张品良_好大夫在线
微信扫码

微信扫码关注医生

有问题随时问

综合推荐热度 3.4

在线服务满意度 暂无

在线问诊量 751

左箭头 返回医生主页 门诊信息 患者投票 科普文章 患者问诊 心意礼物 患友会
张品良

张品良

副主任医师 
左箭头 返回医生主页 门诊信息 患者投票 科普文章 患者问诊 心意礼物 患友会

指南阅读

非小细胞肺癌NCCN2017第4版:复发与转移的治疗

发表者:张品良 1170人已读

Treatment of Recurrences and Distant Metastases 复发与远处转移的治疗

Recurrences are subdivided into locoregional recurrences and distant metastases. Management of locoregional recurrences (eg, endobronchial obstruction, mediastinal lymph node recurrence, superior vena cava obstructions, severe hemoptysis) is described in the NCCN Guidelines (see Therapy for Recurrence and Metastasis in the NCCN Guidelines for NSCLC). For patients with endobronchial obstruction, relieving airway obstruction may increase survival, especially in patients who are severely compromised, and may improve the quality of life. After treatment for the locoregional recurrence, observation or systemic therapy (category 2B for systemic therapy) is recommended if disseminated disease is not evident. However, systemic therapy is recommended for disseminated disease. The type of systemic therapy depends on the histologic type, whether genetic alterations are present that can be treated with targeted therapy, and PS (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC). For the 2017 update (Version 1), the NCCN Panel now recommends response assessment after 2 cycles of systemic therapy then after every 2 to 4 cycles of therapy or when clinically indicated; assessment is done using CT with (or without contrast) of known sites of disease. 复发分为局部复发和远处转移。在NCCN指南中描述了局部复发(如支气管阻塞、纵隔淋巴结复发、上腔静脉阻塞、严重咯血)的处理(见NSCLC NCCN指南中复发与转移的治疗)。对于支气管阻塞的患者,解除气道阻塞可改善生存,尤其是在严重损害的患者中,并可提高生活质量。局部区域复发治疗后,如果疾病播散不明显,建议观察或全身治疗(全身治疗为2B类)。不过,对于播散性疾病建议全身治疗。全身治疗的类型取决于组织学类型、是否存在可以使用靶向治疗的遗传学改变和一般情况(见NSCLC NCCN指南中晚期或转移性疾病的全身治疗)。2017第1版更新,NCCN小组目前推荐在两周期全身治疗后疗效评估,然后每治疗2-4周期或有临床指征时进行疗效评估;对已知病变部位使用增强或平扫CT评估。山东省肿瘤医院呼吸内科张品良

Management of distant metastases (eg, localized symptoms; bone, limited, diffuse brain, or disseminated metastases) is described in the NCCN Guidelines (see Therapy for Recurrence and Metastasis in the NCCN Guidelines for NSCLC). Palliation of symptoms throughout the disease course can be achieved with external-beam RT for distant metastases with localized symptoms, diffuse brain metastases, or bone metastasis (bisphosphonate or denosumab therapy can be considered). For patients at risk of fracture in weight-bearing bone, orthopedic stabilization and palliative RT are recommended. 在NCCN指南中描述了远处转移(如局部症状;局限性骨、弥漫性脑或播散性转移)的处理(见NSCLC NCCN指南中复发和转移的治疗)。对于有局部症状的远处转移、弥漫性脑转移或骨转移(可考虑双磷酸盐或地诺单抗治疗),外放疗可缓解整个病程期间的症状。对于有承重骨骨折风险的患者,推荐使用矫形稳定和姑息性放疗。

Of note, recurrent and metastatic disease have historically been regarded as incurable. However, selected limited locoregional recurrences may be treated with curative intent therapy (surgery or RT with [or without] chemotherapy) (see Therapy for Recurrence and Metastasis in the NCCN Guidelines for NSCLC). Similarly, patients with limited-site oligometastatic disease and good PS may benefit from aggressive local therapies to the metastatic and primary sites, with clinical data suggesting the possibility of long-term survival (see Initial Treatment for Stage IV, M1b: Limited Sites in the NCCN Guidelines for NSCLC). In addition, emerging clinical data suggest the feasibility of definitive reirradiation of local recurrences within prior RT fields using highly conformal techniques, although this should be limited to highly selected cases in specialty centers with appropriate expertise because of the potential for severe toxicity with high cumulative radiation doses to critical structures. 值得注意的是,复发和转移性疾病一直被认为是不可治愈的。不过,经过挑选的局限性局部区域复发可以给予根治性治疗(手术或放疗±化疗)(见NSCLC NCCN指南中复发和转移的治疗)。同样,在一般情况良好、部位局限的寡转移患者中,可能受益于对转移灶和原发灶积极的局部治疗,临床资料提示有可能长期生存(见NSCLC NCCN指南中IV期M1b:部位局限的初始治疗)。此外,新的临床数据表明,既往放射野内局部复发使用高度适形技术根治性再放疗是可行的,不过,这应限于拥有合适专家的专科中心的高选择性病例,因为累积放疗剂量高对关键结构有可能带来严重的毒性。

Denosumab or intravenous bisphosphonate therapy can be considered in patients with bone metastasis. In patients with NSCLC who have bone metastases, data suggest that denosumab increases median overall survival when compared with zoledronic acid (9.5 vs. 8 months). Denosumab and bisphosphonate therapy can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk for hypocalcemia. The FDA has approved the use of zoledronic acid and denosumab in patients with bone metastases from solid tumors. 骨转移的患者可以考虑地诺单抗或静脉注射双膦酸盐治疗。数据表明,在有骨转移的NSCLC患者中,与唑来膦酸相比,地诺单抗延长中位总生存期(9.5个月对8个月)。地诺单抗和双膦酸盐治疗可能与严重低血钙有关;甲状旁腺功能减退症与维生素D缺乏的患者低钙血症的风险增加。FDA已批准使用唑来膦酸与地诺单抗治疗实体瘤骨转移患者。

For patients with recurrent and metastatic disease, the NCCN Guidelines recommend that histologic subtype should be determined before therapy so that the best treatment can be selected (see Metastatic Disease: Histologic Subtype in the NCCN Guidelines for NSCLC). In addition, testing for genetic alterations (ie, driver events) is recommended in patients with NSCLC, because targeted therapy has been shown to decrease tumor burden, decrease symptoms, and dramatically improve the quality of life for patients with specific genetic alterations. The number of available targeted agents is increasing. Several targeted agents have category 1 recommendations for first-line therapy based on larger trials such as erlotinib, gefitinib, afatinib, and crizotinib. 对于复发和转移性患者,NCCN指南推荐在治疗前应确定组织学亚型,以便选择最佳治疗(见NSCLC NCCN指南中的转移性疾病:组织学亚型)。 此外,在NSCLC患者中,推荐检测遗传改变(即,驱动事件),因为已经证明靶向治疗可降低肿瘤负荷、减轻症状,并戏剧性地改善具有特定遗传改变患者的生活质量。可用的靶向药物越来越多。基于更大的试验,一些靶向药物如厄洛替尼、吉非替尼、阿法替尼和克唑替尼为一线治疗的1类推荐。

Additional targeted therapies for patients with other genetic alterations are also recommended, although there is less evidence for these agents (see Emerging Targeted Agents for Patients with Genetic Alterations in the NCCN Guidelines for NSCLC). The following targeted agents are recommended (category 2A) for patients with specific genetic alterations: crizotinib (for high-level MET amplification or MET exon 14 skipping mutation); dabrafenib (with or without trametinib) and vemurafenib (for BRAF V600E mutations); and cabozantinib and vandetanib (for RET rearrangements). The dabrafenib/trametinib regimen is recommended for patients with BRAF V600E mutations based on data from a recent phase II study; patients had a response rate of 63% (36/57). Grade 3 to 4 adverse events included neutropenia (9%), hyponatremia (7%), and anemia (5%). For the 2017 update (Version 1), the NCCN Panel added a recommendation for vandetanib (category 2A) based on preliminary data from a phase 2 study in 18 patients. Partial remission (17%) was reported in 3 patients; stable disease (44%) was reported in another 8 patients. Six (33%) patients died within 3 months of enrollment of the study due to rapid tumor progression. The recommendation for cabozantinib for RET rearrangements is based on data from a phase II study. Trastuzumab and afatinib (both for HER2 mutations) are category 2B recommendations, because response rates are lower and treatment is less effective when these agents are used for patients with the indicated genetic alterations. Other targeted therapies (such as ceritinib, alectinib, and osimertinib) are recommended as subsequent therapies for patients whose disease becomes resistant to first-line targeted therapies; other targeted therapies are being investigated for resistance. 对于具有其他基因改变的患者还建议其他靶向治疗,虽然这些药物的证据较少(见NSCLC NCCN指南中的具有遗传改变患者的新兴靶向药物)。对于具有特定基因改变的患者,以下是推荐的靶向药物(2A类):克唑替尼(用于高水平MET扩增或MET外显子14跳跃突变);达拉非尼(±曲美替尼)和维罗非尼(用于BRAF V600E突变);以及卡博替尼和凡德他尼(用于RET重排)。根据最近一项Ⅱ期研究数据,对于具有BRAF V600E突变的患者,NCCN小组推荐达拉菲尼/曲美替尼方案。患者的有效率为63%(36/57)。3-4度不良事件包括中性粒细胞减少(9%)、低钠血症(7%)和贫血(5%)。基于一项18例患者的2期初步数据,2017第1版更新,NCCN小组增加了一个凡德他尼的推荐。3例部分缓解(17%);另外8例疾病稳定(44%)。6例(33%)患者由于肿瘤快速进展在研究入组的3个月内死亡。基于一项Ⅱ期研究数据,推荐卡博替尼用于RET重排。曲妥珠单抗和阿法替尼(均用于HER2突变)是2B类推荐,因为当这些药物用于指定遗传改变的患者时,有效率较低且治疗效果较差。推荐其他靶向治疗(如色瑞替尼、阿雷替尼和奥希替尼)作为对一线靶向治疗耐药患者的后续治疗;正在研究耐药的其他靶向治疗。

EGFR mutation testing (category 1) is recommended in patients with non-squamous NSCLC (ie, adenocarcinoma, large cell carcinoma) or in NSCLC NOS, because erlotinib, gefitinib, and afatinib (category 1 for all) are recommended for patients who are positive for sensitizing EGFR mutations (see EGFR Mutation Positive/First-Line Therapy in the NCCN Guidelines for NSCLC). Testing for ALK rearrangements (category 1) is also recommended in patients with non-squamous NSCLC, because crizotinib is recommended (category 1) for patients who are positive for ALK rearrangements. Crizotinib is also recommended for patients who are positive for ROS1 rearrangements and MET amplification. For the 2017 update (Version 1), the NCCN Panel added a recommendation for testing for ROS1 rearrangements (category 2A). Testing for ROS1 has typically been done using FISH; however, a validated NGS platform that can detect this gene fusion may also be used. The NCCN Panel recommends that EGFR mutation testing be done as part of broad molecular profiling (eg, multiplex mutation screening assays or NGS). Testing for ALK gene rearrangements can be done with FISH or with NGS if the platform is validated and can identify gene fusions. For the 2017 update (Version 1), the NCCN Panel also added a recommendation for upfront PD-L1 expression testing before first-line therapy in patients with metastatic NSCLC to assess whether patients are candidates for immune checkpoint inhibitors (see Pembrolizumab in this Discussion). 在非鳞NSCLC(即腺癌、大细胞癌)或NSCLC非特指患者中,推荐EGFR突变检测(1类),因为厄洛替尼、吉非替尼和阿法替尼(均为1类)推荐用于那些敏感EGFR突变阳性的患者(见NSCLC NCCN指南中的EGFR突变阳性/一线治疗)。在非鳞NSCLC患者中还推荐(1类)ALK重排检测,因为克唑替尼推荐(1类)用于ALK重排阳性的患者。对于ROS1重排阳性和MET扩增的患者也推荐克唑替尼。2017第1版更新,NCCN小组增加了检测ROS1重排的推荐(2A类)。通常使用FISH检测ROS1;不过,也可以使用一个批准的二代测序技术平台检测该基因融合。NCCN小组组推荐EGFR突变检测可作为广泛分子分析的一部分(例如,多重突变筛选试验或NGS)。如果平台已经验证并可以鉴定基因融合,则可以用FISH或NGS检测ALK基因重排。2017第1版更新,对于一线治疗前的转移性NSCLC患者,NCCN小组还增加了一个检测PD-L1表达的推荐,以评估患者是否适于免疫检查点抑制剂(见本讨论中的派姆单抗)。

As previously mentioned, recent recommendations from an international panel suggest that general histologic categories be avoided (eg, NSCLC), because more effective treatment can be selected when the histology is known. Patients with pure squamous cell carcinoma do not seem to have ALK rearrangements, ROS1 rearrangements, or sensitizing EGFR mutations; therefore, routine testing is not recommended in these patients. However, testing for ALK rearrangements, ROS1 rearrangements, or EGFR mutations can be considered in patients with squamous cell carcinomas who never smoked and those whose histology was determined using small biopsy specimens or mixed histology specimens. Treatment recommendations and eligibility criteria for patients with non-squamous NSCLC (or NSCLC NOS) who are negative or unknown for ALK or ROS1 rearrangements, sensitizing EGFR mutations, or PD-L1 expression are described in the NCCN Guidelines. Treatment recommendations and eligibility criteria for patients with squamous cell carcinoma are also described in the NCCN Guidelines. These recommendations are briefly summarized in the following paragraphs. Data supporting these recommendations are described in the following section (see Trial Data in this Discussion). 如前所述,一个国际小组最近的推荐表明,避免概括的组织学类型(如NSCLC),因为当组织学已知时,可以选择更有效的治疗。纯鳞状细胞癌患者似乎没有ALK重排、ROS1重排或敏感EGFR突变;因此,在这些患者中不推荐常规检测。然而,在从不吸烟以及那些使用小活检标本确定的鳞癌患者或混合性组织学患者中,可以考虑检测ALK重排、ROS1重排或EGFR突变。NCCN指南对ALK或ROS1重排、敏感EGFR突变或PD-L1表达阴性或未知的非鳞NSCLC(或NSCLC非特指)患者的治疗推荐和入选标准进行了描述。NCCN指南也描述了鳞癌患者的治疗推荐和入选标准。这些推荐在下文中进行了简要的总结。下面的章节描述支持这些推荐的数据(见本讨论中的试验数据)。

In general, 2-drug regimens (ie, doublet chemotherapy) are recommended over single agents (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC); however, targeted therapy is sometimes added to the 2-drug regimen (eg, the addition of bevacizumab to carboplatin/paclitaxel). Single-agent targeted therapy is recommended for patients with ALK or ROS1 rearrangements, sensitizing EGFR mutations, or other driver mutations (see Emerging Targeted Agents for Patients With Genetic Alterations in the NCCN Guidelines for NSCLC). Pembrolizumab is now recommended as first-line therapy for patients with PD-L1 expression of 50% or more. 总的来说,推荐双药方案(即双药化疗)优于单药(见NSCLC NCCN指南中晚期或转移性疾病的全身治疗);然而,有时将靶向治疗添加到双药治疗方案中(如贝伐单抗加入到卡铂/紫杉醇)。还推荐单药靶向治疗用于ALK或ROS1重排、敏感EGFR突变或其他驱动突变的患者(见NSCLC NCCN指南中遗传学改变患者的新兴靶向药物治疗)。目前推荐派姆单抗用于PD-L1表达≥50%患者的一线治疗。

Doublet chemotherapy regimens, such as cisplatin/pemetrexed, are recommended (category 1) for patients with non-squamous NSCLC who are negative or unknown for ALK or ROS1 rearrangements, sensitizing EGFR mutations, or PD-L1 expression (also known as wild-type) (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC, the NCCN Drugs & Biologics Compendium [NCCN Compendium(R)] for NSCLC, and the NCCN Evidence Blocks(TM) for NSCLC). For the 2017 update (Version 1), the NCCN Panel revised the lists of recommended doublet and single-agent systemic therapy regimens for patients with non-squamous NSCLC or NSCLC NOS who are negative or unknown for mutations, rearrangements, or PD-L1 expression by deleting regimens that are rarely used in the United States. Deleted regimens include carboplatin/vinorelbine, cisplatin/vinorelbine, etoposide, irinotecan, and vinorelbine. 推荐(1类)双药化疗方案,如顺铂/培美曲塞用于ALK或ROS1重排、敏感EGFR突变或PD-L1表达阴性(即野生型)或未知的非鳞NSCLC患者(见NSCLC NCCN指南中的晚期或转移性疾病的全身治疗、NSCLC NCCN药物&生物制剂纲要[NCCN纲要®]和NSCLC NCCN证据组成™)。2017第1版更新,对于突变、重排或PD-L1表达阴性或未知的非鳞NSCLC或NSCLC非特指患者,NCCN小组修改了双药和单药全身治疗方案的推荐列表,删除了在美国很少用的方案。删除的方案包括卡铂/长春瑞滨、顺铂/长春瑞滨、依托泊苷、伊立替康和长春瑞滨。

Bevacizumab/chemotherapy is another option for patients with non-squamous NSCLC who are negative or unknown for mutations, rearrangements, or PD-L1 expression if eligibility criteria are met. Previously, patients with brain metastases were excluded from receiving bevacizumab because of concerns about CNS hemorrhage; however, data suggest that bevacizumab can be used in patients with treated CNS metastases. For the 2017 update (Version 1), the NCCN Panel deleted the bevacizumab/cisplatin/pemetrexed regimen because it is rarely used. Other chemotherapy options are also recommended, although some regimens may be more appropriate for certain patients, depending on histology, PS, and other factors (see Trial Data in this Discussion, Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC, the NCCN Compendium(R) for NSCLC, and the NCCN Evidence Blocks(TM) for NSCLC). A phase 3 randomized trial in elderly patients (70–89 years) with advanced NSCLC reported that combined therapy with weekly paclitaxel and monthly carboplatin improved survival when compared with single-agent therapy using either gemcitabine or vinorelbine (10.3 vs. 6.2 months). Systemic therapy for elderly patients with advanced NSCLC needs to be carefully selected to avoid adverse reactions. 对于突变、重排或PD-L1表达阴性或未知的非鳞NSCLC患者,如果符合标准,贝伐单抗/化疗是另外一个选择。此前,由于担心CNS出血,脑转移患者被排除在接受贝伐单抗之外;然而,数据表明,贝伐珠单抗可用于治疗CNS转移的患者。2017第1版更新,NCCN小组删除了贝伐单抗/顺铂/培美曲塞方案,因为很少使用。虽然有些方案可能更适于某些患者,但是也推荐其他化疗方案,这取决于组织学、一般情况和其他因素(见本讨论中的试验数据、NSCLC NCCN指南中的晚期或转移性疾病的全身治疗、NCCN药物&生物制剂纲要[NCCN纲要®]以及NSCLC的NCCN证据组成(TM))。在老年晚期NSCLC患者(70–89岁)中的一项3期随机试验报道,与吉西他滨或长春瑞滨单药治疗相比,每周一次紫杉醇和每月一次卡铂联合治疗改善生存(10.3个月对6.2个月)。老年晚期NSCLC的全身治疗需要仔细选择,以避免不良反应。

Cisplatin/gemcitabine (category 1) is a recommended doublet option for patients with squamous cell carcinoma. Carboplatin/paclitaxel, carboplatin/gemcitabine (category 1 for both), and other regimens listed in the NSCLC algorithm may also be used (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC, the NCCN Compendium(R) for NSCLC, and the NCCN Evidence Blocks(TM) for NSCLC). For the 2017 update (Version 1), the NCCN Panel revised the lists of recommended doublet systemic therapy regimens for patients with squamous cell NSCLC who are negative or unknown for mutations, rearrangements, or PD-L1 expression by deleting regimens that are rarely used. Deleted regimens include carboplatin/etoposide, carboplatin/vinorelbine, cisplatin/vinorelbine, cisplatin/gemcitabine/necitumumab, etoposide, irinotecan, and vinorelbine. Regimens containing pemetrexed or bevacizumab are not recommended for squamous cell carcinoma. Currently, there are fewer treatment options for patients with squamous cell carcinoma when compared with non-squamous NSCLC. Research is ongoing to find newer options. 对于鳞癌患者,顺铂/吉西他滨(1类)是一个推荐的双药选择。卡铂/紫杉醇、卡铂/吉西他滨(二者均为1类)以及在NSCLC工作步骤中列出的其他方案也可以使用(见NSCLC NCCN指南中的晚期或转移性疾病的全身治疗、NCCN纲要®以及NSCLC NCCN证据组成(TM))。对于突变、重排或PD-L1表达阴性或未知的肺鳞癌患者,2017第1版更新,NCCN小组修改了双药全身治疗方案的推荐列表,删除了很少用的方案。删除的方案包括卡铂/依托泊苷、卡铂/长春瑞滨、顺铂/长春瑞滨、顺铂/吉西他滨/奈昔妥珠单抗、依托泊苷、伊立替康和长春瑞滨。 对于鳞癌,不推荐含培美曲塞或贝伐单抗方案。目前,与非鳞NSCLC相比,鳞癌患者的治疗方案更少。正在研究寻找新的选择。

Trial Data 试验数据

In a phase 2/3 trial (ECOG 4599), 878 patients were randomly assigned to either 1) bevacizumab in combination with paclitaxel/carboplatin; or 2) paclitaxel/carboplatin alone. Both regimens were well tolerated with selected toxicities. Patients receiving bevacizumab/paclitaxel/carboplatin showed an improved median survival (12.3 vs. 10.3 months, P = .003) when compared to patients receiving paclitaxel/carboplatin alone. The overall 1-year and 2-year survival was 51% vs. 44% and 23% vs. 15%, respectively, in favor of the bevacizumab/paclitaxel/carboplatin arm. However, more significant toxicities were observed with bevacizumab/paclitaxel/carboplatin compared to paclitaxel/carboplatin (grade 4 neutropenia: 25.5% vs. 16.8%, grade 5 hemoptysis: 1.2% vs. 0%, and grade 3 hypertension: 6.8% vs. 0.5%). Treatment-related deaths were more common with bevacizumab/paclitaxel/carboplatin (15 patients) than with paclitaxel/carboplatin (2 patients) (P = .001). A recent analysis of ECOG 4599 found that patients with adenocarcinoma histology receiving bevacizumab/paclitaxel/carboplatin had improved survival compared with chemotherapy alone (14.2 vs. 10.3 months). 在一项2/3期试验(ECOG 4599)中,878例患者被随机分配到1)贝伐单抗联合紫杉醇/卡铂;或2)单纯紫杉醇/卡铂。这两种方案的耐受性均良好,具有已知的毒性。与单纯接受紫杉醇/卡铂的患者相比,接受贝伐单抗/紫杉醇/卡铂的患者中位生存期延长(12.3个月对10.3个月,P = 0.003)。总的1、2年生存率分别为51%和44%、23%和15%,支持贝伐单抗/紫杉醇/卡铂组。然而,与紫杉醇/卡铂相比,观察到贝伐单抗/紫杉醇/卡铂的毒性更显著(4级中性粒细胞减少:25.5%对16.8%,5级咯血:1.2%对0%,3级高血压:6.8%对0.5%)。 治疗相关死亡贝伐单抗/紫杉醇/卡铂(15例)比紫杉醇/卡铂(2例)更常见(P = 0.001)。最近ECOG 4599的一项分析发现,接受贝伐单抗/紫杉醇/卡铂的腺癌组织学患者生存期比单纯化疗长(14.2对10.3个月)。

However, a trial (AVAiL) comparing cisplatin/gemcitabine with (or without) bevacizumab did not show an increase in survival with the addition of bevacizumab. 不过,一项比较顺铂/吉西他滨±贝伐单抗的试验(AVAiL)未显示增加贝伐单抗改善生存。

A noninferiority trial in 1725 patients with advanced NSCLC (either stage IIIB or IV; most were stage IV) assessed cisplatin/gemcitabine compared with cisplatin/pemetrexed. Patients with either adenocarcinoma or large cell carcinoma (ie, non-squamous NSCLC) had improved survival with cisplatin/pemetrexed (adenocarcinoma: 12.6 vs. 10.9 months). Patients with squamous cell carcinoma had improved survival with the cisplatin/gemcitabine regimen (10.8 vs. 9.4 months). 一项非劣效性试验在1725例晚期NSCLC患者(ⅢB或Ⅳ期;大多数是Ⅳ期)中评估比较了顺铂/吉西他滨与顺铂/培美曲塞。顺铂/培美曲塞延长腺癌或大细胞癌(即非鳞NSCLC)患者的生存期(腺癌:12.6对10.9个月)。顺铂/吉西他滨方案延长鳞癌患者的生存期(10.8对9.4个月)。

When compared with the cisplatin/gemcitabine regimen, the cisplatin/pemetrexed regimen had significantly lower rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤.001); febrile neutropenia (P = .002); and alopecia (P < .001). Treatment-related deaths were similar for both regimens (cisplatin/pemetrexed, 9 patients [1.0%]; cisplatin/gemcitabine, 6 patients [0.7%]). A recent analysis of three phase 3 trials confirmed that pemetrexed improves survival for patients with non-squamous NSCLC in first-line, subsequent, and maintenance therapy. 与顺铂/吉西他滨方案相比,顺铂/培美曲塞方案具有显著更低的3或4级中性粒细胞减少、贫血和血小板减少(P≤0.001)、发热性中性粒细胞减少(P = 0.002)和脱发(P≤0.001)。两种方案的治疗相关死亡率相似(顺铂/培美曲塞9例[ 1% ];顺铂/吉西他滨6例[ 0.7% ])。最近一项对3个3期试验的分析证实培美曲塞一线、后续以及维持治疗均改善非鳞NSCLC患者的生存。

Data show that platinum-based combination therapy is superior to best supportive care for patients with advanced, incurable disease. Cisplatin or carboplatin have been proven effective in combination with many of the following agents: docetaxel, etoposide, gemcitabine, paclitaxel (and albumin-bound paclitaxel), pemetrexed, and vinorelbine (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC). Non-platinum regimens (eg, gemcitabine/docetaxel, gemcitabine/vinorelbine) are reasonable alternatives, because data show they are active and less toxic than platinum-based regimens. 数据显示,对于晚期、无法治愈的患者,以铂类为基础的联合治疗优于最佳支持治疗。已证明顺铂或卡铂联合下列许多药物均有效:多西他赛、依托泊苷、吉西他滨、紫杉醇(和白蛋白结合型紫杉醇)、培美曲塞以及长春瑞滨(见NSCLC NCCN指南中晚期或转移性疾病的全身治疗)。非铂方案(如吉西他滨/多西他赛、吉西他滨/长春瑞滨)是合理的选择,因为数据显示这些方案有效,且毒性比以铂类为基础的方案低。

Number of Cycles of First-Line Systemic Therapy 一线全身治疗的周期数

Patients receiving first-line systemic therapy for advanced disease should be evaluated for tumor response with a CT scan. Approximately 25% of patients show disease progression after the initial cycle of chemotherapy; subsequent therapy is recommended for these patients (see the NCCN Guidelines for NSCLC). Patients with responsive or stable disease can continue to receive a total of 4 to 6 cycles of systemic therapy. Currently, the NCCN Guidelines do not recommend continuing chemotherapy beyond 4 to 6 cycles. 接受一线全身治疗的晚期患者应该用CT扫描评估肿瘤应答。大约有25%的患者在初始化疗周期后疾病进展;对这些患者推荐进行后续治疗(见NSCLC NCCN指南)。有效或疾病稳定的患者可以继续接受4-6个周期的全身治疗。目前,NCCN指南不推荐持续化疗超过4-6个周期。

Recent data from the PARAMOUNT trial suggest that 4 cycles of platinum-based therapy is not optimal; tumors can shrink between 4 to 6 cycles of chemotherapy. However, patients may not be able to tolerate more than 4 cycles of chemotherapy, and most of the maintenance trials used only 4 cycles of chemotherapy. A meta-analysis suggests that continuing the initial regimen beyond 4 to 6 cycles is associated with increased PFS; however, patients have more adverse events. A phase 3 randomized trial suggested that continuing chemotherapy beyond 4 to 6 cycles is not beneficial; however, many patients assigned to longer duration of therapy did not receive the planned number of cycles. In this phase 3 trial, taxane-based regimens were used and patients had increasing neurotoxicity as more cycles were used. 来自PARAMOUNT试验的最新数据表明,4个周期的以铂为基础的治疗不是最佳的;肿瘤可在4-6周期的化疗期间缩小。不过,患者可能无法耐受4个周期以上的化疗,因此,大部分的维持试验只使用4个周期的化疗。一项meta分析表明,初始治疗持续超过4-6周期与PFS延长相关;不过,患者的不良事件更多。一期3项随机试验表明,持续超过4-6周期的化疗没有获益;然而,许多患者被分配到一个持续时间更长的治疗却未接受计划的周期数。在这项3期试验中,使用以紫杉烷为基础的方案,随着使用更多周期,患者的神经毒性逐渐增加。

Many patients with adenocarcinoma now receive pemetrexed-based regimens and not taxane-based regimens. Pemetrexed-based regimens are less toxic than taxane-based regimens. Thus, data suggesting that more than 6 cycles of first-line chemotherapy are not appropriate may only apply to taxane-based regimens. Studies report that 60% of patients were able to receive 6 cycles of pemetrexed-based chemotherapy (and had a low incidence of toxicity), whereas only 42% were able to receive more than 5 cycles of taxane-based chemotherapy and often stopped therapy because of neurotoxicity. 许多腺癌患者目前接受以培美曲塞为基础的方案而不是以紫杉烷为基础的方案。以培美曲塞为基础的方案比以紫杉烷为基础的方案毒性低。因此,数据显示一线化疗超过6周期不合适可能只适用于以紫杉烷为基础的方案。研究报告指出,60%的患者能够接受6周期以培美曲塞为基础的化疗(且毒性发生率低),而只有42%的患者能够接受超过5周期以紫杉烷为基础的化疗且经常因毒性而终止治疗。

Maintenance Therapy 维持治疗

For patients with non-squamous NSCLC and negative or unknown test results for ALK or ROS1 rearrangements, sensitizing EGFR mutations, or PD-L1 expression, maintenance therapy is another option for those with responsive or stable disease after first-line systemic therapy (see the NCCN Guidelines for NSCLC). Continuation maintenance therapy includes bevacizumab (category 1), pemetrexed (category 1), bevacizumab/pemetrexed, or gemcitabine (category 2B) (see the NCCN Guidelines for NSCLC). Switch maintenance therapy for these patients includes pemetrexed (category 2B). 对于ALK或ROS1重排、敏感EGFR突变或PD-L1表达阴性或未知的晚期非鳞NSCLC患者,一线全身治疗后有效或疾病稳定者,维持治疗是另一种选择(见NSCLC NCCN指南)。继续维持治疗包括贝伐单抗(1类)、培美曲塞(1类)、贝伐单抗/培美曲塞或吉西他滨(2B类)(见NSCLC NCCN指南)。这些患者的转换维持治疗包括培美曲塞(2B类)。

For the 2017 update (Version 2.2017), the NCCN Panel deleted the recommendation for erlotinib as switch maintenance therapy (and as subsequent therapy) for patients with non-squamous NSCLC and PS 0-2 but without EGFR mutations based on preliminary results from a randomized trial (IUNO) and revised indication by the FDA. The data showed that overall survival and PFS were not improved in patients receiving erlotinib when compared with placebo. A phase 3 randomized trial (n = 663) assessed the effect of best supportive care with (or without) switch maintenance pemetrexed in patients with advanced NSCLC who had received platinum-based chemotherapy but had not progressed. In patients with non-squamous NSCLC, overall survival was increased with pemetrexed when compared with placebo (15.5 vs. 10.3 months, P = .002). Close observation is another option. Maintenance therapy is discussed in greater detail earlier in this Discussion (see Combined Modality Therapy: Maintenance Therapy). 2017第2版更新,对于非鳞NSCLC和PS 0-2但没有EGFR突变的患者,基于一项随机试验(IUNO)的初步结果和FDA修订的适应症,NCCN小组删除了厄洛替尼作为转换维持治疗(和后续治疗)的推荐。数据显示,与安慰剂相比,接受厄洛替尼的患者总生存期和无进展生存期未改善。一项3期随机试验(n=663)评估了最佳支持治疗±培美曲塞转换维持治疗既往已接受以铂为基础的化疗但未进展的晚期NSCLC患者的效果。在非鳞NSCLC患者中,与安慰剂相比培美曲塞延长总生存期(15.5个月对10.3个月,P=0.002)。密切观察是另一种选择。在本讨论中更详细的讨论早期维持治疗(见综合疗法:维持治疗)。

For patients with squamous cell carcinoma, gemcitabine (category 2B) is recommended as continuation maintenance therapy (see the NCCN Guidelines for NSCLC). Switch maintenance therapy for these patients includes docetaxel (category 2B). Close observation is a category 2A option. As previously mentioned, a phase 3 randomized trial compared using maintenance therapy with either gemcitabine or erlotinib after first-line therapy with cisplatin-gemcitabine. Continuation maintenance therapy with single-agent gemcitabine increased PFS to a greater extent (3.8 months) than switch maintenance therapy with erlotinib (2.9 months) when compared with observation (1.9 months). However, the benefits of maintenance therapy were very slight; therefore, the recommendation is only category 2B for maintenance therapy with gemcitabine. A phase 3 trial assessed switch maintenance therapy with docetaxel given either immediately after chemotherapy or delayed until progression. However, switch maintenance therapy with docetaxel is a category 2B recommendation in the NCCN Guidelines, because many patients in the delayed chemotherapy arm did not receive docetaxel.对于鳞癌患者,推荐吉西他滨(2B类)继续维持治疗(见NSCLC NCCN指南)。这些患者的转换维持治疗包括多西他赛(2B类)。密切观察是2A类选择。如前所述,一项3期随机试验比较了在顺铂-吉西他滨一线治疗后使用吉西他滨或厄洛替尼维持治疗。PFS与观察相比(1.9个月),单药吉西他滨继续维持治疗(3.8个月)比用厄洛替尼转换维持治疗(2.9个月)改善程度更大。但是,维持治疗获益非常少;因此,用吉西他滨维持治疗只是2B类推荐。一项3期试验评估了在化疗后立即给予或延迟至进展再给予多西他赛转换维持治疗。不过,在NCCN指南中,多西他赛转换维持治疗是2B类推荐,因为延迟化疗组很多患者并未接受多西他赛。

Continuation of Erlotinib, Gefitinib, or Afatinib After Progression 进展后继续厄洛替尼、吉非替尼或阿法替尼

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 re-approved by the FDA based on a phase 4 study and is now available in the United States. Patients may continue to derive benefit from erlotinib, gefitinib, or afatinib after disease progression; discontinuation of these TKIs leads to more rapid progression of disease (symptoms, tumor size, and FDG-avidity on PET scan). This strategy mirrors the experience in other oncogene-addicted cancers, particularly HER2-amplified breast cancer. In women with HER2-amplified breast cancer who have had progression of disease on trastuzumab, improved radiographic response rate, time to progression, and overall survival are observed when conventional chemotherapy is added to trastuzumab. 以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最近重新审批通过吉非替尼,因此目前在美国可以使用。疾病进展后,患者可能继续受益于厄洛替尼、吉非替尼或阿法替尼;停用这些TKIs药物会导致更快速的疾病进展(症状、肿瘤大小和PET扫描时的FDG活性)。在其他癌基因依赖性癌症尤其是HER2扩增的乳腺癌中反映此策略经验。在曲妥珠单抗疾病进展的HER2扩增乳腺癌女性中,在传统化疗外加曲妥珠单抗时观察到改善影像学缓解率、至疾病进展时间和总生存期。

After development of acquired resistance in patients with lung adenocarcinoma and sensitizing EGFR mutations, erlotinib, gefitinib, or afatinib may be continued, but osimertinib is also an option for select patients; local therapy should be considered (eg, SRS to brain metastases or other sites, SABR for thoracic disease). The NCCN Panel recommends continuing erlotinib, gefitinib, or afatinib and considering local therapy in patients with asymptomatic progression; however, treatment varies for patients with symptomatic progression (see Sensitizing EGFR Mutation Positive: Subsequent Therapy in the NCCN Guidelines for NSCLC). For the 2017 update (Version 1), the NCCN Panel revised the recommendations for patients with sensitizing EGFR mutations who have progressed on erlotinib, gefitinib, or afatinib. Osimertinib is now recommended (category 1) for patients with symptomatic brain metastases. Another option is to continue use of erlotinib, gefitinib, or afatinib for these patients; however, additional therapy may be added or substituted (eg, local therapy, systemic therapy). First-line systemic therapy options are recommended for patients with multiple symptomatic lesions who are negative for T790M; osimertinib is recommended (category 1) for patients positive for T790M. 敏感EGFR突变的肺腺癌患者中,在发生获得性耐药后,可以继续给予厄洛替尼、吉非替尼或阿法替尼,不过,在选择性患者中,奥希替尼也是一个选择;应考虑局部治疗(如对于脑或其他部位的转移灶使用立体定向放疗,对胸腔病变使用立体定向消融放疗)。NCCN专家推荐无症状的进展患者继续厄洛替尼、吉非替尼或阿法替尼并考虑局部治疗;不过,有症状的进展患者的治疗则不同(见NSCLC NCCN指南中的敏感EGFR突变阳性:后续治疗)。2017第1版更新,NCCN小组修订了具有敏感EGFR突变、厄洛替尼、吉非替尼或阿法替尼进展患者的推荐。对于有症状的脑转移患者,目前推荐(1类)奥希替尼。对于这些患者,另一个选择是继续使用厄洛替尼、吉非替尼或阿法替尼;不过,可以增加其他治疗(如局部治疗、全身治疗)或用其他治疗代替。对于有症状的多发病变的T790M阴性患者,推荐的一线全身治疗方案选择;T790M阳性者,推荐(1类)奥希替尼。

Accumulating data suggest how cancers become resistant to EGFR inhibitors. The most common known mechanism is the acquisition of T790M (which is a secondary mutation in EGFR), that renders the kinase resistant to erlotinib, gefitinib, or afatinib. Therefore, if patients are T790M positive, osimertinib is recommended (category 1) and erlotinib, gefitinib, or afatinib are discontinued. Amplification of the MET oncogene is another validated resistance mechanism. To overcome resistance, EGFR must still be inhibited. In the case of MET amplification, new inhibitors must be added to the EGFR inhibitor; however, EGFR inhibition is still required to induce remission. Furthermore, data by Riely et al show that when cancers start to progress, which were once sensitive to EGFR inhibitors, discontinuation of the EGFR TKI can lead to a much more accelerated progression of the cancer. Thus, continuing EGFR TKIs is beneficial in many patients even after they develop resistance to EGFR TKIs. 越来越多的数据显示癌症是如何变得对EGFR抑制剂耐药。已知最常见的机制是获得性T790M(这是EGFR中的一个继发性突变),使得激酶对厄洛替尼、吉非替尼或阿法替尼耐药。因此,如果患者T790M阳性,推荐(1类)奥希替尼并停用厄洛替尼、吉非替尼或阿法替尼。另一个确认的耐药机制是MET癌基因扩增。为了克服耐药,仍有必要抑制EGFR。MET扩增的患者,必须在EGFR抑制剂之外添加新的抑制剂;不过,为诱导缓解仍需要EGFR抑制。此外,Riely等的数据显示,当曾经对EGFR抑制剂敏感的肿瘤开始进展时,停用EGFR TKI会使癌症更加速进展。因此,在许多患者中继续EGFR TKIs是有益的,即使是在其对EGFR TKIs发生耐药后。

Second-Line and Beyond (Subsequent) Systemic Therapy 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. 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 NSCLC). For the 2017 update (Version 1), the NCCN Panel now recommends response assessment of known sites of disease with CT (with contrast) every 6 to 12 weeks in patients receiving subsequent therapy. Note that traditional RECIST response criteria (1.1) are used to assess response for most types of systemic therapy but different response criteria may be useful for assessing response in patients receiving immunotherapy. 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异。在NSCLC工作步骤中描述了在一线治疗期间或者一线治疗后疾病进展者的后续全身治疗方案,方案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NSCLC NCCN指南)。2017第1版更新,在接受后续治疗的患者中,NCCN小组目前推荐每6-12周对已知病变部位使用强化CT疗效评估。值得注意的是,大多数情况下,使用传统RECIST疗效标准(1.1)评估全身治疗的疗效,但是在接受免疫治疗患者中,使用特殊的疗效标准疗效评估可能是有益的。

The NCCN Panel recommends immune checkpoint inhibitors, as 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, Pembrolizumab, and Atezolizumab in this Discussion). 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. The NCCN Panel recommends nivolumab (category 1) as subsequent therapy for patients with metastatic non-squamous or squamous NSCLC based on a phase 3 randomized trial (CheckMate-057) and FDA approval. The NCCN Panel recommends pembrolizumab (category 1) 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 FDA approval. The NCCN Panel also recommends atezolizumab (category 1) as subsequent therapy for patients with metastatic non-squamous or squamous NSCLC based on a phase 3 randomized trial (OAK), data from a phase 2 trial (POPLAR), and recent FDA approval. 基于与细胞毒化疗相比,免疫检查点抑制剂提高生存率、缓解持续时间更长且几乎没有不良事件,NCCN专家组推荐作为转移性NSCLC患者后续治疗的首选药物(见本讨论中的尼鲁单抗、派姆单抗和阿特朱单抗)。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;PD-1受体表达于活化的细胞毒T细胞。基于一项3期随机试验(CheckMate-057)和FDA的批准,NCCN小组推荐尼鲁单抗(1类)作为转移性非鳞或鳞型NSCLC患者的后续治疗。基于最近一项2/3期随机试验(KEYNOTE-010试验)、KEYNOTE-001试验和FDA的批准,NCCN小组推荐(1类)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。基于一项3期随机试验(OAK)的初步数据、一项2期试验(POPLAR)的数据和最近FDA的批准,NCCN小组也推荐阿特朱单抗(1类)作为转移性非鳞或鳞型NSCLC患者的后续治疗。

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 based on recent data and on the FDA approval (see Osimertinib in this Discussion). Osimertinib (AZD9291) is an oral TKI that inhibits both EGFR-sensitizing mutations and T790M. Data from a recent phase 3 trial report that osimertinib is associated with a response rate of about 71% and disease control rate of about 93% (95% CI, 90%–96%) in patients who have progressed on sensitizing EGFR TKI therapy; 23% of patients had drug-related grade 3 or higher adverse events with 4 fatal events. 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. Most patients with sensitizing EGFR mutations and metastatic NSCLC typically progress after about 9 to 13 months of erlotinib or gefitinib therapy. EGFR T790M 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. T790M can be assessed using an FDA-approved test or other validated laboratory test done in a CLIA-approved laboratory. 基于最新的数据和FDA的批准,NCCN小组推荐奥希替尼(1类)作为转移性EGFR T790M阳性、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(见本讨论中的奥希替尼)。奥希替尼(AZD9291)是一种口服的TKI,抑制EGFR敏感突变和T790M。最近一项2期试验报告的数据,在敏感EGFR TKI治疗已经进展的患者中,奥希替尼的缓解率约71%、疾病控制率约93%(95%CI,90%-96%);23%的患者有≥3度的药物相关不良事件,4例致命事件。FDA已批准奥西替尼用于以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。大多数敏感EGFR突变的患者和转移性NSCLC患者通常大约在厄洛替尼或吉非替尼治疗9至13个月后进展。EGFR T790M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) continuing erlotinib, afatinib, or gefitinib with (or without) local therapy; 2) osimertinib; or 3) a first-line systemic therapy regimen for either non-squamous or squamous cell NSCLC (such as cisplatin/pemetrexed or cisplatin/gemcitabine, respectively). For the 2017 update (Version 4), the NCCN Panel now also recommends osimertinib (category 1) for patients with T790M who have brain metastases. Data suggest that an afatinib/cetuximab regimen may be useful for patients who have progressed after receiving EGFR TKI therapy and chemotherapy. Patients with T790M-positive and T790M-negative tumors had a similar response rate to an afatinib/cetuximab regimen (32% vs. 25%; P = .341). The NCCN Panel recommends (category 2A) considering an afatinib/cetuximab regimen for patients who have progressed after receiving EGFR TKIs and chemotherapy based on these data. 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)继续厄洛替尼、阿法替尼或吉非替尼±局部治疗;2)奥希替尼;或3)用非鳞或鳞型NSCLC的一线全身治疗方案(如分别为顺铂/培美曲塞或顺铂/吉西他滨)。对于具有T790M的脑转移患者,2017第1版更新,NCCN小组现在也推荐奥希替尼(1类)。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。肿瘤T790M阳性与阴性的患者阿法替尼/西妥昔单抗方案的有效率相似(32%对25%;P = 0.341)。基于这些数据,对于在接受EGFR TKIs和化疗后进展的患者,NCCN小组推荐(2A类)考虑阿法替尼/西妥昔单抗方案治疗。

Among patients with sensitizing EFGR mutations, no improvement in overall survival has been noted in the phase 3 trials assessing pembrolizumab, nivolumab, or atezolizumab compared to docetaxel, but there were not enough patients with these mutations to determine whether there were statistically significant differences (see next paragraph). Immunotherapy was not worse than chemotherapy and was better tolerated. In the phase 3 trials for pembrolizumab, nivolumab, or atezolizumab 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. The HRs for overall survival do not favor docetaxel over nivolumab (HR, 1.18; CI, 0.69–2.0), pembrolizumab (HR, 0.88; CI, 0.45–1.7), or atezolizumab (HR, 1.24; CI, 0.7–2.2); the CIs for the HRs are wide probably because there were so few patients with EGFR mutations. 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). But again, the CIs are wide. The evidence is weak for recommending docetaxel, pembrolizumab, nivolumab, or atezolizumab as subsequent therapy for patients with EGFR mutations. Recent data suggest that patients with EGFR mutations or ALK rearrangements have a low response rate to PD-1 or PD-L1 inhibitors when compared with patients without these genetic alterations (response rate, 3.6% vs. 23%, respectively). 在敏感EGFR突变的患者当中,评估派姆单抗、尼鲁单抗或阿特珠单抗的3期试验已注意到,与多西他赛相比,总生存期无改善,但是具有这些突变的患者数量不足以确定差异是否有统计学意义(见下段)。免疫治疗不比化疗更糟糕,而耐受性更好。派姆单抗、尼鲁单抗或阿特朱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突变患者进行了亚组分析,以确定最佳的后续治疗。总生存期风险比多西他赛不优于尼鲁单抗(风险比 = 1.18;CI,0.69-2.0)、派姆单抗(风险比,0.88;CI,0.45-1.7)或阿特珠单抗(风险比,1.24;CI,0.7 - 2.2);风险比(HRs)的可信区间(CIs)范围大可能是因为EGFR突变的患者太少。对于EGFR突变的患者,PFS的风险均比得上派姆单抗(HR,1.79;CI,0.94-3.42)或尼鲁单抗(风险比 = 1.46;CI,0.90-2.37)。但是可信区间范围仍大。推荐多西紫杉醇、派姆单抗、尼鲁单抗或阿特珠单抗作为EGFR突变患者后续治疗的证据不充分。最新数据表明,具有EGFR突变或ALK重排的患者,与没有这些遗传学改变的患者相比,PD-1或PD-L1抑制剂的有效率低(有效率分别为3.6%对23%)。

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 crizotinib with (or without) local therapy; 2) ceritinib; 3) alectinib; or 4) a first-line systemic therapy regimen for either non-squamous or squamous cell NSCLC. 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 (both are category 1), respectively. Other chemotherapy options are also recommended for patients with PS 2, such as docetaxel (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for 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,同样根据进展是否有症状,推荐的治疗包括:1)继续克唑替尼±局部治疗2)色瑞替尼;3)阿雷替尼;或4)非鳞或鳞型NSCLC的一线全身治疗方案。在后续靶向治疗再次进展后,对于非鳞NSCLC或鳞癌、PS评分0-1的患者,分别推荐一线联合化疗选择如顺铂/培美曲塞或顺铂/吉西他滨(二者均为1类)。对于PS评分2的患者还推荐其他化疗选择,如多西他赛(见NSCLC 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, ROS1 rearrangements, or sensitizing EGFR mutations. For patients with all histologic subtypes and PS of 0 to 2 but without these genetic alterations who have disease progression during or after first-line therapy, recommended subsequent systemic therapy options include nivolumab (category 1), pembrolizumab (category 1), atezolizumab (category 1), docetaxel with (or without) ramucirumab, or gemcitabine if not already given; pemetrexed is recommended for patients with non-squamous NSCLC. For the 2017 update (Version 4), the NCCN Panel revised the recommendation for atezolizumab to category 1 (from category 2A) as subsequent therapy. The NCCN Panel recommends immune checkpoint inhibitors—nivolumab, pembrolizumab, and atezolizumab—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, Pembrolizumab, and Atezolizumab in this Discussion). 大多数NSCLC患者没有ALK重排、ROS1重排或敏感EGFR突变。对于各种组织学亚型、PS 0-2但没有这些遗传学改变、一线治疗期间或治疗后疾病进展的患者,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)、阿特珠单抗(1类)、多西他赛±雷莫芦单抗或吉西他滨(如果未曾给予);对于非鳞NSCLC患者推荐使用培美曲塞。2017第4版更新,NCCN小组将阿特珠单抗作为后续治疗的推荐从2A类修改为1类。基于与细胞毒性化疗相比,免疫检查点抑制剂——尼鲁单抗、派姆单抗和阿特珠单抗——改善生存率、疗效持续时间更长且不良事件更少,NCCN小组推荐作为所有组织学亚型的首选后续治疗(见本讨论中的尼鲁单抗、派姆单抗和阿特珠单抗)。

For the 2017 update (Version 2.2017), the NCCN Panel deleted the recommendation for erlotinib as subsequent therapy (and as switch maintenance therapy) for patients with non-squamous NSCLC and PS 0-2 but without EGFR mutations based on preliminary results from a randomized trial (IUNO) and revised indication by the FDA. The data showed that overall survival and PFS were not improved in patients receiving erlotinib when compared with placebo. Ramucirumab/docetaxel is an option for all histologic subtypes for subsequent therapy based on a phase 3 randomized trial. The median overall survival was slightly increased with ramucirumab/docetaxel versus docetaxel alone (10.5 vs. 9.1 months, respectively). Contraindications for ramucirumab/docetaxel therapy include risk for severe hemorrhage, grade 3 to 4 gastrointestinal bleeding, gastrointestinal perforation or fistula, and poorly controlled hypertension. 2017第2版更新,对于PS 0-2但没有EGFR突变的非鳞NSCLC患者,基于一项随机试验(IUNO)的初步结果和FDA修订的适应症,NCCN小组删除了厄洛替尼作为后续治疗(和作为转换维持治疗)的推荐。资料显示,与安慰剂相比,接受厄洛替尼的患者总生存期和无进展生存期未改善。根据一项3期随机试验,对于所有组织学亚型的后续治疗,雷莫芦单抗/多西他赛是一个选择。与多西他赛单药相比,雷莫芦单抗/多西他赛组的中位总生存期略微延长(分别为9.1个月对10.5个月)。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

Docetaxel has been proven superior to best supportive care, vinorelbine, or ifosfamide with improved survival and quality of life. When compared with docetaxel, pemetrexed has similar median survival but less toxicity. Pemetrexed is recommended in patients with non-squamous NSCLC. Docetaxel is recommended for patients with wild-type EGFR tumors based on 2 randomized trials comparing erlotinib versus docetaxel. In patients with PS of 3 to 4, best supportive care is recommended (see the NCCN Guidelines for NSCLC). Patients often have a limited response to subsequent chemotherapy other than immune checkpoint inhibitors, although it may serve a useful palliative role. 已经证明在改善生存和生活质量方面,多西他赛优于最佳支持治疗、长春瑞滨或异环磷酰胺。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。非鳞NSCLC患者推荐培美曲塞。根据比较厄洛替尼与多西他赛的两项随机试验,对于野生型EGFR肿瘤患者推荐多西他赛。在PS评分3-4的患者中,推荐最佳支持治疗(见NSCLC NCCN指南)。除了免疫检查点抑制剂外,患者对后续化疗常常应答有限,尽管它可能是一个有效的姑息手段。

Recently, the NCCN Panel deleted erlotinib as an option for subsequent therapy for patients with squamous cell NSCLC based on a study comparing afatinib with erlotinib; this study was statistically significant but not clinically significant. 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. 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. In addition, only 7% of patients receiving nivolumab had grade 3 or higher adverse events. Erlotinib and afatinib are not recommended as second-line therapy for squamous cell carcinoma based on a phase 3 randomized trial showing low response rates and because they are less efficacious and safe compared to other available options. 基于一项比较阿法替尼与厄洛替尼的研究,最近,NCCN小组删除了厄洛替尼作为肺鳞癌患者的后续治疗选择;该研究有统计学意义,但无临床意义。阿法替尼组的总生存略微好于厄洛替尼组(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=0.0077);不过,每组将近60%的患者有≥3度的不良事件。相反,对于肺鳞癌患者,中位总生存期尼鲁单抗是9.2个月,而多西他赛为6.0个月。此外,接受尼鲁单抗的患者仅7%有≥3度的不良事件。基于一项3期随机试验显示有效率低,而且与其他可用选择相比,安全性与有效性较差,因此不推荐厄洛替尼和阿法替尼作为鳞癌的二线治疗。

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. Erlotinib, gefitinib, or afatinib may be continued in patients with sensitizing EGFR mutations who have progressed after first-line therapy. Osimertinib is recommended for patients with T790M whose disease becomes resistant to erlotinib, afatinib, or gefitinib. Afatinib/cetuximab may be considered for patients with sensitizing EGFR mutations who have progressed after EGFR TKI therapy and chemotherapy. Ceritinib or alectinib are recommended in patients with ALK-positive NSCLC who have progressed after first-line therapy with crizotinib or are intolerant to crizotinib. Nivolumab, pembrolizumab, atezolizumab, 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.对于非鳞NSCLC或鳞癌,如果患者有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、阿雷替尼或奥希替尼治疗后,全身多发病变出现有症状的进展,则推荐选择一线双药化疗。在具有敏感EGFR突变、一线治疗后进展的患者中,可以继续使用厄洛替尼、吉非替尼或阿法替尼。对厄洛替尼、阿法替尼或吉非替尼耐药的T790M患者,推荐奥希替尼。对于具有敏感EGFR突变、在EGFR TKI治疗和化疗后进展的患者,可以考虑阿法替尼/西妥昔单抗。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患者中,推荐色瑞替尼或阿雷替尼。尼鲁单抗、派姆单抗、阿特珠单抗、多西他赛±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)推荐用于二次进展后PS 0-2的晚期NSCLC患者的后续治疗(如果这些药物未曾给予)。

本文是张品良医生版权所有,未经授权请勿转载。

问医生

与医生电话交流 开始

图文问诊开始

预约就诊
×
分享到微信
打开微信“扫一扫”,即可分享该文章

发表于:2017-03-14 09:17

张品良大夫的信息

  • 感谢信: 0 感谢信 礼物: 0 礼物

张品良大夫电话咨询

张品良大夫已经开通电话咨询服务
直接与大夫本人通话,方便!快捷!

电话咨询

网上咨询张品良大夫

张品良的咨询范围: 肺癌、头颈部肿瘤

咨询张品良大夫