Analysis Of Efficacy And Safety Of Immune Checkpoint Inhibitors In The Treatment Of KRAS Mutant Advanced Non-small Cell Lung Cancer

Objective: At present,lung cancer is one of the malignant tumors with a high incidence and mortality in China.Kirsten rat sarcoma viral oncogene(KRAS)mutation occur in about 15%-20% of non-small cell lung cancer(NSCLC)patients.Due to the lack of pockets in KRAS protein that can bind to small molecule drugs,the research on drugs targeting KRAS has not made great progress.Therefore,the optimal treatment mode for NSCLC patients with KRAS mutation is still being explored.In recent years,immunotherapy has become a very effective tumor therapy after chemotherapy and targeted therapy.Previous studies have indicated that NSCLC patients with KRAS mutation can benefit from immunotherapy.Common co-mutations of KRAS include comutation with TP53 and co-mutation with STK11 with frequencies of about 50% and 18%-28%,respectively.And KRAS co-mutation status can also affect the prognosis of patients treated with immunotherapy.However,the co-mutation status can only be revealed through next-generation sequencing(NGS)gene testing,leading to no consistent conclusions in co-mutation-related studies.The purpose of this study was to explore the efficacy of immune checkpoint inhibitors in advanced NSCLC patients with KRAS mutation,evaluate the safety of immunotherapy and explore the effect of co-mutation status on the prognosis of patients treated with immunotherapy.Methods: Data of NSCLC patients using immune checkpoint inhibitors with a clear safety record from the first hospital of China Medical University from January 2017 to November 2022 and data of advanced NSCLC patients with KRAS mutation confirmed by genetic testing from January 2017 to November 2022 were retrospectively collected.Clinicopathological features,therapeutic schedule,survival information,adverse reactions and co-mutation status of the patients were collected.Comparisons between groups were made using Chi-square test.Survival curves were plotted by Kaplan-Meier(K-M)method and compared by log-rank test.Multivariate analysis was performed using Cox regression simulation.In order to reduce the selection bias between groups,propensity score matching(PSM)method was used for matching,matching was performed as 1:1,and the caliper value was set as 0.02 for propensity matching analysis.Results: Part I: Immuno-checkpoint inhibitors in patients with advanced NSCLC.A retrospective study was conducted on 2,595 NSCLC patients treated with immune checkpoint inhibitors with a clear safety record in the oncology department of the first hospital of China Medical University from January 2017 to November 2022,and a total of200 patients were finally included in the study.The objective response rate(ORR)and disease control rate(DCR)of different clinical features was compared,and the results suggested that the ORR of different treatment lines showed statistical difference.There were statistical differences in DCR between different genders,different treatment lines and with or without combined treatment.A total of 169 patients had disease progression by the end of the last follow-up,with a median progression-free survival(m PFS)of 5.0 months(95%CI:3.9-6.1).72 patients developed immunotherapy-related adverse reactions(36%),and Grade 3 or above adverse reactions were found in 13 patients,with an incidence of 6.5%.Part II: About immune-checkpoint inhibitors in patients with KRAS mutated NSCLC.Among 2595 patients diagnosed with NSCLC,142 patients with KRAS mutation were included in the study.The median follow-up time was 25.7(1.3-60.0)months.Efficacy analysis showed that patients treated with first-line immunotherapy had higher ORR and DCR,which were 55.3% and 94.7%,respectively.ORR and DCR of patients treated without first-line immunotherapy were 28.8% and 85.6%,respectively.In subgroup analysis,patients treated with immunotherapy combined with chemotherapy in the first-line treatment had higher ORR and DCR(53.3% and 96.7%,respectively),and the ORR and DCR of patients treated with chemotherapy in the first-line treatment were31.2% and 87%,respectively.Further comparison of ORR and DCR among patients with different clinical characteristics was made,and it showed that there was no statistical difference in ORR and DCR among different clinical characteristics such as gender,age,smoking history,family history,etc.Survival analysis showed that patients treated with immunotherapy in the first-line treatment had longer m PFS(12.7 months vs 5.1 months,P < 0.001)and median overall survival(m OS)(NA vs 17.0 months,P < 0.001)than those treated without immunotherapy in the first-line treatment.In subgroup analysis,first-line immunotherapy combined with chemotherapy resulted in better survival benefits than chemotherapy alone,with m PFS of11.0 months vs 4.9 months(P<0.001)and m OS of NA vs 17.0 months(P<0.001).To further reduce selection bias between groups,1:1 propensity score matching was used for matching.After matching,32 cases of first-line immunotherapy group and first-line nonimmunotherapy group were successfully matched,and 26 cases of first-line immunotherapy combined with chemotherapy group and first-line chemotherapy group were successfully matched.Survival analysis of the matched data suggested that patients treated with first-line immunotherapy had longer m PFS(11.1 months vs 3.0 months,P <0.001)and m OS(NA vs 17.0 months,P=0.003)than those treated without first-line immunotherapy.Patients treated with first-line immunotherapy combined with chemotherapy benefited from m PFS compared with chemotherapy alone(9.8 months vs3.7 months,P < 0.001),while the difference in m OS(NA vs NA,P=0.115)was not statistically significant.Survival analysis of 55 patients who started immunotherapy at different lines suggested that the number of lines at the beginning of immunotherapy affected the median overall survival time.The m OS of patients who started immunotherapy at first line,second line,third line and after were NA vs 16.2 vs 12.7 months,respectively(P=0.013).Among the 55 patients treated with immunotherapy,a total of 16 patients(29.1%)developed immunotherapy-related adverse events,among which common adverse events included immunotherapy-related pneumonia,endocrine-related adverse events,rash,etc.Survival analysis suggested that patients with immunotherapy-related adverse events had longer m PFS(16.0 months vs 6.9 months,P=0.026),while m OS had no statistically significant difference(29.5 months vs NA,P=0.463).We further collect the data of patients undergoing next generation sequencing(NGS)(36 in total).There were 5 patients with STK11 co-mutation,17 patients with TP53 comutation,1 patient with STK11 and KEAP1 co-mutation,2 patients with STK11 and TP53co-mutation,and 11 patients without STK11/TP53/KEAP1 co-mutation.The co-mutation rate of STK11 and TP53 was 22.2% and 52.8% respectively.Survival analysis of patients with different co-mutation states showed that: In patients treated with first-line immunotherapy,those with STK11 co-mutation had shorter m PFS(2.8 months vs 12.7months,P=0.005)and those with TP53 co-mutation had longer m PFS(12.7 months vs 7.1months,P=0.014).In patients with STK11 co-mutation,m PFS were 3.0 months vs 2.8months(P=0.869)and m OS were 17.4 months vs 9.2 months(P= 0.984),respectively,for those who did not receive first-line immunotherapy versus those who did.Patients with TP53 co-mutants tended to have longer m PFS(12.7 months vs 9.0 months,P=0.179)and m OS(NA vs 29.6 months,P=0.221)in patients treated with first-line immunotherapy,but the difference was not statistically significant.Conclusions: In the analysis of efficacy and safety of immune checkpoint inhibitors in patients with advanced NSCLC,the median PFS of the population was 5.0 months.The incidence of immunotherapy-related adverse reactions in patients was consistent with previous reports.In NSCLC patients with KRAS mutations,first-line immunotherapy can benefit patients with PFS and OS.The number of lines of initiation of immunotherapy is related to the prognosis of patients,and the earlier the use of immunotherapy,the more likely patients will benefit from OS.The incidence of immunotherapy-related adverse events was approximately 30%.Among immunotherapy-related adverse events,the incidence of immunotherapy-related pneumonia was the highest,and the occurrence of immunotherapy-related adverse events would cause patients to have longer PFS.In the comutation analysis,patients with STK11 co-mutation had shorter m PFS and those with TP53 co-mutation had longer m PFS in first-line immunotherapy.For patients with STK11co-mutation,patients treated with immunotherapy tended to have shorter m PFS and m OS,while those with TP53 co-mutation tended to have longer m PFS and m OS.