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...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(KRAS^(G12C))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 EGFRL858Rand 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 EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min 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 KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed 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.展开更多
基金the National Natural Science Foundation of China(Nos.21976155,81802881,and 81773016)the Zhejiang Provincial Natural Science Foundation of China(No.LY18C060001)+1 种基金the Fundamental Research Funds for the Central Universitiesthe Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(No.2019-I2M-5-044),China。
文摘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(KRAS^(G12C))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 EGFRL858Rand 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 EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min 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 KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed 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.
