晚期NSCLC靶向和化疗方案选择的几个问题

像我父亲，没有做基因检测，按照这个帖子应该还是首先选择一线化疗，然后二线TKI？http://www.yuaigongwu.com/forum. ... 8&fromuid=29490
父亲伽玛刀治疗快结束了！看到你关于空窗期的风险，压力山大啊！

ASCO: Treating Lung Cancer After Targeted Therapy–Resistance
By Howard West, MD1 | 2013年6月11日
1Medical Oncologist, Swedish Cancer Institute, Seattle
Interviewed by Anna Azvolinsky, PhD

Cancer Network: Dr. West, non–small-cell lung cancer is becoming increasingly defined by molecular subtypes. Could you go over what the established subtypes are and the available agents that target these?
Dr. West: Well, we are increasingly doing molecular testing on the vast majority of patients with non–small-cell lung cancer. When we talk about molecular testing, we are really focusing this point on patients with non–small-cell lung cancer subtypes, so the approximately 87% or 88% of lung cancer that is non–small-cell. Then, within that group, adenocarcinoma comprises about 60% or so of the patients in the United States, and most of our patients who have an actionable target have an adenocarcinoma, but there are some patients who have the squamous subtype, which is about 20% to 25% of non–small-cell, and they are less commonly found to have an actionable mutation and are a subgroup of patients that we don’t routinely send for molecular testing. There is another small group of patients who don’t fit into the adeno or squamous non–small-cell, and they have a variable probability of having mutations so we still test them. Specifically, the mutations we are looking for are EGFR, or the epidermal growth factor receptor, which is seen in about 10% to 15% of patients in North America and more like 25% to 30% of those in Asia—also ALK rearrangements, which occur in about 4% of patients with non–small-cell and predominantly those with adenocarcinoma. Both of these mutations are more commonly seen in patients with no smoking or minimal smoking history. Finally, there is a mutation called the ROS1 rearrangement that is less common, only about 1% of patients, and these patients seem to respond to the ALK inhibitor drug crizotinib that was approved for patients with the more common ALK rearrangement. So, this testing for ROS1 is not as prevalent yet, not as widely available but is increasingly being tested for, at least by many lung cancer specialists who have found patients who can benefit greatly from these treatments. Because when you do have a driver mutation and the right target, we see a probability of response and depth of response that we just don’t see with chemotherapy.

Cancer Network: So, what is the best time for patients to receive the targeted therapies you mentioned, the EGFR inhibitors and the ALK inhibitors?

Dr. West: In general, there is a consensus that we should be giving these therapies as early as possible, as soon as you know a patient has a mutation that could have a high association with a good response. The treatments that we are talking about in the United States, erlotinib for patients with EGFR mutations or crizotinib for patients with an ALK rearrangement, are oral therapies that are typically better tolerated than chemotherapy, or at least generally very well tolerated. They certainly lend themselves to longitudinal administration because they tend to not have many cumulative side effects. They give a high probability of response in the range of 60% to 75% and a degree of response that we just don’t see with standard chemotherapy. We do tend to favor these being the first therapy that you give if you find that a patient has one of these driver mutations before you start them on systemic therapy. We don’t have complete proof that it is better in terms of overall survival to give these therapies first rather than a maintenance therapy or second-line or later. I think many patients will do just as well if they end up getting these very effective drugs as second-line or later therapy. But, unfortunately, some patients do have unforeseen and catastrophic complications—perhaps leptomeningeal disease, which is involvement of the brain with the cancer that can lead to a rapid decline. Patients can miss that opportunity for treatment that can produce rapid and long-lasting responses, and that is exactly what we want to avoid. So, in general, just about everybody is inclined to give the drugs early on.

Cancer Network: How long do patients generally respond to EGFR inhibitors or crizotinib, and is there a way to predict response length?

Dr. West: There is not a good way to predict this in both EGFR mutation patients and those with an ALK rearrangement. The median duration of response before patients progress is in the range of 8 to 12 months, varying from one patient to another. Typically within a year, but there are a minority of patients who continue to do well for several years at a time, even a few beyond 3 or 4 years. There is a little bit of evidence that is not as consistently reported that patients with a particular mutation in EGFR, called exon 19, have the greatest probability of prolonged response compared with those with another activating mutation on exon 21. But, that is about the only predictive marker we have and even that is not that consistent, so we really can’t say whether someone is likely to respond for a few months or several years to these agents. That said, the degree of response that we see in a patient tends to be correlated with how well they do, so the patients who immediately feel better and whose imaging shows a dramatic response are also often the patients who have the longest responses.

Cancer Network: Most patients’ tumors eventually acquire resistance to the targeted therapies you mentioned. How is resistance typically detected and defined, and what are the issues with defining resistance in the clinic?

Dr. West: Resistance is typically detected by routine imaging. When we are following someone with lung cancer and we do chest CT scans or sometimes PET-CT every few months, we will generally see a new lesion in the liver, the lungs, or the bone, or a growing lesion that we have been following for a while. If the changes are significant enough, that will be considered progressing disease; it has to do with the dimensions of the tumor. It is important to recognize that small subtle changes, or even a new lesion or two, don’t necessarily lead most experts to want to make a change in therapy. We can see very slow, indolent, and not clinically significant progression of disease long before a patient actually needs to make any change at all. Many patients will go 3 months, 6 months, even a year or longer before they have enough change that the treating physician with a lot of experience concludes that there is an incentive to make a change in treatment—whether that is discontinuing the targeted therapy and making a switch to chemotherapy, or adding chemotherapy and continuing the targeted therapy. There are also some patients who will have new symptoms related to their cancer, whether an area of pain from a bone lesion or new headaches, vision changes that lead to a head MRI and show that someone has a new brain metastases, that are of course clinically significant. But with regards to brain lesions in particular, many experts are really not inclined to discontinue the targeted therapy because brain lesions that arise in this setting don’t necessarily represent resistance to the drug as much as the drug just not being able to get into the central nervous system. Many of these patients can be treated for their brain metastases, with radiation for instance, and continue to do extremely well for months or even years on the ongoing targeted therapy.

Cancer Network: What are the current treatment options for patients who do become resistant to targeted agents? Is it mostly chemotherapy?

Dr. West: Well, there are a growing number of clinical trials, sometimes with novel agents, and certainly these are very appealing options when they are available. Outside of that, we do generally favor chemotherapy. If patients have received first-line targeted therapy, then we generally try to approach treatment with the same chemotherapy options as for someone who is being treated in the first-line setting and who doesn’t have a mutation. Typically, this would be a platinum-based doublet, potentially with bevacizumab(Drug information on bevacizumab), the antiangiogenic agent. Some experts favor continuing the EGFR or ALK inhibitor, and some favor discontinuing it and even potentially restarting it later because we sometimes do see responses or at least prolonged stable disease after rechallenging the patient, even with a drug that they had progressed on earlier because sometimes patients’ tumors can become resensitized to that targeted therapy after a period off of these drugs.

Cancer Network: Lastly, are there any issues with developing resistance to targeted therapies and treatment of patients that we haven’t touched upon yet?

Dr. West: I would say that there is a lot of controversy about whether repeat biopsies should be done in all patients, whether this is a desirable option or whether this should really be bothered with at all. We will sometimes see a change in the histology of the cancer from non–small-cell lung cancer to small-cell lung cancer in somewhere between 3% to 14% of patients who develop resistance. This was actually a very hard to believe finding when it was first reported several years ago, but it has been confirmed by several different studies. You can sometimes see small-cell lung cancer lesions that developed while the patient was on an EGFR inhibitor for months or years, and these patients even have EGFR mutations in non–small-cell lung cancer, so it seems to be an actual transformation. Many of these patients can respond very well to the chemotherapy approaches used routinely for small-cell lung cancer, which is typically a platinum drug with etoposide(Drug information on etoposide) in North America. So, that is one incentive to potentially do a biopsy on a progressing lesion. But, that is also a minority of patients. Outside of that, we really don’t have examples of an actionable result that will lead to a change in treatment based on a biopsy. I don’t consider this a standard of care. That said, I do favor getting tissue whenever possible because this has been the way the field has moved forward to understand the molecular mechanisms underpinning acquired resistance. There have been a growing number of clinical trials with targeted therapies that require tissue. I would say that our biggest advances that we have made in the field in non–small-cell lung cancer have been based on molecular oncology, so the limitation of not having enough tissue is going to limit our understanding and the availability of new therapies. The best thing we can do, even if it is not yet the standard of care, is to get more tissue to try to understand things better.

Progression-free and overall survival according to response

PFS was not reached for the 24 patients who attained CR, while it was 15 months (95% CI, 12.2&17.8 months) for the 115 patients with PR, 9 months (95% CI, 5.9 to 12.1 months) for the 38 patients with SD, and 2 months (95% CI, 0 to4.2 months) for the 20 patients with PD (P<0.001)(Fig. 2A in the Supplementary Appendix). For patients with CR, median survival was not reached and 3&year survival was 58.7%. For patients with PR, median survival was 28 months(95% CI, 21.7 to 34.3 months) and 3&year survival was 32.5%. For patients with SD, median survival was 18 months (95%CI, 10.6 to 25.4 months) and 3&year survival was 0%. For patients with PD, median survival was 9 months (95% CI, 6.6. to11.4 months) (P < 0.001) (Fig. 2B in the Supplementary Appendix).

收藏了，谢谢！

Effect of Simvastatin on Cetuximab Resistance in Human Colorectal Cancer with KRAS Mutations
http://www.medscape.com/viewarticle/741431_4
Discussion
In this study, we demonstrated that the addition of 0.2 μM simvastatin to cetuximab statistically significantly enhanced antitumor activity in KRAS mutant but not in BRAF mutant CRC cells. Simvastatin could overcome cetuximab resistance via modulation of BRAF activity and induced apoptosis by inducing the proapoptotic proteins BCL2L11 and BAD. In a mouse model, the growth of KRAS mutant xenograft tumors was statistically significantly inhibited when simvastatin was added to cetuximab during treatment; however, the antitumor effect was not observed in KRAS wild-type BRAFV600E mutant xenograft tumors. To our knowledge, this is the first report to show the potential role of simvastatin as an anticancer drug that may overcome cetuximab resistance in KRAS mutant CRC cells.

Several studies have reported the antitumor activity of statins via inhibiting cellular proliferation or inducing apoptosis of various cancer cells.[16,17,36–38] However, most studies used high concentrations of statin ranging from 2 to 100 μM in vitro to demonstrate an antitumor effect.[36,37,39] Of note, to reach serum concentrations of 2–20 μM, simvastatin has to be administered at a dose of 20–200 mg kg&#8722;1 d&#8722;1, a dose not feasible for human use. We have previously reported that high-dose lovastatin monotherapy produced a high toxicity profile with a low response rate in metastatic gastric cancer patients, which precluded lovastatin from further clinical use as an antitumor drug. Our current study is important because we demonstrated antitumor effect of simvastatin using a dose level that is equivalent to cardiovascular therapeutic dose level in humans.

Recently, the potential beneficial effect of statins beyond lipid-lowering effect has been underscored in several epidemiology studies.[40–42] One of the studies, the Molecular Epidemiology of Colorectal Cancer (MECC) study,[42] demonstrated that the use of statins for more than 5 years was associated with a 47% relative reduction in the risk of CRC after adjustment for other known risk factors such as age, sex, ethnic group, hypercholesterolemia, history of CRC in a first-degree relative, and level of vegetable consumption. Although the results from these studies support the hypothesis that statins may reduce the risk of cancer, overall results from observational studies still remain elusive.

Recently, BAD and BCL2L11 were shown to be major BRAF-responsive proteins regulating apoptosis in melanoma cells.[33] One previous study showed that BRAF-MAP2K1 signaling regulated the phosphorylation of BAD and decreased the mRNA expression of BAD.[25] Additionally, BRAF-MAP2K1 signaling regulated the expression of BCL2L11, mainly through control of its protein turnover.[25] In concordance, the addition of simvastatin in our study induced BAD and BCL2L11 proteins in KRAS mutant, but not in BRAF mutant, CRC cells. Based on our experiments, simvastatin modulated BRAF protein stability in KRAS mutant but not in BRAF mutant cells and reduced phosphorylated MAPK1 and phosphorylated MAP2K1 protein levels implicating the MAPK1-MAP2K1 axis in the activity of simvastatin.

Our study has a few limitations. The mice were not randomly assigned to the different treatment groups or the researchers blinded to treatments, per Animalsin Research Reporting In Vivo Experiments guidelines.[43] However, we attempted to assign mice with approximately similar mean tumor volumes to each treatment group. In addition, the mechanism of action for simvastatin in modulating BRAF protein needs to be defined in future studies. Although based on the fact that simvastatin did not reverse cetuximab resistance in BRAF mutant CRC cells, we hypothesized and demonstrated in this study that simvastatin decreased BRAF protein stability and BRAF enzymatic activity, the precise mechanism responsible for the effect of simvastatin need to be elucidated in future studies.

The results of this study indicate that the addition of simvastatin at a dose (40–80 mg once daily) used in patients with cardiovascular disease may overcome cetuximab resistance in KRAS mutant CRC via modulating BRAF protein stability and inducing apoptosis via BCL2L11 and BAD proteins. We have previously demonstrated that the combination of simvastatin to the standard FOLFIRI regimen was safe with no additional toxicity profile.[23] Based on these preclinical and clinical studies, we are currently planning a phase II study (clinicaltrials.gov registration number NCT01281761) to evaluate the effect of addition of simvastatin to cetuximab and irinotecan combination in metastatic CRC patients with KRAS mutations who have failed standard chemotherapy, including oxaliplatin- and irinotecan-based combination chemotherapy.
　美国《国立癌症研究所杂志》（J Natl Cancer Inst）3月11日在线发表的一项研究显示，对于有KRAS突变的结肠癌细胞系，辛伐他汀可能通过调节BRAF活性和诱导细胞凋亡克服其对西妥昔单抗的耐药。

　　该研究检测了西妥昔单抗、辛伐他汀和西妥昔单抗+辛伐他汀对有KRAS或BRAF突变的转移性结直肠癌（CRC）细胞系细胞增殖和凋亡的影响。

　　结果显示，在体外，加辛伐他汀至西妥昔单抗可减少KRAS突变细胞的增殖（P<0.001），但对BRAF突变CRC细胞系无作用。用辛伐他汀处理KRAS突变细胞系可减少BRAF活性并诱导细胞凋亡。与单用西妥昔单抗相比，用西妥昔单抗+辛伐他汀处理可减少KRAS突变细胞异种移植肿瘤的生长；单用西妥昔单抗或与辛伐他汀联合应用对BRAF突变肿瘤的生长无影响。

一线治疗方案选择化疗还是靶向？

老马讲得太专业深奥了，我看不懂，能否深入浅出的谈谈，感谢！

感谢老马分享

老马哥这个帖能否置顶？不然老是要找。

新型EGFR抑制剂XL647一线治疗EGFR-突变型肺腺癌随后应用厄洛替尼治疗仍可保持适度的敏感性
EGFR-Mutant Lung Adenocarcinomas Treated First-Line with the Novel EGFR Inhibitor, XL647, Can Subsequently Retain Moderate Sensitivity to Erlotinib
中文摘要:
      引言: EGFR-突变型肺癌患者对于EGFR酪氨酸激酶抑制剂(EGFR TKIs)敏感。然而不幸的是，其通常会由于获得二次点突变(T790M)而发展成为耐药。在一些获得性耐药的临床前研究模型中，目前的EGFR TKIs对T790M具选择性。我们使用早期临床试验及已建立的获得性耐药的体外模型的数据，探讨是否所有的EGFR TKIs对T790M突变具有相似地选择性。方法: 我们对8例经XL647一线治疗并随后疾病进展的转移性EGFR-突变型肺腺癌患者的临床特征进行分析。XL647是一种ATP-竞争性EGFR、HER2、KDR和EPHB4的抑制剂。我们还进行临床前分子研究以确定耐药的特征。结果: 4例患者证实为部分缓解 (PRs)、3例患者未证实PRs、1例患者为疾病稳定。5例携带T790M突变的患者疾病进展后，仅1例患者的肿瘤标本可供研究。8例患者随后接受厄洛替尼治疗，伴有(n=3)或不伴有(n=5)化疗。接受厄洛替尼单药治疗的5例患者中有3例患者获得更多的益处，持续用药达9个月。对XL647获得性耐药的EGFR-突变的PC-9细胞未携带T790M突变，显示出与携带T790M-介导耐药的PC-9细胞不同的mRNA谱，并在生长抑制试验中对厄洛替尼具有一定的敏感性。XL647/EGFR T790M的晶体结构分析没有显示与厄洛替尼有不同的结合模式。结论: 本探索性研究的结果显示，不同的EGFR TKIs也许会选择不同的耐药机制。这些结果提高了顺序使用不同的EGFR TKIs以改善EGFR-突变型肺癌患者预后的可能性。但需要进行进一步的研究来对这一假设进行验证。
英文摘要:
      Introduction: EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, they develop resistance, often due to acquisition of a second-site mutation (T790M). Current EGFR TKIs select for T790M in preclinical models of acquired resistance. We explored whether all EGFR TKIs similarly select for the T790M mutation using data from early clinical trials and established in vitro models of acquired resistance. Methods: We analyzed the clinical characteristics of eight patients with metastatic EGFR-mutant lung adenocarcinoma who were treated first-line with XL647 and then progressed. XL647 is an ATP-competitive inhibitor of EGFR, HER2, KDR, and EPHB4. Additional molecular preclinical studies were performed to characterize resistance. Results: Four patients displayed confirmed partial responses (PRs), three patients had unconfirmed PRs, and one patient displayed stable disease. Only one of five patients' tumor samples available for analysis after disease progression harbored the T790M mutation. Eight patients subsequently received erlotinib, with (n = 3) or without (n = 5) chemotherapy. Three of five patients treated with single-agent erlotinib derived additional benefit, staying on drug up to 9 months. EGFR-mutant PC-9 cells with acquired resistance to XL647 did not harbor the T790M mutation, displayed a distinct mRNA profile from PC-9 cells with T790M-mediated resistance, and were moderately sensitive to erlotinib in growth inhibition assays. Crystal structure analyses of XL647/EGFR T790M did not reveal a different binding mode from that of erlotinib. Conclusions: The findings of this exploratory study suggest that different EGFR TKIs may select for distinct mechanisms of resistance. These results raise the possibility that different EGFR TKIs could be sequentially used to improve outcomes in patients with EGFR-mutant lung cancer. Further work investigating this hypothesis is warranted.

http://www.jtochina.com.cn/ch/re ... 201202007&flag=
==========================================================
XL647耐药后不会产生T790突变，仍可使用特罗凯。而阿法替尼和凡德他尼耐药仍可能会产生T790突变。

老马 发表于 2013-6-25 22:38

                               
登录/注册后可看大图

新型EGFR抑制剂XL647一线治疗EGFR-突变型肺腺癌随后应用厄洛替尼治疗仍可保持适度的敏感性
EGFR-Mutant L ...

这个XL647在11年和12年的帖子里都出现过,不知道为什么后来就没有下文了.