This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‒1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‒2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48‒1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‒1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‒0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‒0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‒8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‒6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.
本研究以探索与免疫检查点抑制剂（ICIs）效果有关联的基因突变亚型为目标，进行了系统文献检索（电子数据库截至2021年5月31日）。与肿瘤基因特征相关联的主要结局事件包括：总生存期、无进展生存期、客观反应率、持久临床获益。我们从14项研究中总计提取了1546个有基因突变数据的肺癌患者，发现ICIs治疗在KRASG12C联合TP53双突变的患者中有更好的疗效，而在携带EGFR经典激活突变（包括EGFRL585R和EGFRΔ19）的患者中的效果则截然相反：总生存期（调整后HR, 1.40; 95% CI, 1.01–1.95; P=0.0411），无进展生存期（调整后HR, 1.98; 95% CI, 1.49–2.63; P<0.0001）。另外，ICIs治疗在EGFR经典突变联合EGFRT790M双突变患者与仅有EGFR经典突变的患者在总生存期（调整后HR, 0.96; 95% CI, 0.48–1.94; P=0.9157）与无进展生存期（调整后HR, 0.72; 95% CI, 0.39–1.35; P=0.3050）中均无明显差异。更重要的是，我们发现ICIs在携带USH2A错义突变的患者中可能有更好的疗效：总生存期（调整后HR, 0.52; 95% CI, 0.32–0.82; P=0.0077），无进展生存期（调整后HR, 0.51; 95% CI, 0.38–0.69; P<0.0001），持久临床获益（调整后OR, 4.74; 95% CI, 2.75–8.17; P<0.0001）与客观反应率（调整后OR, 3.45; 95% CI, 1.88–6.33; P<0.0001）。综上，我们的研究发现在使用ICIs疗法的肺癌患者中，USH2A错义突变、KRASG12C联合TP53双突变与更好的疗效和生存结局有关，而EGFR经典突变无论是否合并EGFRT790M突变都预示着不良结局，我们的结果可能会对在肿瘤ICIs的精准治疗方案提供新的依据和靶标。.
本研究以探索与免疫检查点抑制剂（ICIs）效果有关联的基因突变亚型为目标，进行了系统文献检索（电子数据库截至2021年5月31日）。与肿瘤基因特征相关联的主要结局事件包括：总生存期、无进展生存期、客观反应率、持久临床获益。我们从14项研究中总计提取了1546个有基因突变数据的肺癌患者，发现ICIs治疗在KRASG12C 联合TP53双突变的患者中有更好的疗效，而在携带EGFR经典激活突变（包括EGFRL585R 和EGFRΔ19 ）的患者中的效果则截然相反：总生存期（调整后HR, 1.40; 95% CI, 1.01–1.95; P=0.0411），无进展生存期（调整后HR, 1.98; 95% CI, 1.49–2.63; P<0.0001）。另外，ICIs治疗在EGFR经典突变联合EGFRT790M 双突变患者与仅有EGFR经典突变的患者在总生存期（调整后HR, 0.96; 95% CI, 0.48–1.94; P=0.9157）与无进展生存期（调整后HR, 0.72; 95% CI, 0.39–1.35; P=0.3050）中均无明显差异。更重要的是，我们发现ICIs在携带USH2A错义突变的患者中可能有更好的疗效：总生存期（调整后HR, 0.52; 95% CI, 0.32–0.82; P=0.0077），无进展生存期（调整后HR, 0.51; 95% CI, 0.38–0.69; P<0.0001），持久临床获益（调整后OR, 4.74; 95% CI, 2.75–8.17; P<0.0001）与客观反应率（调整后OR, 3.45; 95% CI, 1.88–6.33; P<0.0001）。综上，我们的研究发现在使用ICIs疗法的肺癌患者中，USH2A错义突变、KRASG12C 联合TP53双突变与更好的疗效和生存结局有关，而EGFR经典突变无论是否合并EGFRT790M 突变都预示着不良结局，我们的结果可能会对在肿瘤ICIs的精准治疗方案提供新的依据和靶标。
Keywords: Epidermal growth factor receptor (EGFR) mutation; Immune checkpoint inhibitor (ICI); Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation combined with tumor protein P53 (TP53) mutation; Lung cancer; Usher syndrome type-2A (USH2A) missense mutation.