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

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。正在开发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），而在多西他赛组中发生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，派姆单抗也可能发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。