A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (&lt;i&gt;EGFR&lt;/i&gt;)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR–Tyrosine Kinase Inhibitors

Han, Ji‐Youn; Lee, Ki Hyeong; Min, Young Joo; Cho, Eunkyung; Lee, Young‐Joo; Lee, Soo-Hyun; Kim, Hyae Young; Lee, Geon Kook; Nam, Byung Ho; Han, Hyesun; Jung, Jina; Lee, Jin Soo

doi:10.4143/crt.2016.058

Cited by 38 publications

(27 citation statements)

References 21 publications

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“…Although many patients required dose reduction, results from phase 1 and 2 clinical testing of poziotinib demonstrate that 16 mg/day doses are tolerable and that a plasma concentration of 150 nM can be achieved 37,38,39,40 . As determined on the basis of our data using cell lines bearing EGFR or HER2 exon 20 mutations, this plasma level is more than 125 times the average IC 50 value calculated in vitro.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Robichaux

Elamin

Tan

et al. 2018

Nat Med

375

403

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Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

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Section: Discussionmentioning

confidence: 99%

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Robichaux

Elamin

Tan

et al. 2018

Nat Med

375

403

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show abstract

“…Because of their genetic instability, cancer cells easily acquire drug resistance during chemotherapy. For example, EGFR mutations in lung adenocarcinoma may cause acquired resistance to erlotinib or gefitinib, and rearrangements in the ALK (anaplastic lymphoma kinase) gene in advanced non‐small cell lung cancer lead to resistance to crizotinib . Angiogenesis is a phenomenon observed in many kinds of tumors, and endothelial cells rarely acquire resistance because of genetic stability.…”

Section: Discussionmentioning

confidence: 99%

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor‐2 inhibitor

et al. 2018

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Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor‐2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited anticancer efficacy. In the present study, we detailed the pharmacological properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP‐binding pocket of VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC 50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF‐induced signaling and cell proliferation in HUVEC with picomolar IC 50 values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well‐known tyrosine kinase inhibitor sunitinib, once‐daily oral dose of anlotinib showed broader and stronger in vivo antitumor efficacy and, in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well‐tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies.

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“…Poziotinib, a second-generation EGFR-TKI in patients with lung adenocarcinoma with EGFR mutation was reported the most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%) in a phase II study (28). AC0010, a mutationselective third-generation TKI, reported the incidence of skin rash was 48% in the treatment-emergent adverse events and grade 3 or higher was 4% in the first-inhuman phase I trial (29).…”

Section: Other Egfris Under Studymentioning

confidence: 99%

Update review of skin adverse events during treatment of lung cancer and colorectal carcinoma with epidermal growth receptor factor inhibitors

Peng

Zhang

et al. 2018

BST

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The past decades have witnessed a rapid increase in the use of molecularly targeted therapies. One class of agents includes the epidermal growth factor receptor inhibitors (EGFRIs), which afford patients longer progression-free survival (PFS) times, especially among non-small cell lung cancer (NSCLC) and metastatic colorectal carcinoma (mCRC). Certain adverse effects, particularly skin toxicity, are mainly manifested as rash, xerosis, pruritus, nails changes, hair changes and mucositis. Previous studies reported the adverse events occurred based on the cutaneous inflammation reaction. Treatment recommended glucocorticoids and antibiotics. It is suggested that skin toxicity is an important issue because it usually affects patients' quality of life (QoL) and still causes dose reduction or discontinuation of targeted therapies. For these reasons, more and more oncologists and dermatologists recognize the importance of recognition and management of skin toxicities with the expansion in availability of EGFRIs. In this review, we conducted a systematic review of recent data to examine the types and frequencies of dermatologic toxicities associated with anti-epidermal growth factor receptor (EGFR) therapies in NSCLC and mCRC. In addition, we would like to explore the management and treatment options currently used by clinicians based on the possible mechanism.

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A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (<i>EGFR</i>)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR–Tyrosine Kinase Inhibitors

Cited by 38 publications

References 21 publications

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor‐2 inhibitor

Update review of skin adverse events during treatment of lung cancer and colorectal carcinoma with epidermal growth receptor factor inhibitors

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