Relationship Between KRAS Gene Status And Immunotherapy Efficacy And Prognosisin Patients With Advanced NSCLC

Background and ObjectiveLung cancer is a malignant tumor that seriously threatens human health.According to different histological types,lung cancer can be divided into non-small cell lung cancer(NSCLC)and small cell lung cancer(SCLC),each accounting for about 85% and 15%.Most patients are in the advanced stage of the disease at the time of diagnosis,have lost the opportunity for surgery,and have a poor prognosis.In recent years,due to the development of precision medicine and the understanding of tumor cell immune escape mechanisms,the treatment of NSCLC has undergone surgery,chemotherapy,radiotherapy,molecular targeted therapy and immunotherapy,and the 5-year survival rate of NSCLC patients has been greatly improved.The quality of life has been greatly improved.Kirsten rat sarcoma viral oncogene homolog(KRAS)is a common oncogenic driver of solid tumors including NSCLC.NSCLC patients with KRAS mutations generally have poor chemotherapy effects.Immune checkpoint inhibitors(ICIs)represented by the monoclonal antibody of programmed cell death receptor 1(PD-1)/programmed cell death receptor ligand 1(PD-L1)provides new treatment options for NSCLC patients,including patients with KRAS gene mutations.However,published research results show that the efficacy of ICIs in NSCLC patients with KRAS gene mutations is still controversial.This study evaluated the relationship between the KRAS gene mutation status of patients with stage ⅢB/IV NSCLC and the efficacy of ICIs through retrospective analysis,and aimed to explore the impact of ICIs on the survival and prognosis of patients with different KRAS gene mutation status in advanced NSCLC.MethodsOur retrospective analysis recruited 168 patients with advanced and recurrent NSCLC diagnosed by histopathology in the Affiliated Cancer Hospital of Zhengzhou University from January 2017 to November 2020,all of these patients without epidermal growth factor receptor(EGFR)and anaplastic lymphoma kinase(ALK)mutation detected by next-generation sequencing(NGS)technology and treated with ICIs during the treatment course.The immunotherapy efficacy and prognosis of the different KRAS gene mutation states were compared,including response rate,progression-free survival(PFS)and overall survival(OS).Statistical analysis was performed using SPSS 25.0 statistical software.The Kaplan-Meier(K-M)method was used to generate the survival curve,and the log-rank test was used for statistical analysis.Comparisons between groups were analyzed by chi-square test(χ2 test),Fisher’s exact probability method or t test.Univariate and multivariate analysis of risk factors for PFS and OS were studied by the Cox proportional hazard model.When the P-value was <0.05,it was considered statistically significant.Results1.The median PFS(mPFS)of the KRAS mutation group and the non-KRAS mutation group was 9.7 months and 7.0 months,respectively,and the difference was not statistically significant(P=0.066).The median OS(m OS)of the KRAS mutation group was immature,non-KRAS mutation group m OS was 33.5 months,the difference was not statistically significant(P=0.159).2.The m PFS data of ICIs combined with anti-angiogenesis therapy in the KRAS mutation group is immature,and the m PFS of the ICIs combined with anti-angiogenesis group in the non-KRAS mutation group is 4.4 months,the difference is statistically significant(P=0.007).The m OS data of ICIs combined with anti-angiogenesis therapy in the KRAS mutation group is immature,and the m OS of ICIs combined with anti-angiogenesis in the non-KRAS mutation group is 23.8months,the difference is statistically significant(P= 0.026).There was no significant difference in m PFS and m OS in patients with ICIs combined with chemotherapy(P=0.227,P=0.879)and ICIs single agent(P=0.549,P=0.442)in KRAS mutation group vs non-KRAS mutation group.3.The ORR and DCR of patients in the KRAS mutation group were higher than those in the non-KRAS mutation group(59.0% vs 33.7%,P=0.001;96.7% vs 83.2%,P=0.009),and the difference was statistically significant.When PD-L1 expression≥1%,the ORR of patients in the KRAS mutation group was higher than that of the non-KRAS mutation group(79.2% vs 40.4%,P=0.002),the difference was statistically significant;but there was no statistical difference in DCR(100% vs89.4%,P=0.159).When PD-L1 expression was less than 1%,there was no significant difference in ORR and DCR between the KRAS mutation group and the non-KRAS mutation group(18.2% vs 28.6%,P=0.661;90.9% vs 78.6%,P=0.604).4.In the KRAS mutation group,the ORR of the PD-L1 expression <1% group was significantly lower than that of the PD-L1 expression ≥1% group(18.2% vs79.2%,P=0.002),the difference was statistically significant.The DCR of the two groups was not statistically significant difference(90.9% vs 100%,P=0.314).In the non-KRAS mutation group,the ORR and DCR of the PD-L1 expression <1% group were lower than those of the PD-L1 expression≥1% group(28.6% vs 40.4%,P=0.422;78.6% vs 89.4%,P=0.369),but the difference between the two groups is not statistically significant.5.The results of multivariate Cox regression analysis showed that in NSCLC patients treated with ICIs,KRAS gene mutations(HR=0.58,95%CI: 0.36-0.94,P=0.026)were associated with prolonged PFS.There were brain metastases(HR=1.67,95%CI: 1.00-2.78,P=0.049),ECOG PS≥2(HR=2.78,95%CI: 1.33-5.79,P=0.006)were associated with shortened PFS.ECOG PS≥2(HR=13.16,95%CI:4.76-36.34,P<0.001)was associated with shortened OS.Conclusion1.The ORR and DCR of NSCLC patients with KRAS mutations treated with ICIs were higher than those of non-KRAS mutations;the m PFS of NSCLC patients with KRAS mutations treated with ICIs had a prolonged trend.2.ICIs combined with anti-angiogenic drugs is a treatment option for KRAS mutant NSCLC.3.Brain metastasis and ECOG PS≥2 are associated with worse PFS;ECOG PS≥2 is associated with worse OS.