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非小细胞肺癌的靶向治疗:奥希替尼

发表者:张品良 人已读

【非小细胞肺癌NCCN指南2017第7版】

Discussion 讨论

Treatment Approaches 治疗手段

Targeted Therapies 靶向治疗

Oral TKIs 口服的酪氨酸激酶抑制剂

Osimertinib 奥希替尼

As previously mentioned, most patients with sensitizing EGFR mutations and metastatic NSCLC typically progress after about 9 to 13 months of erlotinib, gefitinib, or afatinib therapy. EGFR T790M is a mutation associated with acquired resistance to EGFR TKI therapy and has been reported in about 60% of patients with disease progression after initial response to sensitizing EGFR TKI therapy. Osimertinib (AZD9291) is an oral TKI that inhibits both EGFR sensitizing mutations and T790M. 山东省肿瘤医院呼吸肿瘤内科张品良

如前所述,大多数敏感EGFR突变的转移性NSCLC患者通常在厄洛替尼、吉非替尼或阿法替尼治疗大约9至13个月后进展。EGFR T790M是一种与对EGFR TKI治疗获得性耐药有关的突变,已报道大约60%的患者在初始对敏感EGFR TKI治疗有应答后疾病进展。奥西替尼(AZD9291)是一种口服的TKI,对EGFR敏感突变和T790M均有抑制。

A recent phase 3 randomized trial assessed osimertinib versus platinum-pemetrexed chemotherapy in patients with EGFR T790M positive metastatic NSCLC. Data show that osimertinib increased PFS when compared with chemotherapy (10.1 vs. 4.4 months; HR, 0.30; 95% CI, 0.23–0.41; P<.001). PFS was also increased in patients with CNS metastases who received osimertinib (8.5 vs. 4.2 months; HR, 0.32; 95% CI, 0.21–0.49). In addition, the objective response rate was improved with osimertinib (71%; 95% CI, 65%–76%) when compared with chemotherapy (31%; 95% CI, 24%–40%) (odds ratio for objective response, 5.39; 95% CI, 3.47–8.48; P<.001). The disease control rate is about 93% with osimertinib (95% CI, 90%–96%) and about 74% with chemotherapy (95% CI, 66%–81%). Patients receiving osimertinib had fewer grade 3 or higher adverse events when compared with those receiving chemotherapy (23% vs. 47% [63/279 vs. 64/136]); however, there were 4 fatal events with osimertinib (respiratory failure [2], pneumonitis, ischemic stroke) and one with chemotherapy (hypovolemic shock). 

最近一项3期随机试验评估了奥希替尼对比铂-培美曲塞化疗治疗EGFR T790M阳性的转移性NSCLC患者。数据显示,与化疗相比,奥希替尼延长PFS (10.1个月对4.4个月;HR,0.30;95 %CI,0.23-0.41;P<0.001)。在接受奥希替尼的中枢神经系统转移的患者中,PFS也延长(8.5个月对4.2个月;HR,0.32;95 %CI,0.21-0.49)。此外,客观应答率与化疗 (31%;95%CI,24%-40%)相比奥希替尼增加(71%;95% CI,65%-76%)(客观应答比值比,5.39;95%CI,3.47-8.48;P<0.001)。疾病控制率奥希替尼约为93%(95%CI,90%-96%),而化疗约为74%(95%CI,66%-81%)。与接受化疗的患者相比,接受奥希替尼者3度或更严重的不良事件更少(23%对47%[63/279对64/136]);不过,奥希替尼有4个致命事件(呼吸衰竭[2]、肺炎、缺血性中风)而化疗为1个(低血容量性休克)。

Data from a multicenter, single-arm phase 2 clinical trial indicate that osimertinib is associated with a response rate of about 61% (78/127; 95% CI, 52–70), PFS of 9.6 months (95% CI, 8.3 to not reached), and disease control rate of about 95% (121/127; 95% CI, 90–98) in patients with EGFR T790M who have progressed on sensitizing EGFR TKI therapy; 13% (33/253) of patients had drug-related grade 3 or higher adverse events with one fatal event from pneumonia possibly related to treatment. In patients without EGFR T790M, the response rate was 21% (13/61; 95% CI, 12–34) and the PFS was 2.8 months (95% CI, 2.1–4.3). 

来自多中心的数据,单臂2期临床试验表明,在敏感EGFR TKI治疗已经进展的EGFR T790M患者中,奥希替尼的应答率约为61%(78/127;95%CI,52-70)、PFS为9.6个月(95%CI,8.3-未达到)、疾病控制率约95%(121/127;95%CI,90-98) ; 13%(33/253)的患者有药物相关的3级或以上不良事件,1例致死性肺炎,可能与治疗有关。无EGFR T790M的患者,有效率为21%(13/61;95%CI,12-34)、PFS为2.8个月(95%CI,2.1-4.3)。

The FDA has approved osimertinib for patients with metastatic EGFR T790M-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy. Based on the data and FDA approval, the NCCN Panel recommends osimertinib (category 1) as subsequent therapy for patients with metastatic EGFR T790M-positive NSCLC who have progressed on erlotinib, gefitinib, or afatinib therapy (see Second-Line and Beyond (Subsequent) Systemic Therapy in this Discussion). For the 2017 update (Version 4), the NCCN Panel revised the recommendation to category 1 (from category 2A) for osimertinib in patients with EGFR T790M-positive metastatic NSCLC based on the recent phase 3 randomized trial. T790M can be assessed using an FDA-approved test or other validated laboratory test done in a CLIA-approved laboratory. Recent data suggest that plasma genotyping (also known as liquid biopsy or plasma biopsy) may be considered instead of tissue biopsy to detect whether patients have T790M; however, if the plasma biopsy is negative, then tissue biopsy is recommended if feasible. For the 2017 update (Version 4), the NCCN Panel now also recommends osimertinib (category 1) for patients with T790M who have progression with symptomatic brain metastases based on data showing an improvement. 

FDA已批准奥希替尼用于以FDA批准的试验检测的EGFR T790M阳性、在EGFR TKI治疗时或治疗后进展的转移性NSCLC患者。基于数据和FDA的批准,NCCN小组推荐奥希替尼(1类)作为EGFR T790M阳性、在厄洛替尼、吉非替尼或阿法替尼治疗后进展的转移性NSCLC患者的后续治疗(见本讨论中的二线和以上(后续)全身治疗)。2017第4版更新,对于EGFR T790M阳性的转移性NSCLC患者,基于最近3期随机试验,NCCN小组将奥希替尼的推荐从2A类修订为1类。T790M可以在CLIA认可的实验室使用FDA批准的试验或其他批准的实验室检测进行评估。最近的数据表明,血浆基因分型(也称为液体活检或血浆活检)认为可代替组织活检来检测患者是否有T790M;不过,如果血浆活检阴性,如果可行,则推荐进行组织活检。2017第4版更新,对于那些具有T790M、病情进展有脑转移症状的患者,根据显示进展的数据,NCCN小组现在也推荐奥希替尼(1类)。

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发表于:2017-07-10 14:05

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