晚期NSCLC靶向和化疗方案选择的几个问题

http://www.eurekalert.org/pub_releases/2014-05/uocd-rwc053014.php
A study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2014 reports the results of a first-in-human, phase 1 dose escalation trial of crizotinib (XALKORI) in 14 patients with advanced, MET-amplified non-small cell lung cancer (NCT00585195).

In 2011, the drug crizotinib earned accelerated approval by the US FDA to target the subset of advanced non-small cell lung cancers caused by rearrangements of the anaplastic lymphoma kinase (ALK) gene, and subsequently was granted regular approval in 2013. The drug also has shown dramatic responses in patients whose lung cancers harbored a different molecular abnormality, namely ROS1 gene rearrangements. Previously unreported phase 1 clinical trial results now show that crizotinib may have a third important molecular target. In advanced non-small cell lung cancer patients with intermediate and high amplifications of the MET gene, crizotinib produced either disease stabilization or tumor response. Sixty-seven percent of patients with high MET amplification showed prolonged response to the drug, which lasted from approximately 6 months to nearly 2.5 years.

"Though more patients are needed to really pin down the exact MET criteria that will predict benefit from MET inhibition, we're hopeful this line of research will define yet another key molecular subtype of lung cancer sensitive to a targeted drug," says Ross Camidge, MD, PhD, director of the thoracic oncology clinical program at the University of Colorado Cancer Center and the study's lead author.

Crizotinib showed early activity against MET-dependent cells in preclinical laboratory studies, and the phase I clinical trial design included plans for treatment of cancer patients preselected for evidence of MET activation once the recommended dose was determined.

Matching the drug to MET amplifications required testing for this genetic abnormality in patient tumors, something that hasn't been part of standard lung cancer screening in most clinical centers. Working at the CU Cancer Center, Marileila Garcia, PhD, was able to rapidly deploy an assay for MET for the trial based on fluorescent in situ hybridization (FISH).

Garcia's previous work, also shown for the first time in this presentation, gives insight into the frequency of MET amplification in lung cancer. Consistent with other reports, Garcia found some degree of MET amplification present in 7.4 percent of 800 consecutive samples of non-small cell lung cancer tested at the Colorado Molecular Correlates Lab from 2009 to 2012. However, the level of MET amplification in these samples was not uniform. Low MET amplification (MET/CEP7 ratio of ≥1.8-≤2.2) was present in 3.8 percent, intermediate amplification (MET/CEP7 ratio of >2.2-<5.0) was present in 3 percent, and high amplification (MET/CEP7 ratio of >2.2-<5.0) was present in 0.8 percent.

In the phase 1 clinical trial, while disease in the 2 patients with low MET amplification did not appear to benefit from the drug, 1 of 6 patients with intermediate MET amplification achieved a partial response with 4 of the 6 having more minor responses (stable disease), and in the high MET amplified group 1 of 6 achieved a complete response, 3 of 6 achieved a partial response and 1 of the 6 had a minor response (stable disease). Overall objective response rates in the low, intermediate and high MET amplified cohorts were 0, 17 and 67%, respectively.

"We've been through a similar experience with ALK-positive lung cancers - patients whose cancers depend on a specific molecular abnormality can see significant benefit when we remove the cancer's access to the driving abnormality," Camidge says. "However, unlike classical activating mutations or gene rearrangements, MET is likely to be a more challenging biomarker because it is not simply black or white - not simply off or on - but rather it is a continuous variable. Although the dataset is still pretty small, there is a strong suggestion that a definable cut-point in MET amplification exists which could really delineate who will or will not benefit from this drug. Screening for MET amplification and treating these patients in clinical trials is the only way we will be able to discover this important threshold."

The implications of crizotinib used to target MET amplifications may go beyond non-small cell lung cancer. The gene is activated in many different ways in many different cancers, and patients with MET-amplified cancers continue to enroll in the crizotinib phase I study.

"With these targeted therapies, it can look at first like a drug may only be useful to a small percentage of patients with the targeted genetic abnormality. But then you start to see the same abnormality across cancer types and the drug that looked like it might have been useful in, say, 3 percent of lung cancer patients, turns out to have a use in x-percent of all these other cancer types as well. It's a new paradigm: we're working to pick off these molecular aberrations one by one," Camidge says.

学习了，谢谢

总结很全面，专业性强，学习中，慢慢来

Ohad Hammer提出一个设想，说azd9291一线治疗的效率不如易，可能是它对egfr靶点不如想象中那么强。覆盖面没有易，特那么广。他建议可以试试9291或者1686联合易，特或者2992。
把9291或1686当成单纯的T790药联合治疗。看动物实验数据，吃9291 20天就能搞定T790，之后就是稳定了。

老马 发表于 2015-1-3 15:26
Ohad Hammer提出一个设想，说azd9291一线治疗的效率不如易，可能是它对egfr靶点不如想象中那么强。覆盖面没 ...

感谢老马分享，请教:是否可以小剂量9291联标准量易或特？

海宁燕子 发表于 2015-1-3 15:35
感谢老马分享，请教:是否可以小剂量9291联标准量易或特？

谢谢老马！这样底气更足了{:soso_e100:}

我爸爸今年刚61岁，8月底因腰背疼痛（吃止痛药不见好）一直到9月30号江苏泰州人民医院核磁怀移骨转移瘤。

      10月6号在天津肿瘤医院入院治疗，10月10日PET-CT检查左肺周围2.5*1.8cm肿瘤，伴多发骨转移颈椎，腰椎，骶骨都有骨质破坏。10月11日打上唑来膦酸（后每月一次），因腰锥T2痛痛压迫神经线于10月18日行腰椎固定骨水泥填充并取病理术，后病理结果肺腺癌怀疑来源于肺，支气管镜取不到病理。     

      11月3日开使用培美+卡铂进行化疗2期后，CEA有点上升，CT显示左肺周围2.8*1.8cm肿瘤，变化不大！12月29日继续化疗培美+卡铂，医生说我爸预后非常不好，能活一年就是奇迹!
      
      2015年1月6号，CEA又上升了，是不是可以说培美+卡铂无效？基因检测6号也出来了，野生型！希望有人能给些建议，现颈椎这里很不舒服，要不要先放疗？医生说要对肺部这里肿瘤做什么射波刀，我也不懂，有没有好的办法能控制肿瘤的发展！
     
      
       谢谢！

收藏一下老马的强帖

感谢老马和翻译的劳动，学习

谢谢老马，一下子还不是很懂，收藏了，以后慢慢学习，不懂还望多指导。