Abstract CT055: A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (MBC) (HER2CLIMB)
Authors: Anders Carey , Murthy Rashmi , Hamilton Erika , Borges Virginia , Cameron David , Carey Lisa , Müller Volkmar , Curigliano Giuseppe , Gelmon Karen , Hortobagyi Gabriel , Krop Ian , Loibl Sibylle , Pivot Xavier , Pegram Mark , Slamon Dennis , Hurvitz Sara , Tsai Michaela , Winer Eric 
Published: July 2017

Abstract
Background: Tucatinib (ONT-380) is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities (severe skin rash and diarrhea). In preclinical studies, tucatinib demonstrated synergistic activity with Tz, and was active in HER2+ models of brain metastases (mets). In a Phase 1b study, tucatinib was combined with C and Tz in pts with HER2+ MBC previously treated with trastuzumab emtansine (T-DM1) 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, equivalent to the single agent MTD). Based on these data, tucatinib is now being evaluated in a study in combination with C and Tz (HER2CLIMB).
Trial Design: The 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 pts with progressive HER2+ locally advanced or MBC who have had prior treatment with a taxane, Tz, pertuzumab and T-DM1. Pts with brain mets, including untreated or progressive mets, may be enrolled. 480 pts will be enrolled in North America, Europe, and Australia. Pts 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. Pts with isolated CNS progression may continue on study treatment after undergoing local CNS therapy. An independent Data Monitoring Committee is monitoring pt safety.
Citation Format: Carey Anders, Rashmi Murthy, Erika Hamilton, Virginia Borges, David Cameron, Lisa Carey, Volkmar Müller, Giuseppe Curigliano, Karen Gelmon, Gabriel Hortobagyi, Ian Krop, Sibylle Loibl, Xavier Pivot, Mark Pegram, Dennis Slamon, Sara Hurvitz, Michaela Tsai, Eric Winer. A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (MBC) (HER2CLIMB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT055. doi:10.1158/1538-7445.AM2017-CT055