AUY922、AP26113、LDK378、CH5424802外加克唑替尼

Data presented at the Developmental Therapeutics session (29 September 2012)also provided an insight into future cancer treatments for non-small-cell lungcancer (NSCLC). Professor Enriqueta Felip from the Valld'Hebron UniversityHospital, Barcelona, Spain,presented data from a Phase 2 trial indicating activity for the HSP90inhibitor, AUY922, in patients with ALK-rearranged (ALK-positive) orEGFR-mutated advanced NSCLC. HSP90 is a chaperone of client proteins relevantin NSCLC pathogenesis, including both ALK and EGFR. ALK positivity occurs in 57% of patients with NSCLC, and EGFR mutation occurs in around 10–17% of cases.In this study, 121 patients with previously treated NSCLC received AUY922 (70mg/m2) as a once-weekly, 1-hour infusion and were stratified by molecularstatus – ALK-positive, EGFR-mutant, KRAS-mutant or EGFR/KRAS/ALK wild-type.AUY922 was associated with an acceptable safety profile and clinical activitywas demonstrated in both ALK-positive and EGFR-mutant patients, with partialresponses in 7/22 (32%) patients and 7/35 (20%) patients, respectively. Ofparticular note, Professor Felip highlighted that in EGFR-mutated patients whohad progressed just after receiving EGFR tyrosine kinase inhibitor (TKI)therapy, the median PFS rate at 18 weeks was 45% versus 21% in patients who hadnot received a TKI as their immediate pre-AUY922 therapy. “These data supportthe further development of AUY922 in NSCLC,” Professor Felip commented,“Expansion of the EGFR-mutated stratum is ongoing and further studies areplanned to confirm these efficacy signals” she added.
在DevelopmentalTherapeutics会议（2012.9.29）上提出的数据也对非小细胞型肺癌（NSCLC）将来的癌症治疗提出了深刻见解。来自瓦尔德希布伦大学医学院的Enriqueta Felip教授提出来自2期试验的数据显示HSP90抑制剂--AUY922的活动性，其分布在ALK阳性或者EGFR突变的晚期NSCLC病患上。HSP90是一种与NSCLC发病机制相关的服务蛋白的伴侣分子，包括ALK和EGFR。ALK阳性在57%的NSCLC病患上显现，EGFR变异则在大约10-17%的案例上显现。在这项研究中，121个之前有过NSCLC治疗的病人接受了一周一次的一小时输液的AUY922(70 mg/m2)，同时按ALK-阳性，EGFR变异型，KRAS变异型或是EGFR/KRAS/ALK野生型的分子状态进行分层。AUY922与一种可接受的安全性方法有关，同时在ALK阳性和EGFR变异型的病人上都显示了临床活动性，分别有7/22(32%)病人和7/35 (20%)病人部分缓解。需要特别注意的是，Felip教授强调EGFR变异型病人刚接受EGFR受体酪氨酸激酶抑制剂疗法后有了改善，其PFS比率的中位数在18周是45%，相比而言，在没有接受TKI作为他们即刻的前AUY922疗法的病患，该中位数是21%。“这些数据支持了在NSCLC上AUY922有更大的发展，”Felip教授评价道，“针对EGFR变异型层面的扩展还在前进着，同时也计划了更多的研究来确认这些有效的信号。”她补充说。

Following this, Dr Scott Gettinger from Yale University School of Medicine, New Haven, USA,presented initial data from a first-in-human dose-finding study of the ALK/EGFRinhibitor, AP26113, in patients with advanced malignancies. AP26113 is a novel,synthetic, orally-active TKI that is thought to inhibit mutant activated formsof ALK-positive and EGFR, as well as TKI-resistant forms including L1196M (ALK)and T790M (EGFR). However, AP26113 does not inhibit native EGFR. Thisdose-finding study is ongoing with 34 patients currently enrolled, 29 of whomhave NSCLC. The most common adverse events were nausea, fatigue and diarrhea,although these were mostly Grade 1/2. Preliminary efficacy data indicateactivity with the 60 mg dose in ALK-positive patients both na?ve and resistantto crizotinib and responses to the 120 mg dose in EGFR-mut patients. DrGettinger highlighted that the Phase 2 expansion study will include 4 cohortsof patients: those with ALK-positive NSCLC who are na?ve or resistant to priorALK-targeted therapy, patients with EGFR-mutant NSCLC who are resistant toEGFR-targeted therapy and patients with other cancers with abnormalities in ALKor other AP26113 targets.
随之，来自美国纽黑文耶鲁大学医学院的Scott Gettinger博士，提出了首次在人类上的进行ALK/EGFR抑制剂- AP26113的剂量调查研究，这是在晚期恶性肿瘤病患身上进行得。AP26113是一种新型，合成，口服活性的TKI，被认为抑制ALK阳性和EGFR的变异型活动性的形式，也有TKI抵抗型形式，其包括L1196M(ALK) 和T790M(EGFR)。不过，AP26113不抑制固定型EGFR。这项剂量调查性研究在目前34名登记的病人上前进着，他们中有29个有NSCLC。尽管这些主要是1/2级的，但其最常见的不良反应是恶心，疲劳和腹泻。最初疗效的数据显示了接受60 mg 剂量的ALK阳性病人包括对克唑替尼固定型和抵抗型上的活动情况，还有接受120 mg 剂量的EGFR变异型病人上的缓解情况。Gettinger博士强调2期进展研究将包括4个病人群体：ALK阳性的NSCLC病人，他们对前ALK靶向治疗疗法呈现固定或抵抗；EGFR变异型的NSCLC病人，他们抵抗EGFR靶向疗法；ALK或是其他AP26113靶子异常性的其他癌症病人。

The next presentation was given by Dr Alice Shaw, from theHarvard Medical School, Boston, USA, who presented a first-in-human Phase 1study of LDK378, a novel, potent small molecule ALK inhibitor that hasdemonstrated tumor regressions in ALK-positive NSCLC xenograft models. Theprimary objective of the study was to determine the maximum tolerated dose(MTD) and safety profile in adult patients with advanced malignancies harboringa genetic alteration in ALK who have either progressed on ALK inhibitor therapyor who were previously untreated. Dr Shaw explained that “daily oral LDK378appears to be well tolerated and the MTD was 750 mg/day”. She also highlightedthat “a high level of activity was seen in patients who had progressedfollowing crizotinib therapy at doses of 400 mg or greater”.
下一个报告由来自美国波士顿哈佛医学院的Alice Shaw博士提交，他呈现了第一次在人类上进行得LDK378上的1期研究，这是一种新型，强烈的小分子ALK抑制剂，其显示了在ALK阳性的NSCLC异种移植模型上肿瘤的退化。这项研究的主要目的是确定在成人患者上的最大耐受剂量（MTD）和安全性范围，病人有在ALK存在隐匿型基因的晚期恶性肿瘤，他们要么在ALK抑制剂疗效上有改善，要么之前没有治疗过。Shaw博士解释到“每日口服LDK378出现了很好的耐受，其MTD为每天750 mg。”她也强调“在克唑替尼疗法之后有改善的病人身上可见在400mg或更大剂量上的高水平活动性。

Following this, Dr Makoto Nishio from the Thoracic OncologyCenter, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan,presented data to support the potential of CH5424802 as a new therapeuticopportunity for patients with ALK-positive NSCLC. Dr Nishio explained that thePhase 1 part of this Phase 1/2 trial had shown that CH5424802, an oral ALKinhibitor, was also well tolerated and had demonstrated promising efficacy inpreviously treated patients with ALK-positive NSCLC. In the Phase 2 portion ofthe trial, 46 patients with ALK-positive NSCLC, advanced or metastatic diseaseand no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg biduntil progressive disease or intolerable toxicity. Overall, 3 peopleexperienced a complete response and a further 36 experienced a partialresponse. Moreover, 40 patients are still receiving study treatment. Dr Nishioadvised that treatment with CH5424802 was well tolerated and treatment-relatedadverse events leading to discontinuation were observed in only 3 patients.“CH5424802 is a new potent ALK inhibitor for NSCLC”, Dr Nishio concluded.
接着来自日本东京Cancer Institute Hospital of JapaneseFoundation for Cancer Research（研究所）胸部肿瘤中心的Makoto Nishio博士，显示了数据来支持CH5424802作为给ALK阳性的NSCLC病人一种新的治疗机会的可能性。Nishio博士解释2期试验的部分-1期试验中显示了CH5424802，一种口服ALK抑制剂，它能很好被耐受，同时也显示了在对有ALK阳性的NSCLC之前经过治疗的病患上有很好的疗效。在2期试验的部分中，46个有ALK阳性的NSCLC的、且有晚期或转移性疾病的同时没有之前ALK抑制剂疗法的病患，他们一日两次接受300 mg的CH5424802，除非疾病有恶化或者有不能姑息的毒性产生才停止。总体而言，3人完全缓解，另外36人部分缓解。此外，40名病患还在接受研究治疗。Nishio博士提示使用CH5424802的治疗达到良好耐受，同时因与治疗相关的不良反应而导致中止的情况只在3名病患上出现。“CH5424802是一种对于NSCLC新的、强效的ALK抑制剂。”Nishio博士总结。

Last year, the US Food and Drug Administration (FDA) approved the ALK tyrosinekinase inhibitor, crizotinib, for the treatment of patients with advanced NSCLCwith translocations of the ALK gene as determined by an FDA-approved companiongenetic test. This was the first new FDA-approved drug for advanced NSCLC for anumber of years, and there was much enthusiasm about the approval amongpatients and practitioners. Following on from this targeted therapy, we areentering an exciting time as it seems that we have only scratched the surfaceof personalized therapy. However, as we move ever forward towardsmolecularly-defined therapies, it will be critical to work out the interplay ofmolecular testing (who to test, which test to use, and when to test),particularly for those agents that are effective but only in small, specificgroups of patients.
去年，美国FDA批准了ALK酪氨酸激酶抑制剂--克唑替尼，这是为了在ALK上有基因移位的晚期NSCLC病人的治疗，这是由FDA批准的伴随着的基因试验所决定的。这是FDA批准的第一个新的可若干年持续对晚期NSCLC使用的药物，同时在病人和从业者（医师）间对这次批准有很大的热情。随着这次靶向疗法的进展，我们正在进入一个令人兴奋的时期，虽然看起来我们只揭开了个体化治疗的表面。然而，当我们一直向分子化疗法前进时，发现分子间相互作用的试验将是极其重要的（谁来试验，试验哪个，还有何时试验），特别是对于那些有积极的但只在小型，特殊病人群体上试验的机构。

基本都是ALK的么

学习了，感谢楼主提供的资讯。