Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models

Abstract

◥ HER2 Po ten cy Tucatinib blocks MAPK and PI3K/AKT signaling through inhibition of HER2 kinase activity

Evolving standards of care and new challenges in the management of HER2‐positive breast cancer

“…The oral, potent, HER2‐specific TKI tucatinib selectively inhibits HER2 and demonstrates activity as monotherapy or combined with chemotherapy or trastuzumab in HER2‐positive murine xenograft models, including intracranial tumor xenograft models 91 . Results from a phase 1 study of tucatinib in HER2‐positive advanced solid tumors, with an expansion cohort of patients who had HER2‐positive MBC (n = 43), noted a lower incidence and severity of diarrhea and rash with tucatinib than that usually associated with dual HER2/EGFR inhibitors, as well as significant antitumor activity in patients with heavily pretreated, HER2‐positive MBC 92 .…”

HER2 splice variants in breast cancer: investigating their impact on diagnosis and treatment outcomes

“…It does not inhibit EGFR, perhaps due to structural differences in the ATP-binding pocket [68]. This inhibitor can reduce activation of HER2, HER3 (through the downregulation of HER2/HER3 dimerization) and Akt resulting in reduced cell proliferation and tumour growth in vivo [69]. Treatment results in anti-tumour activity in patients who have previously received trastuzumab, pertuzumab, T-DM1 and lapatinib [70,71].…”

“…Interest surrounds a positive response in patients with brain metastases [72]. Owing to the selective nature of this inhibitor combinations with other HER2-targetting agents may result in lower toxicity than other dual inhibitors [69]. Further advancements continue which may lead to the approval of further anti-HER2 treatments in breast cancer [68].…”

“…Alternatively, T-DXd contains the cell permeable drug DXd and cells expressing ∆16-HER2 adjacent to HER2 WT expressing cells may be targeted by the chemotherapy molecules, dubbed 'the bystander effect' [121]. As the tyrosine kinase domain is not altered inhibitors such as lapatinib, neratinib and tucatinib should retain efficacy and may provide prolonged reduction in signalling, as these receptors will remain at the cell surface [65,69]. HER2 WT and ∆16-HER2 appear to be independently modulated during treatment [89].…”

<p>Up-and-Coming Experimental Drug Options for Metastatic Colorectal Cancer</p>

“…41 Trastuzumab synergizes with tucatinib by binding HER2 extracellularly. 48 Twenty-two patients were evaluable, and 12 (55%) of patients had a PR or CR. 49 The most common treatment-related adverse events were AST and/or ALT elevation and diarrhea.…”