Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies.
Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies.
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DOI：
10.3389/fonc.2021.635007
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发表时间：
2021
影响因子：
4.7
通讯作者：
Cho WCS
中科院分区：
文献类型：
--
作者：
To KKW;Fong W;Cho WCS
肺癌是全球癌症相关死亡的主要原因。免疫检查点抑制剂，包括针对程序性死亡-1（PD-1）和程序性死亡配体-1（PD-L1）的单克隆抗体，已显著改善了一部分非小细胞肺癌（NSCLC）患者的生存率和生活质量。已经提出了多种预测生物标志物来选择可能从免疫检查点抑制剂中受益的患者。EGFR突变型NSCLC是亚洲肺癌患者中最常见的分子亚型。然而，EGFR突变型NSCLC患者对抗PD-1/PD-L1治疗的反应较差。虽然小分子EGFR酪氨酸激酶抑制剂（TKI）是EGFR突变型NSCLC的首选初始治疗，但获得性耐药严重限制了长期疗效。然而，对于TKI难治性EGFR突变型NSCLC患者，目前没有进一步有效的治疗选择。介导EGFR突变的NSCLC患者对免疫治疗反应差的原因尚不清楚。初步研究显示，EGFR突变的NSCLC具有较低的PD-L1表达和较低的肿瘤突变负荷，因此导致免疫原性较弱。此外，据报告，在奥希替尼之前或与奥希替尼同时使用PD-1/PD-L1阻滞剂会增加肺毒性风险。此外，新出现的证据表明，NSCLC患者中的PD-1/PD-L1阻断可导致与预后不良相关的疾病过度进展。然而，很难预测治疗毒性。迫切需要新的生物标志物来预测EGFR突变的NSCLC中使用PD-1/PD-L1免疫疗法相关的反应和毒性。最近，出现了有希望的数据，表明抗血管生成剂和一些其他新型治疗剂可增强PD-1/PD-L1阻断治疗。本文就EGFR突变型NSCLC对抗PD-1/PD-L1治疗的不良反应的研究现状进行综述，并对今后可能采取的新策略进行探讨。
Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.
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期刊：
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