Correlation Between LRP1B Mutation And Tumor Mutation Load And Efficacy Of Immune Checkpoint Inhibitors

Background: LRP1B gene is among the top 10 most commonly mutated genes in human cancers.LRP1 Bv is associated with higher TMB and better survival from immunotherapy than LRP1 Bwt.The objective is to assess the effect of TMB on the association between LRP1 B status and immunotherapy outcomes.Methods: Cancer patients who recorded LRP1 B gene status were identified after treatment with ICIs using TCGA and their age,gender,tumor type,TMB,treatment regimen and programmed cell death protein ligand expression were recorded.Patients meeting inclusion criteria were divided into h TMB/LRP1 Bwt group,nh TMB/LRP1 Bv group,h TMB/LRP1 Bv group and nh TMB/LRP1 Bwt group according to LRP1 B status(LRP1Bwt and LRP1Bv)and TMB status(h TMB and nh TMB).The primary endpoint was objective response rate(ORR),and the secondary endpoints were durable clinical benefit(DCB),overall survival(OS)and progression-free survival(PFS).Logistic regression models and Cox proportional hazards regression models were used to examine the association between LRP1 Bv status and ORR、DCB、OS and PFS.Results: 1.A total of 11 datasets with 523 patients were identified after ICIs treatment.Main cancer types included melanoma(43.0%,n = 225)and non-small cell lung cancer(NSCLC,34.2%,n = 179).All patients had locally advanced stage,recurrent,or metastatic disease and received palliative therapy.Most patients(82.4%,n = 431)received first-line treatment,and 75.9% patients(n = 397)received ICIs monotherapy.2.In patients treated with immune checkpoint inhibitors,the LRP1 Bv group had better ORR,DCB,OS,and PFS than the LRP1 Bwt group.TMB is divided into h TMB and nh TMB according to the top 50%-top 20%.As the cutoff point of TMB went from the top 50% to top20%,LRP1 Bv was increasingly associated with better results(ORR,DCB,OS)in nh TMB,but not in h TMB.The correlation was most significant when TMB was divided into h TMB and nh TMB with the top 20% as the cut-off value,but no significant correlation was found in PFS.3.Taking top20% as the cutoff point,TMB was divided into h TMB and nh TMB.There was no significant difference in the ORR,DCB and OS of h TMB/LRP1 Bwt,nh TMB/LRP1 Bv and h TMB/LRP1 Bv,which were all better than nh TMB/LRP1 Bwt.The OS of nh TMB/LRP1 Bv group was significantly longer than nh TMB/LRP1 Bwt group.There was no statistical difference in PFS among the four groups.Consistent results were shown in multivariable analyses.4.There was no significant difference between nh TMB/LRP1 Bv ORR and h TMB,both of which were higher than nh TMB/LRP1 Bwt.This result still existed in major patient subgroups,including patients receiving ICIs monotherapy(75.9%)or patients after first-line treatment(82.4%).Conclusion: 1.In nhTMB patients treated with ICIs,LRP1 Bv was associated with better ORR,DCB,and OS.The clinical benefits of patients is mainly mediated by LRP1 Bv.2.nh TMB/LRP1 Bv patients are potential to benefit from immunotherapy.3.In LRP1 Bwt patients treated with ICIs,h TMB was significantly correlated with better ORR and DCB.In h TMB patients,both LRP1 Bv and LRP1 Bwt patients can benefit from immunotherapy,but LRP1 Bv has little influence on the outcome of immunotherapy,and the clinical benefits of patients is mainly mediated by h TMB.4.In nh TMB patients treated with ICIs,LRP1 Bv was associated with better immunotherapy outcomes,and this association was not related by hTMB.