The Efficacy And Safety Of RANKL Inhibitor In Advanced KRAS-mutated Non-small Cell Lung Cancer

BackgroundAdvanced lung cancers carrying KRAS mutation remain a group that lacks effective treatments.Receptor activator of nuclear factor-κB ligand(RANKL)has been demonstrated to drive malignant phenotypes in lung cancer;however,its role in KRASmutant(mt)LUAD is not yet fully elucidated.ObjectiveTo elucidate the role of RANKL in KRAS-mt LUAD,and to provide new therapeutic ideas for patients with KRAS-mutated LUAD.Materials and methodsThe data used to explore expression and prognosis were obtained from the TCGA,GTEx databases and from our hospital.The proliferation,invasion,and migration capacities of KRAS-mt LUAD cells were evaluated.The prediction model was established via Lasso regression method.ResultsRANKL is strongly expressed in advanced KTAS-mt LUAD,and significantly distinct association exists between high RANKL expression and poor survival.The enriched expression of RANKL in advanced KRAS-mt LUAD was confirmed by specimens from our hospital.Further,though not statistically significant,our clinical cohort(n=57)revealed a longer median progression-free survival in advanced KRAS-mt LUAD patients treated with RANKL inhibitor than those without(300 vs 133 days,p=0.210),but not in KRAS-wt ones(208 vs 250 days,p=0.334).Decrease of KRAS-mt LUAD cells’ capacity for proliferation,invasion,and migration was observed when RANKL was knocked down.Enrichment analysis suggested distinct roles of RANKL between KRAS-mt and KRAS-wt LUAD,with adhesion-related pathways and molecules significantly down-regulated in the KRAS-mt RANKL-high tumors.Finally,a model for predicting OS of KRAS-wt LUAD was established according to four related key genes(BCAM,ICAM5,ITGA3,and LAMA3),which had good performance in prediction concordance.ConclusionsRANKL acts as an unfavorable prognostic biomarker for patients with advanced KRASmt LUAD.Inhibition of RANKL may be a feasible strategy for this subset of patients.BackgroundPatients with advanced non-small cell lung cancer(NSCLC)carrying bone metastases have a dismal prognosis.Previous in vivo studies have revealed a synergistic mechanism in improving the immune microenvironment between immune checkpoint inhibitors(ICIs)and the RANKL inhibitor denosumab.In addition,retrospective studies suggest that this combination appears to provide a survival benefit for patients with malignant tumors.However,the clinical efficacy and safety of this combination regimen in advanced NSCLC carrying bone metastases has not been fully evaluated.MethodsIn the Chinese National Cancer Center,consecutive charts of patients with NSCLC who had bone metastases were reviewed between December 31st,2020 and December 31st,2021.The entire cohort was categorized into one experimental(denosumab+ICIs[DI])and three control(denosumab+non-ICIs[DnI],phosphates+ICIs[PI],and phosphates+non-ICIs[PnI])groups.In addition,the real-world objective response rates(ORRs),median progression-free survival(mPFS),skeletal-related events(SREs),and adverse events(AEs)were compared between the groups.ResultsOverall,171/410(41.7%)patients with advanced or recurrent NSCLC who had bone metastases and received bone-targeted therapy,were eligible for analysis.Although the DI group showed a better benefit trend,differences were not statistically significant regarding the therapeutic efficacy among the DI(n=40),PI(n=74),DnI(n=15),and PnI groups(n=42)(ORRs:47.5%,43.2%,33.3%,and 40.5%,respectively,p=0.799;mPFS:378,190,170,and 172 days,respectively,p=0.115;and SREs:5%,10.8%,13.3%,and 11.9%,respectively,p=0.733).Nevertheless,further analysis in the NONDRIVER cohort revealed a greater benefit for the DI group(p=0.045).Furthermore,the multivariate analysis revealed that DI treatment played an independent prognostic role for PFS in the overall cohort.In addition,the AEs of the DI group were not significantly different from those of the PI,DnI,and PnI groups(AEs:27.5%,39.2%,26.7%,and 28.6%,respectively,p=0.742).In the subgroup analysis,within the DI group,no differences in benefit were observed among the different mutational subgroups(p=0.814).However,patients with single-site bone metastasis and high programmed cell death ligand-1(PD-L1)expression appeared to benefit more,though they showed no significant differences(p=0.319 and p=0.100,respectively).ConclusionsDenosumab showed a synergistic antitumor efficacy without any increased toxicity when used concurrently with ICIs in patients with advanced NSCLC who had bone metastases.BackgroundPatients with advanced NSCLC carrying KRAS mutations have a poor prognosis.Currently,the first-line treatment of such patients follows the principles of treatment of driver-negative patients and is based on immunotherapy.However,a challenge is to identify new targets and combination therapy options for patients who show resistance or poor response to immunotherapy.For now,patients with KRAS-mutated NSCLC still lack adequate and effective therapies,posing a great challenge to clinicians.It has been shown that the RANKL/RANK pathway can suppress the immune microenvironment,and the combination of RANKL inhibitors and PD-1 inhibitors can expand the population of NSCLC immune beneficiaries through a complementary enhancement mechanism,especially for this group carrying KRAS mutations.However,no prospective clinical trials of RANKL inhibitors in combination with PD-1 inhibitors have been conducted in patients with KRAS-mutated NSCLC.ObjectiveThe aim of this study was to evaluate the efficacy and safety of denosumab combined with the PD-1 inhibitor for maintenance therapy after first-line immunotherapy in patients with advanced NSCLC harboring KRAS mutations.MethodsPatients with advanced NSCLC harboring KRAS mutations who were to be treated with maintenance therapy after first-line immunotherapy were prospectively enrolled,while a historical control cohort was retrospectively included for controlled comparison.Patients included in the prospective study received a maintenance regimen of denosumab(120 mg,q4w)in combination with PD-1 inhibitor(dose determined by specific drug,q3w).The primary endpoint was PFS,and secondary endpoints included ORR,OS,and safety.Efficacy evaluations were performed every 3 cycles and were interpreted according to RECIST v1.1 criteria.Adverse events were interpreted according to CTCAE v5.0 criteria.ResultA total of 20 patients were prospectively enrolled in this single-arm phase II clinical trial at our institution between July 1,2021 and March 30,2023.The median follow-up time for the prospective cohort was 479.0 days(95%CI,263.4-694.6 days).A total of 13(65%)subjects exceeded the preset value of mPFSl by 9.2 months,with an overall mPFS1 of 329.0 days(95%CI,277.3-380.7 days)and mPFS2 of 196.0 days(95%CI,145.0-247.0 days).The mOS was not reached,with the 1-year OS rate of 100%and the 2-year OS rate of 92.3%.Between January 1,2019 and December 31,2022,a total of 50 patients were enrolled in the historical cohort,including 3 maintenance modalities:PD-1 inhibitor maintenance alone(n=18),PD-1.inhibitor+chemotherapy(Chemo)maintenance(n=22),and PD-1 inhibitor+Chemo+Bevacizumab(Bev)maintenance(n=10).The overall median follow-up was 361.0 days(95%CI,291.8-430.2 days).ORR was 0%.Survival analysis suggested that neither mPFS1 nor mPFS2 was inferior in the PD-1 inhibitor+denosumab group compared to the PD-1 inhibitor +Chemo group and the PD-1 inhibitor+Chemo+Bev group(p=0.419;p=0.397).Stratified analysis suggested that for patients with PD-L1 TPS<1%and those carrying KRASG12D,maintenance treatment with PD-1 inhibitor+denosumab resulted in significantly longer PFS1(365.0 vs 189.0 vs 225.0 vs 260.0 days,p=0.026;189.0 vs 229.0 vs NR vs 319.0 days,p=0.017).Safety analysis suggested the lowest incidence of AEs in the singleagent PD-1 inhibitor maintenance group at 22.2%.This was followed by the PD-1 inhibitor+denosumab group at 55%and was dominated by dental-related AEs.AEs were higher in the PD-1 inhibitor combined with Chemo maintenance group as well as in the three-drug maintenance group at 81.8%and 80%,respectively,and were dominated by liver and renal impairment and immune thyroid function abnormalities.ConclusionThe RANKL inhibitor denosumab in combination with PD-1 inhibitor showed anti-tumor activity with a good safety profile when used for maintenance therapy after first-line immunotherapy in patients with advanced KRAS mutation-carrying NSCLC.Our study provides a new idea for the treatment of patients with NSCLC carrying KRAS mutations.