什么是ALK？

lulu0280

昨天去了广东省人民医院吴一龙院长说到有ALK试验组，有哪位知道ALK是什么？针剂或口服？

jimmy112199

http://cancergrace.org/lung/2010/06/09/alk-talk/

All the Talk About ALK, and Crizotinib (PF-02341066)

Probably the leading story in lung cancer at ASCO this year was about ALK inhibitor therapy and the Pfizer drug crizotinib (PF-02341066).  Though we’ve covered it before, last year the promising story remained under the radar for a while after having the initial work presented in a session on developmental therapeutics.  This year was the official coming out party for crizotinib, with the phase II study previously described in prior work re-presented with additional patients, but now in the most visible forum in the oncology world.

In fact, you could certainly hear some grumbling about whether this work merited being part of the ASCO Plenary Session, being a phase II study that is applicable to only a small minority of patients with an ALK rearrangement (about 4-5% of NSCLC overall, though disproportionately never-smokers and those with an adenocarcinoma, and especially younger patients) and a story that had already been broken.  However, this information was largely known primarily to the lung cancer community and well-informed members of the patient/caregiver communities (especially GRACE participants).  It hasn’t really penetrated throughout the oncology community.

So what did we learn this year?  The Plenary Session presentation by Dr. Bang and colleagues began with a scientific review of the biology, largely covered in the very excellent GRACE webinar presentation by Dr. Ross Camidge.  It also reviewed clinical data by Dr. Alice Shaw from Massachusetts General Hospital (MGH), which highlighted that patients with ALK rearrangements do not appear to do particularly well with standard chemo or EGFR inhibitors like Tarceva (erlotinib) or Iressa (gefitinib), in contrast with patients with EGFR activating mutations, who we know tend to have very high response rates and prolonged progression-free and overall survival to EGFR inhibitors (and also chemotherapy in some studies).

shaw-clinical-data-on-alk-pos-pts (click on image to enlarge)

The current data set of patients with an identified ALK mutation who received crizotinib includes results for 82 patients being followed through April of this year, a group of patients for whom several distinct features are notable.  First, their median age is 51, nearly 20 years younger than the median age for a patient with a new diagnosis of NSCLC in the US today; the oldest patient with an ALK rearrangement is 78.  They are predominantly (76%) never-smokers, and most of the remaining patients have a very limited prior smoking history of 10 pack-years (the product of average number of packs smoked per day x number of years smoking).  While the vast majority (96%) have an adenocarcinoma, a single patient with a squamous cancer had an ALK rearrangement detected, and a couple were categorized as “other” (presumably so poorly differentiated a histology couldn’t be defined, or not enough tissue available).   Importantly, the majority had received at least two prior lines of therapy, with 41% actually receiving three or more prior regimens.

With more patients and longer follow-up, the initial promise of crizotinib has held up, with a “waterfall plot” (in which bars extending down from the horizontal line represent tumor shrinkage) showing that nearly every patient demonstrated benefit as measured by some degree of tumor shrinkage:

bang-asco-2010-waterfall-plot-of-responses

These aren’t the kind of results we expect to see in NSCLC, especially for heavily pre-treated patients.  The current rate of significant tumor shrinkage is 63% (including uncomfirmed responses), with 87% of patients demonstrating stable disease or better eight weeks into treatment.  In addition, responses or non-progression was generally prolonged, with 72% of patients on this study showing no progression at six months, and median progression-free survival still not reached.

Importantly, there appear to be no new safety issues for this oral therapy, with mild nausea, vomiting, diarrhea, and mild visual symptoms being among the more commonly reported symptoms, along with a minority of patients experiencing moderate elevations in their liver function tests.

As was discussed in the podcast by Dr. Camidge, this agent is not currently available outside of clinical trials, of which there are two ongoing large efforts:

crizotinib-clinical-trials (details about trials here and here)

Another important issue is that there have been rare cases (though I’ve seen two in the last two months) in which patients have had ALK inhibitor testing come out positive at lab that isn’t the official central lab (University of Colorado, MGH, and University of Chicago are doing it, along with the official central lab that is a joint venture between Pfizer and Abbott), then have had testing at the official central lab that was reported as negative, rendering them ineligible for these trials.  All of the researchers involved are working to determine the cause(s) for these rare discrepancies.  In the meantime, Pfizer is changing the eligibility for the single arm trial to permit patients who test positive at one of their broader range of approved labs, so that they would be defined as ALK rearrangement positive but ineligible for the randomized phase III trial.

Another interesting result was presented by Dr. Lecia Sequist, also at MGH, who went back and tested a limited number of tissue samples from her study of the heat shock protein inhibitor IPI-504 that showed very limited activity.  Three of the 14 samples tested had an ALK rearrangement, and two of those three had responded to IPI-504, with the third also demonstrating tumor shrinkage.  Though we obviously can’t draw any firm conclusions from results in three patients, it is a lead suggesting that once we have identified distinct subgroups, we may be able to demonstrate that they show sensitivity to other agents, whether standard chemotherapy are targeted biologics, that can continue to define new treatment options for limited populations.

Though this is still a small population, the evidence is very convincing that ALK inhibitors can have a major impact for these patients, with the potential that we may also identify agents that can offer additional benefit to patients with an ALK rearrangement.
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lulu0280

总体是倾向有效还是没什么效果呢？

200204121

ALK抑制剂：可能是肺癌的新治疗   

二零一零年一月十五日（科罗拉多） - 标靶治疗，包括单株抗体与小分子抑制剂，改变了癌症的治疗，现在，很快会新增一种治疗方式 - ALK抑制剂。

最近在非小细胞肺癌（NSCLC）中的研究中，提及间变性淋巴瘤激酶（ALK）的基因的致癌性重组。而发表于“美国癌症研究协会与国际肺癌研究协会之肺癌分子起源联合研讨会：个人化预防与治疗的前景“中的一篇第1期研究提出正面的结果指出，ALK代表非小细胞肺癌的分子治疗新目标。

PF02341066，辉瑞药厂研发的一个口服ALK抑制剂，在ALK阳性病患显示有效，迄今为止，有31个具有游动基因重组的非小细胞肺癌病患被纳入研究，观察到的反应率为65％。

科罗拉多大学癌症研究詹姆斯达德利讲座医学教授保罗邦恩小医师表示，现在至少有12种可以容易辨识的致癌基因，可能有新的治疗制剂可以对抗它们，ALK是一种致癌基因，而且，对肺癌而言，它不是因为突变造成，而是与另一个基因融合。

这个染色体重组会打断ALK基因且将它与另一个基因融合，导致造成致癌性的ALK融合基因，然后，这些基因会促进细胞增生与存活。

未参与该研究的邦恩医师表示，就我的观点，根据这些资料，这个药物应可被准许在全球使用，但是美国食品药物管理局认为，资料还不够而无法核准，所以现在正在美国开始一个随机试验，在该试验中，将随机让病患接受此研发中的药物或标准化疗。

邦恩医师也指出，虽然PF02341066显示可以比标准化疗诱导更多反应，但是它不具治愈性，他推测，想必病患很快就会发生抗药性。

【正确的药物用于适合的病患】
根据研究作者表示，ALK是一个“受体型酪胺酸激酶”，在发育中神经系统的分离区域正常表现，在10多年前，异生性大细胞淋巴瘤上首次描述染色体2的短臂上的致癌性ALK重组，之后，在其他恶性肿瘤也有发现，包括弥漫性大乙细胞淋巴瘤以及恶性组织球增多症，还有多种实质肿瘤也有，包括发炎性肌纤维母细胞瘤，食道鳞状上皮细胞癌，神经母细胞瘤以及最近提出的非小细胞肺癌。

第一作者，科罗拉多大学胸腔肿瘤计画临床主任D.罗斯Camidge博士解释，非小细胞肺癌上的ALK重组相对较罕见，在不特定的非小细胞肺癌病患中，ALK基因重组的发生频率约为3％至5％。

Camidge博士解释，除了聚焦在特定的分子标靶，本研究代表药物从实验室转到人类试验的计画转变。

他向Medscape肿瘤学表示，当正确的标靶制剂被适当地用于有该标靶的适当病患时，可以在首次用于人类的第1期试验中即有效地检测分子效果假设，这样聚焦在可以从药物获得最大利益的病患，将可以大幅地缩短药物获得核准的时间。

ALK基因重组几乎都发生在腺瘤，各种族之间似乎没有变异，Camidge博士表示，但是几乎没有在鳞状细胞癌或其他类型肺癌发现过，此外，抽烟量少的戒烟者或未曾抽烟者，发生ALK基因重组的频率显著较高。

【早期结果显示有效】
Camidge医师等人在2006年开始第1期试验，该试验原本聚焦在有cMET活化标记（人类癌症中最常见的基因改变型酪胺酸激酶）的肿瘤，不过，在剂量调升期时，发现在非小细胞肺癌也有ALK基因重组，当时，将证实有ALK基因重组肿瘤的肺癌病患开始被纳入研究。

Camidge博士解释，迄今为止，31名有ALK基因重组，可评估的治疗前非小细胞肺癌病患被纳入研究，在这个世代中，1人有完整反应19人有部份反应;病患维持治疗的中位数为24周。

他表示，还没有到达无恶化存活的程度。

根据PF02341066的效果，证实了在这类特定的非小细胞肺癌病患中，致癌性ALK重组的确是可治疗的标靶，这使得PF02341066可以进行随机的第3期试验，而不需要另一个第2期研究。

邦恩医师表示，有其他药厂也在研究ALK抑制剂，但是进度远远落后于此研究，这个特殊的药物抑制了ALK以及气象，这也是首次发展出的药物。

【多数腺瘤的基因检测】
邦恩医师指出，这个研究显示的是，只要有正确的环境设定，研究可以更迅速，肺癌的融合基因在2007年被首次报告，2009年时，对于病患的帮助就被提出，有时候，癌症研究被批评为进展过于缓慢，但是，这是一个可以在两年后就让实验室中的发现对病患产生帮助的例证。

田纳西州范德比尔特，英格拉姆癌症研究中心肺癌精进研究专案计画主任，哈罗德湖摩西讲座大卫卡沃医师强调，基因检测的重要性与日俱增，就更广的方面看来，藉由对这些抑制剂的了解，我们认为，多数肺腺癌病患应进行例行性基因检测的重要性日益清晰。

未参与该研究的卡沃内医师表示，这是相当重要的观点，这些病患都无法用临床参数确认，而是需藉由检视某种突变来辨识病患，这类药物在将来也会越来越多。

美国癌症研究协会与国际肺癌研究协会（2003年AACR -肺癌研究协会）之肺癌分子起源联合研讨会：个人化预防与治疗的前景：摘要答24。发表于2010年1月13日。
发布时间：2010年01月27日

神的拣选

其实是EML4-ALK联合基因,有4%的人有这个突变.基因突变EGFR成阳性的这个联合基因就会呈阴性,也就是能吃特罗凯的人就说明联合基因是阴性.目前美国辉瑞公司在做临床试验,应该很快FDA就会批准上市,在中国如果能入组课题试验组,那真是太幸运了,因为它的有效率高达70%.(在4%有突变人当中).

lulu0280

是指吃特罗凯无效的人ALK才有可能有用吗？

[ 本帖最后由 lulu0280 于 2011-3-23 20:22 编辑 ]

lulu0280

我妈妈已经在广东省人民医院做了ALK的基因检测！

zise408

不知道楼主妈妈的入组效果怎么样啊，希望能跟大家分享心得。