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  5. 晚期NSCLC一线免疫治疗：帕博利珠、纳武利尤与阿替利珠单抗的疗效、安全性及市场推广规范

晚期NSCLC一线免疫治疗：帕博利珠、纳武利尤与阿替利珠单抗的疗效、安全性及市场推广规范

文献检索Suppr助手发表于 2026年05月20日 17:457阅读
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帕博利珠单抗、纳武利尤单抗和阿替利珠单抗在晚期非小细胞肺癌一线治疗中的总生存、无进展生存、PD-L1表达亚组、安全性和适用人群有什么差异？请按关键临床试验、系统综述和指南推荐整理，并说明肿瘤药市场推广表达边界。

好的，我将根据您提供的证据，详细阐述帕博利珠单抗（Pembrolizumab）、纳武利尤单抗（Nivolumab）和阿替利珠单抗（Atezolizumab）在晚期非小细胞肺癌（NSCLC）一线治疗中的总生存（OS）、无进展生存（PFS）、PD-L1表达亚组、安全性和适用人群的差异，并按关键临床试验、系统综述和指南推荐进行整理，最后说明肿瘤药市场推广的表达边界。

帕博利珠单抗（Pembrolizumab）

关键临床试验结果

  1. KEYNOTE-024 (PD-L1 ≥ 50% 肿瘤)

    • 适用人群： 针对PD-L1肿瘤比例评分（TPS）≥50%且无EGFR或ALK敏感突变的初治晚期NSCLC患者 。
    • 总生存 (OS)：
      • 在6个月时的估计OS率为帕博利珠单抗组80.2% vs 化疗组72.4% 。
      • 帕博利珠单抗相较于铂类化疗显著延长了OS（死亡风险比[HR] = 0.60；95% CI 0.41-0.89；P=0.005）。
      • 1年OS率帕博利珠单抗组约为70% 。
    • 无进展生存 (PFS)：
      • 帕博利珠单抗组中位PFS为10.4个月，化疗组为6.0个月（HR = 0.50；95% CI 0.37-0.68；P<0.001）。
      • 这表明帕博利珠单抗显著延长了PFS 。
    • 客观缓解率 (ORR)： 帕博利珠单抗组为44.8%，化疗组为27.8%（P = 0.0011）。
    • 安全性： 帕博利珠单抗组的任何级别治疗相关不良事件（TRAEs）发生率低于化疗组（73.4% vs 90.0%），3、4或5级TRAEs发生率也较低（26.6% vs 53.3%）。
    • 结论： 帕博利珠单抗单药一线治疗PD-L1 ≥ 50%的晚期NSCLC患者，相较于铂类化疗，具有显著更长的PFS和OS，且不良事件发生率更低，被认为是这类患者的一线标准治疗 。

  2. KEYNOTE-021 (与化疗联用，非选择性NSCLC)

    • 适用人群： 未经选择的NSCLC患者（该试验报告了与化疗联用的一线治疗效果）。
    • 客观缓解率 (ORR)： 帕博利珠单抗联合化疗组ORR为55%，化疗单独组为29%（P = 0.0016），显示出令人鼓舞的疗效 。

  3. KEYNOTE-189 (与化疗联用，转移性非鳞状NSCLC)

    • 适用人群： 未经治疗的转移性非鳞状NSCLC患者，无EGFR或ALK致敏突变 。
    • 治疗方案： 帕博利珠单抗（200 mg，每3周一次，最多35周期）联合培美曲塞和铂类药物（4周期），随后培美曲塞维持治疗，对比安慰剂联合培美曲塞和铂类药物 。
    • 总生存 (OS)：
      • 中位随访10.5个月后，帕博利珠单抗联合化疗组的12个月OS估计率为69.2%，安慰剂联合化疗组为49.4%（死亡风险比[HR]=0.49；95% CI 0.38-0.64；P<0.001）。
      • OS的改善在所有评估的PD-L1类别中均可见 。
      • 5年随访结果显示，帕博利珠单抗联合培美曲塞-铂类组的OS HR为0.60（95% CI 0.50-0.72），5年OS率分别为19.4% vs 11.3% 。
    • 无进展生存 (PFS)：
      • 帕博利珠单抗联合化疗组中位PFS为8.8个月，安慰剂联合化疗组为4.9个月（疾病进展或死亡风险比[HR]=0.52；95% CI 0.43-0.64；P<0.001）。
      • 5年随访结果显示，帕博利珠单抗联合培美曲塞-铂类组的PFS HR为0.50（95% CI 0.42-0.60）。
    • 安全性： 3级或更高级别不良事件在帕博利珠单抗联合化疗组发生率为67.2%，安慰剂联合化疗组为65.8% 。毒性可控 。
    • 结论： 帕博利珠单抗联合标准化疗显著延长了未经治疗的转移性非鳞状NSCLC患者的OS和PFS，无论PD-L1表达水平如何，支持其作为标准治疗 。

  4. KEYNOTE-042 (PD-L1 ≥ 1% 中国患者亚组研究)

    • 适用人群： PD-L1 TPS ≥ 1%的局部晚期或转移性NSCLC中国患者，无EGFR/ALK突变 。
    • 总生存 (OS)： 帕博利珠单抗单药相较于化疗改善了OS，在PD-L1 TPS ≥ 50%（HR=0.63）、≥ 20%（HR=0.66）和 ≥ 1%（HR=0.67）的患者中均有益 。
    • 安全性： 帕博利珠单抗组3-5级TRAEs发生率显著低于化疗组（19.5% vs 68.8%）。

  5. LOXO-RAS-20001 (Olomorasib 联合 Pembrolizumab，KRAS G12C 突变 NSCLC)

    • 适用人群： 晚期KRAS G12C突变NSCLC患者，不限治疗线和PD-L1水平，包括一线治疗患者 。
    • 客观缓解率 (ORR)： 50或100 mg Olomorasib联合帕博利珠单抗的ORR为57.1%（95% CI 46.3-67.5），一线治疗患者中ORR为73.9%（95% CI 58.9-85.7），一线治疗PD-L1 ≥ 50%患者中ORR高达90%（95% CI 68.3-98.8）。
    • 安全性： 81.7%的患者发生TRAEs，最常见为腹泻（34.4%）和ALT/AST升高（24.7%/22.6%）。3级或更高级别TRAEs发生率为33.3%。6.5%的患者因TRAEs停止两种治疗 。
    • 结论： 在KRAS G12C突变晚期NSCLC患者中，Olomorasib联合帕博利珠单抗显示出可控的安全性及有前景的抗肿瘤活性，特别是在PD-L1高表达的一线治疗患者中 。

  6. LEAP-007 (Lenvatinib 联合 Pembrolizumab，PD-L1 ≥ 1% NSCLC)

    • 适用人群： 未经治疗的IV期NSCLC患者，PD-L1 TPS ≥ 1%，无EGFR/ROS1/ALK靶向变异 。
    • 治疗方案： Lenvatinib 20mg 或安慰剂每日一次，所有患者每3周接受帕博利珠单抗 200mg，最多35周期 。
    • 总生存 (OS)： Lenvatinib联合帕博利珠单抗组中位OS为14.1个月，安慰剂联合帕博利珠单抗组为16.4个月（HR=1.10；95% CI 0.87-1.39；P=0.79744）。研究因未能达到预设的无进展生存终点而被解除盲态和终止 。
    • 无进展生存 (PFS)： Lenvatinib联合帕博利珠单抗组中位PFS为6.6个月，安慰剂联合帕博利珠单抗组为4.2个月（HR=0.78；95% CI 0.64-0.95）。
    • 安全性： Lenvatinib联合帕博利珠单抗组3-5级TRAEs发生率为57.9%，安慰剂联合帕博利珠单抗组为24.4% 。
    • 结论： Lenvatinib联合帕博利珠单抗相比帕博利珠单抗单药并未显示出有利的获益-风险特征。帕博利珠单抗单药仍是PD-L1 ≥ 1%且无EGFR/ALK改变的转移性NSCLC一线治疗的批准选项 。

系统综述和指南推荐

  • 系统综述： 在PD-L1表达 ≥ 50%的NSCLC患者中，帕博利珠单抗单药作为一线治疗是标准护理 。在PD-L1表达 < 50%时，或在没有可靶向突变的情况下，帕博利珠单抗联合化疗已成为首选一线治疗 。
  • 适用人群：
    • PD-L1 ≥ 50%： 帕博利珠单抗单药是标准治疗选择，相较于化疗显著改善OS和PFS，且不良事件较少 。
    • PD-L1 < 50%（或不限PD-L1表达）： 帕博利珠单抗联合铂类化疗，特别是在非鳞状NSCLC中，可显著改善OS和PFS，是标准治疗之一 。对于PD-L1 ≥ 1%的患者，帕博利珠单抗单药也显示出OS改善 。
    • KRAS G12C突变： Olomorasib联合帕博利珠单抗在一线治疗中显示出高ORR，尤其在PD-L1高表达患者中 。
    • 无EGFR或ALK突变： 免疫检查点抑制剂（包括帕博利珠单抗）无论单药或联合化疗，都是无驱动基因突变晚期NSCLC的一线标准治疗 。

纳武利尤单抗（Nivolumab）

关键临床试验结果

  1. Checkmate-026 (单药，PD-L1 ≥ 5% NSCLC)

    • 适用人群： PD-L1 ≥ 5%的晚期NSCLC患者 。
    • 结果： 纳武利尤单抗单药未能显示出相较于标准化疗的任何益处。在PD-L1 ≥ 5%的NSCLC组中，纳武利尤单抗组的中位PFS为4.2个月，化疗组为5.9个月（HR = 1.15；95% CI 0.91-1.45；P=0.25）。在PD-L1 ≥ 50%亚组中也未观察到益处 。
    • 结论： 单药纳武利尤单抗在这一特定患者群体和PD-L1表达水平下，作为一线治疗未获成功 。

  2. CheckMate 227 (Nivolumab 联合 Ipilimumab)

    • 适用人群： 未经治疗的IV期或复发性NSCLC患者 。
    • 治疗方案： 纳武利尤单抗联合伊匹木单抗（抗CTLA-4抗体），对比纳武利尤单抗单药或化疗。对于PD-L1 ≥ 1%的患者，主要终点是纳武利尤单抗联合伊匹木单抗对比化疗的OS；对于PD-L1 < 1%的患者，则对比纳武利尤单抗联合化疗与化疗单药 。
    • 总生存 (OS)：
      • PD-L1 ≥ 1%： 纳武利尤单抗联合伊匹木单抗组中位OS为17.1个月，化疗组为14.9个月（P=0.007），2年OS率分别为40.0%和32.8% 。
      • PD-L1 < 1%： 纳武利尤单抗联合伊匹木单抗组中位OS为17.2个月，化疗组为12.2个月。在所有患者中，联合治疗组中位OS为17.1个月，化疗组为13.9个月 。
      • 4年随访结果： 纳武利尤单抗联合伊匹木单抗组相较于化疗组OS持续延长，PD-L1 ≥ 1%患者的HR=0.76，PD-L1 < 1%患者的HR=0.64。4年OS率在PD-L1 ≥ 1%患者中分别为29% vs 18%，在PD-L1 < 1%患者中分别为24% vs 10% 。益处在鳞状和非鳞状组织学类型中均观察到 。
    • 无进展生存 (PFS)： 试验数据主要关注OS，但在早期研究中，纳武利尤单抗联合伊匹木单抗的缓解率高于纳武利尤单抗单药，尤其在PD-L1表达肿瘤中 。
    • 客观缓解持续时间： 纳武利尤单抗联合伊匹木单抗组中位缓解持续时间为23.2个月，化疗组为6.2个月 。
    • 安全性： 在总人群中，纳武利尤单抗联合伊匹木单抗组的3或4级治疗相关不良事件发生率为32.8%，化疗组为36.0% 。最常见的免疫介导不良事件是皮疹，多数在治疗开始后6个月内发生，并在3个月内通过系统性皮质类固醇解决 。因TRAEs停止治疗的患者仍显示出长期OS获益 。
    • 结论： 纳武利尤单抗联合伊匹木单抗作为一线治疗，无论PD-L1表达水平如何，均能延长NSCLC患者的OS，且长期随访未出现新的安全问题 。

系统综述和指南推荐

  • 系统综述： 纳武利尤单抗单药在一线治疗中的效果不佳 。然而，纳武利尤单抗联合伊匹木单抗（双重免疫检查点抑制剂）已获得FDA批准，适用于所有PD-L1表达 ≥ 1%的患者，并被认为可延长OS，无论PD-L1表达水平如何 。
  • 适用人群：
    • PD-L1 ≥ 1% 和 < 1%： 纳武利尤单抗联合伊匹木单抗被推荐用于所有PD-L1表达 ≥ 1%的患者，且在PD-L1 < 1%的患者中也显示出OS益处 。
    • 无EGFR或ALK突变： 作为双重免疫疗法，适用于无驱动基因突变晚期NSCLC的一线治疗 。

阿替利珠单抗（Atezolizumab）

关键临床试验结果

  1. OAK Phase III Study (二线治疗)

    • 适用人群： 二线治疗，与多西他赛对比 。
    • 结果： 阿替利珠单抗在二线治疗中显示出疗效，中位OS为13.8个月，多西他赛组为9.6个月 。

  2. IMpower150 (阿替利珠单抗 + 贝伐珠单抗 + 化疗)

    • 适用人群： 未经治疗的转移性非鳞状NSCLC患者，无论PD-L1表达和EGFR或ALK基因改变状态 。
    • 治疗方案： 阿替利珠单抗联合贝伐珠单抗、卡铂和紫杉醇（ABCP），对比贝伐珠单抗、卡铂和紫杉醇（BCP），或阿替利珠单抗、卡铂和紫杉醇（ACP）。
    • 总生存 (OS)：
      • 在野生型（WT）人群中（排除EGFR或ALK突变），ABCP组中位OS为19.2个月，BCP组为14.7个月（死亡风险比[HR]=0.78；95% CI 0.64-0.96；P=0.02）。
      • OS和PFS的改善在整个意向治疗人群中均有体现，包括PD-L1低表达或阴性，以及肝转移的患者 。
    • 无进展生存 (PFS)：
      • 在WT人群中，ABCP组中位PFS为8.3个月，BCP组为6.8个月（疾病进展或死亡风险比[HR]=0.62；95% CI 0.52-0.74；P<0.001）。
      • 在具有高效应T细胞（Teff）基因表达特征的WT人群中，ABCP组中位PFS为11.3个月，BCP组为6.8个月（HR=0.51；95% CI 0.38-0.68；P<0.001）。
    • 安全性： ABCP的安全谱与各药物单独使用的已知风险一致 。
    • 分子亚型分析 (IMpower150 NMF亚型)：
      • 通过转录组学分析识别出四种分子亚型（NMF1-4）。
      • NMF4亚型（富集B细胞和T细胞，PD-L1表达升高）患者显示ABCP相较于BCP或ACP有PFS和OS获益 。
      • NMF1亚型（富集基底和鳞状样细胞）患者在ABCP治疗下相较于ACP或BCP有改善的结局 。
      • NMF3亚型（富集腺癌特征）患者在不同治疗之间结果相似 。
    • 结论： 阿替利珠单抗联合贝伐珠单抗和化疗显著改善了转移性非鳞状NSCLC患者的PFS和OS，无论PD-L1表达状态或EGFR/ALK改变状态如何 。这为个体化一线治疗提供了新见解 。

系统综述和指南推荐

  • 系统综述： 阿替利珠单抗联合化疗和贝伐珠单抗已被批准用于一线治疗NSCLC，无论PD-L1表达如何 。
  • 适用人群：
    • 所有PD-L1表达水平： 阿替利珠单抗联合化疗和贝伐珠单抗（ABCP方案）适用于转移性非鳞状NSCLC，无论PD-L1表达或EGFR/ALK改变状态，均显示OS和PFS益处 。

汇总比较与总结

特征帕博利珠单抗 (Pembrolizumab)纳武利尤单抗 (Nivolumab)阿替利珠单抗 (Atezolizumab)
总生存 (OS)单药： PD-L1 ≥ 50% 显著优于化疗（KEYNOTE-024，1年OS约70%，HR=0.60）。
联用化疗： 无论PD-L1表达，显著优于化疗（KEYNOTE-189，12个月OS率为69.2% vs 49.4%，HR=0.49；5年OS率为19.4% vs 11.3%，HR=0.60）。		单药： PD-L1 ≥ 5% 未显示益处（Checkmate-026）。
联合Ipilimumab： 无论PD-L1表达，显著优于化疗（CheckMate 227，中位OS 17.1个月 vs 13.9个月，HR=0.76/0.64；4年OS率在PD-L1≥1%时为29% vs 18%）。		联合Bevacizumab+化疗： 无论PD-L1表达和EGFR/ALK状态，显著优于Bevacizumab+化疗（IMpower150，中位OS 19.2个月 vs 14.7个月，HR=0.78）。
无进展生存 (PFS)单药： PD-L1 ≥ 50% 显著优于化疗（KEYNOTE-024，中位PFS 10.3个月 vs 6.0个月，HR=0.50）。
联用化疗： 无论PD-L1表达，显著优于化疗（KEYNOTE-189，中位PFS 8.8个月 vs 4.9个月，HR=0.52；5年PFS HR=0.50）。		单药： PD-L1 ≥ 5% 未显示益处（Checkmate-026，中位PFS 4.2个月 vs 5.9个月）。
联合Ipilimumab： 缺乏直接PFS对比数据，但反应持续时间长 。		联合Bevacizumab+化疗： 无论PD-L1表达和EGFR/ALK状态，显著优于Bevacizumab+化疗（IMpower150，中位PFS 8.3个月 vs 6.8个月，HR=0.62）。
PD-L1表达亚组≥ 50%： 帕博利珠单抗单药是标准治疗 。
< 50%： 帕博利珠单抗联合化疗优于化疗 。
≥ 1%： 帕博利珠单抗单药显示OS改善 。		≥ 1%： 纳武利尤单抗联合伊匹木单抗显示OS益处 。
< 1%： 纳武利尤单抗联合伊匹木单抗同样显示OS益处 。		所有PD-L1表达水平： 阿替利珠单抗联合Bevacizumab+化疗显示OS和PFS益处 。
安全性单药： 任何级别和3-5级TRAEs均少于化疗（KEYNOTE-024）。
联用化疗： 3级及以上不良事件发生率与化疗组相似（KEYNOTE-189，67.2% vs 65.8%）。		联合Ipilimumab： 3-4级TRAEs发生率与化疗组相似（32.8% vs 36.0%），免疫介导不良事件多在早期发生并可通过皮质类固醇处理 。联合Bevacizumab+化疗： 安全性与各药物单独使用风险一致（IMpower150）。
适用人群PD-L1 ≥ 50%： 单药一线治疗。
PD-L1 < 50%（或不限PD-L1表达）无EGFR/ALK突变： 联合化疗一线治疗。
KRAS G12C突变： 联合Olomorasib显示前景 。
无EGFR/ALK/ROS1驱动突变： 单药或联合化疗是标准治疗 。		无论PD-L1表达水平的晚期NSCLC患者： 联合伊匹木单抗一线治疗 。
无EGFR/ALK驱动突变： 双免疫治疗是标准治疗 。		转移性非鳞状NSCLC，无论PD-L1表达和EGFR/ALK状态： 联合Bevacizumab+化疗一线治疗 。
主要区别帕博利珠单抗单药在PD-L1高表达人群中效果显著且毒性较低；与化疗联用在更广泛PD-L1人群中有效。纳武利尤单抗单药效果不佳； 联合伊匹木单抗（双免疫）则在所有PD-L1表达水平的患者中显示OS益处，但安全性可能需要更积极管理。阿替利珠单抗通常与贝伐珠单抗和化疗联用， 对广泛的非鳞状NSCLC患者有效，包括低PD-L1表达和驱动基因突变阴性患者。

系统综述和指南推荐总结

  • 第一线治疗的范式转变： 免疫检查点抑制剂（ICIs）已彻底改变了晚期NSCLC的治疗标准 。
  • PD-L1作为生物标志物： PD-L1表达水平是选择一线ICI治疗的重要生物标志物 。
    • PD-L1 ≥ 50%： 帕博利珠单抗单药是标准一线治疗，因为它显著改善了OS和PFS，并且毒性低于化疗 。Cemiplimab单药在PD-L1 ≥ 50%且有脑转移的NSCLC患者中也显示出显著的OS和PFS益处 。
    • PD-L1 < 50% 或不限PD-L1：
      • 帕博利珠单抗联合化疗（如KEYNOTE-189）已被证实可显著延长OS和PFS，并成为无EGFR或ALK突变的转移性非鳞状NSCLC的一线标准治疗 。
      • 阿替利珠单抗联合贝伐珠单抗和化疗（ABCP方案，IMpower150）对转移性非鳞状NSCLC患者（无论PD-L1表达和EGFR/ALK改变状态）均有效，显著改善OS和PFS 。
      • 纳武利尤单抗联合伊匹木单抗（双重ICI）在PD-L1表达 ≥ 1% 和 < 1% 的NSCLC患者中均显示出OS益处，且已获得FDA批准，是标准治疗之一 。
  • 靶向突变： 对于存在EGFR、ALK等可靶向突变的NSCLC，分子靶向治疗仍是首选 。对于KRAS G12C突变，Olomorasib与帕博利珠单抗的组合显示出潜力，尤其在PD-L1高表达的一线患者中 。
  • 个性化治疗： 结合PD-L1表达、肿瘤突变负荷（TMB）等生物标志物，可以更好地选择最能受益于一线ICI的患者 。最新的研究也探索了基于血浆蛋白质组学的检测方法，结合PD-L1检测，可以进一步提高转移性NSCLC一线治疗的精准度，例如PROphet检测可以区分对免疫治疗或免疫治疗联合化疗有不同反应的患者亚组 。

肿瘤药市场推广表达边界

肿瘤药的市场推广必须严格遵守伦理规范和法律法规，确保信息的准确性、客观性和平衡性，避免误导性宣传。具体表达边界包括：

  1. 基于证据的宣传：

    • 所有推广信息必须有充分的临床试验数据支持，并明确引用来源（如关键临床试验的名称、发表期刊和PMID/DOI等）。
    • 宣传应基于已发表的、经过同行评审的科学文献，而非未经证实的临床观察或推测。
    • 例如，在推广帕博利珠单抗时，可以明确指出在KEYNOTE-024研究中，PD-L1 ≥ 50%的NSCLC患者单药治疗的PFS和OS获益情况，并引用该研究 。在推广其联合化疗方案时，需引用KEYNOTE-189的数据，说明其在非鳞状NSCLC中无论PD-L1表达的OS和PFS改善 。
    • 对于纳武利尤单抗，应明确其单药在一线治疗中的局限性（Checkmate-026），并着重宣传其联合伊匹木单抗在更广泛PD-L1表达人群中的OS益处，引用CheckMate 227的数据 。
    • 对于阿替利珠单抗，应强调其与贝伐珠单抗和化疗联用在非鳞状NSCLC中的疗效，引用IMpower150研究结果 。

  2. 明确适用人群和适应症：

    • 推广必须清晰地界定药物的批准适应症和适用的患者群体，包括疾病类型、分期、分子标志物状态（如PD-L1表达水平、EGFR/ALK突变状态等）和治疗线次。
    • 例如，不能将帕博利珠单抗单药用于PD-L1 < 50%的患者作为一线标准治疗进行推广，因为在此类患者中，联合化疗或双免疫治疗可能更优 。
    • 应强调这些治疗方案主要针对无EGFR、ALK等驱动基因突变的晚期NSCLC患者 。
    • 对于新兴的KRAS G12C突变治疗，如Olomorasib联合Pembrolizumab，应明确其仍在早期阶段，且数据主要来自特定亚组，不应过度泛化 。

  3. 客观陈述疗效和风险：

    • 应平衡地呈现药物的疗效数据（如OS、PFS、ORR等）和安全性数据（不良事件发生率、级别、常见不良反应等），不能只强调益处而忽略风险。
    • 必须包含不良事件的详细信息，例如帕博利珠单抗联合Lenvatinib的方案因不良事件发生率高而未显示出有利的获益-风险比 。
    • 对于免疫检查点抑制剂，应提及免疫介导的不良事件及其管理 。
    • 推广材料中应使用准确的统计学数据（如HR、P值、95% CI），并解释其临床意义，避免夸大或片面解读数据。

  4. 避免比较性偏见：

    • 在进行药物间比较时，必须基于头对头（head-to-head）临床试验的结果。如果没有直接比较数据，则应谨慎进行间接比较，并明确指出这是基于不同试验的间接推论，可能存在局限性。
    • 例如，虽然帕博利珠单抗单药在PD-L1 ≥ 50%人群中表现优异，而纳武利尤单抗单药在该人群中失败，但不能由此推断帕博利珠单抗在所有情况下都优于纳武利尤单抗，因为纳武利尤单抗联合疗法有其独特的优势 。

  5. 遵守法规：

    • 必须遵守各国药品监管机构（如FDA、NMPA）关于药品广告和推广的法律法规。例如，中国在临床试验质量方面持续提升，并在国家药品监督管理局（NMPA）的科学监管体系下，新药审批和上市流程日益完善，推广应符合相关要求 。
    • 涉及行业与学术界的合作时，需注意潜在的利益冲突，并确保科学诚信和产品质量不受影响 。推广活动应透明，避免误导公众和医疗专业人员。

  6. 强调个体化治疗：

    • 认识到NSCLC治疗的复杂性，推广应强调根据患者的具体情况（包括肿瘤特征、患者健康状况和偏好）进行个体化治疗决策的重要性。
    • 不应将任何单一治疗方案宣传为适用于所有患者的“万能药”。

通过严格遵守这些推广边界，可以确保肿瘤药物的推广活动既能有效传递科学信息，又能保障患者的权益和公共健康。

References

1Immunotherapy revolutionises non-small-cell lung cancer therapy: Results, perspectives and new challenges.PubMed

Etienne Giroux Leprieur, Coraline Dumenil, Catherine Julie, et al.
Immune checkpoint inhibitors (ICIs) are antibodies that target key signalling pathways such as programmed death 1 (PD1)/programmed death-ligands 1 and 2 (PDL1 and PDL2) to improve anti-tumour immune responses. Until recently, nivolumab was the only ICI validated for advanced non-small-cell lung cancer (NSCLC) in a second-line treatment setting. Results from recent phase II and phase III randomised trials testing other ICIs have been presented. In Keynote-024, pembrolizumab, an anti-PD1 antibody, was reported to have great efficacy in the first-line treatment of PDL1 ≥ 50% tumours (30% of screened tumours), with a progression-free survival (PFS, median) of 10.4 months versus 6.0 months with chemotherapy (CT; hazard ratio [HR] = 0.50; 95% confidence interval [95% CI] 0.37-0.68, P < 0.001), overall response rate (ORR) of 45% versus 28% with CT (P = 0.0011), and a 1-year overall survival (OS) of around 70%. In contrast, Checkmate-026 reported that nivolumab failed to show any benefit compared with standard platinum-based CT, with a PFS (median) in the PDL1 ≥ 5% NSCLC group of 4.2 months (nivolumab) versus 5.9 months (CT; HR = 1.15: 95% CI 0.91-1.45, P = 0.25). No benefit was observed in the PDL1 ≥ 50% subgroup. An encouraging report of the efficacy of pembrolizumab in addition to CT in first-line treatment in unselected NSCLC was also presented (Keynote-021) with an ORR of 55% versus 29% with CT alone (P = 0.0016). Atezolizumab, an anti-PDL1 antibody, showed efficacy for second-line treatment compared with docetaxel (OAK phase III study) with an OS (median) of 13.8 months versus 9.6 months with docetaxel. These results suggest a new paradigm for the treatment of advanced NSCLC using pembrolizumab for the first-line treatment of PDL1 ≥ 50% tumours.

2Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.PubMed

Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, et al.
BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).

3Efficacy and Safety of Olomorasib in Combination With Pembrolizumab in Treatment of Patients With KRAS G12C-Mutant Advanced NSCLC.PubMed

Timothy F Burns, Natraj Reddy Ammakkanavar, Antoine Hollebecque, et al.
INTRODUCTION: Immunotherapy-based regimens are the standard first-line treatment for KRAS G12C-mutant NSCLC, but outcomes remain suboptimal. Prior attempts to combine KRAS G12C inhibitors with immunotherapy have been challenged by toxicity. We report results from LOXO-RAS-20001, a phase 1/2 trial evaluating the combination of olomorasib with pembrolizumab in KRAS G12C-mutant NSCLC, including in first-line setting. METHODS: Patients with advanced KRAS G12C-mutant NSCLC in any treatment line, including prior KRAS G12Ci and immunotherapy were eligible. Any PD-L1 level (0%-100%) was permitted. Three dose levels of olomorasib (50, 100, and 150 mg twice daily) plus pembrolizumab were evaluated, focusing on 50 and 100 mg twice daily for safety and efficacy. RESULTS: A total of 99 enrolled patients had a median age of 68 (range, 42-83) years; 52% of tumors were PD-L1 0% to 49%, 36% were PD-L1 more than or equal to 50%, and 51% were first line. Of 93 patients treated at 50 or 100 mg twice daily, 76 (81.7%) experienced treatment-related adverse event (TRAEs) of any grade, most often, diarrhea (34.4%) and increased alanine aminotransferase/aspartate aminotransferase level (24.7%/22.6%). Grade more than or equal to 3 TRAEs were found in 33.3%. TRAEs led to olomorasib dose reductions in 20.4% and discontinuation of both therapies in 6.5% of patients. Among 91 efficacy-evaluable patients, at a median follow-up of 12.5 months (interquartile range, 6.2-16.9), objective response rate was 57.1% (95% confidence interval [CI], 46.3-67.5) across all PD-L1 expression levels, 73.9% (95% CI, 58.9-85.7) in first line, and 90% (95% CI, 68.3-98.8) in first-line patients with PD-L1 more than or equal to 50%. CONCLUSION: Olomorasib plus pembrolizumab demonstrated manageable safety and promising antitumor activity in patients with KRAS G12C-mutant advanced NSCLC across PD-L1 expression levels, especially in the high PD-L1 first-line setting.

4[International comparison and assessment of the quality of drug clinical trial implementation in China based on scientific regulatory system].PubMed

H Fang, Y R Hou, H Y Huang, et al.
To analyze the international status and level of clinical trial quality in China, and explore the advantages and value of scientific regulation of clinical research quality in China. The data is sourced from the relevant reports publicly released by the National Medical Products Administration (NMPA), the inspection reports and announcements published by the Center for Food and Drug Inspection of the NMPA, the inspection data displayed on the official website of the U.S. Food and Drug Administration (FDA), as well as clinical diagnosis and treatment guidelines issued by the National Comprehensive Cancer Network (NCCN) of United States and the Chinese Society of Clinical Oncology (CSCO) (data as of July 21, 2023). This data provides an analysis of the regulatory status of the implementation of clinical drug trials in China, inspection data, and the approval and market entry of new oncology drugs and feedback from their practical application. The clinical trial quality inspection systems of China and the United States are generally aligned, with similar inspection subjects, focus areas, and public disclosure pathways. However, each has its characteristics in terms of inspection targets and types. The quality of clinical trial data in China has been continuously improving. Between 2009-2015 and 2016-July 2023, China underwent 25 and 20 FDA Bioresearch Monitoring (BIMO) inspections, respectively. The inspection results showing "No Action Indicated" (NAI) improved from 48.0% to 85.0%, while "Voluntary Action Indicated" (VAI) decreased from 44.0% to 15.0%. Official Action Indicated (OAI) measures were required in 2009 and 2012. Compared to the 2009-2015 period, there has been a clear upward trend in the quality of clinical trial data since 2016. From 2016 to July 2023, the number of new oncology drugs developed by Chinese pharmaceutical companies and included in professional guidelines has steadily increased. Specifically, 37 drugs (58.7%) were included in the 2022 edition of the CSCO guidelines, and 15 drugs (23.8%) were included in the 2023 edition of the NCCN guidelines, with 10 of these drugs featured in both guidelines. The implementation quality of clinical trials in China has gained a certain level of international recognition and competitiveness. This progress is attributed to national macro-level guidance, a unique institutional model, and clinical practices aligned with international standards. In the future, it will be necessary to further strengthen the scientific regulatory system and enhance clinical research capabilities to continue advancing the high-quality development of clinical trials.

5Characterization of industry relationships in oncology.PubMed

Rebecca A Harrison, Nazanin K Majd, Margaret O Johnson, et al.
BACKGROUND: Collaborative relationships between academic oncology and industry (pharmaceutical, biotechnology, "omic," and medical device companies) are essential for therapeutic development in oncology; however, limited research on engagement in and perceptions of these relationships has been done. METHODS: Survey questions were developed to evaluate relationships between academic oncology and industry. An electronic survey was delivered to 1000 randomly selected members of the American Society of Clinical Oncology, a professional organization for oncologists, eliciting respondents' views around oncology-industry collaborations. The responses were analyzed according to prespecified plans. RESULTS: There were 225 survey respondents. Most were from the United States (70.0%), worked at an academic institution (60.1%), worked in medical oncology (81.2%), and had an active relationship with industry (85.8%). One quarter (26.7%) of respondents reported difficulty establishing a relationship with industry collaborators, and most respondents (75%) did not report having had mentorship in developing these relationships. The majority (85.3%) of respondents considered these collaborations important to their careers. Respondents generally thought that scientific integrity was preserved (92%), and most respondents (95%) had little concern over the quality of the collaborative product. Many (60%) shared concerns over potential conflict of interest if an individual with a compensated relationship promoted an industry product for clinical care/research, yet most respondents (67%) stated these relationships did not shape their interactions with patients. CONCLUSIONS: This study provides novel data characterizing the nature of collaborative relationships between clinicians, researchers, and industry in oncology. Although respondents considered these collaborations an important part of clinical and academic oncology, formal education or mentorship around these relationships was rare. Conflicting findings around conflict of interest highlight the importance of more dedicated research in this area. PLAIN LANGUAGE SUMMARY: Business enterprises in health care play a central role in cancer research and care, driving the development of new medical testing, drugs, and devices. Effective working relationships among clinicians, researchers, and these industry partners can promote innovative research and enhance patient care. Study of these collaborations has been limited to date. Through distribution of a questionnaire to cancer clinicians and researchers, we found that most participants consider these relationships valuable, though they find establishing such relationships challenging partly because of gaps in educational programs in this area. Our findings also highlight the need for further policy around the potential bias these relationships can introduce.

6First-Line Treatment of Non-Small-Cell Lung Cancer (NSCLC) with Immune Checkpoint Inhibitors.PubMed

Olivier Bylicki, Helene Barazzutti, Nicolas Paleiron, et al.
Treatment of advanced-stage or metastatic non-small-cell lung cancers (NSCLCs) without EGFR mutations or ALK rearrangements, which can now be treated with molecularly targeted therapies, had been based on cytotoxic chemotherapy for a long time. Immune checkpoint inhibitors (ICIs), notably antibodies directed against programmed cell-death protein-1 (PD-1) and its ligand (PD-L1) have transformed therapeutic standards in thoracic oncology. These ICIs are now the reference second-line treatment and numerous phase III trials have examined their efficacy in treatment-naïve patients. First-line pembrolizumab monotherapy was validated for patients with ≥ 50% of tumor cells expressing PD-L1; pembrolizumab, atezolizumab, and nivolumab have obtained good outcomes in combination with chemotherapy or another immunotherapy. However, in this context, other phase III trials yielded negative findings for nivolumab alone (CheckMate-026) or in combination (MYSTIC trial). Biomarkers, such as PD-L1 and the tumor mutation burden (TMB), enable better selection of patients who should benefit the most from first-line ICI use.

7Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study.PubMed

Marina C Garassino, Shirish Gadgeel, Giovanna Speranza, et al.
JCO We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without alterations.

8Cemiplimab monotherapy as first-line treatment of patients with brain metastases from advanced non-small cell lung cancer with programmed cell death-ligand 1 ≥50.PubMed

Saadettin Kilickap, Mustafa Özgüroğlu, Ahmet Sezer, et al.
BACKGROUND: In the phase 3 EMPOWER-Lung 1 study, first-line cemiplimab monotherapy provided significant survival benefit versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. This exploratory subgroup analysis investigated the clinical outcomes of cemiplimab treatment in patients with advanced NSCLC with brain metastases. METHODS: Patients with advanced NSCLC were randomized (1:1) to cemiplimab 350 mg every 3 weeks or four cycles of platinum doublet chemotherapy (NCT03088540). Patients with symptomatic radiotherapy-treated brain metastases were eligible to enroll. Of the 565 patients with confirmed PD-L1 expression ≥50%, 69 (12%) had brain metastases at baseline. RESULTS: Patients with brain metastases who received cemiplimab had a median overall survival (OS) of 52.4 months compared with 20.7 months for those who received chemotherapy (hazard ratio [HR], 0.40; p = .0031) and a median progression-free survival (PFS) of 12.5 versus 5.3 months (HR, 0.33; p = .0002), respectively. Patients without brain metastases had a median OS of 24.3 months with cemiplimab versus 12.5 months with chemotherapy (HR, 0.63; p < .0001); their median PFS was 6.5 months versus 5.2 months (HR, 0.55; p < .0001), respectively. Cemiplimab was associated with a significant improvement in global health status/quality of life in all patients, including those with brain metastases. The cemiplimab safety profile was generally similar in all patients. CONCLUSIONS: In patients with advanced NSCLC with PD-L1 ≥50%, first-line cemiplimab monotherapy improved survival and patient-reported outcomes over chemotherapy for those who received prior radiotherapy for symptomatic brain metastases.

9Targeted therapeutic options in early and metastatic NSCLC-overview.PubMed

Gabriella Gálffy, Éva Morócz, Réka Korompay, et al.
The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

10The impact of industry on oncology research and practice.PubMed

Beverly Moy, Reshma Jagsi, Richard B Gaynor, et al.
Public scrutiny has increased over potential conflicts of interest among oncology researchers and providers. Given the increased prevalence and complexity of industry relationships, oncologists are increasingly faced with ethical challenges when navigating their financial relationships with industry. Oncologists are continually dealing with changing conflict of interest policies within academic centers and professional societies. With the recent passage of The Sunshine Act, oncologists are beginning to understand the repercussions of this new law. The consequences of the increasing use of direct-to-consumer advertising on patients with cancer are also unclear. Finally, industry's perspective on the evolution of these relationships is not clearly understood. This manuscript discusses issues related to industry's influence on oncology practice and research.

11Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer.PubMed

Roberto Ferrara, Martina Imbimbo, Reem Malouf, et al.
BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have changed the first-line treatment of people with advanced non-small cell lung cancer (NSCLC). Single-agent pembrolizumab (a PD-1 inhibitor) is currently the standard of care as monotherapy in patients with PD-L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD-L1 expression is less than 50%. Atezolizumab (PD-L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti-angiogenic antibody) in first-line NSCLC regardless of PD-L1 expression. The combination of first-line PD-1/PD-L1 inhibitors with anti-CTLA-4 antibodies has also been shown to improve survival compared to platinum-based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD-1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD-L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best-treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics. OBJECTIVES: To determine the effectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression. SEARCH METHODS: We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards. SELECTION CRITERIA: We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first-line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single- or double-ICI treatment to standard first-line therapy (platinum-based chemotherapy +/- bevacizumab). All data come from 'international multicentre studies involving adults, age 18 or over, with histologically-confirmed stage IV NSCLC. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment-related adverse events (AEs) (CTCAE v 5.0) and health-related quality of life (HRQoL). We performed meta-analyses where appropriate using the random-effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity. MAIN RESULTS: Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first-line single- (six trials) or double- (two trials) agent ICI with platinum-based chemotherapy, one trial comparing both first-line single- and double-agent ICsI with platinum-based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate-to-low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD-L1 expressions, with PD-L1 ≥ 50 being considered the most clinically useful cut-off level for decision makers. Also, iIn order to avoid overlaps between various PDL-1 expressions we prioritised the review outcomes according to PD-L1 ≥ 50. Single-agent ICI In the PD-L1 expression ≥ 50% group single-agent ICI probably improved OS compared to platinum-based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate-certainty evidence). In this group, single-agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low-certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low-certainty evidence). HRQoL data were available for only one study including only people with PD-L1 expression ≥ 50%, which suggested that single-agent ICI may improve HRQoL at 15 weeks compared to platinum-based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low-certainty evidence). In the included studies, treatment-related AEs were not reported according to PD-L1 expression levels. Grade 3-4 AEs may be less frequent with single-agent ICI compared to platinum-based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low-certainty evidence). More information about efficacy of single-agent ICI compared to platinum-based chemotherapy according to the level of PD-L1 expression and to TMB status or specific clinical characteristics is available in the full text. Double-agent ICI Double-ICI treatment probably prolonged OS compared to platinum-based chemotherapy in people with PD-L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate-certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD-L1 groups. Treatment related AEs were not reported according to PD-L1 expression levels. The frequency of grade 3-4 AEs may not differ between double-ICI treatment and platinum-based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low-certainty evidence). More information about efficacy of double-agent ICI according to the level of PD-L1 expression and to TMB status is available in the full text. AUTHORS' CONCLUSIONS: Authors' conclusions The evidence in this review suggests that single-agent ICI in people with NSCLC and PD-L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression-free survival and overall response rate when compared to platinum-based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD-L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum-based chemotherapy, but its effect on progression-free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups. This review used to be a living review. It is transitioned out of living mode because current research is exploring ICI in association with chemotherapy or other immunotherapeutic drugs versus ICI as single agent rather than platinum based chemotherapy.

12Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.PubMed

Martin Reck, Delvys Rodríguez-Abreu, Andrew G Robinson, et al.
BACKGROUND: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). METHODS: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. RESULTS: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%). CONCLUSIONS: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).

13Non-small cell lung cancer molecular subtypes and vulnerability to immunotherapy treatment combinations.PubMed

Tianshi Lu, Habib Hamidi, Mark A Socinski, et al.
The phase 3 IMpower150 trial in treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC) demonstrates significantly longer progression-free (PFS) and overall survival (OS) with first-line atezolizumab (anti-PD-L1)-bevacizumab (anti-VEGF)-carboplatin-paclitaxel (ABCP) than with bevacizumab-carboplatin-paclitaxel (BCP). We characterise four molecular NSCLC subtypes identified by unsupervised clustering of transcriptomes of 564 pre-treatment primary tumour samples from IMpower150 using non-negative matrix factorization (NMF1-4). Each subtype has distinct tumour PD-L1 expression levels, epithelial characteristics, immune composition, and treatment outcomes. Both NMF2 (enriched in tumour proliferation signal, macrophages, and monocytes) and NMF4 (enriched in B cells and T cells) have elevated tumour PD-L1 expression. Of these two, only NMF4 demonstrates PFS and OS benefits with ABCP versus either BCP or atezolizumab-carboplatin-paclitaxel (ACP). Patients with NMF1 (enriched in basal and squamous-like cells) have improved outcomes on ABCP compared with ACP or BCP; those with NMF3 (enriched in adenocarcinoma signatures) show similar outcomes among treatments. These insights could help inform individualised first-line treatment for metastatic NSCLC.

14First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial.PubMed

Luis G Paz-Ares, Suresh S Ramalingam, Tudor-Eliade Ciuleanu, et al.
INTRODUCTION: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up. METHODS: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs). RESULTS: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65-0.90) and PD-L1 less than 1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population. CONCLUSIONS: At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.

15Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.PubMed

Matthew D Hellmann, Luis Paz-Ares, Reyes Bernabe Caro, et al.
BACKGROUND: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more. RESULTS: Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy. CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).

16Immunotherapy in the First-Line Setting in Wild-Type NSCLC.PubMed

Marie-Hélène Denault, Barbara Melosky
Treatment algorithms in the treatment of advanced non-small cell lung cancer (NSCLC) continue to evolve as new therapeutics show positive efficacy improvements. This review article summarizes the data for the use of immunotherapy for treatment in first-line stage IV NSCLC, organized by the following four sections: single-agent immunotherapy, immunotherapy and chemotherapy, dual immunotherapy, and dual immunotherapy and chemotherapy. The results are summarized and tabulated. Finally, application of the trial data is illustrated in four clinical scenarios depending on the programmed death-ligand 1 (PD-L1) expression levels. Single checkpoint inhibitors have become an easy and excellent treatment in patients whose tumors have high PD-L1 expression. Adding chemotherapy to immunotherapy benefits our patients. Immunotherapy, with or without chemotherapy, is now the standard of care in the first-line setting in patients without EGFR, ALK, or ROS driver mutations.

17Pembrolizumab With or Without Lenvatinib for First-Line Metastatic NSCLC With Programmed Cell Death-Ligand 1 Tumor Proportion Score of at least 1% (LEAP-007): A Randomized, Double-Blind, Phase 3 Trial.PubMed

James Chih-Hsin Yang, Baohui Han, Emmanuel De La Mora Jiménez, et al.
INTRODUCTION: Lenvatinib plus pembrolizumab was found to have antitumor activity and acceptable safety in previously treated metastatic NSCLC. We evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in metastatic NSCLC in the LEAP-007 study (NCT03829332/NCT04676412). METHODS: Patients with previously untreated stage IV NSCLC with programmed cell death-ligand 1 tumor proportion score of at least 1% without targetable EGFR/ROS1/ALK aberrations were randomized 1:1 to lenvatinib 20 mg or placebo once daily; all patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary end points were progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival (OS). We report results from a prespecified nonbinding futility analysis of OS performed at the fourth independent data and safety monitoring committee review (futility bound: one-sided p < 0.4960). RESULTS: A total of 623 patients were randomized. At median follow-up of 15.9 months, median (95% confidence interval [CI]) OS was 14.1 (11.4‒19.0) months in the lenvatinib plus pembrolizumab group versus 16.4 (12.6‒20.6) months in the placebo plus pembrolizumab group (hazard ratio = 1.10 [95% CI: 0.87‒1.39], p = 0.79744 [futility criterion met]). Median (95% CI) PFS was 6.6 (6.1‒8.2) months versus 4.2 (4.1‒6.2) months, respectively (hazard ratio = 0.78 [95% CI: 0.64‒0.95]). Grade 3 to 5 treatment-related adverse events occurred in 57.9% of patients (179 of 309) versus 24.4% (76 of 312). Per data and safety monitoring committee recommendation, the study was unblinded and lenvatinib and placebo were discontinued. CONCLUSIONS: Lenvatinib plus pembrolizumab did not have a favorable benefit‒risk profile versus placebo plus pembrolizumab. Pembrolizumab monotherapy remains an approved treatment option in many regions for first-line metastatic NSCLC with programmed cell death-ligand 1 tumor proportion score of at least 1% without EGFR/ALK alterations.

18Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.PubMed

Mark A Socinski, Robert M Jotte, Federico Cappuzzo, et al.
BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS: In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS: The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143 .).

19Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer.PubMed

Petros Christopoulos, Michal Harel, Kimberly McGregor, et al.
PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB ( = 0.98, < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], = .424). CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

20Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study.PubMed

Yi-Long Wu, Li Zhang, Yun Fan, et al.
In the global KEYNOTE-042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD-L1)-positive locally advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE-042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD-L1 tumor proportion score [TPS] ≥50% vs 1%-49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty-two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow-up, 33.0 [range, 25.6-41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD-L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43-0.94]), TPS ≥20% (0.66 [0.47-0.92]) and TPS ≥1% (0.67 [0.50-0.89]). Grade 3 to 5 treatment-related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE-042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD-L1 TPS ≥1%, supporting first-line pembrolizumab monotherapy for PD-L1-positive advanced/metastatic NSCLC in China.
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