The Efficacy Of Immune Checkpoint Inhibitors In EGFR-Mutated NSCLC Patients With Brain Metastases Who Are Resistant To TKIs Therapy

BackgroundNon-small cell lung cancer(NSCLC)accounts for approximately 85%of all lung cancer cases and brain is one of the most frequent metastatic sites,leading to extremely poor prognosis.More seriously,epidermal growth factor receptor(EGFR)mutations are associated with a higher risk of developing BM for NSCLC patients.EGFR-tyrosine kinase inhibitors(EGFR-TKIs)is the standard of care for EGFR-mutated NSCLC patients with brain metastases(BMs).However,EGFR-TKIs resistance and disease recurrence inevitably occur with prolonged duration of treatment.Due to the existence of blood-brain barrier,salvage chemotherapy provides suboptimal benefits.Therefore,there is an urgent need to explore better systemic therapy for these patients.In recent years,immune checkpoint inhibitors(ICIs)have revolutionized the treatment of advanced NSCLC patients by harnessing the power of their own immune system.While EGFR-mutated NSCLC patients respond poorly to ICIs monotherapy when compared with wild-type patients,recent studies suggested that the efficacy can be improved by combining ICIs with other treatment agents.In this study,we aimed to evaluate the efficacy of ICIsbased therapies in NSCLC patients with EGFR mutations and BMs who were resistant to EGFR-TKIs.MethodsPatients diagnosed with EGFR-mutated NSCLC with BMs,previously resistant to EGFR-TKIs and subsequently receiving ICIs-based therapies,were screened between 2019 and 2021.All patients were included in the description of baseline clinical characteristics and efficacy analysis.Intracranial and overall objective response rate(ORR)were used to evaluate the treatment response according to Response Evaluation Criteria in Solid Tumors(RECIST)version 1.1.Intracranial and overall progression-free survival(PFS)were estimated by the Kaplan-Meier method and differences between groups were compared with log-rank tests.Univariate and multivariable Cox regression analyses were used to identify the independent risk factors of PFS.ResultsA total of 53 patients met the inclusion criteria.50(94.3%)had a histological diagnosis of adenocarcinoma,25(47.2%)had high tumor burden(defined as having 3 or more metastatic organs),and 28(52.8%)had multiple BMs.Regrading EGFR mutations,23(43.4%)patients had EGFR 21L858R mutations,22(41.5%)had EGFR 19del mutations,and 8(15.1%)had rare EGFR mutations.All patients had been previously treated with EGFR-TKIs therapy,among them,29(54.7%)had previously received treatment of the third-generation EGFR-TKIs.Regarding ICIs-based therapies,19 patients(35.8%)received ICIs plus chemotherapy,18(34.0%)received ICIs plus chemotherapy plus anti-angiogenic therapy,12(22.6%)received ICIs plus anti-angiogenic therapy,and 4(7.5%)received ICIs monotherapy.In the overall cohort,the intracranial ORR was 21.0%and the overall ORR was 20.8%.The median intracranial PFS was 5.1 months and the overall PFS was 4.2 months.Compared with other therapies,patients receiving ICIs plus chemotherapy showed the best efficacy with an intracranial ORR of 37.6%,a median intracranial PFS of 6.4 months,and a median overall PFS of 6.2 months,while patients receiving ICIs monotherapy showed the worst efficacy with no intracranial response,a median intracranial PFS of 1.7 months,and a median overall PFS of 2.3 months.Given that current guidelines recommend chemotherapy as a standard salvage therapy for advanced EGFR-mutant NSCLC patients who were resistant to EGFR-TKIs,we additionally included 40 patients who received only chemotherapy to compare them with 19 patients treated with ICIs plus chemotherapy.The proportion of patients with ≥2 lines of prior systemic therapy was significantly higher in ICIs plus chemotherapy group than in chemotherapy group(P=0.001).The median intracranial and overall PFS were both numerically longer in ICIs plus chemotherapy group than in chemotherapy group(median intracranial PFS:6.4 months vs.5.1 months,P=0.110;median overall PFS:6.2 months vs.4.6 months,P=0.054).Results from univariable and multivariable Cox analysis suggested that poor immune prognostic index(LIPI)(P=0.012),high tumor burden(P=0.019),and prior third-generation EGFR-TKIs treatment(P=0.032)were independent risk predicators for overall PFS,and that multiple BMs(P=0.049)was an independent risk factor for intracranial PFS.Conclusions1.ICIs plus chemotherapy had a favorable efficacy in the treatment of NSCLC patients with EGFR mutations and BMs who had experienced EGFR-TKIs treatment failure.2.ICIs plus chemotherapy may be a better salvage treatment compared with chemotherapy.3.Poor LIPI,high tumor burden,and prior third-generation EGFR-TKIs treatment were independent risk factors for overall PFS with multiple BMs for intracranial PFS.