昨天我和一位新诊的胃癌患者谈临床试验,我们有一项针对弥漫型胃癌患者的研究,一线对比SOX(S1+奥沙利铂)和SP(S1+顺铂)的疗效,这两个方案都是临床常用的方案,只是还没有大型的研究去对比奥沙利铂和顺铂的优劣性,在该研究中患者可以获得140片的爱斯万(S1)。患者听到是临床研究,马上拒绝了,他说不想接受赠予,内心会受煎熬。我说其实您也为科学事业做出了贡献,我们会收集您的用药数据,疗效和不良反应,患者再次拒绝了我,说不想做小白鼠。最后我们为患者选择了SOX方案治疗。2014年我有幸参加了中山大学和美国医学排名前茅的约翰霍普金斯大学关于临床研究的合作项目,在美国学习的2年期间,我不止一次的在门诊遇到主动前来咨询临床研究的患者及家属。很多患者会主动问医生:是否有适合我的临床试验?也有患者是在医院的网站上查到正在进行的临床试验项目,然后前来接受筛选,看是否能够入组。同样是临床试验,为什么患者的接受程度差异如此之大?是医生介绍的不够清楚?是患者及家属对临床试验存在误解?抑或是其他什么原因...首先我觉得有必要科普一下什么是临床试验,以及我们为什么要做临床试验。什么是临床试验?临床试验(Clinical Trial),指任何在人体(病人或健康志愿者)进行药物的系统性研究,以证实或揭示试验药物的作用、不良反应及/或试验药物的吸收、分布、代谢和排泄,目的是确定试验药物的疗效与安全性。为什么要开展临床试验?出于对患者利益的保护,一个新药在进入临床实践之前需要先经过临床试验,获得药理(效果)和毒理(不良反应)的数据,同时也需要得到有效率和生存期的数据。那么获得这些数据的有效途径就是开展临床试验。美国NCCN指南推荐在没有标准治疗的情况下, 鼓励患者参加临床试验。肿瘤的治疗仍是世界性难题,攻克肿瘤的希望寄托于科学家对肿瘤病因的不断探索,随着我们对肿瘤发生发展认识的深入,不断地有新的药物诞生,人体的内环境是一个复杂的机体,在细胞和其他动物体内证明有效的药物到了人体内部不一定有效,因此我们需要设计不同阶段的临床试验来验证药物的作用。虽然我们不能确保每个参与其中的患者都能从中获益, 但是从长远来看人类攻克肿瘤的点滴进步, 都离不开临床试验的功劳。而事实上临床试验也是奇迹诞生的地方,我有一位朋友患了黑色素瘤,已经接受了所有的标准治疗,一般状况还很好,肿瘤却仍在进展,按照常规只能观察或者接受对症支持治疗,刚好有抗PDL1的临床研究,他接受了2次治疗之后肿瘤消失了。为什么抗拒临床试验?我和很多不接受临床试验的患者聊过,他们抗拒的最常见原因是认为临床试验存在很多不确定因素,参加临床试验相当于小白鼠。事实上在进行人体临床试验之前,这些药物往往已经获得在动物(如鼠、狗、猴子等动物)体内的安全数据,而且在正式开展人体临床试验之前需要报伦理委员会审批,伦理委员会的成员里规定一定要有非医学专业的人员,他们代表的就是患者的观点和利益。所有的临床试验都不能损害受试者的利益(这是最起码的要求),很多临床试验还要求患者可以获得一定的利益,比如交通或营养补贴,有些研究还可能给患者买相关的保险。此外临床试验需要获得患者的知情同意,在临床试验过程中患者有权利随时决定退出研究,这本身也是对患者权益的一种保护。目前在中国开展的临床试验可以分为两大类。(1)Me too研究一些在国外临床试验中证实有效的药物,在进入中国市场之前需要证实对中国人群同样有效,因此需要开展类似的临床试验。比如已经完成的Artist研究就是安维汀在中国的注册研究,开展该研究的时候国际多中心III期研究AVF2107已经证实安维汀可以给晚期肠癌患者带来生存获益,患者在参加Artist研究时不仅可以获得免费的药物和检查,还可以获得一定的交通补贴。等到这些药物正式上市,平均每个月的治疗费用高达3万人民币。(2)新药研究随着我国制药产业研发能力的提高,我们也逐渐有了自主创新的药物,这些药物在获得适应症之前同样需要开展临床研究,这类研究的不确定性相对多一些,需要摸索有效的药物剂量,收集安全性的数据。即使在这种情况下,患者的利益和安全仍是研究团队最关心的头等大事。(3)扩大适应症的研究有些药物已经在其中病种中证明有效,我们想观察在新的病种中是否仍然有效。很多药物都有光谱抗肿瘤的作用,类似的研究安全性比较有保障。如何获得临床试验的信息?如果您对临床试验感兴趣,可通过https://clinicaltrials.gov/ 网站或中国临床试验注册中心查询正在进行的临床试验。
Adjuvant TKI Therapy for Early-StageEGFRMutation-Positive NSCLC: Is Disease-Free Survival Enough?The headline inASCO Postseemed promising enough: "Adjuvant Gefitinib Delays Recurrence in EGFR-Positive NSCLC."[1]It describes the provocative result of a trial reported as highly positive at ASCO 2017,[2]in which 222 Chinese patients with N1 or N2 node-positive, resected, activatingEGFRmutation-positive non-small cell lung cancer (NSCLC) were randomly assigned to receive either standard cisplatin/vinorelbine chemotherapy for four cycles or 2 years of adjuvant daily gefitinib at the standard dose of 250 mg daily. The highlight was a more than 10-month difference in median disease-free survival (DFS) (28.7 vs 18.0 months; hazard ratio, 0.60;P= .005); lower toxicities across many parameters with gefitinib; and more patients reporting improved quality of life using various measures if they received gefitinib rather than conventional chemotherapy.Despite such promise at first blush, this study is mired in glaring shortcomings that undermine any argument that it should change practice, and it raises major questions about what our goal should be in running trials of novel therapies in a curative setting for patients with cancer.First, many people favor shaping the question as whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy should be added sequentially to adjuvant platinum-based chemotherapy, with its well-established survival benefit in higher-risk resected NSCLC, rather than replacing a proven therapy with an unproven one. This is especially true in a trial in which two thirds of the patients had stage IIIA disease, with a risk for recurrence in the range of 80% or more, and a setting in which adjuvant chemotherapy can significantly reduce that risk, far more than the difference achieved in lower-stage resected NSCLC.[3]Moreover, the staging procedures in this trial were not clearly articulated but did not include uniform PET or brain imaging during preoperative staging, making it likely that many patients had more advanced disease than was reported. This concern is underscored by the finding that the DFS curves for both arms decline precipitously beyond 2 years out, nearly converging by 3 years (34% vs 27%, favoring gefitinib) and continuing to drop steadily after that, with no plateau for either arm. There is no suggestion of any plateau of prolonged DFS for either arm, which is a far worse result than we would expect to see in an adjuvant therapy trial—strongly suggesting that most of these patients had metastatic disease that was not detected in a potentially suboptimal preoperative staging workup.With these severe limitations, it is unlikely that these results will or should lead to a marked change in recommendations for adjuvant therapy and don't suggest a clear mandate to do molecular marker testing for patients with resected NSCLC. I'm afraid that what we most clearly learned from this study was how even a phase 3 randomized trial can undermine its utility with poor rigor when enrolling appropriate patients.The bigger question I see is whether an improvement in an endpoint such as DFS is an appropriate goal when we're treating for cure. The general premise of adjuvant therapy is that we administer it to eradicate micrometastatic disease that may persist after surgery, thereby converting a subgroup of patients with invisible metastatic disease from being destined to experience relapse and die of their disease to truly cured through additional systemic therapy. Although we might hope that DFS serves as a reliable early surrogate for overall survival (OS) here, the evidence in this setting suggests otherwise, particularly in studies of adjuvant targeted therapy, such as an EGFR TKI for patients withEGFRmutation-positive NSCLC. Single-arm[4]and randomized trials[5]have tested adjuvant erlotinib after standard adjuvant chemotherapy and reported improvement in DFS for patients withEGFRmutation-positive disease that was not associated with any evidence of an improvement in OS from what would otherwise be expected.These data suggest that postoperative EGFR TKI therapy may not eradicate micrometastatic disease, but instead may only postpone progression after acquired resistance develops. If we consider giving 1-2 years of therapy and then reliably see a convergence of the DFS curves with no improvement in OS, I think this is an insufficient benefit to subject a large population of patients, some of whom are already cured with no further therapy, to prolonged adjuvant therapy. This is especially true if this added intervention entails skin, gastrointestinal, and sometimes other toxicities, as well as the financial toxicity of extremely expensive therapy that will be conferred on some patients as well as broader society.We may need to debate these issues further as we consider whether the emerging results of the PACIFIC trial of consolidation durvalumab versus placebo for a year after concurrent chemotherapy and radiation for stage III, unresectable NSCLC warrant a change in practice. We've recently learned from a press release[6]that this trial is positive for a significant improvement in progression-free survival (PFS), which was the primary endpoint of the trial. However, PFS can be especially challenging to assess following the marked treatment-related changes in and around the primary tumor after chemotherapy/radiation. If the difference in PFS is profound, it will probably serve as an effective surrogate for improved OS, particularly because the cure rate in this locally advanced setting is only about 20% at best. But if it is only a modest improvement in PFS that won't necessarily translate to an OS benefit, a significant PFS benefit may not be sufficient to warrant an extra year of intravenous therapy for every patient, at a cost approaching $200,000 for the full course of treatment. For that price, both in patient time and financial burden, we should expect a profound survival benefit.This question may become even more challenging if the preponderance of data from our adjuvant and consolidation therapy trials suggest that the benefits of these therapies dissipate after discontinuation of the treatment. If a fixed course of treatment is not conferring true cures, we will need to be very judicious in considering whether patients who may already be cured should receive longitudinal therapies that could possibly be just as effective when administered upon progression, but only to the patients with recurrent/progressing disease, who are then proven to actually need subsequent therapy.
Could Gefitinib Replace Adjuvant Chemo in NSCLC?New results could lead lung cancer experts to rethink adjuvant therapy for patients with resected stage II-IIIA non–small cell lung cancer (NSCLC).The usual standard of care is cisplatin-based chemotherapy, but a new trial found that targeted therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa, AstraZeneca) was better in patients withEGFRmutations.The results come from the ADJUVANT (CTONG 1104) trial and were highlighted in a premeeting presscast for the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting."The authors reported a remarkable difference in disease-free survival," said Tony Mok, MD, from State Key Laboratory in Oncology in South China, Hong Kong, who was not involved in the study."The current standard is not to offer adjuvant EGFR TKI after resection of an early-stageEGFR-mutation-positive lung cancer, but the CTONG study helps us to rethink this paradigm. In other words, patients may be spared the toxicity of adjuvant chemotherapy and still attain a better disease-free survival," he toldMedscape Medical News.The study is "clear evidence that we can use precision medicine not only in patients with advanced cancer but also in those with earlier-stage disease," said ASCO President-elect Bruce E. Johnson, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts.About 30% ― or 140,000 people worldwide ― have anEGFRmutation and may benefit from adjuvant treatment with EGFR-targeted therapy to reduce the chance of recurrence, according to ASCO."With this information now available, I suspect many doctors will begin testing these lung cancer tumors right after surgery to see if they actually have anEGFRmutation," said ASCO's chief medical officer, Richard Schilsky, MD, during the briefing."That is not currently standard of care in the US, where typically the testing doesn't take place until the cancer recurs or becomes metastatic," he added.However, he suggested that even if other studies replicate these results, there are still issues such as cost and treatment duration to weigh in the balance.Study DetailsThe phase 3 trial randomly allocated 222 patients withEGFRmutations to receive either gefitinib 250 mg daily for 2 years or the standard of care cisplatin/vinorelbine-based chemotherapy every 3 weeks for four cycles.After a median follow-up of 36.5 months, there was a significant difference between the groups in recurrence-free survival: 28.7 months for patients who received gefinitib, and 18 months for those who received chemotherapy (hazard ratio [HR], 0.60;P= .005), reported lead study author Yi-Long Wu, MD, from the Guangdong Lung Cancer Institute, Guangdong General Hospital, in Guangzhou, China.There was also a significant difference in the rate of serious adverse events (grade 3 or higher): 12.3% in the gefitinib group vs 48.3% with chemotherapy (P< .001).Dr Wu noted that two recent trials of adjuvant targeted therapy did not show benefit in NSCLC and suggested that the negative results were due in part to the fact that they included disease of stages I, II, and III in their study. He also said that these "earlier trials only looked to see if patients showed overexpression or overactivity ofEGFR, but not mutations inEGFR."He noted that the current trial recruited patients "who had been confirmed to have activatingEGFRmutations, so we believe these reasons account for why other trials showed no benefit of a targeted therapy while ours did."Overall survival data in the current study is as yet immature, noted Dr Mok, and the results are limited because of the small sample size. But when considered along with the similar, ongoing Japanese IMPACT (WJOG6410L) study, "I trust we shall have a strong argument to offer adjuvant EGFR TKI instead of chemotherapy," he toldMedscape Medscape News.However, Dr Schilsky said that it is also important to bear in mind that in Dr Wu's trial, "we're talking about 12 weeks of chemotherapy vs 2 years of gefitinib. So it's a big commitment on the part of patients to adhere to 2 years of continuous treatment."In addition, the cost of gefitinib is "far, far greater than the cost of 12 weeks of chemotherapy. And so I think at the end of the day, once the survival data are known, doctors and patients are going to have to have very thoughtful discussions about what is the magnitude of the survival benefit, what is the burden of the patients who take either cytotoxic chemotherapy for 12 weeks or 2 years of an oral treatment which, while it is less toxic, is not without toxicity, and what's the financial burden of that treatment choice going to be for the patient?"
After causing a sensation at the recent European Society for Medical Oncology (ESMO) meeting, the new data for pembrolizumab (Keytruda, Merck & Co) in the first-line treatment of non-small cell lung cancer (NSCLC) have now secured an approval from the US Food and Drug Administration (FDA).Pembrolizumabis now the first immunotherapy to be approved for first-line use in NSCLC and is expected to change practice,experts saidat the meeting. Up to now, a chemotherapy doublet has been the standard of care, except in patients with NSCLC who have targetable mutations (EGFRorALK).Several immunotherapy agents are already approved for second-line use in NSCLC, among patients who have stopped responding to chemotherapy, but pembrolizumab is the only agent approved in the first line.The new indication restricts the use of pembrolizumab to patients with NSCLC who do not haveEGFRorALKgenetic tumor abnormalities (found in about 20% of NSCLC cases) and whose tumors have high programmed death ligand-1 (PD-L1) expression (tumor proportion score of 50% or more), as determined by an FDA-approved test. (In the pivotal clinical trial, this was found in about 30% of screened patients with NSCLC and without mutations.)Superior to ChemoThe approval for the new indication is based on results showing that pembrolizumab was superior to chemotherapy in the first-line setting.These results come from the phase 3KEYNOTE-024study, which was presented at a presidential session at ESMO andsimultaneously published inThe New England Journal of Medicine (NEJM).This study was conducted in 305 patients with advanced NSCLC who hadn't yet received treatment and whose lung cancer biopsy specimens showed no targetable mutations (EGFRorALK) and showed high expression of PD-L1.In this patient population, pembrolizumab alone had results superior to those of a platinum-containing doublet chemotherapy: median progression-free survival times were 10.3 vs 6 months (hazard ratio [HR], 0.50), respectively.The secondary endpoint of overall survival (OS) was also significantly improved with pembrolizumab. OS at 6 months was 80% vs 72% (HR, 0.60) and 1-year OS was 70% vs 54%.The significant reduction in risk for death (by 40%) was "remarkable" because it was seen despite a high crossover rate (50%), commented lead investigator Martin Reck, MD, chief oncology physician, Lung Clinic, Grosshansdorf, Germany. He was referring to the patients in the chemotherapy group who were given pembrolizumab upon disease progression.Pembrolizumab also showed a higher overall response rate (45% vs 28%) and a longer response duration (median, not reached for pembrolizumab vs 6.3 months with chemotherapy).
目前表皮生长因子酪氨酸激酶抑制剂(EGFR-TKI)已广泛应用于一线EGFR突变的非小细胞肺癌(NSCLC)患者,本文就EGFR突变晚期NSCLC患者的全程管理作一简要阐述。一、背景:NSCLC已进入分子分型时代,根据不同的分子特征来选择相应的分子靶向药物治疗,患者的中位生存时间有望达到3.5年。基于驱动基因的靶向药物不断涌现, EGFR突变NSCLC患者已有了越来越多的治疗选择,目前TKI是EGFR突变患者一线治疗的最佳选择.EGFR-TKI一代药物主要包含了吉非替尼、厄洛替尼和埃克替尼,二代药物主要包含了阿法替尼、Dacomitinib, 三代药物主要包Osimertinib(AZD9291)和CO1686等。二、一线用药的江湖地位既往研究,包括 IPASS研究即第一个在EGFR突变患者中证实一线TK I治疗与一线化疗相比有更长的PFS、更高的缓解率;及此后的类似研究,NEJ002、WJTOG3405、OPTIMAL、EURTAC、LUX-LUNG 3及LUX-LUNG 6等III期随机对照研究都证实了:一线应用TKI治疗EGFR突变患者时有效率高达55%-82.9%,PFS长达9.2个月-13.1个月,与一线含铂的两药化疗相比,PFS和客观缓解率均显著提高。奠定了EGFR-TKI在EGFR敏感突变患者中一线治疗的地位,成为此类患者首选的治疗方案;近年,各权威指南均做出了相应的治疗推荐;但一、二代TKI孰优孰劣,尚未见充足证据。中国大陆上市的EGFR-TKI吉非替尼(Gefitinib,易瑞沙Iressa)吉非替尼作为首个被证实可单药用于EGFR突变阳性的晚期NSCLC的TKI药物,被国际国内多个指南推荐。吉非替尼可获得有效的疗效和较好的耐受性:中位PFS达8.4-10.8月,ORR达62.1-84.6%,中位OS达21.6-34.8月;在中国上市10年来,中国晚期肺腺癌患者在吉非替尼获批后中位OS从14.1月提高到33.5月。厄洛替尼(Erlotinib,特罗凯Tarceva)中国第二个上市的TKI厄洛替尼,与吉非替尼相比较,CTONG0901研究以及WJOG 5108L均验证了这两个药物的疗效无明显差异。而CTONG–0803及一些回顾性研究表明,厄洛替尼在脑脊液中的浓度似乎优于吉非替尼,且对脑转移具有较好的作用,但与吉非替尼头对头研究CTONG0901并未见阳性结果。埃克替尼(Icotinib,凯美纳Conmana)第一个中国自主研发的EGFR-TKI,ICOGEN、CONVINCE研究的验证,现已批准上市,单药适用于EGFR敏感突变的局部晚期或转移性NSCLC患者一线治疗。而即将在2016 WCLC公布结果的CTONG1201(BRAIN)研究将会公布其脑转移患者的疗效及安全性。二代TKI阿法替尼是不可逆的二代EGFR-TKI,于2013年7月在美国获批用于一线治疗晚期或转移性非小细胞肺癌EGFR19和21外显子突变的适应症,目前已在港澳台上市,尚未在中国大陆上市。而另一个二代TKI达克替尼(Dacomitinib)与一代TKI吉非替尼及厄洛替尼相比较,在疾病无进展生存期和总生存期有一定延长作用,但严重的不良反应有可能会限制该药物的发展;其在一线用药的III期临床研究(ARCHER 1050)也即将公布,作用有待进一步验证。三、一线TKI与其他治疗的联合TKI联合化疗治疗早些年开展的靶向同步化疗模式的INTACT、TRIBUTE、TALENT研究均因入组非选择人群而未能得到阳性结果,虽换药维持治疗模式(SATURN)或间插治疗模式(FASTACT-II)均有生存获益,但NEJ005研究证实对于EGFR突变的晚期NSCLC患者,同步联合治疗较序贯治疗模式更胜一筹,并开展了同步联合治疗对比单药靶向治疗的III期临床研究(NEJ009),由此可见联合治疗模式可能是提高一线治疗获益的较优选择。今年JCO 报道的JMIT研究[1],以 EGFR高频突变的东亚人群为研究对象,对靶向药物和化疗的同步联合治疗模式进行了进一步探索,虽然OS尚未成熟,但培美曲塞联合吉非替尼的PFS为15.8个月,相对于吉非替尼单药可带来将近5个月的PFS改善,且没有明显增加不良反应的发生率,这对EGFR敏感突变患者的一线治疗策略的选择有较大的指导意义,但OS是评价该治疗策略有效性的最重要指标,期待OS数据的后续报道。TKI与贝伐单抗联合治疗在联合治疗模式中,EGFR TKIs 的最佳拍档如何选择也需要仔细斟酌。 JO25567研究中厄洛替尼联合贝伐珠单抗一线治疗EGFR突变患者的治疗模式的PFS为16.0个月(16.0月 vs 9.7月,P=0.001,5),与JMIT研究接近。III期A+T研究目前正开展中,最终结果需等待进一步研究。两种模式比较:培美曲塞无论是在不良反应发生率还是在效价比方面都比贝伐单抗更具优势。但厄洛替尼联合贝伐珠单抗(A+T)具有协同作用,进一步促进抗肿瘤作用。联合方案的设计中对药物协同作用以及毒性反应的考量也至关重要, JMIT研究与NEJ009研究设计类似,但JMIT研究并未联合铂类药物,一方面因为有部分临床前研究显示EGFR-TKIs与铂类直接联合可能产生拮抗作用,另一方面铂类联合带来生存获益的同时也可能增加相关的治疗毒性,未来的临床应用中是否采用靶向联合含铂双药化疗方案仍值得探讨。四、EGFR-TKI耐药发生机制:再活检的重要性一线TKI治疗后,其无可避免的耐药现象,成为进一步提高靶向药物疗效的瓶颈。耐药分为两类:原发性耐药即为最初就对TKI耐药,而继发性耐药则是原本对TKI有效的患者治疗6-12月后发生耐药,又称为获得性耐药,是在EGFR-TKIs治疗中值得关注的问题。Camidge 将EGFR TKI 耐药分为4 类,包括:①出现耐药突变,如T790M 突变;②旁路激活,如c-MET 扩增;③表型改变,如腺癌向小细胞肺癌转化,上皮细胞向间叶细胞转化(epithelial to mesenchymal transformation,EMT);④下游信号通路激活,如BIM 的多态性导致EGFR-TKI 的原发耐药,通过MAPK1 扩增直接激活下游增殖信号通路产生EGFR-TKI 的获得性耐药[2]。见图二。图二:EGFR-TKI耐药机制50-60% 的耐药机制是EGFR20 号外显子第790 位点上的苏氨酸为蛋氨酸所取代(T790M),从而改变了ATP 的亲和性,导致EGFR TKI 不能有效阻断信号通路而产生耐药。也有一些研究支持T790M 突变具有选择性,经TKI 治疗敏感的克隆被杀灭,而含有T790M 突变的耐药克隆得以保留下来产生耐药。5%~20% 的EGFR TKI 耐药是由C-Met 所引起,C-Met 扩增的耐药机制为C-Met 与ErbB3 结合,绕过EGFR 激活下游PIK3/AKT 介导的信号通路,促使肿瘤细胞增殖,抑制凋亡[3]。另外K-ras 基因突变和BRAF 基因突变及细胞类型的转变、HER-2 突变等均是耐药的机制。针对再活检所检测到的明确耐药靶点,再根据靶点确定方案。四、TKIs治疗策略选择:不同的进展方式予以不同治疗方式一线TKI耐药应根据每个患者的具体情况,进行再穿刺活检,在精准医学的指导下,实施个体化治疗。根据既往报道总结三个主要进展模型的建议[4],爆发性进展建议改为二线化疗;缓慢进展则继续TKI治疗联合化疗;局部进展,如有增大或出现1~2 处新的非靶病灶,没有症状或症状没有变化,可认为属于癌基因成瘾,此阶段停药可能会出现疾病暴发进展,因此可以继续靶向治疗联合局部治疗(见下图3)。美国Colorado 大学将适合局部治疗的情况归纳为:适合全脑放疗或脑立体反射或手术切除的没有脑膜转移的颅内进展;颅外≤4 个病灶、同时适于体部立体放射或常规分割放射或外科切除的进展[5]。如出现广泛进展,则可以根据IMPRESS 研究的结果(一线TKI耐药后,予吉非替尼联合PP化疗治疗组对比PP化疗组,PFS 并无显著改善,中位PFS 均为5.4 个月,初步结果显示对照组较吉非替尼治疗组具有更好OS),一线耐药进展后不再给予TKI,双药化疗应继续作为一线吉非替尼耐药后疾病进展患者的标准治疗。EGFR-TKI 获得性耐药后的NSCLC 不是单一疾病,而是多种多样,采用相同的治疗方法进行处理显然是不合适的。EGFR-TKIs耐药后(1)如果患者的疾病进展不明显,特别是无症状,则继续使用EGFR-TKIs进行治疗;(2)应该寻找RECIST评估疗效外的治疗终点,特别是在患者分层的背景下,选择新的治疗组合及;(3)第三代EGFR-TKIs针对T790M的突变,可以应用于使用第一、二代分子靶向药后,有T790M突变且疾病进展的患者;(4)除了T790M之外,其他的致耐药机制也应加紧研究,同时应鼓励患者参与临床试验。以铂类为基础的化疗,可供耐药后使用。(5)当出现耐药后,若转向第三代EGFR-TKIs,应以影像学疾病进展的情况为依据,而不应该单独检测cfDNA中T790M的情况。这是基于cfDNA中T790M的灵敏度变化范围而决定的。三代TKI选择:奥希替尼Osimertinib(AZD9291):是新一代不可逆性EGFR-TKI,对EGFR 敏感突变和T790M耐药突变均有更好的作用6。Osimertinib于2015年11月13日经FDA加速批准上市,用于治疗EGFR-TKI耐药后携带T790M突变的NSCLC患者。针对T790M突变患者,Osimertinib能够带来61%的缓解率和9.6个月的中位PFS获益,且皮疹等不良反应发生率较低,因此Osimertinib是这部分患者的最佳治疗选择。同时Osimertinib一线治疗EGFR突变患者也有着令人满意的效果,从2015 ASCO公布的60例患者数据来看, ORR为73%,DCR达到97%。目前Osimertinib对比一代EGFR-TKI一线治疗EGFR突变晚期非小细胞肺癌III期临床研究(FLAURA)研究尚在进行中,期望该研究能告诉我们三代EGFR-TKI一线治疗能否超越一/二代TKI,进一步延缓耐药?Rociletinib(CO-1686)是另一个第三代EGFR-TKI 药物,2015年4月NEJM发表TIGER-X的初步研究结果显示,未经确认的T790M阳性500mg组CO-1686治疗的ORR=60%,625mg组ORR=54%;2015年11月FDA要求对疗效再次进行确认,结果显示500mg组ORR=28%,625mg ORR=34%,疗效稳定性欠佳,由于CO-1686同时伴有较严重的毒副反应,即高血糖症及心电图QT波延长,因此美国FDA并未批准其上市,要求继续对其毒副反应和疗效进行深入研究。Clovis必须完成现在的TIGER-3三期临床,即使上市也得2019年。BI 1482694 (HM61713) 在EGFR-TKI耐药之后携带T790M突变的患者,使用II期推荐剂量800mg/天,显示了有效性和良好的安全性;独立评估且确认的ORR为46%;最常见药物相关不良反应是恶心,腹泻以及皮疹、瘙痒;一项正在进行的II期研究ELUXA1将进一步验证BI 1482694在T790M突变NSCLC中的疗效和安全性。艾维替尼中国自主研发的第三代TKI,临床前期数据示一线TKI耐药后可起作用,目前正进行临床研究,结果有待进一步公布。颅内进展大概25%–30%的患者初诊时即诊断为颅内转移,而40-50%患者会在治疗的过程中出现CNS转移。既往零星报道,CNS转移更常见于EGFR突变患者,而今年刚发表在JTO的文章证实,脑膜转移在EGFR突变患者常见(发生率9.4% vs 1.7%),其可能与突变患者生存期延长,一、二代TKI在颅内浓度低相关。CNS转移成为制约患者生存的重大因素之一。IASLC 2015年共识推荐:(1)需根据患者脑转移灶的个数和大小进行选择, SRS相比WBRT的神经系统后遗症更小,是临床常用的一种颅内局部治疗手段,可在合适的条件下采用;(2)对于转移灶个数相对局限且无症状的脑转移患者,可在治疗初期使用TKI进行治疗。然而,在2016年ASCO报道的AZD9291及AZD3759对颅内病灶的控制,有可能改变常规临床治疗策略。最受关注的无疑就是在2016 ASCO上大放异彩的奥希替尼(AZD9291)。BLOOM研究中,7例患者(33%)达到已确认的影像学好转; 9例患者(43%)达到已确认的颅内疾病稳定(SD),2例未确认的颅内SD。提示奥希替尼在CNS转移中具有显著的疗效。AZD3759 是第一个为有效透过血脑屏障治疗脑转移而设计的EGFR抑制剂,旨在克服EGFR突变的CNS转移,ASCO中报道AZD3759治疗脑实质转移和脑膜转移NSCLC的I期研究提示AZD3759是可耐受的,可达到抑制靶病灶,颅内抗肿瘤效果可观。提示AZD3759在CNS转移中获得显著疗效。五、总结“同样生活在一个世界,为什么中国没有这么多的治疗选择”,最后引用吴一龙教授在2015年肺癌年终大盘点中的两张总结,这仍需要一代代人的努力,更好地改善肺癌患者生活质量,延长寿命。
对于驱动基因阳性(EGFR/ALK)的晚期NSCLC患者,优先考虑用靶向药物一线治疗。对于无驱动基因突变的晚期NSCLC患者,基本策略是以铂类药物为基础的化疗。可以选择贝伐珠单抗联合化疗作为一线治疗方案。 孤立性转移IV期NSCLC应结合局部治疗与系统性治疗。展望未来,在靶向药接力赛的同时,免疫治疗及相关联合治疗方案也将为晚期NSCLC患者带来更多的治疗选择和可能的生存获益。