AZD9291耐药的癌细胞对elumetinib (AZD6244，MEK抑制剂）敏感，两者联用有可能延迟肿瘤耐药的发生。
#1722 Investigating resistance to AZD9291.
Cath Eberlein,1 Laura Ratcliffe,2 Lucy O'Brien,2 Katie Al-Khadimi,1 Henry Brown,1 Paul Fisher,1 Daniel Stetson,3 Zhongwu Lai,3 Gayle Marshall,1 Claire Barnes,1 Kenneth Thress,3 Brian Dougherty,3 William Pao,4 Darren Cross1. 1AstraZeneca, Cheshire, United Kingdom; 2Former employee of Astrazeneca, Cheshire, United Kingdom; 3AstraZeneca, Waltham, Boston, MA; 4Vanderbilt University, Nasville, TN.
First- and second-generation EGFR TKIs are established first line therapy for patients with NSCLC with activating mutations in EGFR. Unfortunately, patients ultimately develop disease progression with acquisition of a second-site EGFR T790M mutation in more than half of cases. This has led to the development of third generation EGFR TKIs which inhibit both the EGFRm+ and T790M mutations in preclinical models and are showing activity in TKI-resistant patients in Phase I studies. Despite the potential improvements brought by third generation EGFR-TKIs, advanced EGFRm+ tumor cells will still remain highly adaptable and the inevitability of further resistance will limit the effectiveness of these drugs. As such, the identification of resistance mechanisms to these agents is essential to guide future therapeutic strategies and identify novel:novel combinations.
To interrogate resistance to AZD9291, we have generated panels of EGFRm+ cell lines resistant to gefitinib (first generation TKI) and EGFRm+ and EGFRm+/T790M cell lines resistant to afatinib and AZD9291 (second and third generation TKIs, respectively). Subsequently, we characterised the cell lines using a variety of molecular profiling techniques including Next Generation Sequencing (NGS), Affymetrix gene expression analysis, and phenotypic profiling following pharmacological modulation by small molecule inhibitors of canonical signaling pathways.
The effects on cell survival across the range of resistant models by a panel of pathway inhibitors indicated that resistance to the EGFR inhibitors, in particular AZD9291, is frequently associated with increased sensitivity to selumetinib (AZD6244; ARRY-142886) (MEK1/2 inhibitor), suggesting that ERK signaling is commonly reactivated to circumvent inhibition of the EGFR pathway. Molecular characterisation of the panel of cell lines suggests a range of different resistance mechanisms may be responsible for reactivation of ERK signaling, including a decrease in negative regulators of ERK such as DUSP6 or an epithelial to mesenchymal transition consistent with previous observations.
Collectively, these data suggest that combining an EGFR TKI with a MEK inhibitor could prevent or delay resistance and drive superior duration of benefit from these agents.
求楼主的9291购买渠道`
nitengfei 发表于 2014-10-25 16:23
求楼主的9291购买渠道`
渠道已经站短！
乐朝夕 发表于 2014-8-31 18:52
已经吃了半年的9291，可能不是剂量的原因，我估计很有可能体内的790已经清除的差不多了，下一步是不是可以 ...
能不能帮帮我 我想也想买9291 能否把途径发到我邮箱181447591@QQ.com
看起来效果不错 我也想试试
据有的病友称可以再吃回易瑞沙
ASH2014：默沙东PD-1抑制剂Keytruda治疗血癌总缓解率66%
2014年12月8日讯 /生物谷BIOON/ --2014年第56届美国血液学会年会（ASH）于12月6日-9日在美国旧金山举行。美国血液学会（ASH）是全球最大的关于血液疾病病因及治疗的专业协会，其使命是能过促进血液学的研究、临床护理、教育、培训及宣传而进一步促进对血液、骨髓、免疫、凝血及脉管系统疾病的了解、诊断与防治。
此次年会上，抗癌免疫疗法PD-1/PD-L1抑制剂是一大热点，目前该领域的佼佼者默沙东、百时美施贵宝、阿斯利康、罗氏均在火速推进各自的临床项目，竞争异常激烈。其中，百时美和默沙东稍微领先，百时美PD-1抑制剂Opdivo（nivolumab）今年7月获日本批准，标志着全球上市的首个PD-1抑制剂；默沙东Keytruda（pembrolizumab）今年9月获美国批准，是美国上市的首个PD-1抑制剂，这2种药物的首个适应症均为黑色素瘤。阿斯利康和罗氏PD-L1抑制剂的黑色素瘤项目也已处于III期临床。
根据已发布的消息，默沙东Keytruda目前在三阴乳腺癌（TNBC）和非小细胞肺癌（NSCLC）临床已取得积极数据，并在胃癌及其他类型癌症表现出治疗潜力。今年10月，FDA已授予Keytruda治疗非小细胞肺癌（NSCLC）的突破性疗法认定（相关阅读：PD-1/PD-L1免疫竞赛肺癌新战场——FDA授予默沙东Keytruda突破性疗法认定）。
近日，Keytruda展现出了治疗血液癌症的潜力。根据默沙东（Merck & Co）在2014年第56届美国血液学会年会（ASH）公布的一项Ib期临床试验（KEYNOTE-013）初步结果，29例复发性/难治性经典霍奇金淋巴瘤（cHL）患者经Keytruda治疗24周后，总缓解率达到66%（n=19/29），有6例实现完全缓解（n=6/29，21%），达到缓解的平均时间为12周，平均缓解持续时间尚未达到，患者将继续接受治疗，直至癌症进展。
这也标志着Keytruda在血液癌症中获得的首批数据，所观察到的高达66%的缓解率支持了PD-1通路在血液癌症中的地位。默沙东已计划于2015年上半年启动一项II期研究，调查Keytruda用于经典霍奇金淋巴瘤（cHL）的治疗。
美国纪念斯隆-凯特琳癌症中心血液肿瘤科临床主任Craig Moskowitz医师指出，尽管该研究的患者群体较小，但Keytruda的表现非常出色，而且具有非常好的耐受性。根据美国白血病和淋巴瘤协会（LLS），2014年美国新增9000例霍奇金淋巴瘤（HL），其中大约有四分之一患者经初步成功治疗后病情可能复发，这类几乎没有其他可用的治疗方案，该形势突出了对新治疗选择的迫切需求。
PD-1/PD-L1免疫疗法是当前备受瞩目的新一类抗癌免疫疗法，旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，具有治疗多种类型肿瘤的潜力,有望实质性改善患者总生存期（OS）。而各大制药巨头也正在火速推进各自的项目，调查单药疗法和组合疗法用于多种癌症的治疗，以彻底发掘该类药物的最大临床潜力。
目前，默沙东正在30多种不同类型的癌症中调查Keytruda的潜力，包括各类血液癌症、肺癌、乳腺癌、膀胱癌、胃癌、头颈部癌症。
关于KEYNOTE-013研究
KEYNOTE-013研究是一项多中心、非随机Ib期研究，在大约106例血液癌症（包括骨髓增生异常综合症、多发性骨髓瘤、霍奇金淋巴瘤、纵膈大B细胞淋巴瘤、非霍奇金淋巴瘤）患者中开展。研究的主要终点包括总体安全性、耐受性、完全缓解率（采用国际协调计划缓解标准（IHPRC）衡量）；次要终点包括总缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）、缓解持续时间（DR）。（生物谷Bioon.com）
英文原文：Data Investigating KEYTRUDA® (pembrolizumab), Merck’s Anti-PD-1 Therapy, in Patients with Classical Hodgkin Lymphoma Presented at ASH Annual Meeting
Overall Response Rate of 66 Percent Observed in KEYTRUDA-treated Patients Whose Cancer Progressed on Brentuximab Vedotin
Phase 2 Study Planned for the First Half of 2015 (KEYNOTE-087)
SAN FRANCISCO--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today early study findings demonstrating that KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, achieved an overall response rate of 66 percent, as assessed by International Harmonization Project response criteria (n=19/29: 95% CI, 46-82), in transplant-ineligible and failure patients with relapsed/refractory classical Hodgkin Lymphoma (cHL) whose disease progressed on or after treatment with brentuximab vedotin. Complete remission was achieved in 21 percent of patients (n=6/29) in the study. At the time of analysis, 89 percent of responses were ongoing (n=17/19) with the median duration of response not yet reached (range 1+ to 185+ days). These early findings, from the ongoing Phase 1b KEYNOTE-013 study, were described for the first time as part of the official press program at the 56th American Society of Hematology (ASH) Annual Meeting in San Francisco (ABSTRACT #290) and will be presented in an oral session on December 8th by Dr. Craig Moskowitz, Memorial Sloan Kettering Cancer Center.
“These early data presented at ASH 2014 are very promising and show response rates of 66 percent with pembrolizumab in patients with classical Hodgkin Lymphoma,” said Dr. Craig Moskowitz, clinical director, division of hematologic oncology, Memorial Sloan Kettering Cancer Center. “There are few options for patients with multiple relapsed or refractory, classical Hodgkin Lymphoma, and pembrolizumab should continue to be studied for the treatment of this cancer.”
“Merck’s immuno-oncology development program spans more than 30 different types of cancer including a focus on blood cancers like classical Hodgkin Lymphoma,” said Dr. Alise Reicin, vice president, global clinical development, oncology, Merck Research Laboratories. “Response rates being observed with KEYTRUDA in these patients support the potential role of the PD-1 pathway in blood cancers. We look forward to initiating additional studies including a Phase 2 trial in classical Hodgkin Lymphoma in the first half of 2015.”
Early Findings for Investigational Use of KEYTRUDA in Relapsed/Refractory cHL
Data from a cohort of the ongoing Phase 1b KEYNOTE-013 study evaluated KEYTRUDA monotherapy at 10 mg/kg every two weeks in patients with relapsed/refractory classical Hodgkin Lymphoma who had progressed on or after treatment with brentuximab vedotin after failure of autologous stem-cell transplant, or who were transplant-ineligible (n=29).
Median time to response was 12 weeks. In the transplant ineligible/refusal patient group, eight patients were ineligible and one patient refused transplant, respectively. The patient who refused transplant achieved a complete remission.
Adverse events were consistent with previously reported safety data for KEYTRUDA. The most common treatment-related adverse events (occurring in greater than or equal to two patients) included hypothyroidism (n=3), pneumonitis (n=3), constipation (n=2), diarrhea (n=2), nausea (n=2), hypercholesterolemia (n=2), hypertriglyceridemia (n=2) and hematuria (n=2). Sixteen patients (55%) experienced at least one treatment-related adverse event of any grade. Grade 3 treatment-related adverse events occurred in a total of three patients and included axillary pain, hypoxia, joint swelling, and pneumonitis. No Grade 4 treatment-related adverse events or treatment-related deaths were reported.
About the KEYNOTE-013 Study
KEYNOTE-013 is an ongoing multi-center, non-randomized Phase 1b trial of approximately 106 patients evaluating the safety, tolerability, and efficacy of KEYTRUDA monotherapy in patients with blood cancers, including myelodysplastic syndromes, multiple myeloma, Hodgkin lymphoma, mediastinal large B cell lymphoma and non-Hodgkin’s lymphoma. The primary endpoints of the study include overall safety, tolerability, and complete remission rate (as measured by International Harmonization Project Response Criteria); secondary endpoints include overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and duration of response.
About KEYTRUDA (pembrolizumab)
KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
KEYTRUDA is indicated in the United States at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
关注中，祝福
PD-1/PD-L1免疫竞赛肺癌新战场——FDA授予默沙东Keytruda突破性疗法认定
2014年10月28日讯 /生物谷BIOON/ --目前，PD-1/PD-L1免疫竞赛异常激烈，该领域的佼佼者——默沙东（Merck & Co）、百时美施贵宝（BMS）、阿斯利康（AZN）、罗氏（Roche）均在火速推进各自的临床项目。此次竞赛中，百时美和默沙东稍微领先。百时美的PD-1抑制剂Opdivo（nivolumab）于今年7月获日本批准，是全球批准的首个PD-1抑制剂；而默沙东的PD-1抑制剂Keytruda（pembrolizumab）于今年9月初获FDA批准，是美国批准的首个PD-1抑制剂；这2种药物获批的首个适应症均为黑色素瘤。阿斯利康和罗氏的PD-L1抑制剂也已处于III期临床。（相关链接：即将结束临床试验的全球重磅药物TOP 15）
然而，业界认为，黑色素瘤适应症的市场潜力有限，PD-1/PD-L1免疫疗法的前景仍依赖于其他肿瘤，如非小细胞肺癌（NSCLC）和乳腺癌。乳腺癌方面，罗氏和默沙东上周相继宣布各自PD-1/PD-L1免疫疗法治疗三阴乳腺癌（TNBC）已取得积极数据，并计划于12月9日在第37届圣安东尼奥乳腺癌大会（SABCS）上公布。(相关链接：PD-1/PD-L1免疫竞赛激烈上演——罗氏、默沙东率先公布乳腺癌临床数据)
而在肺癌领域，百时美已向欧盟提交了Opdivo治疗非小细胞肺癌（NSCLC）适应症的上市申请，标志着PD-1/PD-L1免疫疗法全球首个肺癌适应症申请。与黑色素瘤相比，肺癌是非常有利可图的治疗领域，而百时美似乎已经抢得先机，将夺取新市场的主要份额。
近日，默沙东又扳回了一局，FDA已授予Keytruda突破性药物（BTD）认定，用于经含铂化疗方案治疗后病情恶化的表皮生长因子受体（EGFR）突变阴性和间变性淋巴瘤激酶（ALK）重排阴性非小细胞肺癌（NSCLC）患者的治疗。而突破性疗法（BTD）认定，可以帮助缩短Keytruda肺癌适应症申请的审查时间表，尤其是FDA已明确表示，计划尽可能快地审批通过。
今年9月底，默沙东在2014年全球第二大肿瘤盛会——第39届欧洲临床肿瘤学会（ESMO）年会上公布了Keytruda治疗非小细胞肺癌（NSCLC）的一项Ib期临床研究的数据，该研究取得了较好的无进展生存期（PFS）数据和总生存期（OS）数据，数据同时表明，Keytruda的抗肿瘤活性与患者的PD-L1水平直接相关。默沙东便是根据该项Ib期的积极数据，向FDA申请了突破性药物认定（BTD）。
目前，业界还很难估量Keytruda对默沙东的重要性。受益于肿瘤学领域的迅速进展，默沙东庞大的研发部门在经历长达5年的临床干旱期后，已部分恢复了往日的风采。在美国，Keytruda获批的首个适应症为黑色素瘤，而百时美Opdivo今年年初获日本批准黑色素瘤适应症，可以说，在美国市场中，默沙东已击败了百时美。但业界认为，与黑色素瘤相比，肺癌才是PD-1/PD-L1免疫疗法最大的市场机会之一。目前，该治疗领域，百时美已计划在今年年底向FDA滚动提交Opdivo肺癌适应症申请。
PD-1/PD-L1免疫疗法是当前备受瞩目的新一类抗癌免疫疗法，旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，具有治疗多种类型肿瘤的潜力,有望实质性改善患者总生存期（OS）。而各大制药巨头也正在火速推进各自的项目，调查单药疗法和组合疗法用于多种癌症的治疗，以彻底发掘该类药物的最大临床潜力。
近日，默沙东公布第三季度销售数据，由于仿制药进一步侵蚀，与去年同期相比，第三季度销售下降4%。默沙东也迫切需要诸如Keytruda的重磅新产品恢复增长。（生物谷Bioon.com）
英文原文：Merck grabs another 'breakthrough' in PD-1 lung cancer race with Bristol-Myers
With the goal line for lung cancer in sight at the FDA as it races with an ambitious R&D team at Bristol-Myers Squibb ($BMY), Merck ($MRK) has grabbed bragging rights to the agency's breakthrough drug designation for the checkpoint inhibitor pembrolizumab (Keytruda) for that golden market opportunity--helping to ease the sting of falling Q3 pharma sales.
The pharma giant put out word that the agency has granted its BTD title for epidermal growth factor receptor (EGFR) mutation-negative, and anaplastic lymphoma kinase (ALK) rearrangement-negative non-small cell lung cancer "whose disease has progressed on or following platinum-based chemotherapy."
Backing up earlier immuno-oncology research on the topic, investigators reported at European Society for Medical Oncology meeting a few weeks ago that pembrolizumab's antitumor activity for NSCLC directly correlated to levels of PD-L1 in patients, a closely linked target for the disease. Better progression-free survival and overall survival times were recorded in that Phase Ib study, which Merck says was used for their BTD application with the feds.
It's hard to overestimate the importance of Keytruda for Merck. The pharma giant's huge R&D division has regained a considerable portion of its lost luster following a grim 5-year drought in the clinic based on its rapid progress with the cancer treatment. The drug was the first approved in the U.S. for melanoma, beating out Bristol-Myers Squibb--which grabbed the first global approval for a checkpoint inhibitor in Japan earlier this year. Bristol-Myers is determined to be the first to get an OK in lung cancer, which is considered one of the largest market opportunities for these drugs. Bristol-Myers has completed its European application for lung cancer and expects to wrap a rolling app at the FDA by the end of this year.
A breakthrough designation could help Merck shave some time off its regulatory timeline, particularly as regulators have made it clear that they plan to push through approvals as quickly as possible.
PD-1 and PD-L1 both play a significant role in cancer. By blocking those two IO targets investigators have found that the immune system can begin to recognize cancer cells and mount an attack that can make a significant difference in terms of survival expectations. And the leaders in the field--which includes Roche ($RHHBY) and AstraZeneca ($AZN)--are scrambling to stake out positions as early leaders.
Merck needs all the good news it can get on the R&D front. Long a laggard among the Big 10 drug developers, Merck reported that its Q3 pharma sales dropped 4% year-over-year as generics took a deeper bite into sales revenue. The prospect that big new products like Keytruda can point those numbers back north is the company's main defense now against unhappy investors.
轮换这么都都有效啊，真幸福