非小细胞肺癌二线及后续系统治疗NCCN指南2016v3

NSCLC NCCN2016V4 Discussion 讨论

Second-Line and Beyond (Subsequent) Systemic Therapy 山东省肿瘤医院呼吸肿瘤内科张品良
二线及以上（后续）系统治疗

The phrase subsequent therapy was recently substituted for the terms second-line, third-line, and beyond systemic therapy, because the line of therapy may vary depending on previous treatment with targeted agents.
短语“后续治疗”最近代替了措辞“二线、三线及以上全身治疗”，因为治疗的“线”可能由于既往靶向药物治疗而有所不同。

Subsequent systemic therapy regimens for patients who have disease progression during or after first-line therapy are described in the NSCLC algorithm and depend on the specific genetic alteration, the histologic subtype, and whether the patient has symptoms (see the NCCN Guidelines for Non-Small Cell Lung Cancer).
在一线治疗期间或者一线治疗后疾病进展患者的后续全身治疗方案在NSCLC工作步骤中描述，取决于特定基因的改变、组织学亚型以及患者是否有症状（见非小细胞肺癌NCCN指南）。

For the 2016 update (Version 1), the NCCN Panel decided that immune checkpoint inhibitors, such as pembrolizumab and nivolumab, are preferred agents for subsequent therapy in patients with metastatic NSCLC based on improved survival rates, longer duration of response, and fewer adverse events when compared with cytotoxic chemotherapy (see Nivolumab and Pembrolizumab in this Discussion).
对2016年第1版更新，基于与细胞毒化疗相比，提高生存率、更长的缓解持续时间且几乎没有不良事件，NCCN专家组决定，免疫检查点抑制剂，如派姆单抗和尼鲁单抗是转移性NSCLC后续治疗的首选药物（见本讨论中的派姆单抗和尼鲁单抗）。

Human immune-checkpoint--inhibitor antibodies inhibit the programmed death (PD-1) receptor, which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T-cells.
人类免疫检查点抑制剂抗体抑制程序性死亡（PD-1）受体，从而改善抗肿瘤免疫；在活化的细胞毒性T细胞上表达PD-1受体。

For 2016 (Version 1 update), the NCCN Panel revised the recommendation for nivolumab to category 1 (from category 2A) based on the published data from a phase 3 randomized trial (CheckMate-057) and the recent FDA approval of nivolumab for patients with metastatic non-squamous NSCLC.
对2016年第1版更新，根据一项3期随机试验（CheckMate-057）公布的数据和近期美国FDA对尼鲁单抗的批准，对于转移性非鳞NSCLC患者，NCCN小组修订了尼鲁单抗为1类推荐（从2A类）。

For this 2016 update (Version 4), the NCCN Panel revised the recommendation for pembrolizumab to category 1 (from category 2A) as subsequent therapy for patients with metastatic non-squamous or squamous NSCLC and PD-L1 expression based on a recent phase 2/3 randomized trial (KEYNOTE-010) trial, KEYNOTE-001 trial, and recent FDA approval.
此2016第4版更新，基于最近一项2/3期随机试验（KEYNOTE-010试验）、KEYNOTE-001试验和最近FDA批准，NCCN小组修订了派姆单抗作为转移性非鳞或鳞型NSCLC且PD-L1表达患者后续治疗的1类推荐（从2A类）。

For 2016 (Version 2 update), the NCCN Panel recommends osimertinib as subsequent therapy for patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on erlotinib, gefitinib, or afatinib therapy based on recent data and on the FDA approval (see Osimertinib in this Discussion).
对2016第2版更新，基于最新的数据和FDA的批准，NCCN小组推荐奥斯默替尼（AZD9291）作为转移性EGFR T790M突变阳性、在厄洛替尼、吉非替尼或阿法替尼治疗后进展的NSCLC患者的后续治疗（见本讨论中的奥斯默替尼）。

Osimertinib (AZD9291) is an oral TKI that inhibits both EGFR sensitizing mutations and T790M mutations.
奥斯默替尼（AZD9291）是一种口服的TKI，对EGFR敏感突变和T790M突变均有抑制。

Preliminary data from recent phase 2 trials (AURA/AURA2) report that osimertinib is associated with a response rate of about 61% and disease control rate of about 91% in patients who have progressed on sensitizing EGFR TKI therapy; 18% of patients had grade 3 or higher adverse events with one fatal event.
最近2期试验（AURA/AURA2）的初步资料报告，在敏感EGFR TKI治疗已经进展的患者中，奥斯默替尼有效率约61%、疾病控制率约91%；18%的患者有≥3度的不良事件，一例致命事件。

The FDA has approved osimertinib for patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy.
FDA已经批准奥斯默替尼用于以FDA批准的试验检测EGFR T790M突变阳性、在EGFR TKI治疗时或治疗后进展的转移性NSCLC患者。

Most patients with sensitizing EGFR mutations and metastatic NSCLC typically progress after about 8 to 16 months of erlotinib or gefitinib therapy.
大多数敏感EGFR突变的转移性NSCLC患者通常大约在厄洛替尼或吉非替尼治疗8至16个月后进展。

The EGFR T790M mutation is associated with acquired resistance to TKI therapy and has been reported in about 60% of patients with disease progression after initial response to sensitizing EGFR TKI therapy.
EGFR T790M突变与对TKI治疗获得性耐药有关，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。

T790M mutations can be assessed using an FDA-approved test or other validated laboratory test done in a CLIA-approved laboratory.
T790M突变可以在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。

For patients with sensitizing EGFR mutations who progress during or after first-line targeted therapy, recommended therapy depends on whether the progression is asymptomatic or symptomatic and includes: 1) switching to osimertinib; 2) continuing erlotinib, afatinib, or gefitinib with (or without) local therapy; or 3) switching to subsequent therapy using a first-line systemic therapy regimen for either non-squamous or squamous cell NSCLC (such as cisplatin/pemetrexed or cisplatin/gemcitabine, respectively).
对于具有敏感EGFR突变、在一线靶向治疗期间或之后进展的患者，根据进展是否有症状，推荐的治疗包括：1）转换至奥斯默替尼；2）继续厄洛替尼、阿法替尼或吉非替尼加（或不加）局部治疗；或3）对于非鳞或鳞状细胞NSCLC，后续治疗转换至一线全身治疗使用的方案（如分别为顺铂/培美曲塞或顺铂/吉西他滨）。

Recent data suggest that an afatinib/cetuximab regimen may be useful for patients who have progressed after receiving EGFR TKI therapy and chemotherapy.
最新数据表明，对于接受EGFR TKI治疗和化疗后进展的患者，阿法替尼/西妥昔单抗方案可能是有用的。

Patients with T790M-positive and T790M-negative tumors had a similar response rate (32% vs. 25%; P = .341).
T790M阳性与阴性的肿瘤患者有效率相似（32%对25%；P = .341)。

For the 2016 update (Version 1), the NCCN Panel added a recommendation (category 2A) to consider an afatinib/cetuximab regimen for patients who have progressed after receiving EGFR TKIs and chemotherapy based on these data.
对2016年第1版更新，基于这些数据，对于在接受EGFR TKIs和化疗后进展的患者，NCCN小组增加了考虑阿法替尼/西妥昔单抗治疗的推荐（2A类）。

For 2016 (Version 1 update), a footnote that stating that afatinib had some efficacy in patients who progressed after EGFR therapy was deleted from the NCCN Guidelines based on a phase 2b/3 trial (LUX-Lung 1).
对2016年第1版更新，基于一项2b/3期试验（LUX-Lung 1），NCCN指南删除了在EGFR治疗后进展的患者中阿法替尼有些疗效的一个脚注说明。

Median overall survival was not better in the afatinib group (10.8 months [95% CI, 10.0–12.0]) when compared with the placebo group (12.0 months [95% CI, 10.2–14.3]) (HR, 1.08; 95% CI, 0.86–1.35; P = .74).
中位总生存期与安慰剂组相比（12.0个月[ 95% CI，10.2–14.3 ]）阿法替尼组并不更好（10.8个月[ 95% CI，10.0–12.0 ]）（HR，1.08；95% CI，0.86-1.35；P = .74)。

In the afatinib group, 2 deaths occurred possibly related to treatment.
在阿法替尼组，发生的2例死亡可能与治疗有关。

In both of the phase 3 trials for pembrolizumab or nivolumab versus docetaxel as subsequent therapy for patients with metastatic NSCLC, subset analyses were done in patients with EGFR mutations to determine the best subsequent therapy.
两项派姆单抗或尼鲁单抗对比多西他赛作为转移性NSCLC患者的后续治疗的3期试验均对EGFR突变患者进行亚组分析，以确定最佳的后续治疗。

The HRs for overall survival do not favor docetaxel over nivolumab (HR = 1.18; CI, 0.69-2.0) or pembrolizumab (HR = 0.88; CI, 0.45-1.7); the CIs for the HRs are wide probably because there were so few patients.
总生存期HRs多西他赛不优于尼鲁单抗（HR = 1.18；CI，0.69-2.0）或派姆单抗（HR = 0.88；CI，0.45-1.7）；风险比（HRs）的可信区间（CIs）范围大可能是因为病例数太少。

The HRs for PFS do favor docetaxel for patients with EGFR mutations when compared with either pembrolizumab (HR = 1.79; CI, 0.94-3.42) or nivolumab (HR = 1.46; CI, 0.90-2.37).
对于EGFR突变的患者，PFS的HRs无论与派姆单抗（HR = 1.79；CI，0.94-3.42）相比还是与尼洛替尼（HR = 1.46；CI，0.90-2.37）相比，均支持多西他赛。

But again, the CIs are wide.
但是又一次CIs范围大。

Thus, the evidence is weak for recommending docetaxel as subsequent therapy for patients with EGFR mutations when compared with either pembrolizumab or nivolumab.
因此，对于EGFR突变的患者，无论与派姆单抗相比还是与尼洛替尼相比，推荐多西他赛的证据均不充分。

For patients with ALK rearrangements who progress during or after first-line targeted therapy, recommended therapy also depends on whether the progression is asymptomatic or symptomatic and includes: 1) continuing ALK inhibitors with (or without) local therapy; 2) switching to ceritinib or alectinib; or 3) switching to a first-line systemic therapy regimen for either non-squamous or squamous cell NSCLC.
对于具有ALK重排、在一线靶向治疗期间或之后进展的患者，也根据进展是否有症状，推荐的治疗包括：2）继续ALK抑制剂加（或不加）局部治疗；2）转换至色瑞替尼或阿雷替尼；或3）对于非鳞或鳞状细胞NSCLC，转换至一线全身治疗方案。

After further progression on subsequent targeted therapy, first-line combination chemotherapy options for non-squamous NSCLC or squamous cell carcinoma are recommended for patients with PS of 0 to 1 such as cisplatin/pemetrexed or cisplatin/gemcitabine, respectively.
在后续靶向治疗进一步进展后，对于非鳞NSCLC或鳞癌、PS评分0-1的患者，分别建议一线联合化疗选择如顺铂/培美曲塞或顺铂/吉西他滨。

Other chemotherapy options are also recommended for patients with PS 2 (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for Non-Small Cell Lung Cancer).
对于PS评分2的患者也推荐其他化疗选择（见非小细胞肺癌NCCN指南中晚期或转移性疾病的全身治疗）。

Most patients with NSCLC do not have ALK rearrangements or sensitizing EGFR mutations.
大多数NSCLC患者没有ALK重排或敏感EGFR突变。

For patients with all histologic subtypes but without ALK rearrangements or sensitizing EGFR mutations with PS of 0 to 2 who have disease progression during or after first-line therapy, recommended subsequent systemic therapy options include nivolumab (category 1), pembrolizumab (category 1), docetaxel with (or without) ramucirumab, or gemcitabine if not already given.
对于无ALK重排或敏感EGFR突变、PS 0-2的所有组织学亚型患者，在一线治疗期间或者一线治疗后疾病进展，推荐的后续全身治疗选择包括尼鲁单抗（1类）、派姆单抗（1类）、多西他赛加（或不加）雷莫芦单抗，或吉西他滨如果未曾给予。

The NCCN Panel recently added nivolumab and pembrolizumab as preferred options for subsequent therapy for all histologic subtypes based on improved survival rates, longer duration of response, and fewer adverse events when compared with cytotoxic chemotherapy (see Nivolumab and Pembrolizumab in this Discussion).
基于与细胞毒化疗相比，提高生存率、更长的缓解持续时间且几乎没有不良事件，NCCN专家组最近增加了尼鲁单抗和派姆单抗作为所有组织学亚型首选的后续治疗（见本讨论中的尼鲁单抗和派姆单抗）。

Panel members also recently added ramucirumab/docetaxel as an additional option for all histologic subtypes for subsequent therapy based on a recent phase 3 randomized trial.
根据最近一项3期随机试验，小组成员最近还增加了雷莫芦单抗/多西他赛作为所有组织学亚型后续治疗的一个额外选择。

The median overall survival was slightly increased with ramucirumab/docetaxel versus docetaxel alone (10.5 vs. 9.1 months, respectively).
中位总生存期与多西他赛单药相比，雷莫芦单抗/多西他赛组略微改善（分别为9.1对10.5个月)。

Contraindications for ramucirumab/docetaxel therapy include risk for severe hemorrhage, grade 3 to 4 gastrointestinal bleeding, gastrointestinal perforation or fistula, and poorly controlled hypertension.
雷莫芦单抗/多西他赛治疗的禁忌证包括严重出血风险、3-4度消化道出血、胃肠穿孔或肠瘘以及难以控制的高血压。

For patients with advanced non-squamous NSCLC but without ALK rearrangements or sensitizing EGFR mutations with PS of 0 to 2 who have disease progression during or after first-line therapy, recommended subsequent systemic therapy options include erlotinib, gefitinib, or pemetrexed in addition to the agents mentioned in the previous paragraph (ie, nivolumab, docetaxel with or without ramucirumab, or gemcitabine) if these agents have not already been given.
对于晚期非鳞NSCLC但无ALK重排或敏感EGFR突变、PS 0-2的患者，在一线治疗期间或者一线治疗后疾病进展，推荐的后续全身治疗选择除了前面提到的药物（即尼鲁单抗、多西他赛加或不加雷莫芦单抗、或吉西他滨）之外还包括厄洛替尼、吉非替尼或培美曲塞，如果这些药物尚未给予。

Docetaxel has been proven superior to best supportive care, vinorelbine, or ifosfamide with improved survival and quality of life.
已经证明改善生存和生活质量多西他赛优于最佳支持治疗、长春瑞滨或异环磷酰胺。

However, ifosfamide was deleted by the NCCN Panel for the 2016 update (Version 1), since it is rarely used.
然而，对于2016第1版更新异环磷酰胺被NCCN小组删除，因为它很少使用。

When compared with docetaxel, pemetrexed has similar median survival but less toxicity.
与多西他赛相比，培美曲塞具有相似的中位生存期但毒性较小。

Pemetrexed is recommended in patients with non-squamous NSCLC.
非鳞NSCLC患者建议使用培美曲塞。

Docetaxel is recommended for patients with wild-type EGFR tumors based on 2 randomized trials comparing erlotinib versus docetaxel.
根据比较厄洛替尼与多西他赛的两项随机试验，对于EGFR野生型肿瘤患者建议使用多西他赛。

Proteomic testing can be used to determine whether erlotinib should be used in patients with unknown EGFR status.
在EGFR状态未知的患者中，为了确定是否应该使用厄洛替尼，可应用蛋白质组学检测。

Erlotinib is superior to best supportive care with significantly improved survival and delayed time to symptom deterioration in patients with non-squamous NSCLC.
在非鳞NSCLC患者中，厄洛替尼优于最佳支持治疗，具有显著改善生存并延缓症状恶化的时间。

In patients with PS of 3 to 4 who have sensitizing EGFR mutations, erlotinib, afatinib, or gefitinib are recommended options for subsequent therapy for progressive disease (see the NCCN Guidelines for Non-Small Cell Lung Cancer).
在PS 3-4、具有敏感EGFR突变的患者中，厄洛替尼、阿法替尼或吉非替尼是疾病进展推荐的后续治疗选择（见非小细胞肺癌NCCN指南）。

Patients often have a limited response to subsequent chemotherapy other than immune checkpoint inhibitors, although it may serve a useful palliative role.
除了免疫检查点抑制剂外，患者对后续化疗常常应答有限，尽管它可能提供一个有效的姑息手段。

For the 2016 update (Version 1), panel members revised the recommendation to preferred for nivolumab as subsequent therapy for patients with squamous cell NSCLC.
对于2016第1版更新，小组成员修订了建议首选尼鲁单抗作为鳞状细胞NSCLC患者的后续治疗。

The NCCN Panel also decided to delete erlotinib as an option for subsequent therapy for patients with squamous cell NSCLC for the 2016 update (Version 1) based on a recent study comparing afatinib with erlotinib; this study was statistically significant but not clinically significant.
对于2016第1版更新，NCCN小组还决定删除厄洛替尼作为鳞状细胞NSCLC患者的后续治疗选择，依据是最近一项研究比较了阿法替尼与厄洛替尼；该研究有统计学意义，但没有临床意义。

Overall survival was slightly better in the afatinib group than in the erlotinib group (median overall survival, 7.9 months [95% CI, 7.2–8.7] vs. 6.8 months [5.9–7.8]; HR, 0.81 [95% CI, 0.69–0.95], P = .0077); however, almost 60% of patients in each arm had grade 3 or higher adverse events.
阿法替尼组的总生存略微比厄洛替尼组好（中位总生存期，7.9个月[ 95% CI，7.2–8.7 ]对6.8个月 [ 5.9–7.8 ] ；HR，0.81 [ 95% CI，0.69-0.95]，P = .0077）；然而，每组将近60%的患者有≥3度的不良事件。

In contrast, the median overall survival was 9.2 months with nivolumab compared with 6.0 months for docetaxel for patients with squamous cell NSCLC.
相反，对于鳞状细胞NSCLC患者，中位总生存期尼鲁单抗是9.2个月，而多西他赛为6个月。

In addition, only 7% of patients receiving nivolumab had grade 3 or higher adverse events.
此外，接受尼鲁单抗的患者仅7%有≥3度的不良事件。

If patients with either ALK fusions or sensitizing EGFR mutations progress with symptomatic systemic multiple lesions after therapy with crizotinib, erlotinib, gefitinib, or afatinib and/or after ceritinib, alectinib, or osimertinib, then first-line doublet chemotherapy options are recommended for either non-squamous NSCLC or squamous cell carcinoma.
对于非鳞NSCLC或鳞状细胞癌，如果患者具有ALK融合或敏感EGFR突变，在克唑替尼、厄洛替尼、吉非替尼或阿法替尼治疗后和/或在色瑞替尼、阿雷替尼或奥斯默替尼治疗后，全身多发病变有症状进展，则推荐选择一线双药化疗。

Erlotinib, gefitinib, or afatinib may be continued in patients with sensitizing EGFR mutations who have progressed after first-line therapy.
在具有敏感EGFR突变、一线治疗后进展的患者中，厄洛替尼、吉非替尼或阿法替尼可以继续使用。

For the 2016 update (Version 1), the NCCN Panel now recommends afatinib/cetuximab for patients with sensitizing EGFR mutations who have progressed after EGFR TKI therapy and chemotherapy.
对于2016年第1版更新，对于具有敏感EGFR突变、在EGFR TKI治疗和化疗后进展的患者，NCCN小组目前推荐阿法替尼/西妥昔单抗。

Ceritinib or alectinib may also be continued in patients with ALK-positive NSCLC who have progressed after first-line therapy with crizotinib or are intolerant to crizotinib.
在ALK阳性、克唑替尼一线治疗后进展或不能耐受克唑替尼的NSCLC病人中，也可继续色瑞替尼或阿雷替尼。

In a randomized trial (NCIC CTG trial), 731 patients (stage IIIB or IV, PS 0–3) were randomly assigned (2:1) to receive either erlotinib or placebo, following failure of first-line or subsequent chemotherapy.
在一项随机试验（NCIC CTG试验）中，731例患者（IIIB或IV期，PS 0–3）在一线或后续化疗失败后被随机分配（2∶1）至接受厄洛替尼或安慰剂。

Patients treated with erlotinib showed an overall survival of 6.7 versus 4.7 months for placebo (HR, 0.70; P < .001).
厄洛替尼治疗的患者总生存期6.7个月而安慰剂为4.7个月（HR，0.70；P＜.001）。

PFS was 2.2 months for the erlotinib group versus 1.8 months for placebo (HR, 0.61; P < .001).
厄洛替尼组PFS为2.2个月而安慰剂组为1.8个月（HR，0.61；P＜.001）。

However, 5% of patients discontinued erlotinib because of toxic side effects.
然而，5%的患者因毒副作用而停止厄洛替尼治疗。

This trial confirms that erlotinib can prolong survival in patients after failure of first-line or subsequent systemic therapy.
该试验证实在一线或后续全身治疗失败后厄洛替尼治疗可延长患者的生存期。

A randomized phase 3 trial in 829 patients found that oral topotecan was not inferior to 774 docetaxel as subsequent therapy for patients with advanced NSCLC.
一项829例患者的随机3期试验发现，对于晚期NSCLC患者，口服拓扑替康后续治疗不劣于多西他赛。

Nivolumab, pembrolizumab, erlotinib (non-squamous only), docetaxel with or without ramucirumab (category 2B for both), gemcitabine (category 2B), or pemetrexed (non-squamous only) (category 2B) are recommended for subsequent therapy after second disease progression in patients with advanced NSCLC and PS 0–2 if these agents have not already been given.
尼鲁单抗、派姆单抗、厄洛替尼（限非鳞）、多西他赛加或不加雷莫芦单抗（两者均为2B类）、吉西他滨（2B类）或培美曲塞（限非鳞）（2B类）推荐用于晚期NSCLC、PS 0-2患者疾病二次进展后的后续治疗，如果这些药物未曾给予。