Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer:final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial

EMERGING-CTONG 1103 showed improved progression-free survival(PFS)with neoadjuvant erlotinib vs.chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer(NSCLC)(NCT01407822).Herein,we report the final results.Recruited patients were randomly allocated 1:1 to the erlotinib group(150 mg/day orally;neoadjuvant phase for 42 days and adjuvant phase to 12 months)or to the GC group(gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously;2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase).Objective response rate(ORR),complete pathologic response(pCR),PFS,and overall survival(OS)were assessed along with safety.Post hoc analysis was performed for subsequent treatments after disease recurrence.Among investigated 72 patients(erlotinib,n=37;GC,n=35),the median follow-up was 62.5 months.The median OS was 42.2 months(erlotinib)and 36.9 months(GC)(hazard ratio[HR],0.83;95%confidence interval[CI],0.47-1.47;p=0.513).The 3-and_(5-y)ear OS rates were 58.6%and 40.8%with erlotinib and 55.9%and 27.6%with GC(p_(3-y)=0.819,p_(5-y)=0.252).Subsequent treatment was administered in 71.9%and 81.8%of patients receiving erlotinib and GC,respectively;targeted therapy contributed mostly to OS(HR,0.35;95%CI,0.18-0.70).After disease progression,the ORR was 53.3%,and the median PFS was 10.9 months during the EGFR-TKI rechallenge.During postoperative therapy,grade 3 or 4 adverse events(AEs)were 13.5%in the erlotinib group and 29.4%in the GC group.No serious adverse events were observed.Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1

Indoleamine 2,3-dioxygenase 1(IDO1),the enzyme that catabolizes tryptophan(Trp)metabolism to promote regulatory T cells(Tregs)and suppress CD8+T cells,is regulated by several intrinsic signaling pathways.Here,we found that tobacco smoke,a major public health concern that kills 8 million people each year worldwide,induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo.The carcinogen nicotine-derived nitrosaminoketone(NNK)was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun,which has a binding site for the IDO1 promoter.The NNK receptorα7 nicotinic acetylcholine receptor(α7nAChR)was required for NNK-induced c-Jun activation and IDO1 upregulation.In A/J mice,NNK reduced CD8+T cells and increased Tregs.Clinically,smoker patients with non-small-cell lung cancer(NSCLC)exhibited high IDO1 levels and low Trp/kynurenine(Kyn)ratios.In NSCLC patients,smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1.These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis,and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients,whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.