非小细胞肺癌NCCN指南2017第4版讨论:阿法替尼

非小细胞肺癌NCCN指南2017第4版讨论:靶向治疗

Afatinib 阿法替尼

A randomized phase 3 trial reported that first-line therapy with afatinib improved PFS when compared with cisplatin/pemetrexed in patients with metastatic adenocarcinoma who have sensitizing EGFR mutations (11.1 vs. 6.9 months, P = .001). The FDA has approved afatinib for first-line treatment of patients with metastatic NSCLC who have sensitizing EGFR mutations. Based on this phase 3 randomized trial and the FDA approval, the NCCN Panel recommends afatinib for first-line therapy (category 1) in patients with metastatic non-squamous NSCLC who have sensitizing EGFR mutations (see the NCCN Guidelines for NSCLC). Afatinib may also be continued in patients who have progressed if patients do not have multiple systemic symptomatic lesions (see Continuation of Erlotinib, Gefitinib, or Afatinib After Progression in this Discussion). However, afatinib is not recommended as subsequent therapy based on a recent phase 3 randomized trial (see Second-Line and Beyond (Subsequent) Systemic Therapy in this Discussion). 一项3期随机试验报告，在敏感EGFR突变的转移性腺癌患者中，与顺铂/培美曲塞相比，一线治疗用阿法替尼改善PFS（11.1个月对6.9个月，P=0.001）。FDA已批准阿法替尼用于具有敏感EGFR突变的转移性NSCLC患者的一线治疗。基于这项3期随机试验和FDA的批准，NCCN专家组推荐阿法替尼用于有敏感EGFR突变的转移性非鳞NSCLC患者的一线治疗（1类）（见NSCLC NCCN指南）。在已经进展的患者中，如果病人没有全身多发有症状的病变，也可以继续给予阿法替尼（见本讨论中的在厄洛替尼、吉非替尼或阿法替尼进展后的延续）。然而，根据最近一项3期随机试验，不推荐阿法替尼作为后续治疗（见本讨论中的二线和更多线[后续]全身治疗）。

A recent phase 2B trial assessed afatinib compared with gefitinib for first-line therapy in patients with metastatic adenocarcinoma and sensitizing EGFR mutations. The PFS was essentially the same in patients receiving afatinib when compared with those receiving gefitinib (median PFS, 11.0 months [95% CI, 10.6–12.9] with afatinib vs. 10.9 months [9.1–11.5] with gefitinib; HR, 0.73 [95% CI, 0.57–0.95]; P=.017). These slight PFS differences are not clinically relevant and the NCCN Guidelines do not state that one EGFR TKI is more efficacious than another (see the NCCN Evidence Blocks for NSCLC, available at NCCN.org). Overall survival data are not yet available. Patients receiving afatinib had more serious treatment-related side effects when compared with those receiving gefitinib (11% [17/160] for afatinib vs.4% [7/159] for gefitinib). One patient receiving gefitinib died from treatment-related hepatic and renal failure; other deaths were not considered to be related to treatment (9% vs. 6% [15/160 vs. 10/159]). More patients receiving afatinib had diarrhea (13% vs. 1%), whereas more patients receiving gefitinib had elevations in liver enzyme levels (0% vs. 9%). For the 2017 update (Version 1), the NCCN Panel revised the afatinib evidence block for efficacy to highly effective (ie, the highest rating of 5), so the value is now the same as that for erlotinib and gefitinib (see the NCCN Evidence Blocks for NSCLC, available at NCCN.org). However, afatinib is rated as slightly less safe than erlotinib or gefitinib (ie, a rating of 3 for afatinib versus 4 for erlotinib and gefitinib). 最近一项2B期试验评估了阿法替尼对比吉非替尼一线治疗EGFR敏感突变的转移性腺癌患者。与接受吉非替尼者相比，接受阿法替尼的患者PFS基本上是相同的（中位PFS，阿法替尼11个月[95% CI，10.6–12.9]对吉非替尼10.9个月[9.1–11.5]；风险比，0.73 [95%CI，0.57-0.95]；P = 0.017）。这些轻微的PFS差异没有临床相关性，因此NCCN指南没有说明一个EGFR TKI比另一个更有效（见NSCLC的NCCN证据组成，可在NCCN.org获得）。总生存数据尚未公布。与接受吉非替尼者相比，接受阿法替尼的患者有更严重的治疗相关副作用（阿法替尼11%[17/160]对吉非替尼4%[7/159]）。一例接受吉非替尼的患者死于治疗相关的肝肾功能衰竭；并不认为其他死亡与治疗相关（9%[15/160]对6%[10/159]）。接受阿法替尼的患者腹泻更多（13%对1%），而接受吉非替尼的患者肝酶水平升高更多（0%对9%）。2017第1版更新，NCCN小组修改阿法替尼疗效非常有效的证据组成（即最高等级5），所以现在与厄洛替尼和吉非替尼的价值相同（见NSCLC的NCCN证据组成，可在NCCN.org获得）。然而，阿法替尼等级安全性比厄洛替尼或吉非替尼略差（即阿法替尼等级3对厄洛替尼和吉非替尼等级4）。