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Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Hae Hyun Jung, Woong-Yang Park, Kyung-Hun Lee, Joohyuk Sohn, Keun Seok Lee, Kyung Hae Jung, Jee Hyun Kim, Ki Hyeong Lee, Seock-Ah Im, Yeon Hee Park
We aimed to investigate the impact of genetic alterations on the efficacy of poziotinib in a phase II clinical trial of patients with heavily treated HER2-positive metastatic breast cancer (BC). We performed targeted ultra-deep sequencing with a customized cancer gene panel and RNA expression assay using BC specimens. Of 106 patients, biomarker data were available for 85. Copy number (CN) amplifications of HER2 were observed in 72 patients (85%), and CN>8 in 50 (59%). Single nucleotide variants (SNVs) of HER2 were found in 16 patients (19%)...
February 5, 2019: International Journal of Cancer. Journal International du Cancer
Takamasa Koga, Yoshihisa Kobayashi, Kenji Tomizawa, Kenichi Suda, Takayuki Kosaka, Yuichi Sesumi, Toshio Fujino, Masaya Nishino, Shuta Ohara, Masato Chiba, Masaki Shimoji, Toshiki Takemoto, Makoto Suzuki, Pasi A Jänne, Tetsuya Mitsudomi
OBJECTIVES: Oncogenic HER2 mutations are present in 2-4% of lung adenocarcinomas, but the relevant clinical trials are unsatisfactory. The novel HER2 inhibitor poziotinib was recently developed and clinical trials are ongoing. We compared poziotinib with nine tyrosine kinase inhibitors (TKIs), and derived poziotinib-resistant clones to investigate the resistant mechanism. MATERIALS AND METHODS: We introduced three common HER2 mutations A775_G776insYVMA (YVMA), G776delinsVC (VC) and P780_Y781insGSP (GSP), which account for 94% of HER2 exon 20 insertions in the literature, into Ba/F3 cells...
December 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Apurva Pandey, Adam M Brufsky
No abstract text is available yet for this article.
October 4, 2018: Clinical Breast Cancer
In-Jae Oh, Jae Young Hur, Cheol-Kyu Park, Young-Chul Kim, Seung Joon Kim, Min Ki Lee, Hee Joung Kim, Kye Young Lee, Jae Cheol Lee, Chang-Min Choi
INTRODUCTION: HER2 mutations are found in 2% to 4% of non-small-cell lung cancer cases and are usually mutually exclusive with other genetic alterations. We screened a large cohort of patients from multiple institutions in Korea, described the characteristics of HER2-mutant cases, and reported on several patients who were treated with pan-HER inhibitors. PATIENTS AND METHODS: The study population consisted of 360 patients diagnosed with adenocarcinoma from 4 institutions in Korea from June 2015 to September 2016...
September 2018: Clinical Lung Cancer
Yeon Hee Park, Kyung-Hun Lee, Joo Hyuk Sohn, Keun Seok Lee, Kyung Hae Jung, Jee-Hyun Kim, Ki Hyeong Lee, Jin Seok Ahn, Tae-Yong Kim, Gun Min Kim, In Hae Park, Sung-Bae Kim, Se Hyun Kim, Hye Sook Han, Young-Hyuck Im, Jin-Hee Ahn, Jung-Yong Kim, Jahoon Kang, Seock-Ah Im
Although the introduction of human epidermal growth factor receptor (HER)2-directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2-positive mBC will eventually progress. Poziotinib is an oral pan-HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive mBC who had progressed from more than two HER2-directed therapies...
December 15, 2018: International Journal of Cancer. Journal International du Cancer
Diana Romero
No abstract text is available yet for this article.
July 2018: Nature Reviews. Clinical Oncology
Jacqulyne P Robichaux, Yasir Y Elamin, Zhi Tan, Brett W Carter, Shuxing Zhang, Shengwu Liu, Shuai Li, Ting Chen, Alissa Poteete, Adriana Estrada-Bernal, Anh T Le, Anna Truini, Monique B Nilsson, Huiying Sun, Emily Roarty, Sarah B Goldberg, Julie R Brahmer, Mehmet Altan, Charles Lu, Vassiliki Papadimitrakopoulou, Katerina Politi, Robert C Doebele, Kwok-Kin Wong, John V Heymach
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...
May 2018: Nature Medicine
(no author information available yet)
Poziotinib, an EGFR inhibitor that was previously shelved as ineffective against non-small cell lung cancer, is showing promising activity in a subset of patients with EGFR exon 20 insertions. According to preliminary data from a phase II trial, the drug led to a 73% overall response rate in patients with this disease subtype, which is typically highly resistant to standard therapy.
January 2018: Cancer Discovery
S E Tahaei, G Couasnay, Y Ma, N Paria, J Gu, B F Lemoine, X Wang, J J Rios, F Elefteriou
Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutations in the NF1 gene. Recalcitrant bone healing following fracture (i.e. pseudarthrosis) is one of the most problematic skeletal complications associated with NF1. The etiology of this condition is still unclear; thus, pharmacological options for clinical management are limited. Multiple studies have shown the reduced osteogenic potential of Nf1-deficient osteoprogenitors. A recent transcriptome profiling investigation revealed that EREG and EGFR, encoding epiregulin and its receptor Epidermal Growth Factor Receptor 1, respectively, were among the top over-expressed genes in cells of the NF1 pseudarthrosis site...
January 2018: Bone
Tae Min Kim, Keun-Wook Lee, Do-Youn Oh, Jong-Seok Lee, Seock-Ah Im, Dong-Wan Kim, Sae-Won Han, Yu Jung Kim, Tae-You Kim, Jee Hyun Kim, Hyesun Han, Woo Ho Kim, Yung-Jue Bang
Purpose: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. Materials and Methods: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect...
July 2018: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Ji-Youn Han, Ki Hyeong Lee, Sang-We Kim, Young Joo Min, Eunkyung Cho, Youngjoo Lee, Soo-Hyun Lee, Hyae Young Kim, Geon Kook Lee, Byung Ho Nam, Hyesun Han, Jina Jung, Jin Soo Lee
PURPOSE: We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs. MATERIALS AND METHODS: This single-arm phase II study included EGFR -mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle...
January 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Yook-Hwan Noh, Hyeong-Seok Lim, Jin-A Jung, Tae Hun Song, Kyun-Seop Bae
PURPOSE: To develop a population pharmacokinetic (PK) model for HM781-36 (poziotinib) and its metabolites in cancer patients. METHODS: Blood samples were collected from three phase I studies in which fifty-two patients received oral HM781-36B tablets (0.5-32 mg) once daily for 2 weeks, and another 20 patients received oral HM781-36B tablets (12, 16, 18, 24 mg) in fasting (12 patients) or fed (eight patients) state once daily for 4 weeks. Nonlinear mixed effect modeling was employed to develop the population pharmacokinetic model...
January 2015: Cancer Chemotherapy and Pharmacology
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