非小细胞肺癌NCCN指南2017第4版:靶向治疗讨论
2018年07月27日 【健康号】 张品良

非小细胞肺癌NCCN指南2017第4版讨论:靶向治疗山东省肿瘤医院呼吸肿瘤内科张品良

(本文内容很多,可跳转至感兴趣的部分阅读(点击相应的靶向药物即可跳转):贝伐单抗 厄洛替尼 吉非替尼 阿法替尼 奥西替尼 克唑替尼 色瑞替尼 阿雷替尼 西妥昔单抗 尼鲁单抗 派姆单抗 阿特珠单抗 雷莫芦单抗)

Targeted Therapies 靶向治疗

Specific targeted therapies are available for the treatment of advanced NSCLC. Bevacizumab is a recombinant monoclonal antibody that blocks the vascular endothelial growth factor. Erlotinib, gefitinib, and afatinib are small molecule inhibitors of EGFR; osimertinib targets T790M. Crizotinib is a small molecule inhibitor that targets ALK, ROS1, and MET (ie, high-level MET amplification, MET exon 14 skipping mutation). Ceritinib is a small molecule inhibitor that targets ALK and IGF-1 receptor. Alectinib is a small molecule inhibitor that targets ALK and RET. Erlotinib, gefitinib, afatinib, crizotinib, ceritinib, alectinib, and osimertinib are oral TKIs. Other targeted therapies are being developed (see Emerging Targeted Agents for Patients with Genetic Alterations in the NCCN Guidelines for NSCLC). 对于晚期非小细胞肺癌的治疗有可用的特异性靶向治疗。贝伐单抗是一种阻断血管内皮生长因子的重组单克隆抗体。厄洛替尼、吉非替尼和阿法替尼是EGFR小分子抑制剂;奥希替尼靶向T790M。克唑替尼是一种靶向ALK、ROS1和MET(即高水平MET扩增、MET外显子14跳跃突变)的小分子抑制剂。色瑞替尼是一种靶向ALK和IGF-1受体的小分子抑制剂。阿雷替尼是一种靶向ALK和RET的小分子抑制剂。厄洛替尼、吉非替尼、阿法替尼、克唑替尼、色瑞替尼、阿雷替尼和奥希替尼是口服的TKIs(酪氨酸激酶抑制剂)。其他靶向治疗正在开中(见NSCLC NCCN指南中的具有遗传学改变患者的新兴靶向药物)。

Bevacizumab 贝伐单抗

In 2006, the FDA approved bevacizumab for patients with unresectable, locally advanced, recurrent, or metastatic non-squamous NSCLC. The ECOG recommends bevacizumab in combination with paclitaxel/carboplatin for select patients with advanced non-squamous NSCLC based on the results of phase 2 to 3 clinical trials (ECOG 4599). To receive treatment with bevacizumab and chemotherapy, patients must meet the following criteria: non-squamous NSCLC and no recent history of hemoptysis. Any regimen with a high risk for thrombocytopenia—and, therefore, possible bleeding—should be used with caution when combined with bevacizumab. Bevacizumab in combination with chemotherapy (ie, carboplatin/paclitaxel, carboplatin/pemetrexed, cisplatin/pemetrexed) is one of the recommended options for patients with a PS 0 to 1 and non-squamous NSCLC or NSCLC NOS and negative or unknown test results for ALK or ROS1 rearrangements, sensitizing EGFR mutations, or PD-L1 expression (see Sensitizing EGFR Mutation Positive/First-Line Therapy or ALK Positive/First-Line Therapy in the NCCN Guidelines for NSCLC). Bevacizumab is not recommended for patients with squamous cell NSCLC. 2006年,FDA批准贝伐单抗用于治疗不能切除的、局部晚期、复或转移性非鳞NSCLC。基于2-3期临床试验(ECOG 4599)的结果,对于选择性晚期非鳞NSCLC患者ECOG推荐贝伐单抗联合紫杉醇/卡铂。接受贝伐单抗和化疗治疗的患者必须满足以下条件:非鳞NSCLC并且近期无咯血史。因此,任何可能出血的高危血小板减少症方案,当联合贝伐单抗时均应慎重。对于PS 0-1、非鳞NSCLC或NSCLC NOS、ALK和ROS1重排检测结果阴性或未知、敏感EGFR突变或PD-L1表达的患者,贝伐单抗联合化疗(即卡铂/紫杉醇、卡铂/培美曲塞、顺铂/培美曲塞)是推荐的一个选择(见NSCLC NCCN指南中的敏感EGFR突变阳性/一线治疗或ALK阳性/一线治疗)。对于肺鳞癌患者不推荐使用贝伐单抗。

Erlotinib and Gefitinib 厄洛替尼和吉非替尼

In 2004, erlotinib was approved by the FDA for the treatment of patients with locally advanced or metastatic NSCLC after progression on at least one prior chemotherapy regimen. The FDA has also approved the use of erlotinib as first-line therapy in patients with sensitizing EGFR mutations. Erlotinib and gefitinib are recommended (category 1) in the NSCLC algorithm as first-line therapy in patients with advanced, recurrent, or metastatic non-squamous NSCLC who have known active sensitizing EGFR mutations regardless of their PS (see Sensitizing EGFR Mutation Positive in the NCCN Guidelines for NSCLC). These recommendations are based on a phase 3 randomized trial (IPASS) in which patients with sensitizing EGFR mutations who received gefitinib had increased PFS (24.9% vs. 6.7%), response rate (71.2% vs. 47.3%), and quality of life with fewer side effects (eg, neutropenia) when compared with those receiving chemotherapy (carboplatin/paclitaxel). Updated results from the IPASS study showed that overall survival was similar in patients receiving gefitinib or chemotherapy regardless of sensitizing EGFR mutation status. However, these results probably occurred because patients who had been assigned to first-line chemotherapy were able to receive TKIs as subsequent therapy if they were found to have sensitizing EGFR mutations. A phase 3 randomized trial (EURTAC) in European patients with metastatic NSCLC and sensitizing EGFR mutations showed increased PFS and response rate for those receiving erlotinib when compared with chemotherapy. For erlotinib, the median PFS was 9.7 months compared with 5.2 months for chemotherapy (HR, 0.37; 95% CI, 0.25–0.54; P < .0001). Fewer patients receiving erlotinib had severe adverse events or died when compared with those receiving chemotherapy. 2004年,FDA批准厄洛替尼用于治疗在既往至少一个化疗方案后进展的局部晚期或转移性NSCLC患者。FDA也已批准厄洛替尼作为敏感EGFR突变患者的一线治疗。在NSCLC工作步骤中推荐厄洛替尼和吉非替尼(1类)作为已知活化敏感EGFR突变的晚期、复或转移性非鳞NSCLC患者的一线治疗,不管其一般情况如何(见NSCLC NCCN指南中的敏感EGFR突变阳性)。这些推荐是基于一项3期随机试验(IPASS):与接受化疗(卡铂/紫杉醇)者相比,接受吉非替尼的敏感EGFR突变患者改善了PFS(24.9%对6.7%)、有效率(71.2%对47.3%)和生活质量,具有较少的副作用(如中性粒细胞减少)。IPASS研究的更新结果表明,接受吉非替尼或化疗的患者总生存相似,与敏感EGFR突变状态无关。然而,出现这些结果可能是因为分配到一线化疗的患者如果现他们有敏感EGFR突变能够接受TKIs作为后续治疗。欧洲在转移性、敏感EGFR突变的NSCLC患者中的一项3期随机试验(EURTAC)显示,与化疗相比,接受厄洛替尼者PFS和有效率增加。厄洛替尼中位PFS为9.7个月,而化疗是5.2个月(HR 0.37,95% CI,0.25–0.54;P < 0.0001)。与接受化疗者相比,接受厄洛替尼的患者严重不良事件或死亡更少。

TKIs are recommended in patients with metastatic NSCLC and sensitizing EGFR mutations, because quality of life is improved when compared with chemotherapy. Previously, erlotinib was commonly used in the United States in patients with sensitizing EGFR mutations because of restrictions on the use of gefitinib. However, gefitinib was reapproved by the FDA based on a phase 4 study and is now available in the United States. Erlotinib and gefitinib are orally active TKIs that are very well tolerated by most patients. An analysis of 5 clinical trials in patients, mainly from the Western hemisphere, (n = 223) with advanced NSCLC (stage IIIB or IV) found that those with sensitizing EGFR mutations who received TKIs had a 67% response rate and an overall survival of about 24 months. The TORCH trial suggested that EGFR mutation testing should be done in patients with advanced non-squamous NSCLC. Survival was increased in patients with wild-type EGFR who received first-line chemotherapy compared with those who received erlotinib first followed by subsequent chemotherapy (11.6 vs. 8.7 months). The OPTIMAL trial reported that PFS was increased in patients with sensitizing EGFR mutations who received erlotinib. ASCO recommends that patients be tested for EGFR mutations. However, the ESMO Guidelines specify that only patients with non-squamous NSCLC (eg, adenocarcinoma) be assessed for EGFR mutations. Patients with pure squamous cell carcinoma are unlikely to have sensitizing EGFR mutations; however, those with adenosquamous carcinoma may have mutations. 具有敏感EGFR突变的转移性NSCLC患者推荐TKIs,因为与接受化疗者相比生活质量改善。从前在美国由于限制吉非替尼的使用,敏感EGFR突变的患者常用厄洛替尼。然而,基于一项4期研究,FDA重新审批通过吉非替尼,因此目前在美国可以使用。厄洛替尼和吉非替尼是口服有效的TKIs,大多数患者耐受性很好。对5个临床试验中的患者,主要来自西半球(n=223)且为晚期(ⅢB或Ⅳ)的一项分析现,具有敏感EGFR突变者接受TKIs治疗的有效率为67%,总生存期约24个月。TORCH试验提示,在晚期非鳞NSCLC患者中应进行EGFR突变检测。在EGFR野生型患者中,与那些先接受厄洛替尼然后序贯化疗者相比,接受一线化疗者生存期延长(11.6对 8.7个月)。OPTIMAL试验报告,敏感EGFR突变接受厄洛替尼的患者PFS延长。ASCO推荐患者检测EGFR突变。但是,ESMO指南规定,只有非鳞NSCLC(如腺癌)患者才评估EGFR突变。纯鳞状细胞癌患者不太可能有敏感EGFR突变;不过,那些腺鳞癌患者可能有突变。

An updated study (CALGB 30406) compared erlotinib alone versus erlotinib/carboplatin/paclitaxel in patients (mainly Caucasian) with advanced NSCLC. The data showed that erlotinib alone was associated with fewer side effects in patients with sensitizing EGFR mutations when compared with erlotinib/chemotherapy. Thus, it is appropriate to interrupt or complete planned chemotherapy and switch to erlotinib, gefitinib, or afatinib therapy in patients found to have sensitizing EGFR mutations during chemotherapy (see EGFR Mutation Positive/First-Line Therapy in the NCCN Guidelines for NSCLC). The NCCN Guidelines do not recommend adding erlotinib, gefitinib, or afatinib to current chemotherapy based on this CALGB study. Erlotinib, gefitinib, or afatinib may 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). 一项更新的研究(CALGB 30406)比较了单独厄洛替尼与厄洛替尼/卡铂/紫杉醇治疗晚期NSCLC患者(主要是白人)。数据表明,与厄洛替尼/化疗相比,敏感EGFR突变患者单纯厄洛替尼治疗副作用更少。因此,化疗期间现具有敏感EGFR突变的患者中断或完成计划的化疗然后转换至厄洛替尼、吉非替尼或阿法替尼治疗是合适的(见NSCLC NCCN指南中的EGFR突变阳性/一线治疗)。基于该CALGB研究,NCCN指南不推荐目前的化疗加厄洛替尼、吉非替尼或阿法替尼。在已经进展的患者中,如果没有全身多有症状的病变,可以继续使用厄洛替尼、吉非替尼或阿法替尼(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)。

A recent phase 3 trial (WJOG 5108L) assessed gefitinib versus erlotinib for patients with advanced lung cancer who had been previously treated with chemotherapy; most patients (72%) were positive for EGFR mutations. The median PFS for gefitinib versus erlotinib was 8.3 and 10.0 months, respectively, in patients positive for EGFR mutations (HR, 1.093; 95% CI, 0.879–1.358; P = .424). The main grade 3 or 4 toxicities included rash (gefitinib: 2.2% vs. erlotinib: 18.1%) and increases in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels (gefitinib: 6.1%/13.0% vs. erlotinib: 2.2%/3.3%). 最近一项3期试验(WJOG 5108L)评估了吉非替尼与厄洛替尼治疗曾接受过化疗的晚期肺癌患者;大多数患者(72%)EGFR突变阳性。在EGFR突变阳性的患者中,中位PFS吉非替尼与厄洛替尼分别为8.3个月和10.0个月(HR,1.093;95% CI,0.879-1.358;P=0.424)。主要的3或4级毒性包括皮疹(吉非替尼:2.2%对厄洛替尼:18.1%)和丙氨酸转氨酶(ALT)/天门冬氨酸氨基转移酶(AST)水平升高(吉非替尼:6.1%/13%对厄洛替尼:2.2%/3.3%)。

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)。

Osimertinib 奥西替尼

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. 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已经批准奥西替尼用于以FDA批准的试验检测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)。

Crizotinib 克唑替尼

Crizotinib is approved by the FDA for patients with locally advanced or metastatic NSCLC who are positive for the ALK gene rearrangement. The approval is based on a phase 2 trial that showed dramatic response rates (>80%) to crizotinib in patients who had previously progressed. Patients receiving crizotinib reported clinically significant improvements in pain, dyspnea, and cough. A phase 3 trial compared first-line crizotinib versus chemotherapy in patients with ALK rearrangements; patients receiving crizotinib had improved PFS, quality of life, and response rates when compared with those receiving chemotherapy. The NCCN Panel recommends first-line therapy with crizotinib (category 1) based on this phase 3 trial and the FDA approval; the panel also feels that crizotinib is appropriate for patients with PS 0 to 4. Crizotinib may also be continued for patients with ALK rearrangements who have progressed if patients do not have multiple systemic symptomatic lesions. FDA批准克唑替尼用于ALK基因重排阳性的局部晚期或转移性NSCLC患者。批准是基于一项2期试验显示既往已经进展的患者对克唑替尼戏剧性的应答(>80%)。接受克唑替尼的患者报告临床上显著改善疼痛、呼吸困难和咳嗽。一项3期试验在ALK重排的患者中对比一线克唑替尼与化疗;与接受化疗者相比,接受克唑替尼的患者PFS、生活质量和有效率均改善。基于这项3期试验和FDA的批准,NCCN专家推荐克唑替尼一线治疗(1类);小组还认为,克唑替尼适于PS 0-4的患者。对于已经进展的ALK重排患者,如果患者没有全身多有症状的病变,克唑替尼也可以继续使用。

Crizotinib is also very effective for patients with ROS1 rearrangements with response rates of about 70% including complete responses (see ROS1 Rearrangements in this Discussion). For the 2017 update (Version 1), the NCCN Panel moved the recommendation for ROS1 testing into the main algorithm (and deleted the footnote recommending ROS1 testing), added a new algorithm for ROS1, and added a new section on ROS1 to the molecular diagnostic studies section based on data showing the efficacy of crizotinib for patients with ROS1 rearrangements and on the recent FDA approval (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). Alectinib and ceritinib are not effective in patients with ROS1 rearrangements whose disease become resistant to crizotinib. 对于具有ROS1重排的患者,克唑替尼也是非常有效的,有效率约70%,包括完全缓解(见本讨论中的ROS1重排)。2017第1版更新,NCCN小组将ROS1检测的推荐移到主要工作步骤中(同时删除了推荐ROS1检测的脚注),根据克唑替尼对ROS1重排患者有效的数据和最近FDA的批准,增加了一个新的ROS1工作步骤,并增加了ROS1分子诊断研究的新章节(见NSCLC NCCN指南中的病理检查原则)。阿雷替尼和色瑞替尼对克唑替尼耐药的ROS1重排患者无效。

Ceritinib 色瑞替尼

Ceritinib is approved by the FDA for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. The approval is based on an expanded phase 1 study (ASCEND-1) showing overall response rates of 56% to ceritinib in patients (92/163) who had previously received crizotinib; the median duration of response was 8.3 months (6.8-9.7). Common grade 3 to 4 adverse events included increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). Some patients with CNS lesions responded to ceritinib. Based on the study and the FDA approval, the NCCN Panel recommends ceritinib as subsequent therapy for patients with ALK-positive NSCLC who have progressed after crizotinib; patients who do not tolerant crizotinib may be switched to ceritinib or alectinib. A recent phase 2 trial (ASCEND-2) assessed ceritinib in patients who had previously received at least 2 or more treatments, had progressed on crizotinib, and had brain metastases. The overall response rate was 38%; the duration of response was 9.7 months (95% CI, 7.1–11.1 months). The intracranial overall response rate was 45.0% (95% CI, 23.1%–68.5%). FDA批准了色瑞替尼用于克唑替尼进展或不能耐受、ALK阳性的转移性NSCLC患者。批准是根据一项扩展的1期研究(ASCEND-1)显示,在既往已接受克唑替尼治疗的患者中,色瑞替尼治疗的总有效率为56%(92/163);中位疗效持续时间是8.3个月(6.8-9.7)。常见的3-4级不良事件包括丙氨酸氨基转移酶升高(73例[30%])及天冬氨酸转氨酶升高(25例[10%])。某些具有CNS病变的患者对色瑞替尼应答。基于该研究和FDA的批准,研究小组建议色瑞替尼作为ALK阳性的NSCLC患者在克唑替尼进展后的后续治疗;不耐受克唑替尼的患者可以转换至色瑞替尼或阿雷替尼。最近一项2期试验(ASCEND-2)评估了色瑞替尼治疗既往曾接受过至少2个或以上治疗、克唑替尼进展并有脑转移的患者。总有效率是38%;疗效持续时间是9.7个月(95%CI,7.1-11.1个月)。颅内病变总有效率为45.0%(95%CI,23.1%-68.5%)。

Alectinib 阿雷替尼

Alectinib is approved by the FDA for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. The approval is based on two phase 2 trials showing overall response rates of 48% to 50% to alectinib in patients who had previously received crizotinib. In the larger trial by Ou et al, the control rate for CNS disease was 83% (95% CI, 74%–91%), and the median duration of response was 10.3 months (95% CI, 7.6–11.2 months). Of 84 patients with baseline CNS metastases, 23 (27%) had a complete CNS response. Of 23 patients with baseline CNS metastases and without previous brain RT, 10 (43%) had a complete CNS response to alectinib. Based on these trials and the FDA approval, the NCCN Panel recommends alectinib as subsequent therapy for patients with ALK-positive NSCLC who have progressed after crizotinib; patients who do not tolerant crizotinib may be switched to alectinib or ceritinib. FDA批准了阿雷替尼用于克唑替尼进展或不能耐受、ALK阳性的转移性NSCLC患者。批准是基于两项2期试验显示在既往接受过克唑替尼的患者中阿雷替尼的总有效率为48%-50%。在Ou等的更大试验中,CNS疾病的控制率为83%(95% CI,74%-91%),中位疗效持续时间是10.3个月(95% CI,7.6-11.2个月)。基线CNS转移的84例患者中,23例(27%)CNS完全缓解。23例基线CNS转移、既往未行脑RT的患者中,阿雷替尼治疗后10例(43%)CNS完全缓解。基于这些试验和FDA的批准,研究小组推荐阿雷替尼作为ALK阳性NSCLC患者在克唑替尼进展后的后续治疗;不耐受克唑替尼的患者可以转换至阿雷替尼或色瑞替尼。

Cetuximab 西妥昔单抗

Cetuximab is a monoclonal antibody that targets EGFR. A large phase 3 randomized trial (FLEX) assessed cisplatin/vinorelbine with (or without) cetuximab for patients with advanced NSCLC; most patients had stage IV disease. Adding cetuximab was reported to slightly increase overall survival (11.3 vs. 10.1 months, HR for death, 0.87 [95% CI, 0.762–0.996]; P=.044). Patients receiving cetuximab had increased grade 4 events versus control (62% vs. 52%, P < .01); cetuximab was also associated with grade 2 acne-like rash. 西妥昔单抗是一种靶向EGFR的单克隆抗体。一项大型3期随机试验(FLEX)评估了顺铂/长春瑞滨±西妥昔单抗治疗晚期NSCLC;大多数患者为Ⅳ期。报道增加西妥昔单抗总生存期略有改善(11.3个月对10.1个月,死亡风险比,0.87[95% CI,0.762–0.996];P=0.044)。与对照组相比,接受西妥昔单抗的患者4度不良事件增加(62%对52%,P<0.01);西妥昔单抗还与2度痤疮样皮疹有关。

The cetuximab/cisplatin/vinorelbine regimen was recently removed from the NCCN Guidelines. The benefits of this cetuximab-based regimen are very slight, it is a difficult regimen to administer, and patients have poorer tolerance for this regimen when compared with other regimens; for example, almost 40% of patients have grade 4 neutropenia. Patients may also have comorbid conditions that prevent them from receiving cisplatin such as poor kidney function. Cisplatin/vinorelbine with (or without) cetuximab is generally not used in the United States because of concerns about toxicity. Some oncologists feel that although the FLEX trial results were reported to be statistically significant they were not clinically significant. For the 2017 update (Version 1), the NCCN Panel deleted the cisplatin/vinorelbine and carboplatin/vinorelbine regimens from the list of recommended systemic therapy regimens for metastatic NSCLC with all histologies. 最近NCCN指南删除了西妥昔单抗/顺铂/长春瑞滨方案。与其他方案相比,这个以西妥昔单抗为基础的方案获益很少、实施困难,而且患者耐受性较差;例如,将近40%的患者有4度中性粒细胞减少症。患者也可能出现妨碍其接受顺铂的合并症,如肾功能差。因为担心毒性,在美国通常不会用顺铂/长春瑞滨±西妥昔单抗。一些肿瘤学家认为虽然FLEX试验报告的结果有显著的统计学意义,但是并没有临床意义。2017第1版更新,NCCN小组从推荐的治疗各种组织学的转移性NSCLC的全身治疗方案列表中删除了顺铂/长春瑞滨和卡铂/长春瑞滨方案。

Nivolumab 尼鲁单抗

The NCCN Panel recommends nivolumab (category 1) as subsequent therapy for patients with metastatic non-squamous NSCLC who have progressed on or after first-line chemotherapy based on data from a phase 3 randomized trial (CheckMate-057) and FDA approval. The NCCN Panel recommends immune checkpoint inhibitors as preferred agents for subsequent therapy based on improved overall survival rates, longer duration of response, and fewer adverse events when compared with cytotoxic chemotherapy. Human immune-checkpoint–inhibitor antibodies inhibit the PD-1 receptor or PD-1 ligand (PD-L1), which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T-cells. Nivolumab inhibits PD-1 receptors. Immune checkpoint inhibitors are associated with a delay in benefit when compared with targeted therapy or cytotoxic chemotherapy. Pseudoprogression has been reported; therefore, traditional RECIST criteria may not be applicable. 基于一项3期随机试验(CheckMate-057)的数据和FDA的批准,NCCN小组推荐尼鲁单抗(1类)作为转移性非鳞NSCLC患者在一线化疗时或一线化疗后进展者的后续治疗。基于与细胞毒性化疗相比,总生存率改善、应答持续时间更长且不良事件更少,NCCN小组推荐免疫检查点抑制剂作为后续治疗的首选药物。人免疫检查点抑制剂抗体抑制PD-1受体或PD-1配体(PD-L1),改善抗肿瘤免疫;在活化的细胞毒性T细胞上表达PD-1受体。尼鲁单抗抑制PD-1受体。与靶向治疗或细胞毒性化疗相比,免疫检查点抑制剂获益延迟。已报道假性进展;因此,传统的RECIST标准可能不适用。

The category 1 recommendation for nivolumab is based on the published data from CheckMate-057 and FDA approval of nivolumab for patients with metastatic non-squamous NSCLC. For patients receiving nivolumab, median overall survival was 12.2 months compared with 9.4 months for docetaxel (HR, 0.73; 95% CI, 0.59–0.89; P = .002). The median duration of response was 17.2 months with nivolumab compared with 5.6 months for docetaxel. At 18 months, the overall survival rate was 39% (95% CI, 34%–45%) with nivolumab compared with 23% (95% CI, 19%–28%) with docetaxel. Fewer grade 3 to 5 adverse events were reported for nivolumab (10%) when compared with docetaxel (54%) in the CheckMate-057 trial. Although many patients with metastatic non-squamous NSCLC benefit from nivolumab, those whose tumors have PD-L1 staining of 1% to 10% or more have overall survival of 17 to 19 months compared with 8 to 9 months for docetaxel. For patients who did not have PD-L1 expression, there was no difference in overall survival for nivolumab versus docetaxel; however, nivolumab was associated with a longer duration of response and fewer side effects. To help clinicians determine which patients with non-squamous NSCLC may benefit most from treatment with nivolumab, the FDA has approved a complementary diagnostic biomarker test to assess for PD-L1 protein expression. Testing for PD-L1 is not required for prescribing nivolumab but may provide useful information. Current or former smoking status correlated with the response rate to immune checkpoint inhibitors. Recent data suggest that mismatch repair deficiency is associated with response to immune checkpoint inhibitors. 根据CheckMate-057公布的数据和FDA对尼鲁单抗的批准,对于转移性非鳞NSCLC患者,尼鲁单抗为1类推荐。对于接受尼鲁单抗治疗的患者,中位总生存期为12.2个月,而多西他赛为9.4个月(HR,0.73;95% CI,0.59-0.89;P= 0.002)。中位疗效持续时间尼鲁单抗是17.2个月,而多西他赛是5.6个月。在18个月时,总生存率尼鲁单抗是39%(95% CI,34%–45%),而多西他赛是23%(95% CI,19%–28%)。在CheckMate-057试验中报道的3至5度不良事件,尼鲁单抗(10 %)比多西他赛(54%)更少。虽然许多转移性非鳞NSCLC患者从尼鲁单抗治疗中获益,但是那些肿瘤PD-L1染色1%-10%或更高的患者总生存期17-19个月,而多西他赛为8-9个月。对于那些无PD-L1表达的患者,与多西他赛相比,尼鲁单抗总生存无差异;然而,尼鲁单抗具有更长的应答持续时间和更少的副作用。为了帮助临床医生确定哪些非鳞NSCLC患者可能从尼鲁单抗治疗中获益最多,FDA已经批准了一项评估PD-L1蛋白表达的辅助诊断性生物标志物检测。对于处方尼鲁单抗,PD-L1的检测不是必需的,但可能提供有用的信息。目前或以前的吸烟情况与对免疫检查点抑制剂的应答率有关。最新数据表明,错配修复缺陷与对免疫检查点抑制剂的应答有关。

The NCCN Panel also recommends (category 1) nivolumab as subsequent therapy for patients with metastatic squamous cell NSCLC who have progressed on or after first-line chemotherapy based on data from a phase 3 randomized trial (CheckMate-017), the recent FDA approval, and results of a phase 2 trial. In the CheckMate-017 trial, the median overall survival was 9.2 months with nivolumab compared with 6.0 months for docetaxel. Patients had a response rate of 20% with nivolumab compared with 9% for docetaxel (P = .008). PD-L1 expression was not associated with response to nivolumab in patients with squamous cell NSCLC. There were fewer grade 3 to 4 adverse events with nivolumab (7%) when compared with docetaxel (55%). No patients died in the nivolumab arm versus 3 deaths in the docetaxel arm. Immune-related adverse events, such as pneumonitis, may occur with nivolumab. Intravenous high-dose corticosteroids should be administered based on the severity of the reaction for patients with immune-mediated adverse events. Nivolumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). 基于一项3期随机试验(CheckMate-017)的数据、最近FDA的批准以及一项2期试验结果,对于在一线化疗时或一线化疗后进展的转移性肺鳞癌患者,NCCN小组也推荐(1类)尼鲁单抗作为后续治疗。在CheckMate-017试验中,尼鲁单抗中位总生存期是9.2个月,而多西他赛是6.0个月。与多西他赛的有效率9%相比,尼鲁单抗为20%(P = 0.008)。PD-L1表达与肺鳞癌患者对尼鲁单抗的应答无关。与多西他赛(55%)相比,尼鲁单抗具有较少的3-4度不良事件(7%)。尼鲁单抗组没有患者死亡而多西他赛组3人死亡。尼鲁单抗可能会生免疫相关不良事件如肺炎。对于具有免疫介导不良事件的患者,应该根据反应的严重程度给予静脉注射大剂量皮质类固醇激素。对于重度或危及生命的肺炎患者,应该停止尼鲁单抗,而对于其他严重或危及生命的免疫介导不良事件,当有指征时(见处方信息)应该拒绝或中止给药。

Pembrolizumab 派姆单抗

For the 2017 updates (Versions 1 and 2), the NCCN Panel now recommends pembrolizumab (category 1) as first-line therapy for patients with PD-L1 expression levels of 50% or more and with negative or unknown tests results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements based on a recent phase 3 randomized trial (Keynote-024) comparing pembrolizumab versus platinum-based chemotherapy; the FDA recently approved pembrolizumab for first-line therapy based on this trial. At 6 months, the rate of overall survival was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (HR for death, 0.60; 95% CI, 0.41–0.89; P=.005). Reponses were higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%). There were fewer severe treatment-related adverse events (grades 3-5) in patients receiving pembrolizumab compared with those receiving chemotherapy (26.6% vs. 53.3%). 2017第1版和第2版更新,根据最近一项比较派姆单抗与铂类为基础的化疗的3期随机试验(Keynote-024),NCCN小组目前推荐派姆单抗(1类)作为PD-L1表达水平≥50%或EGFR突变、ALK重排以及ROS1重排检测结果阴性或未知患者的一线治疗;基于该试验FDA最近批准了派姆单抗用于一线治疗。在6个月时,总生存率派姆单抗组为80.2%,化疗组为72.4%(死亡风险比,0.60;95%CI,0.41–0.89;P=0.005)。派姆单抗组疗效明显高于化疗组(44.8%对27.8%)。与接受化疗的患者相比,接受派姆单抗的患者严重的治疗相关的不良事件(3-5级)较少(26.6%对53.3%)。

For the 2017 update (Version 1), the NCCN Panel now recommends (category 2A) IHC testing for PD-L1 expression before first-line treatment in patients with metastatic NSCLC with negative or unknown tests results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements. Although it is not an optimal biomarker, PD-L1 expression is currently the best available biomarker to assess whether patients are candidates for pembrolizumab. PD-L1 expression is continuously variable and dynamic; thus, a cutoff value for a positive result is artificial. Patients with PD-L1 expression levels just below and just above 50% will probably have similar responses. Unique anti-PD-L1 IHC assays are being developed for each one of the different immune checkpoint inhibitors currently in clinical trials. The definition of a positive PD-L1 test result varies depending on which biomarker assay is used. 2017第1版更新,在EGFR突变、ALK重排和ROS1重排检测结果阴性或未知的转移性NSCLC患者中,NCCN小组目前推荐(2A类)在一线治疗前免疫组化检测PD-L1的表达。尽管它不是一个最佳的生物标志物,但是目前评估患者是否适合派姆单抗,PD-L1的表达是最好的生物标志物。PD-L1的表达是持续动态变化的;因此,阳性截断值是人为的。PD-L1表达水平略低于和略高于50%的患者有可能具有相似的疗效。正在开针对每个不同免疫检查点抑制剂的特异性抗PD-L1免疫组化检测,目前在临床试验中。PD-L1检测结果阳性的定义取决于使用的生物标记法。

Ideally, PD-L1 expression levels are assessed in patients with negative or unknown test results for EGFR mutations, ALK rearrangements, or ROS1 rearrangements. Every effort needs to be made to establish the genetic alteration status. However, if the risk of biopsy is high and genetic alteration testing is not feasible and therefore technically unknown, then it is appropriate to test for PD-L1 expression levels. Of note, there are blood assays to evaluate for EGFR mutations and ALK rearrangements although they are less sensitive than tissue assays. 理想情况下,在EGFR突变、ALK重排或ROS1重排检测结果阴性或未知的患者中评估PD-L1表达水平。需要尽力确定遗传改变情况。不过,如果活检的风险很高、遗传学改变检测不可行、在技术上来说未知,那么检测PD-L1表达水平是合适的。值得注意的是,有EGFR突变和ALK重排的血液检测评估,尽管比组织检测敏感性差。

The NCCN Panel also recommends pembrolizumab (category 1) as subsequent therapy for patients with metastatic non-squamous or squamous NSCLC and PD-L1 expression based on the randomized phase 2/3 trial (KEYNOTE-010), the phase 1 KEYNOTE-001 trial, and FDA approval. In addition, the NCCN Panel recommends immune checkpoint inhibitors as preferred agents for subsequent therapy. As previously mentioned, human immune-checkpoint–inhibitor antibodies inhibit the PD-1 receptor or PD-L1, which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T-cells. Pembrolizumab inhibits the PD-1 receptor. 基于2/3期随机试验(KEYNOTE-010)、1期KEYNOTE-001试验和FDA的批准,NCCN小组也推荐派姆单抗作为PD-L1表达的转移性非鳞或鳞型NSCLC患者的后续治疗(1类)。此外,NCCN小组推荐免疫检查点抑制剂作为后续治疗的首选药物。如前所述,人免疫检查点抑制剂抗体抑制PD-1或PD-L1,提高抗肿瘤免疫;在活化的细胞毒性T细胞上表达PD-1受体。派姆单抗抑制PD-1受体。

A randomized phase 2/3 trial (KEYNOTE-010) assessed pembrolizumab in patients with previously treated advanced non-squamous and squamous NSCLC who were PD-L1 positive ( 1%); most patients were current or former smokers. There were 3 arms in this trial: pembrolizumab at 2 mg/kg, pembrolizumab at 10 mg/kg, and docetaxel at 75 mg/m2 every 3 weeks. The median overall survival was 10.4 months for the lower dose of pembrolizumab, 12.7 months for the higher dose, and 8.5 months for docetaxel. Overall survival was significantly longer for both doses of pembrolizumab when compared with docetaxel (pembrolizumab 2 mg/kg: HR, 0.71; 95% CI, 0.58–0.88; P=.0008) (pembrolizumab 10 mg/kg: HR, 0.61; CI, 0.49–0.75; P<.0001). For those patients with at least 50% PD-L1 expression in tumor cells, overall survival was also significantly longer at either dose of pembrolizumab when compared with docetaxel (pembrolizumab 2 mg/kg: 14.9 vs. 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P=.0002) (pembrolizumab 10 mg/kg: 17.3 vs. 8.2 months; HR, 0.50; CI, 0.36–0.70; P<.0001). When compared with docetaxel, there were fewer grade 3 to 5 treatment-related adverse events at either dose of pembrolizumab (pembrolizumab 2 mg/kg: 13% [43/339] of patients, pembrolizumab 10 mg/kg: 16% [55/343], and docetaxel: 35% [109/309]). A total of 6 treatment-related deaths occurred in patients receiving pembrolizumab (3 at each dose) and 5 treatment-related deaths occurred in the docetaxel arm. 一项随机2/3试验(KEYNOTE-010)评估了派姆单抗治疗既往治疗过的、PD-L1阳性(≥1%)的晚期非鳞和鳞型NSCLC患者;大部分都是当前或既往吸烟者。在这项试验中有3组:派姆单抗2mg/kg、派姆单抗10mg/kg、多西他赛75mg/㎡每3周1次。中位总生存期:派姆单抗较低剂量组为10.4个月、高剂量组为12.7 个月,而多西他赛组为8.5个月。与多西他赛相比,两个剂量的派姆单抗组总生存期显著更长(派姆单抗2mg/kg:HR 0.71;95%CI,0.58–0.88;P =0.0008)(派姆单抗10mg/kg:HR 0.61;CI,0.49–0.75;P<0.0001)。对于那些至少50%的肿瘤细胞表达PD-L1的患者,与多西他赛相比,派姆单抗两个剂量中的任一剂量总生存期也显著更长(派姆单抗2mg/kg:14.9对8.2个月;HR 0.54;95%CI,0.38-0.77;P =0.0002) (派姆单抗10mg/kg:17.3对8.2个月;HR 0.50;CI,0.36-0.70;P <0.0001)。与多西他赛相比,任一剂量的派姆单抗3-5度治疗相关不良事件较少(派姆单抗2mg/kg:13% [43/339]、派姆单抗10mg/kg:16% [55/343],而多西他赛:35% [109/309])。在接受派姆单抗的患者中共有6例治疗相关死亡(每个剂量各3例),而在多西他赛组中生5例治疗相关死亡。

A phase I trial (KEYNOTE-001) assessed the safety and efficacy of pembrolizumab for patients with metastatic NSCLC. Among all patients, the response rate was 19%, the median duration of response was 12.5 months, PFS was 3.7 months, and median overall survival was 12.0 months. Patients with a PD-L1 expression score of at least 50% had a response rate of 45%, PFS of 6.3 months, and overall survival was not reached. Current or former smoking status also correlated with the response rate. Less than 10% of patients had serious grade 3 or more toxicity. 一项I期试验(KEYNOTE-001)评估了派姆单抗治疗转移性NSCLC患者的安全性和有效性。在所有患者中,有效率是19%,中位疗效持续时间是12.5个月,PFS是3.7个月,中位总生存期是12.0个月。PD-L1表达评分至少50%的患者有效率为45%,PFS为6.3个月,总生存期是尚未达到。目前或以前的吸烟情况也与有效率有关。有严重的3级或以上毒性的患者不到10%。

Similar to nivolumab, immune-mediated adverse events may also occur with pembrolizumab. For patients with immune-mediated adverse events, intravenous high-dose corticosteroids should be administered based on the severity of the reaction. Pembrolizumab should also be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). The FDA has approved pembrolizumab as subsequent therapy for patients with metastatic NSCLC whose disease has progressed after platinum-based chemotherapy if their tumors express PD-L1. The FDA has approved a companion diagnostic biomarker test for assessing PD-L1 expression and determining which patients are eligible for pembrolizumab therapy. Other immunotherapeutic agents are being investigated. 与尼鲁单抗相似,派姆单抗也可能生免疫介导的不良事件。对于有免疫介导的不良事件患者,应该根据反应的严重程度给予静脉大剂量糖皮质激素。对于重度或危及生命的肺炎患者也应该停止派姆单抗,并且对于其他严重或危及生命的免疫介导不良事件当有指征时(见处方信息)应该拒绝或中止给药 。FDA已经批准派姆单抗作为转移性NSCLC患者在铂基化疗后疾病进展者的后续治疗,如果其肿瘤表达PD-L1。FDA已经批准了一种评估PD-L1表达的辅助诊断性生物标志物检测,以确定哪些患者适于派姆单抗治疗。其他免疫治疗药物正在研究中。

Atezolizumab 阿特珠单抗

For the 2017 update (Version 4), the NCCN Panel revised the recommendation to category 1 for atezolizumab as subsequent therapy for patients with metastatic non-squamous or squamous cell NSCLC based on a recent phase 3 trial; previously this was a category 2A recommendation based on preliminary data from a phase 3 randomized trial, data from a phase 2 trial, and recent FDA approval. Testing for PD-L1 expression levels is not required for prescribing atezolizumab but may provide useful information. Human immune-checkpoint–inhibitor antibodies inhibit the PD-1 receptor or PD-L1, which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T-cells. Atezolizumab inhibits PD-L1. 2017第4版更新,基于最近一项3期试验,NCCN小组将阿特珠单抗作为转移性非鳞或鳞型NSCLC患者后续治疗的推荐修订为1类;以前这是2A类推荐,基于一项3期随机试验的初步数据、一项2期试验的数据以及最近FDA的批准。处方阿特珠单抗不需要检测PD-L1表达水平,但可能提供有用的信息。人免疫检查点抑制剂抗体抑制PD-1受体或PD-L1,改善抗肿瘤免疫;在活化的细胞毒性T细胞上表达PD-1受体。阿特珠单抗抑制PD-L1。

A phase 3 randomized trial (OAK) assessed atezolizumab versus docetaxel alone in patients with metastatic NSCLC who had progressed during or after systemic therapy. Most patients were current or former smokers and had received platinum-based chemotherapy; few patients (10%) had EGFR mutations and ALK rearrangements were not reported. Data show that patients with non-squamous NSCLC who received atezolizumab had improved overall survival when compared with those receiving docetaxel (15.6 vs. 11.2 months; HR, 0.73 [0.6–0.89]; P = .0015). Overall survival was only slightly improved in patients with squamous cell NSCLC receiving atezolizumab versus docetaxel (8.9 vs. 7.7 months; HR, 0.73 [0.54– 0.98]; P = .038); however, there were fewer patients in the squamous group when compared with the nonsquamous group (222 vs. 628). There were fewer treatment-related severe adverse events (grades 3-4) for atezolizumab versus docetaxel (15% vs. 43% [90/609 vs. 247/578]). For the 2017 update (Version 4), the NCCN Panel revised the atezolizumab evidence block for efficacy to a rating of 4 (very effective); previously the rating was 3 (moderately effective) (see the NCCN Evidence Blocks for NSCLC, available at NCCN.org). 一项3期随机试验(OAK)评估了阿特珠单抗对比多西他赛单药治疗在全身治疗期间或之后进展的转移性NSCLC患者。大多数患者目前或既往吸烟,并接受了以铂为基础的化疗;少数患者(10%)有EGFR突变和ALK重排未报道。初步数据显示,与接受多西他赛的非鳞NSCLC患者相比,接受阿阿特珠单抗者总生存期延长(15.6个月对11.2个月;风险比,0.73[0.6,0.89];P=0.0015)。接受阿特朱单抗的非鳞NSCLC患者的总生存期比多西他赛仅略有改善(8.9个月对7.7个月;风险比,0.73[0.54-0.98];P=0.038);不过,与非鳞组相比,鳞状上皮组患者较少(222对628)。与多西他赛相比,阿特珠单抗治疗相关的严重不良事件(3-4级)较少(15%对43%[60/609对247/578])。2017第4版更新,NCCN小组修订阿特珠单抗的疗效证据组成评级为4(非常有效);以前的评级是3(中等有效)(见NSCLC的NCCN证据组成,可在NCCN.org获得)。

Ramucirumab 雷莫芦单抗

A phase 3 randomized trial (REVEL) assessed ramucirumab/docetaxel versus docetaxel alone in patients with metastatic NSCLC that had progressed. The median overall survival was reported to be slightly increased with ramucirumab/docetaxel versus docetaxel alone (10.5 vs. 9.1 months; HR, 0.86, 95% CI, 0.75–0.98; P<.023). Ramucirumab in combination with docetaxel is approved by the FDA for patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. The NCCN Panel added ramucirumab/docetaxel (category 2A) as an option for subsequent therapy for metastatic NSCLC that has progressed after first-line chemotherapy based on the phase 3 randomized trial and the FDA approval. Some panel members feel that the data are statistically significant but not clinically relevant. More than 70% of patients had grade 3 or higher adverse events in both groups (79% for ramucirumab/docetaxel vs. 71% for docetaxel alone). Adverse events of special concern with ramucirumab/docetaxel therapy include risk for severe hemorrhage, grade 3 to 4 gastrointestinal bleeding, gastrointestinal perforation or fistula, impaired wound healing, and poorly controlled hypertension. There were 16 deaths from grade 3 or worse pulmonary hemorrhage and other adverse events in the REVEL trial: 8 in the ramucirumab/docetaxel arm and 8 in the docetaxel alone arm. 一项3期随机试验(REVEL)评估了雷莫芦单抗/多西他赛与多西他赛单药相比治疗已经进展的转移性NSCLC患者。与多西他赛单药相比,报告的中位总生存期雷莫芦单抗/多西他赛组略微改善(10.5个月对9.1个月;HR 0.86,95%CI,0.75-0.98;P<0.023)。FDA批准了雷莫芦单抗联合多西他赛治疗在铂基化疗时或在化疗后疾病进展的转移性NSCLC患者。基于该3期随机试验和FDA的批准,NCCN小组增加了雷莫芦单抗/多西他赛(2A类)作为转移性NSCLC一线化疗后进展者后续治疗的一个选择。部分小组成员认为,数据统计学上有显著意义但无临床意义。在两组中70%以上的患者有≥3度的不良事件(多西他赛/雷莫芦单抗79%对多西他赛单药71%) 。雷莫芦单抗/多西他赛治疗需要特别关注的不良事件包括严重出血风险、3-4度消化道出血、胃肠穿孔或肠瘘、伤口愈合不良和难以控制的高血压。在REVEL试验中有16人死于≥3度肺出血和其他不良事件:8例在雷莫芦单抗/多西他赛组,8例在多西他赛单药组。

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