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《Expert opinion on pharmacotherapy》2013,14(9):1203-1213
Introduction: Activating mutations of the EGFR and rearrangement of anaplastic lymphoma kinase (ALK) best illustrate the therapeutic relevance of molecular characterization in NSCLC patients. Areas covered: For this review article, all published data on the most relevant Phase III trials with tyrosine kinase inhibitors (TKIs) for the treatment of NSCLC were collected and analyzed. Expert opinion: Eight Phase III trials clearly established EGFR TKIs as the best therapeutic option for front-line therapy in EGFR-mutated patients. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy to docetaxel or pemetrexed in term of survival has been demonstrated. In ALK-translocated NSCLC, a Phase III trial demonstrated the superiority of a multi-target TKI, including ALK, in terms of progression-free survival, response rate and toxicity profile when compared to standard second-line chemotherapy. New agents targeting EGFR or ALK are under evaluation particularly in individuals with acquired resistance to EGFR TKIs or crizotinib. 相似文献
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《Expert opinion on pharmacotherapy》2013,14(9):1277-1288
Introduction: Human epidermal growth factor receptor (HER) 2 is overexpressed in 20 – 25% of breast cancers, and has historically been a poor prognostic marker. The introduction of trastuzumab, the first fully humanized monoclonal antibody targeting HER2, has drastically changed the outcomes of metastatic breast cancers. However, despite initial response, most patients develop resistance. Recent data suggest that strategies targeting more than one member of HER family may circumvent trastuzumab resistance and confer synergistic effects. Areas covered: Following a literature search on PubMed, national meetings and clinicaltrials.gov using ‘afatinib’, ‘neratinib’, ‘HER2’ and ‘breast cancer’ as keywords, we critically analyzed the different HER2-targeted therapies for their drug development and evidence-based therapeutic strategies. Afatinib and neratinib, two second-generation tyrosine kinase inhibitors (TKIs) that irreversibly inhibit more than one HER family member, are being actively investigated in clinical trials either as monotherapy or in combination. We reviewed the efficacy and optimal use of these agents in various settings, such as systemic therapy for advanced breast cancer including brain metastases, and neoadjuvant therapy in early-stage breast cancer. Expert opinion: HER2-targeted therapies have been widely used and greatly improved the outcome of HER2-positive breast cancer. Despite the accelerated advancement in recent years, several crucial questions remain unanswered, such as how to treat a prior resistance or affect a sanctuary site, that is, CNS metastasis. The novel next-generation TKIs, afatinib and neratinib, were rationally designed to overcome the resistance by targeting multiple HER family members and irreversibly binding the targets. In spite of the encouraging results of the afatinib and neratinib monotherapies, they have not been proven more efficacious in the combination therapies yet, even though multicenter international trials are still ongoing. The key tasks in the future are to study resistance pathways, design novel strategies to more efficiently test combinations for synergistic effects and identify biomarkers and novel imaging tools to guide individualized therapies. 相似文献
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《Expert review of anticancer therapy》2013,13(12):1391-1406
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have an established role in the treatment of non-small-cell lung cancer (NSCLC). First-generation reversible ATP-competitive EGFR-TKIs are approved for the initial treatment of patients with EGFR mutation-positive advanced NSCLC. Afatinib is an irreversible second-generation EGFR-TKI with potent preclinical activity against EGFR (wild type and mutant), HER2, HER4 and EGFR-mutant NSCLC with acquired resistance to reversible EGFR-TKI. LUX-Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment-naïve patients with advanced adenocarcinoma of the lung and EGFR mutation. Based on these results, afatinib was recently approved for the first-line treatment of NSCLC patients with EGFR mutation. This article summarizes current status of preclinical and clinical development of afatinib in NSCLC. 相似文献
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Siao-Syun Guan Jungshan Chang Chun-Chia Cheng Tsai-Yueh Luo Ai-Sheng Ho Chia-Chi Wang Cheng-Tien Wu Shing-Hwa Liu 《Oncotarget》2014,5(13):4868-4880
Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo. 相似文献
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Tomomi Nakamura Akemi Sato Chiho Nakashima Tomonori Abe Kentaro Iwanaga Hitomi Umeguchi Atsushi Kawaguchi Naoko Sueoka-Aragane 《Cancer science》2023,114(3):1045-1055
Treatment efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is diverse even in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Extraordinary long-term responses sustained over 3 years among NSCLC patients treated with afatinib, an EGFR-TKI, have been reported, but how to predict such long survivors has not been clarified. A multi-institutional prospective observational study, based on comprehensive genomic examination performed with next-generation sequencing of circulating tumor DNA (ctDNA), was conducted to identify potential predictive markers of long-term response to afatinib. Twenty-nine patients with advanced stage NSCLC and EGFR driver mutations detected by standard techniques were enrolled in the study. ctDNA from plasma collected before afatinib treatment was analyzed by Guardant360. ctDNA was detected in 25 of the 29 samples. Median progression-free survival was shorter in patients whose tumors had EGFR copy number gain (7.0 vs 23.0 months, p = 0.022). The impact of EGFR copy number on cell proliferation and the antitumor effect of afatinib were evaluated using genome-editing lung cancer cell lines. HCC827 with EGFR amplification was relatively resistant to afatinib at concentrations below 0.5 nM, but genome-edited derivatives of HCC827 with decreased EGFR copy number demonstrated growth inhibition with 0.1 nM afatinib. The absence of EGFR copy number gain detected in ctDNA may be a predictive marker of long-term response to afatinib. Comprehensive genomic analysis could lead to a more accurate prediction of EGFR-TKI efficacy. 相似文献
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Afatinib successfully treated leptomeningeal metastasis during erlotinib treatment in a patient with EGFR‐mutant (Exon18:G719S) lung adenocarcinoma as a second‐line chemotherapy 下载免费PDF全文
Motohiro Tamiya Takayuki Shiroyama Takashi Nishihara Takuji Nishida Manabu Hayama Ayako Tanaka Naoko Morishita Hidekazu Suzuki Norio Okamoto Tomonori Hirashima 《Asia-Pacific Journal of Clinical Oncology》2017,13(5):e531-e533
Exon18 mutations are detected in 3.6% of epidermal growth factor receptor mutations. Exon 18 mutations as driver mutations have higher sensitivities in vitro to second‐generation (G)‐tyrosine kinase inhibitors (TKIs) than to first G‐ and third G‐TKIs at clinically relevant doses. In clinical trial, first G‐TKIs have moderate but insufficient efficacy, and afatinib was more active in uncommon epidermal growth factor receptor mutations. Here, we present a case of a woman who was initially prescribed erlotinib for lung adenocarcinoma with an exon18 mutation. She developed a leptomeningeal metastasis during treatment and was switched to afatinib. Subsequently, her symptoms improved and she is currently treated with maintenance afatinib therapy. This report suggests improved efficacy of afatinib compared to erlotinib for refractory leptomeningeal metastasis in exon18 mutation. 相似文献
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Melania Brzozowska Waldemar Wierzba Sylwia Szafraniec-Buryo Marcin Czech Gabriela Majkut Joanna Poowinczak-Przybyek Piotr Potemski Andrzej
liwczyski 《Archives of Medical Science》2021,17(6):1618
IntroductionThe aim of the study was to estimate the overall survival of patients with EGFR mutation-positive non-small-cell lung cancer treated with erlotinib, gefitinib or afatinib.Material and methodsReal-world patients who received afatinib, erlotinib or gefitinib between 1 July 2012 and 30 October 2017 were analysed in five subgroups.ResultsAmong 267 patients treated with afatinib financed as the first line of treatment, 76 (28.46%) deaths occurred. Median observation time was 12.8 months (95% CI: 11.2–13.9). Median OS was 22.8 months (95% CI: 19.2–27.1). Among 83 patients who received erlotinib financed exclusively as the second line of treatment the number of deaths was 74 (89.16%). Median observation time was 64.3 months (95% CI: 60.4–64.6). Median OS was 16 months (95% CI: 13.2–22.9). Among 622 patients who received erlotinib financed both as first and second line treatment, there were 400 (64.3%) deaths. Median observation time was 33.3 months (95% CI: 31.2–37.6). Median OS was 17.8 months (95% CI: 16.4–19.7). Among 137 patients who received gefitinib financed only as the first line of treatment, there were 128 (93.4%) deaths. Median observation time was 58.3 months (95% CI: 49.4–62.5). Median OS was 16 months (95% CI: 13.8–19.7). Among 348 patients who received gefitinib financed both as the first and second line of treatment the number of deaths was 208 (59.8%). Median observation time was 23.7 months (95% CI: 20.7–28.7). Median OS was 15.5 months (95% CI: 12.9–17.5).ConclusionsOur real-world data regarding OS confirm the benefits found in clinical trials from the use of afatinib, erlotinib or gefitinib. However, the lower overall survival rate of Polish patients compared to similar studies from other research centres suggests the need for deeper investigation of this issue. 相似文献
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Rationale:Tyrosine kinase inhibitors (TKIs) have significant efficacy in patients with advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations. No clear evidence exists that EGFR-L861R is sensitive to TKIs, and the best treatment for NSCLC patients with EGFR-L861R mutation is undetermined.Patient concerns:We report the characteristics, efficacy, and adverse events of a patient harboring rare EGFR mutations L861R treated with afatinib, and summarize the currently available evidence and ongoing clinical trials regarding it.Diagnosis:The patient was diagnosed with advanced lung cancer that had progressed after previous osimertinib drug therapy, based on the clinical course and imaging findings.Interventions:The patient underwent genetic testing, and next-generation sequencing detected rare EGFR mutations L861R in the plasma (mutation abundance 8.1%). The patient was then administered afatinib at 30 mg quaque die combined with bevacizumab at 300 mg every 2 weeks.Outcomes:After 1 month of treatment, the patient achieved a quick response, and symptoms improved significantly. Repeat evaluation imaging demonstrated that the lesions in the lung and brain were significantly smaller and evaluation showed partial remission. However, despite showing an initial response, the patient presented with behavioral abnormalities, headaches, and sudden confusion after 2 months, and subsequently appeared coma. The family elected to forgo further therapy due to the patient''s age and enrolled in hospice care, passing 14 months after the initial diagnosis.Lesson:EGFR-L861R mutation could help predict the sensitivity of patients with advanced NSCLC to TKIs. 相似文献