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泰瑞沙 神药

(2017-06-07 08:14:21) 下一个

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国内的肺癌患者有接近30%的概率发生EGFR基因突变,意味着可以使用第一代EGFR抑制剂,比如易瑞沙、特罗凯或者凯美纳等药物,效果非常好,肿瘤可以迅速缩小,患者的生活状态很快回归正常,关键是副作用还非常小。

但是,多数患者在用药1年左右会产生耐药【每个病人对第一代药物产生的抗药性原因不尽相同,但60%以上的病人是因为“EGFR基因”有产生一个新的突变:T790M(EGFR蛋白的第790氨基酸由T变成了M)】,肿瘤会卷土重来,需要换药了。于是科学家开发了第二代的靶向药物,如阿法替尼【近期也被CFDA批准上市】,这个药物的特点是对新的突变点“T790M”也有作用,不过由于这个药物副作用也较大,总体表现马马虎虎。

科学家们并没有放弃,于是开发了第三代的靶向药物,阿斯利康生产的神药Tagrisso(奥希替尼,AZD9291),试验结果表现惊人,那效果到底有多好?根据已经发表的临床数据,跟化疗相比,AZD9291的有效率是71%,意味着超过70%的患者肿瘤都会明显缩小,而化疗药物的有效率只有30%,足足提高了一倍多。

CFDA开挂,加速疗效确切的新药上市

从时间上算,AZD9291此次在中国获批上市,距离其在中国正式提交注册申请不过2年半左右的时间,距离其正式提交上市申请不到2个月,距离其获得美国FDA加速批准(2015年11月13日)也仅仅晚了15个月左右。

 

At the 16th World Conference on Lung Cancer, several studies showed consistent activity with the investigational third-generation inhibitor AZD9291 in patients with advanced non–small cell lung cancer (NSCLC) that is resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Confirmed objective response rates ranged from 61% to 75% in three AURA trials.

AZD9291 is a potent oral, irreversible EGFR tyrosine kinase inhibitor that is selective for EGFR-activating mutations and the T790M resistance mutation. The T790M mutation confers resistance to treatment with first-generation EGFR inhibitors, such as erlotinib and gefitinib (Iressa) and the second-generation tyrosine kinase inhibitor afatinib (Gilotrif).

Studies are assessing AZD9291 for use in the first-line setting and beyond. The question is whether to use agents sequentially, as patients develop resistance, or perhaps start with a stronger drug—one that seems less likely to cause resistance, like this one—upfront, researchers indicated. AZD9291 also appears to provoke less skin toxicity than current agents, which suggests its potential for combining with other agents.

First-Line, High Response Rate

Pasi Jänne, MD, PhD, Director of the Lower Center for Thoracic Oncology at Dana-Farber Cancer Institute, Boston, presented an update of the phase I first-line AURA trial,1 noting that in treatment-naive patients, AZD9291 “demonstrated encouraging clinical activity and a manageable tolerability profile.” Suresh S. Ramalingam, MD, of Emory University School of Medicine in Atlanta, was the study’s first author.

The patients were found to have several EGFR-mutation subtypes, including L858R (40%), exon 19 deletion (37%), other EGFR-sensitizing mutations (3%), and T790M (8%). Patients received 80 mg or 160 mg of AZD9291.

After 12.3 months of follow-up, the confirmed objective response rate was 75%, with some responses ongoing at 18 months. The disease-control rate was 97%. A total of 72% of patients remained alive and progression-free at 12 months.

“This has prompted the initiation of the phase III FLAURA study, comparing AZD9291 at the 80-mg dose vs the current standard-of-care EGFR tyrosine kinase inhibitors for treatment-naive patients,” Dr. Jänne said.

The data in the first-line setting are still relatively immature, Dr. Jänne said. “For progression-free survival, it is only at 35% maturity.” Although the median progression-free survival has not yet been reached, “if you look at the curves, the lower limit of the 95% confidence interval for progression-free survival was about 12 to 13 months, which is higher than we normally see the medians for EGFR inhibitors…”. He added, “That part is incredibly exciting because, as you move an effective therapy that works in patients that have developed resistance and give it early on in treatment, it may in fact work even better.”

Phase II Studies

Two phase II studies that are part of the AURA clinical program were also presented: the AURA extension and AURA2 cohorts. They evaluated AZD9291 in patients with EGFR-mutated, T790M-mutation–positive advanced NSCLC who progressed after EGFR tyrosine kinase inhibitor treatment.

The AURA extension trial is a continuation of a phase I dose-escalation study of 201 patients receiving AZD9291 80 mg once daily.2 The findings were reported by James Chih-Hsin Yang, MD, ­Director of the Departments of Oncology and Medical Research, National Taiwan University Hospital in Taipei City.

The overall response rate was 61% (all partial responses), and the disease-control rate was 91%, with “only a few patients having progressive disease as their best response,” he said. Although the median duration of response and median progression-free survival have not yet reached maturity, Dr. Yang indicated, “The curve shows there is a very long progression-free survival in up to 12 months of follow-up.”

Findings were similar in AURA2, a global, open-label, single-arm phase II trial of 210 patients with T790M mutations.3 The response rate was 71%, including two complete responses. The disease-control rate was 92%, and median progression-free survival was 8.6 months, but the follow-up is not mature, Tetsuya ­Mitsudomi, MD, PhD, Professor, Division of Thoracic Surgery, Kinki University, Japan, said.

“AZD9291 has demonstrated a positive clinical benefit across two phase II studies, with encouraging duration of response and progression-free survival. A longer follow-up is needed…,” Dr. Mitsudomi said.

The ongoing phase III AURA3 trial is evaluating AZD9291 vs a platinum-based doublet in patients with T790M-positive advanced NSCLC who progress after tyrosine kinase inhibitor treatment. The planned enrollment is 410 patients. ■

Disclosure: Dr. Jänne has been a consultant for AstraZeneca, Roche Genentech, Pfizer, and Merrimack, owns stock in Gatekeeper Pharmaceuticals, and has received postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations licensed to Lab Corp. Dr. Ramalingam serves on advisory boards for AstraZeneca, Genentech, Boehringer Ingelheim, and Clovis. Dr. Yang serves on advisory boards for Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Merck, Bayer, and Clovis Oncology and has received research support from Boehringer Ingelheim. Dr. Mitsudomi has received grants/research support from AstraZeneca, Pfizer, Chugai, Taiho, and Boehringer Ingelheim, has been a consultant for AstraZeneca, Pfizer, Chugai, Novartis, Boehringer Ingelheim, Kyowa Hakko-Kirin, MSD, and Clovis, and has received honoraria from AstraZeneca, Pfizer, Chugai, Taiho, and Boehringer Ingelheim.

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