Efficacy And Safety Of First-line And Salvage Systemic Therapies For Unresectable Malignant Mesothelioma And A Lung Adenocarcinoma With Rare EGFR V774M Mutation:A Case Report And Molecular Structural Analysis

Background:A series of randomized controlled trials(RCTs)of first-line and salvage systemic therapies for unresectable malignant mesothelioma have reported equivocal results.There is an urgent need to find out the optimal treatment for this poor prognosis malignancy.Methods:To compare the efficacy,safety and weigh the benefit of different systemic treatments in first-line and salvage settings for unresectable malignant mesothelioma,we performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed,EMBASE,Cochrane Library,ClinicalTrials.gov,and major international conferences.The primary outcomes were overall survival(OS)and progression-free survival(PFS);the secondary outcomes were overall response rate(ORR)and grade≥3 treatment-related adverse events(TRAEs).This study was registered in the Prospective Register of Systematic Reviews(CRD42022331496)to ensure transparency.Results:15 RCTs(6 for first-line therapies and 9 for salvage therapies)with a total of 4578 patients were analyzed.For first-line therapies,the combination of nivolumab and ipilimumab appeared to significantly increase OS(HR 0.65,95%CI:0.44-0.96),and also had relatively fewer grade≥3 TRAEs.Bevacizumab plus chemotherapy appeared to significantly increase PFS(HR 0.66,95%CI:0.55-0.79).For salvage therapies,ramucirumab plus chemotherapy was associated with the best OS(HR 0.51,95%CI:0.320.81)and PFS(HR 0.48,95%CI:0.31-0.74),but appeared to have relatively more grade≥3 TRAEs.Subgroup analysis by histologic types suggested that in frontline settings,bevacizumab plus chemotherapy may better increase OS for epithelioid type and nivolumab plus ipilimumab may better increase OS for non-epithelioid type.In salvage settings,ramucirumab plus chemotherapy may better increase OS for both epithelioid type and non-epithelioid type.Conclusion:Nivolumab plus ipilimumab appeared to be the most effective and safest treatment in frontline settings for unresectable malignant mesothelioma especially for the non-epithelioid subtype.For the epithelioid malignant mesothelioma,bevacizumab plus chemotherapy ranked first to extend OS.Ramucirumab plus chemotherapy improved OS and PFS in salvage settings,while with an increase in the number of grade ≥3 TRAEs.Background:Epidermal growth factor receptor(EGFR)mutations are the most common driver mutations in non-small cell lung cancer(NSCLC).EGFR tyrosine kinase inhibitors(EGFR-TKIs)have remarkably improved the prognosis of patients with classical activating mutations(EGFR exon 19 deletion and L858R mutations),but the efficacy of EGFR-TKIs in rare EGFR mutations remains heterogeneous and controversial.Case presentation:A 77-year-old man was diagnosed with lung adenocarcinoma.The staging was cT3N3M1c(stage IVB).Next-generation sequencing(NGS)confirmed a rare EGFR V774M mutation.He received osimertinib as first-line therapy and then CT scan demonstrated tumor regression.The tumor response evaluation maintained at a stable disease(SD).Five months later,the tumor in lung enlarged.Based on the molecular structure prediction model,V774M showed a narrower binding pocket compared with EGFR L858R,which might influence the binding ability of EGFR-TKIs.The results of molecular dynamic simulation showed that osimertinib demonstrated relatively weaker binding ability to V774M compared with EGFR L858R.However,when comparing different EGFR-TKIs,the second-generation EGFR-TKIs dacomitinib and afatinib showed better binding ability to EGFR V774M than first-generation EGFRTKI icotinib and third-generation EGFR-TKI osimertinib.Conclusion:EGFR V774M showed moderate sensitivity to second generation of EGFRTKIs.EGFR V774M also showed a narrower binding pocket than EGFR L858R,which might affect the clinical efficacy of EGFR-TKIs.