本帖最后由 痛恨癌症 于 2011-6-9 10:25 编辑
outan 发表于 2011-6-8 23:25 static/image/common/back.gif
还有副作用如何
二期临床已经有6个人死亡了，这是某参加ASCO的医生前几天TWITTE刚发表的
回复 outan 的帖子
全身治疗的MET，VEGFR抑制剂当然是全身治疗的，怎么可能是单一对付骨转的。只是同时对骨转的效果不错而已
outan 发表于 2011-6-9 10:45 static/image/common/back.gif
啊???
是副作用导致的吗????
不清楚不过基本上临床都会有人死亡的
We’ve received several questions about agents that might be helpful for patients who have already responded to inhibitors of the epidermal growth factor receptor (EGFR) like Tarceva (erlotinib) and Iressa (gefitinib) and then demonstrate progression.These latter agents are reversible inhibitors of of the tyrosine kinase domain (signalling portion inside the cell) of the EGFR molecule, meaning that they attach to and periodically detach from the receptor.Other inhibitors, like the novel Pfizer agent PF299804, bind to EGFR irreversibly, never coming off of the receptor, and requiring the cell to make new EGFR molecules without an inhibitor on them.Such agents can kill many kinds of cancer cells in a lab-based model, and appear that they may do somore effectively than currently agents like Tarceva and Iressa, but how well they work in real patients has remained an open question.
Another unresolved issue is whether PF299804, an inhibitor of not only EGFR but of other members of the human epidermal growth factor receptor (HER) family, of which EGFR (also known as HER1) is just one type, are more effective in patients than agents that inhibit EGFR alone.Such agents that block multiple members of the HER family are sometimes referred to as “pan-HER” inhibitors (as in “across the HER family“), but they’re still in clinical studies to determine whether such agents provide incremental benefit beyond what we see with the EGFR-specific agents we already use.
Though results with the orally available irreversible pan-HER inhibitor PF299804 weren’t a lead story at ASCO 2010, I think several of these trials were quite encouraging, both for patients with an EGFR mutation who might seek something after they become resistant to an EGFR inhibitor that previously was very beneficial, and also for people who don’t have an EGFR mutation and hope to do better than they might expect to do with an agent like Tarceva or Iressa.
A pair of studies were done on patients with advanced NSCLC who had previously been pretty treated with both chemotherapy and an EGFR inhibitor.First, one done in Asia by Park and colleagues enrolled 12 patients in an initial phase I portion, followed by an additional 42 patients in the subsequent phase II study after a dose of 45 mg by mouth daily had been identified as the appropriate target dose. The analysis focused on the patients in the phase II portion at the 45 mg daily dose, of whom 40 had response data available.
Overall, these results were quite encouraging, with 48% of patients still without progression 4 months after starting treatment, 15% showing a partial response (PR), and another 52.5% demonstrating stable disease (SD) as their best response.The duration of treatment is shown in the figure below, with the length of the horizontal line extending to the right proportional to the duration of time on the drug and without progression:
http://cancergrace.net/lung/files/2010/08/park-pf299-duration-of-therapy-300x168.jpg
(click on image to enlarge)
The waterfall plot below shows the distribution of tumor shrinkage (proportional to the length of the lines going down from the horizontal line, clustered to the right), progression (upward lines clustered to the left), and stable disease (short lines not going much down or up):
http://cancergrace.net/lung/files/2010/08/park-pf299-waterfall-plot-300x168.jpg
Of course, the other important factor is tolerability, which was pretty good.The leading side effects were diarrhea, rash, and mouth sores, all typically in the mild to moderate range.
A very similar trial of American patients was reported by Campbell and colleagues.This study enrolled 66 patients with advanced NSCLC, previously treated with both chemotherapy and erlotinib, and over 80% had tumor tissue available for molecular marker studies. They divided their population into the 50 with an adenocarcinoma, of whom more than half were never-smokers and the majority had an EGFR mutation, and the other 16 with a non-adenocarcinoma, who were much less likely to be never-smokers or have an EGFR mutation.
They saw a wide range in duration of treatment, with 13 patients (23%) demonstrating prolonged clinical benefit (either a complete response (CR), PR, or SD lasting at least 24 weeks). Not all of these patients had an EGFR mutation (7 did, 4 were EGFR wild type (no mutation), and 2 were unknown).Overall, though, progression-free survival was longer in patients who had an EGFR mutation:
http://cancergrace.net/lung/files/2010/08/campbell-pf299-pfs-curves-egfr-mut-vs-egfr-wt-300x220.jpg
The side effect profile was remarkably similar to the Asian experience, though the investigators noted that the side effects seemed to gradually decrease with ongoing treatment.
Overall, then, these studies both demonstrate that an encouraging fraction of pretty extensively treated patients with advanced NSCLC show tumor shrinkage or at least prolonged stable disease with this oral agent, and that the results, while perhaps most encouraging in patients with an EGFR mutation or the demographic features where it is prevalent, convincingly reveal activity in patients who don’t have an EGFR mutation.
How does PF-299 stack up against erlotinib in patients who haven’t received an EGFR inhibitor previously?I’ll cover that next.
这个药也是非常值得关注的，因为他对EGFR突变和野生型都有一定的效果，但是对于有EGFR的无进展生存期更长
PF299804（EGFR和HER抑制剂）：2期临床每天剂量45mg。 48%的患者无进展生存期达到4个月，15%取得部分缓解，52.5%取得SD
本帖最后由 痛恨癌症 于 2011-6-10 09:58 编辑
前面已经说了，MET抑制剂联合特罗凯能将单用特的生存期延长9个月（前提需要是MET扩增/阳性）。除了我非常关注的ARQ197，再来个MET抑制剂吧，今年ASCO也公布最新结果了
MET inhibition becomes more crowded
One of the most intriguing data sets will be for Roche’s Metmab, an antibody targeting the MET receptor. This phase II evaluated the antibody in combination with Tarceva in lung cancer patients.
According to the already published results, when combined with Tarceva, Metmab led to a dramatic effect in patients who overexpressed MET on their tumors. The drug appeared deleterious in MET negative patients. Although the number of patients is relatively small, the overall survival benefit was astounding (12.6 vs. 4.6 months). This trial will surely lead to a phase III study in MET positive lung cancer in the coming future.
Given the spectacular results, Metmab has become a real threat to Arqule’s ARQ197, a small molecule MET inhibitor that also generated a positive signal in combination with Tarceva in lung cancer. It is very hard to compare the two drugs due to patient selection and stratification issues (discussed here). Arqule is currently evaluating patients in its phase II trial retrospectively using the same criteria used for Metmab, so it would be very interesting to see whether a similar trend is observed.
Amgen (AMGN) will present results for another combination using a MET inhibitor and an EGFR inhibitor. In contrast to Roche, Amgen’s agent is an antibody against HGF, a soluble protein that binds and activates MET. AMG102 was given in combination with Vectibix to colon cancer patients and appeared more active than Vectibix alone based tumor shrinkage and PFS, even though the numbers were small and the difference was limited in the overall population. Amgen will present biomarker data and potentially survival data.
Metmab：在MET扩增人群中取得了惊人的效果， 但在MET阴性人群中可能是有害的（和随机服用易一样），生存期十分惊人（12.6个月对于4.6个月）
我可以要求给简单翻译成中文么？英文不好，大段英文看起来实在费力。
这个论坛的引擎非常不好用
:L我也觉得是，回头升级看看能否好用点，无法搜索，烦。