz (6 mg/kg IV once every 21 days), and are being randomized in a 2:1 ratio to tucatinib 300 mg PO BID or placebo. Patients with isolated CNS progression may continue on study treatment after undergoing local CNS therapy.