成纤维细胞生长因子受体（FGFR）

跟着老马哥学习！期待针对FGFR靶点高效率的靶向药出现！希望爸爸来的及！

同问，FREG如果是易特无效的话这个是不是有效较高

最有效的FGFR抑制剂Lucitanib（AL3810，德立替尼）
德立替尼是同时靶向成纤维细胞生长因子受体1、2（FGFR1-2）和内皮生长因子受体1-3（VEGFR1-3）的受体酪氨酸激酶抑制剂，在特异治疗FGFR1-2依赖型肿瘤的同时，还具有广泛的抑制肿瘤新生血管生成的作用，知识产权属于意大利私营企业EOS SPA。
　　在2012年召开的欧洲临床肿瘤协会年会（ESMO）上，德立替尼因其在临床IIa期试验中对乳腺癌患者的显著治疗效果，被认为是最有希望取得新突破的抗肿瘤候选药物。同年9月，法国施维雅制药公司从EOS SPA获得了德立替尼在除中国、日本和美国以外的全球研发权。该药在中国的专利权由上海药物所、美国Advenchen公司共同拥有。
        2013年11月底，Clovis Oncology Inc.斥资2亿美元收购了EOS SPA，取得德立替尼在美国和日本的研发权。
        目前有10多种小分子FGFR抑制剂在临床试验中，诺华（BGJ398和Dovitinib）、勃林格殷格翰（Nintedanib）、阿斯利康（AZD4547）和礼来（LY2874455）等公司研发的多靶点抑制剂对FGFR的临床活性并不强，有些还具有较大副作用。
        德立替尼不是一个纯粹的FGFR抑制剂，但它是目前唯一具有良好临床活性的FGFR抑制剂。

FGFR单靶点似乎不怎么样，联合其他靶点才行。看看这个LUCITANIB能不能延长乳腺癌的OS。

Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors

Background: Fibroblast growth factor receptors (FGFRs) play a role in cell proliferation and survival. Genetic alterations of FGFRs can lead to deregulated activation in various cancers, including squamous cell carcinoma (SCC) of the lung and urothelial bladder cancer. Here, we report on a phase I study of BGJ398 a potent, selective pan-FGFR inhibitor.
Methods: Eligible patients (pts; ≥ 18 years of age) had tumors with any FGFR genetic alteration identified by central or local prescreening. Pts received BGJ398 once or twice daily (qd or bid) in 28-day cycles in escalating cohorts. Dose-limiting toxicities (DLTs) were predefined and included both severe events and those resulting in significant dosing delays. Upon determination of maximum tolerated dose (MTD), 3 expansion arms were treated: arm 1 included FGFR1-amplified SCC of the lung (continuous qd dosing); arms 2 and 3 included FGFR-altered solid tumors given qd continuous doses (arm 2) or qd doses on a 3-weeks-on/1-week-off schedule (arm 3).
Results: As of September 24, 2013, 94 pts were enrolled (median age 57.5 years). Pts were treated in qd dose cohorts (5-150 mg; n = 90) or a bid dose cohort (50 mg; n = 4). Arms 1 and 3 are ongoing. Of the 82 pts who discontinued, the most common reasons were disease progression (n = 56), consent withdrawal (n = 12), and adverse events (AEs; n = 10). DLTs during dose escalation were grade 3 aminotransferase increases (1 each at 100 and 125 mg), hyperphosphatemia (125 mg), and grade 1 corneal toxicity (150 mg). The 125-mg qd dose was identified as the MTD. Common treatment-emergent AEs (any grade, suspected to be related) at 125 mg qd (n = 41) include hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), decreased appetite (32%), and fatigue (22%) and were generally mild, with stomatitis (7%) the only grade 3/4 AE occurring ≥ 5%. Elevated serum phosphate levels, a pharmacodynamic marker of FGFR pathway inhibition, could be managed through diet, phosphate lowering therapy, and drug interruptions. Preliminary analysis of efficacy data indicates tumor regressions in pts with various FGFR genetic alterations, including 4 of 5 pts with urothelial cell carcinomas (4 of which originated in the bladder) with FGFR3-activating mutations (with tumor reductions ranging from 27% to 48%). Additionally, 1 pt with FGFR1-amplified SCC lung cancer achieved confirmed partial response (PR) while another pt achieved a PR confirmed after 27 days. Tumor reductions were also observed in cholangiocarcinoma with an FGFR2 gene fusion, and FGFR1-amplified breast cancer.
Conclusions: BGJ398 had a tolerable safety profile and demonstrated single-agent activity in pts with FGFR-genetically altered solid tumors. The 3-weeks-on/1-week-off schedule has been chosen for future studies based on its improved safety profile. Clinical activity was observed in multiple tumor types, and pts with FGFR3-mutated bladder cancer may be especially sensitive to BGJ398.

老马大哥，我父亲今年51 确诊鳞癌，我今年才24，看了好多帖子，都是腺癌，鳞癌治疗方案好少，我爸现在状态非常好，求助。

几个观点：1，ponatinib副作用是非常大的，导致FDA去年10月一度停止其销售，主要是有致命的血管堵塞现象。2，FGFR抑制剂目前很多都是多靶点的抑制剂，没有很好的选择性。3， FGFR1的高表达主要在非小细胞鳞癌中占大概15-20%，比例还是不能和EGFR相比。4，的确有数据证明FGFR抑制剂可以抑制易特抵抗的肿瘤的生长。

FGFR inhibitors – Clovis still in the lead

This year’s meeting will have several presentations of FGFR inhibitors. Despite strong scientific evidence for the implication of the FGF pathway in many tumor types, FGFR inhibitors have demonstrated limited activity as monotherapy. The only exception to date is Clovis’ lucitanib, a dual FGFR/VEGFR inhibitor that demonstrated the promising results in a small data set of breast cancer patients with “FGF-aberrant” tumors. Lucitanib’s efficacy is attributed to the parallel inhibition of the VEGF and FGF pathways.

At ASCO, Clovis will present updated results which may corroborate the initial efficacy signal in breast cancer and potentially other tumor types. The abstract discloses the previously reported 50% response rate in 12 heavily pre-treated breast cancer patients.

Other companies will have data for their selective FGFR programs. AstraZeneca will report data for AZD4547 in 2 trials (gastric cancer and solid tumors). The drug generated responses in 1/38 and 1/7 patients with FGF aberrations, respectively. Novartis (NVS) will report phase I data for BGJ398 in squamous NSCLC patients with FGFR1 amplification. The abstract reports encouraging preliminary signs of activity with 4 responses among 21 patients. J&J (JNJ) will present phase I data for JNJ-42756493, including a subset of FGF pathway aberrations. According to the abstract, of 8 biomarker positive patients, two urothelial cancer patients achieved a response.

Hutchison MediPharma will report data for its dual FGFR/VEGFR inhibitor, which should be viewed as a direct competitor to lucitanib. Of 17 patients who received an improved formulation of the drug, 4 achieved a response. It is not disclosed whether these patients had FGF aberrations so it is unclear whether their responses are mediated by FGFR inhibition.
http://www.orf-blog.com/drugs-to-watch-at-asco-2014/

每次老马发布新药，都有很长很长的下文！

陈海泉教授：我是上海复旦大学附属肿瘤医院的陈海泉，我今天给大家讲一讲FGFR融合基因的一些研究，大家都知道，FGFR融合基因是定位在细胞膜上的受体酪氨酸激酶，它可以通过激活这个PI3K-AKT-mTOR信号通路促进细胞的增值，目前已在研究的呢，有很多FGFR-TKI的药物，这个通过前期的大规模的测序，反复出现异常的FGFR融合基因。那么在2012年和13年，首先在人的胶质瘤细胞中发现和鉴定，有关的报道在science和JCI上进行了公开的报道，  而且他发现呢，FGFR融合基因3 与胶质瘤已知的基因突变是不共存的，那么在细胞实验上，就发现，用了这个FGFR-TKI的药物可以抑制细胞的增值，从而达到治疗肿瘤的目的，就是说，这个肿瘤细胞，它有FGFR融合基因，它的TKI药物，可以抑制这个细胞的增值，所以呢，目前发现FGFR融合基因的类型呢，大概有14种类型，在非小细胞肺癌里面，到底有多少，我们说，我们不清楚，所以我们的研究呢，主要是做了中国人群里面FGFR非小细胞肺癌的研究。

第一个呢，想说明几个问题，FGFR融合基因在非小细胞肺癌中它发生的频率是多少。第二，这些人群，他的分子病理学的特征是什么？为我们今后做临床试验里面，哪一部分人，从FGFR-TKI治疗中，是潜在的获益的人群，所以我们总共对我们1238例非小细胞肺癌经过RT-PCR直接测序，检测14种已知的融合基因的形式，我们总共发现了14种已知的FGFR  1-3的融合基因，在非小细胞肺癌里面总共发现了有17个非小细胞肺癌FGFR融合基因阳性的，那么在整个这个人群里面，占1.3%，其中鳞癌里面，我们发现了11个，占我们312个鳞癌人群的3.5%，1016例腺癌里面，我们只发现了6个，这里面占腺癌里面0.6%，那么我们发现这个FGFR  1-3的融合基因，与其它的已知的突变基因是不共存的。如果这个病人已经有EGFR、KRAS、HER2、ALK在这些样本里面没有发现FGFR 1或者3的融合基因。

这里面我们就发现这些病人具有独立的临床和病理特征，主要是这部分病人具有FGFR融合基因的主要是存在于男性病人，这10几个病人里面只有一个发现在女性病人，16个发生在男性里面，从统计学处理上它也是有明显的统计学差异。第二个，大部分FGFR 融合基因出现在重度吸烟的患者，17个里面有16是吸烟的，只有一个人是不吸烟的，在统计学上也有差异。另外在腺癌和鳞癌上，绝大部分存在于鳞癌，17个里面，11个存在于鳞癌，只有6个存在腺癌，非常有趣的是，这6个腺癌都是吸烟的病人，另外因为我们这批病人的样本都来自我们手术的病人，可切除的非小细胞肺癌人群里面，所以呢，我们发现呢，这部分具有FGFR融合基因的病人在开刀的时候呢，都是一个大块头，有15个肿块大小大于3公分，只有两个是小于3公分的，所以说它的临床病理学特征，1个是男性，吸烟，鳞癌，和大肿块。所以呢，肿瘤大小我们通过单因素分析，是FGFR融合基因的一个独立的预测因子，多见于肿瘤大于3公分的患者。

所以，我们总结下，FGFR融合基因是非小细胞肺癌中一类新的分子亚型，占非小细胞肺癌肺癌病人的1.3%。肺鳞癌的3.5%，那么在我们国家，非小细胞肺癌人群里面，融合基因主要为FGFR1 和 FGFR3，且主要存在于男性，吸烟和肿瘤较大的患者中，具有FGFR融合基因异常的患者可能受益于TKI的靶向治疗，这可能为今后的临床试验，开展比较大规模的临床试验打下一定的基础，那么这个呢，有待进一步的临床试验验证这些结论，谢谢大家。