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HER-2 as a Prognostic and Predictive Biomarker in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alexandra S. Zimmer, Suparna B. Wedamb, Stanley Lipkowitza
Tucatinib is a reversible tyrosine kinase inhibitor that is highly selective for HER-2 with minimal activity against the EGFR (HER-1) [130]. Tucatinib showed promising activity in combination with capecitabine and trastuzumab in a phase I trial for patients with HER-2 positive (defined as IHC of 3+ or amplification by FISH) breast cancer, and notably included responses in brain metastases [130]. The HER2CLIMB phase III trial randomized 612 patients with HER-2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab and T-DM1, to trastuzumab and capecitabine, plus tucatinib or placebo [131]. The addition of tucatinib to capecitabine and trastuzumab improved PFS at 1 year (33.1% versus 12.3%, HR 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), with improvements in the duration of median PFS of 7.8 months and 5.6 months, respectively. Median OS at 2 years was 44.9% in the patients treated with tucatinib compared to 26.6% in those treated with placebo (HR 0.66; 95% CI, 0.50 to 0.88; P = 0.005). The addition of tucatinib improved median OS (21.9 months in the tucatinib treated patients versus 17.4 months in the control patients). Patients with brain metastases were allowed to enroll and the 1-year PFS in this group was 24.9% with addition of tucatinib versus 0% in the placebo-combination group (HR 0.48; 95% CI, 0.34 to 0.69; P<0.001). Median PFS for those with brain metastases was 7.6 months with tucatinib versus 5.4 months without tucatinib. The regimen of tucatinib, capecitabine and trastuzumab was approved in April 2020 for adult patients with advanced unresectable or metastatic HER-2-positive breast cancer, including those with brain metastases. No studies testing tucatinib in patients with HER-2 expression without amplification have been performed.
Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy
Published in OncoImmunology, 2022
Adriana Petrazzuolo, M. Chiara Maiuri, Laurence Zitvogel, Guido Kroemer, Oliver Kepp
Lapatinib reversibly inhibits HER2 and EGFR and is approved in combination with capecitabine for the treatment of HER2-positive advanced breast cancer, offering an effect on PFS as compared to monochemotherapy.102,103 Neratinib is a pan-HER inhibitor that irreversibly binds to its target. It is approved for second-line combinations with capecitabine in HER2-positive advanced breast cancer that progressed after HER2 directed therapy. Neratinib cotreatment with capecitabine increased OS as compared to lapatinib continuation.104 Tucatinib, yet another HER2 inhibitor, has recently been approved in combination with trastuzumab and capecitabine, for advanced unresectable or metastatic HER2 positive breast cancer. Tucatinib increased the median PFS to 7.8 months as compared to 5.6 months in patients that received only trastuzumab and capecitabine.
Evaluation of the inhibitory effect of quercetin on the pharmacokinetics of tucatinib in rats by a novel UPLC–MS/MS assay
Published in Pharmaceutical Biology, 2022
Ying Zhang, Ya-nan Liu, Saili Xie, Xuegu Xu, Ren-ai Xu
Quercetin is a naturally occurring flavonoid and is mainly present as a glycoside in several components of the daily diet. It has been proved that quercetin is a potent CYP2C8 inhibitor and inhibits CYP2C8-catalysed metabolism in vivo (Kim et al. 2005). From the results of our study, when tucatinib was co-administered with 25 mg/kg quercetin in group B, the main pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, Tmax, CLz/F and Cmax) of tucatinib had no significant differences compared with the control group A. However, compared with group A, groups C and D raised the AUC0→t, AUC0→∞ and Cmax of tucatinib (p < 0.05), while decreased CLz/F (p < 0.05), indicating that the total tucatinib systemic exposure increased. Also, 100 mg/kg quercetin exhibited a more substantial inhibition on tucatinib metabolism than 50 mg/kg quercetin. Therefore, the concurrent use of tucatinib with high dose of quercetin should be treated with extreme caution. If their combined use is unavoidable, our data suggested dose reduction or interruption of tucatinib should be taken. Otherwise, the patient might suffer from some severe side effects (such as diarrhoea, palmar-plantar erythrodysesthesia syndrome and nausea) caused by increased tucatinib plasma levels (Murthy et al. 2020). The limitation of our research lies in the small number of rats used in the experiment.
Tucatinib: an investigational novel therapeutic agent for the treatment of HER-2 colorectal cancer
Published in Expert Opinion on Investigational Drugs, 2022
Daniel Ahn, Daniel Walden, Tanios Bekaii-Saab
HER-2 overexpression has been identified across several tumor types and established as an oncogenic driver and its association with tumorigenesis and treatment resistance. While HER-2 overexpression has been associated with treatment resistance to anti-EGFR monoclonal antibody therapies, its prognostic implication in mCRC is undefined. Given its incidence, role as therapeutic target in other solid tumor malignancies and highlighting an unmet need for more effective therapies, inhibitors that can potently and effectively target HER-2 has remained an area of interest in mCRC. Tucatinib is an orally available HER-2 specific tyrosine kinase inhibitor with minimal inhibition of EGFR. The selectively against HER-2 has allowed tucatinib to be combined effectively with other therapeutic agents with limited overlapping toxicities and encouraging signals of enhanced tumor activity. While early results in CRC have been encouraging, future directions include its investigation in earlier lines of treatment and in combination with other therapeutic agents including chemotherapy, immune checkpoint inhibitors, and other HER-2-directed therapies.