A randomized, double-blinded, controlled study of tucatinib (ONT- 380) vs placebo in combination with capecitabine (C) and trastuzumab (T) in patients with pretreated HER21 unresectable locally advanced or metastatic breast carcinoma (mBC) (HER2CLIMB)

Background: Tucatinib (ONT-380) is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Because tucatinib does not inhibit EGFR at clinically relevant concentrations, it potentially decreases EGFR-related toxicities (severe skin rash, diarrhea). In preclinical studies, tucatinib has demonstrated synergistic activity with T and is active in HER2+models of brain metastases (BM). In a Phase 1b study, tucatinib showed encouraging antitumor activity when combined with C and T in pts with HER2+ mBC previously treated with ado-trastuzumab emtansine (T-DM1) and T. Objective responses were seen, including in pts with BM. The combination was well tolerated with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Tucatinib is being evaluated in an ongoing international randomized, double blind, phase 2 study in combination with C and T (HER2CLIMB). Trial design: HER2CLIMB is recruiting in North America, Europe, Israel, and Australia. The primary study objective is to assess the effect of tucatinib vs. placebo in combination with C + T on progression-free survival (PFS) based on independent central review. Additional objectives include PFS in pts with BM, overall survival (OS), objective response rate, and safety. To increase the power of key secondary endpoints, the sample size was expanded from 480 to 600 pts. The study population includes adult pts with progressive HER2+ locally advanced or mBC who have had prior treatment with T, pertuzumab, and T-DM1 but not TKIs. A contrast-enhanced brain MRI is required at screening. Pts with untreated or progressive BM may be enrolled if they do not require immediate local therapy. Pts with isolated CNS progression on study may continue study treatment after undergoing local CNS-directed therapy. Pts receive C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and T (6 mg/kg IV once every 21 days after a loading dose of 8 mg/kg IV), and are randomized in a 2:1 ratio to tucatinib 300 mg PO BID or placebo. Safety is monitored by an independent Data Monitoring Committee.