Pub Date : 2018-09-01DOI: 10.1158/1557-3265.AACRIASLC18-IA38
L. Sequist
A summary of the major advances in management of EGFR mutation-positive lung cancer will be provided, along with a discussion of missing pieces of information that could improve the care of patients. Citation Format: Lecia V. Sequist. Progress and unanswered questions in EGFR mutation-positive lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA38.
本文将总结EGFR突变阳性肺癌治疗的主要进展，并讨论可能改善患者护理的缺失信息。引文格式:Lecia V. Sequist。EGFR突变阳性肺癌的研究进展及未解之谜[摘要]。第五届AACR-IASLC国际联合会议论文集:肺癌转化科学从实验室到临床;2018年1月8日至11日;费城(PA): AACR;临床肿瘤杂志，2018;24(17 -增刊):摘要nr - IA38。
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Pub Date : 2018-09-01DOI: 10.1158/1557-3265.aacriaslc18-b01
R. Rahal, Michelle A Maynard, Wei Hu, Jason D. Brubaker, Q. Cao, Joseph L. Kim, M. Sheets, Douglas Wilson, Kevin Wilson, L. DiPietro, T. LaBranche, B. Wolf, T. Guzi, C. Lengauer, E. Evans
Activating RET fusions have been observed in 1-2% of non-small cell lung adenocarcinomas (NSCLC). These tumors often occur in non-smokers and lack other driver mutations, similar to NSCLC driven by activation of the tyrosine kinases EGFR, ALK or ROS. Multi-kinase inhibitors (mKIs) with in vitro activity against RET, such as cabozantinib and vandetanib, have been tested in RET-rearranged NSCLC, but without the high response rate often seen with targeted therapies in genetically-defined NSCLC, likely a result of off-toxicities that limit the ability to fully inhibit RET kinase activation. BLU-667 is a next-generation kinase inhibitor specifically tailored to target the activated forms of RET, while sparing kinases that contribute to dose-limiting toxicities, such as VEGFR-2. BLU-667 potently inhibited both RET fusion activity (IC50 = 0.4 nM) and demonstrated 88-fold selectivity over VEGFR-2 in enzymatic assays. In a cellular setting, BLU 667 inhibited the most prevalent RET fusion observed in NSCLC, KIF5B-RET, over 20X more potently than the multikinase inhibitors cabozantinib, vandetanib or RXDX-105. KIF5B-RET autophosphorylation and proliferation driven by RET fusions was inhibited with BLU-667 in the low nanomolar range (4 – 15 nM). In vivo oral administration of BLU 667 was well tolerated in mice at all doses and exhibited dose-dependent modulation of oncogenic RET kinase activity in all in vivo models tested, including a KIF5B-RET NSCLC PDX, as well as a KIF5B-RET V804L-driven tumor model with a mutation at the gatekeeper position, a position susceptible to on-target mutation in many oncogenic kinases. Notably, BLU-667, but not cabozantinib, induced tumor growth inhibition without impacting biomarkers of VEGFR-2 inhibition, providing strong evidence that selective inhibition of RET alone is sufficient for antitumor activity in vivo. By sparing off-target kinases with known toxicity profiles, BLU-667 is predicted to robustly inhibit RET at clinically achievable doses. Moreover, with activity against predicted resistance mutations such as those at the gatekeeper position, BLU-667 may prevent or delay the emergence of resistance and therefore provide patients with RET-driven malignancies an opportunity for more durable and effective therapies. As such, BLU-667 is currently in the dose-escalation segment of a first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations (NCT03037385). Citation Format: Rami Rahal, Michelle Maynard, Wei Hu, Jason Brubaker, Qiangfang Cao, Joseph L. Kim, Michael P. Sheets, Douglas P. Wilson, Kevin J. Wilson, Lucian DiPietro, Timothy LaBranche, Beni Wolf, Timothy Guzi, Christoph Lengauer, Erica K. Evans. BLU-667: A highly selective RET inhibitor to target RET-driven NSCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin C
在1-2%的非小细胞肺腺癌(NSCLC)中观察到激活RET融合。这些肿瘤通常发生在非吸烟者中，缺乏其他驱动突变，类似于由酪氨酸激酶EGFR、ALK或ROS激活驱动的非小细胞肺癌。具有RET体外活性的多激酶抑制剂(mKIs)，如cabozantinib和vandetanib，已经在RET重排的NSCLC中进行了测试，但在遗传定义的NSCLC中，没有靶向治疗中常见的高反应率，可能是由于脱毒限制了完全抑制RET激酶激活的能力。BLU-667是一种新一代激酶抑制剂，专门针对RET的活化形式，同时保留了导致剂量限制性毒性的激酶，如VEGFR-2。BLU-667能有效抑制RET融合活性(IC50 = 0.4 nM)，并在酶促实验中表现出比VEGFR-2高88倍的选择性。在细胞环境中，BLU 667抑制NSCLC中最常见的RET融合，KIF5B-RET，比多激酶抑制剂cabozantinib, vandetanib或RXDX-105的效力高20倍以上。在低纳摩尔范围内(4 - 15 nM)， BLU-667抑制了KIF5B-RET的自磷酸化和RET融合驱动的增殖。在小鼠体内口服BLU 667在所有剂量下都具有良好的耐受性，并且在所有测试的体内模型中显示出剂量依赖性的致癌RET激酶活性调节，包括KIF5B-RET NSCLC PDX，以及KIF5B-RET v804l驱动的肿瘤模型，该模型在gatekeeper位置突变，这是许多致癌激酶靶突变的易感位置。值得注意的是，BLU-667，而不是cabozantinib，诱导肿瘤生长抑制而不影响VEGFR-2抑制的生物标志物，这提供了强有力的证据，表明单独选择性抑制RET足以在体内产生抗肿瘤活性。通过保留具有已知毒性的脱靶激酶，预计BLU-667在临床可达到的剂量下可有效抑制RET。此外，由于BLU-667具有抗预期耐药突变的活性，例如那些处于守门人位置的耐药突变，因此可以预防或延迟耐药的出现，从而为ret驱动的恶性肿瘤患者提供更持久和有效的治疗机会。因此，BLU-667目前正处于RET驱动实体肿瘤患者激活RET改变(NCT03037385)的人体i期临床试验的剂量递增阶段。引文格式:Rami Rahal, Michelle Maynard，胡卫，Jason Brubaker，曹强芳，Joseph L. Kim, Michael P. Sheets, Douglas P. Wilson, Kevin J. Wilson, Lucian DiPietro, Timothy LaBranche, Beni Wolf, Timothy Guzi, Christoph Lengauer, Erica K. Evans。BLU-667:一种靶向RET驱动NSCLC的高选择性RET抑制剂[摘要]。第五届AACR-IASLC国际联合会议论文集:肺癌转化科学从实验室到临床;2018年1月8日至11日;费城(PA): AACR;临床肿瘤杂志，2018;24(17 -增刊):摘要nr B01。
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The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.
{"title":"Neoadjuvant Chemotherapy Considerations in Triple-Negative Breast Cancer.","authors":"Nicholas McAndrew, Angela DeMichele","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.</p>","PeriodicalId":92149,"journal":{"name":"The journal of targeted therapies in cancer","volume":"7 1","pages":"52-69"},"PeriodicalIF":0.0,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865448/pdf/nihms943480.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35946404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immunotherapy has emerged as a promising strategy for glioblastoma (GBM), a disease that remains universally fatal despite currently available standard-of-care. Adoptive T cell therapy has been shown to produce potent antitumor immunity while obviating the need for traditional antigen presentation and primary immune responses. Chimeric antigen receptors (CARs) are specialized molecules that can be expressed on the surface of T cells allowing for redirected cytotoxicity against tumor antigens of interest. To date, the application of CAR T cells for GBM has been relatively limited, in large part due to a dearth of well-described tumor specific antigens that are both homogenously and frequently expressed. A mutated version of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase that is expressed on the surface of GBM and other common neoplasms, but completely absent from all normal tissues. We have recently generated CAR T cells directed against EGFRvIII and reported results from a Phase I clinical trial investigating this platform in patients with EGFRvIII-expressing GBM. Our study showed that despite conventional notions of central nervous system "immune-privilege," EGFRvIII CAR T cells trafficked to intracerebral tumors, leading to successful targeting and eradication of this antigen in the brain. Here, we review our experience with EGFRvIII CAR T cells and highlight important considerations for the clinical translation of this therapy in patients with GBM.
免疫疗法已成为治疗胶质母细胞瘤(GBM)的一种有希望的策略，尽管目前有标准治疗，但这种疾病仍然普遍致命。过继性T细胞疗法已被证明可以产生有效的抗肿瘤免疫，同时避免了传统抗原呈递和原发性免疫反应的需要。嵌合抗原受体(CARs)是一种特殊的分子，可以在T细胞表面表达，允许对感兴趣的肿瘤抗原进行重定向细胞毒性。迄今为止，CAR - T细胞在GBM中的应用相对有限，这在很大程度上是由于缺乏描述良好的、均匀且频繁表达的肿瘤特异性抗原。表皮生长因子受体EGFRvIII的突变版本是一种组成型激活的酪氨酸激酶，在GBM和其他常见肿瘤表面表达，但在所有正常组织中完全不存在。我们最近生产了针对EGFRvIII的CAR - T细胞，并报告了一项I期临床试验的结果，该试验研究了该平台在表达EGFRvIII的GBM患者中的应用。我们的研究表明，尽管传统观念认为中枢神经系统具有“免疫特权”，但EGFRvIII CAR - T细胞运输到脑肿瘤，导致成功靶向和根除大脑中的这种抗原。在这里，我们回顾了我们使用EGFRvIII CAR - T细胞的经验，并强调了该疗法在GBM患者中的临床转化的重要考虑因素。
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