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本帖最后由 sharkxf 于 2015-4-27 22:20 编辑

AZD9291 Shows Promising Response in T790M-Mutated NSCLC
Pasi A. Jänne MD, PhD

Treatment with AZD9291 at 80 mg per day elicited a response in 66% of patients with EGFR T790M-positive non–small cell lung cancer (NSCLC), according to investigator-assessed findings from the phase I AURA study presented at the 2015 European Lung Cancer Conference.

In the updated analysis of patients with EGFR T790M-positive NSCLC, the median duration of response has not yet been reached, although data are still immature. The longest duration of response was >8 months and the immature median progression-free survival (PFS) was 10.9 months with the 80 mg dose AZD9291, according to investigator-assessed criteria. An independent review of the data for the 80 mg cohort found an objective response rate (ORR) of 54%. The duration of response was 12.4 months and the PFS was 13.5 months.

“There are few treatment options currently available for patients with advanced EGFR-mutated non–small cell lung cancer who experience disease progression due to a second mutation known as T790M,” principal investigator Pasi A. Jänne MD, PhD, director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, said in a statement. “Management is usually limited to chemotherapy or rechallenge with EGFR tyrosine kinase inhibitors. As AURA continues to mature, and the trend in progression-free survival and durable clinical response is maintained, this may support the potential for AZD9291 as a future treatment option for advanced EGFR-mutated NSCLC.”

AZD9291 is an irreversible inhibitor of EGFR T790M mutations. In about 60% of patients with NSCLC, resistance to first-generation EGFR inhibition has been associated with an acquired mutation in EGFR T790M.

In 2013, AZD9291 was granted a breakthrough therapy designation for the treatment of patients with EGFR T790M-positive NSCLC, based on earlier data from the AURA trial. The company developing the drug, AstraZeneca, expects to submit a new drug application to the FDA within the next few months.

Included in the analysis of the ongoing phase I AURA study were 283 patients with EGFR-mutant advanced NSCLC who received treatment with AZD9291 at 5 doses ranging from 20 to 240 mg once daily. T790M-positive tumors were found in 163 of these patients.

Patients included in the study were a median age of 60 years old, and 62% were female; 61% were Asian and 31% were Caucasian. AZD9291 was administered to patients with advanced NSCLC who were experiencing disease progression after treatment with an EGFR inhibitor.
At all dose levels, the ORR was 59% for patients with EGFR T790M-positive tumors. The ORR was 23% in patients with T790M-negative tumors.
In patients treated with the 80 mg dose of AZD9291, the most common adverse events of any grade were rash which occurred in 38% of patients (0% grade ≥3) and diarrhea in 36% of patients (1% grade ≥3). Grade 3/4 treatment-related adverse events occurred in 14% of patients.

In all patients treated with AZD9291 at all doses, diarrhea was reported by 50% and rash by 46%. The most common adverse events were primarily low-grade. Grade 3/4 treatment-related adverse events occurred in 17% of patients.
We are committed to developing novel medicines that address the significant unmet need in lung cancer by focusing on the genetic drivers underlying the disease,” said Antoine Yver, Head of Oncology, Global Medicines Development, AstraZeneca, the company developing the drug. “We are on track for a regulatory submission of AZD9291 in the United States in the second quarter of this year.”

In addition to the AURA trial, AZD9291 is also being investigated as a first-line therapy for patients with EGFR-mutated NSCLC. Additionally, the therapy is under exploration in combination with MEDI4736, an anti-PD-L1 immunotherapy, and with the MEK inhibitors selumetinib and AZD6094 in NSCLC. Initial data from these combination studies will be presented at the 2015 ASCO Annual Meeting.

“Our extensive clinical research program is also investigating the potential of AZD9291 in earlier disease and in combination with other pipeline assets, including immuno-oncology molecules,” Yver said. “With this comprehensive approach, our goal is to develop a broad range of potential treatment options for patients with EGFR mutation positive non-small cell lung cancer.”

sharkxf · 发表于 2015-4-27 22:16:46

本帖最后由 sharkxf 于 2015-4-28 09:31 编辑

AZD9291在T790M突变的非小细胞肺癌中显示出有效响应

根据在2015年欧洲肺癌会议上提出的第一期AURA研究发现，EGFR T790M阳性的非小细胞患者在给予80毫克/天的AZD9291后，响应率达到66%。
受制于研究进程及相关数据的不成熟，针对EGFR T790M突变阳性的非小细胞肺癌患者最新分析尚未达到有效持续时间。但依据研究者相关评估标准，给予80毫克/天的AZD9291治疗后，患者最长持续响应时间大于8个月，而无进展生存期（PFS）为10.9个月。一项独立的针对给予80毫克/天的AZD9291被试群体的回顾审查发现，其客观响应率为54%，而有效持续时间和无进展生存期分别为12.4个月和13.5个月。
“对于因T790M继发性突变导致进展的晚期EGFR突变的非小细胞肺癌患者而言，目前可供选择的治疗措施少得可怜。”英格兰胸部肿瘤中心、 Dana-Farber肺癌研究所首席研究员、医学博士、主任在其一份声明中提到。“解决办法往往仅限于再次进行化疗或者接受EGFR酪氨酸激酶抑制剂。随着AURA研究不断进展，临床反应和无进展生存期趋势的稳定延续，将有可能支持以AZD9291作为晚期EGFR突变非小细胞肺癌的治疗策略”
AZD9291是一种不可逆的EGFR T790M突变抑制剂。在大约60%的非小细胞肺癌患者中，产生耐药情况往往与第一代EGFR靶向药引起的T790M突变有关。
基于先前AURA试验数据，在2013年，AZD9291被允许作为一种突破性治疗手段对付EGFR T790M突变的非小细胞肺癌患者。作为该药的研发公司，阿斯利康预计在数月内向FDA提出药物投入应用的申请。
此外，眼下进行第一阶段AURA研究中，在283例接受20mg至240mg等5中剂量AZD9291治疗的晚期非小细胞肺癌患者中，163位患者被发现体内存在T790突变的肿瘤。
纳入试验组缓则平均年龄为60岁，其中女性占62%，亚洲人占61%,白人占31%。AZD9291被给予那些在经历EGFR抑制剂治疗后疾病进展的晚期非小细胞肺癌患者。
纵观所有剂量水平，对具有EGFR T790M突变的肿瘤患者总缓解率为59%，而在T790M突变阴性的肿瘤患者中，总缓解率为23%。
在接受80mg剂量AZD9291治疗的患者中，最为常见的不良反应为皮疹，约占38%（≥3级 0%）；腹泻约占36%（≥3级 1%）。3/4级别（笔者认为是高级别、高程度的意思）的治疗相关副作用生在14%的患者中。
在接受不同剂量治疗的所有患者中，腹泻发生率为50%，皮疹发生率为46%。副作用普遍为低级别的。3/4级的治疗引起的副作用发生在17%的患者中。
我们正通过关注那些疾病潜在的基因驱动因素来努力开发药物，阿斯利康全球药物研发负责人安东尼说道，“我们将在今年第二季度向美国提交AZD9291监管意见书。”
除了AURA试验，AZD9291研究中也被用于EGFR突变非小细胞肺癌患者一线治疗。此外，该疗法也被和MEDI4736，一种抗PD-L1免疫治疗相结合，或与MEK抑制剂司美替尼相结合，或与AZD6094相结合，用于非小细胞肺癌。相关研究数据将在2015ASCO会议上发布。
“我们外延的临床研究项目致力于发掘AZD9291在疾病早期治疗以及联合其他渠道药物，包括免疫肿瘤分子的潜力”安东尼说：“依靠此综合研究方法，我们正在着眼于开发一种有广泛潜力的针对EGFR突变阳性的非小细胞肺癌患者的治疗策略。”