Long-Term Responders to Erlotinib for Pulmonary Adenocarcinoma With Wild-Type Epidermal Growth Factor Receptor: Two Case Reports and a Single-Institutional Retrospective Study.

Erlotinib is an oral and reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is now used exclusively to non-small cell lung carcinoma (NSCLC) harboring mutated EGFR. However, there was historically a transient period when erlotinib was widely used regardless of EGFR mutation status. We report two cases with adenocarcinoma and wild-type EGFR status, which responded to erlotinib for unusual long time. We also retrospectively analyzed patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital. A 60-year-old woman received the second-line and tri-weekly regimen of pemetrexed (500 mg/m2 on day 1) and intermittent erlotinib (150 mg on days 2 - 16). Pemetexed was discontinued 18 months after the initiation of this regimen, but erlotinib was continued for more than 11 years. This chemotherapy successfully reduced her brain metastasis and prevented recurrence. A 58-year-old man received erlotinib monotherapy as the third-line regimen, by which multiple brain metastases disappeared. Although we tried stopping erlotinib 9 years after the initiation of erlotinib, a solitary metastasis appeared in the brain 3 months after the discontinuation of erlotinib. Between December 2007 and October 2015, 39 patients with wild-type EGFR status initiated erlotinib-containing regimens at our hospital. The response rate, progression-free survival and overall survival were 17.9% (95% confidence interval (CI): 7.5-33.5%), 2.7 months (95% CI: 1.8 - 5.0 months) and 10.3 months (95% CI: 5.0 - 15.7 months), respectively. We reported two long-term responders and survivors to erlotinib for more than 9 years, which was much longer than patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital.

Novel 4-arylaminoquinazolines bearing N,N-diethyl(aminoethyl)amino moiety with antitumour activity as EGFRwt-TK inhibitor.

Herein, four novel 4-arylaminoquinazoline derivatives with N,N-diethyl(aminoethyl)amino moiety were designed, synthesised and evaluated on biological activities in vitro. All synthesised compounds have inhibitory effects against tumour cells (SW480, A549, A431 and NCI-H1975). In particular, 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((N,N-diethyl(aminoethyl))aminomethyl)furan-2-yl)quinazoline (6a) and 6-(5-((N,N-diethylethyl)aminomethyl)furan-2-yl)-4-(4-(E)-(propen-1-yl)phenylamino)quinazoline (6d) were potent antitumour agents which showed high antiproliferative activities against tumour cells in vitro. Moreover, compound 6a could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G0/G1 phase at tested concentrations. Also, compound 6a could inhibit the activity of wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) with IC50 value of 15.60 nM. Molecular docking showed that compound 6a formed three hydrogen bonds with EGFRwt-TK, while lapatinib formed only two hydrogen bonds with the receptor protein. It is believed that this work would be giving a reference for developing anti-cancer drugs targeted EGFR-TK.

Chemotherapy versus erlotinib as second-line treatment in patients with advanced non-small cell lung cancer and wild-type epidermal growth factor receptor: an individual patient data (IPD) analysis.

The efficacy of second-line treatment in patients with epidermal growth factor receptor (EGFR) wild-type tumours is still debatable. We assessed the efficacy of a standard second-line chemotherapy compared with erlotinib in an individual patient data approach for meta-analysis. The primary endpoint was overall survival (OS), and secondary endpoint was progression-free survival (PFS). Both were compared by log-rank test. The 'restricted mean survival time' (RMST) was estimated in each study and the difference in mean survival time up to the last available time point was calculated. The Cox proportional hazards model was used on survival analyses to provide HRs, to adjust for confounding variables and to test possible interaction with selected factors. Three randomised trials comparing chemotherapy versus erlotinib were analysed, including 587 randomised patients. Overall, 74% of patients included in the original trials were considered. 464 deaths and 570 progressions or deaths were observed. Compared with erlotinib, chemotherapy was associated to a decreased risk of progression (29%; HR: 0.71, 95% CI: 0.60 to 0.84, p< 0.0001;) but with no statistical significant reduction in OS (HR: 0.89, 95% CI: 0.74 to 1.06; p<0.20). No heterogeneity was found in both analyses. Patients treated with chemotherapy gained an absolute 1.5 and 1.6 months, respectively, in PFS and lifetime (RMST 95% CI: PFS 0.49 to 2.44; OS 95% CI: -1.04 to 4.25). These results showed that patients without a constitutively activated EGFR had better PFS with chemotherapy rather than with erlotinib while no statistical difference was observed in OS.

Lymphocyte to Monocyte Ratio and Modified Glasgow Prognostic Score Predict Prognosis of Lung Adenocarcinoma Without Driver Mutation.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR) and modified Glasgow prognostic score (mGPS) are useful prognostic markers based on host-related systemic inflammatory response. They have been shown as independent prognostic biomarkers in various cancers, including non-small cell lung cancer. However, there has been little evidence for a specific population of pulmonary adenocarcinoma without active epidermal growth factor receptor (EGFR) mutation. METHODS: We retrospectively reviewed 159 patients who met the following criteria: histologically or cytologically diagnosed adenocarcinoma, confirmed wild-type EGFR, started first-line cytotoxic chemotherapy between July 2007 and March 2017 at our hospital, and c-stage IIIB or IV. We compared overall survival (OS) between dichotomized groups by the optimal cut-off points of NLR and LMR, and mGPS 0 - 1 vs. 2. Univariate and multivariate Cox proportional hazard analyses also detected prognostic factors for OS. RESULTS: As favorable prognostic factors for OS, multivariate analysis detected Eastern Cooperative Oncology Group performance status (ECOG PS) 0 - 1 (hazard ratio (HR) 3.43, 95% confidence interval (CI): 2.12 - 5.53; P < 0.01), LMR ≥ 1.97 (HR 0.39, 95% CI: 0.21 - 0.72; P < 0.01) and mGPS 0 - 1 (HR 1.95, 95% CI: 1.20 - 3.16; P < 0.01). The OS of LMR ≥ 1.97 and mGPS 0 - 1 groups were significantly longer than those of LMR < 1.97 and mGPS 2 groups, respectively. We divided 159 patients into three groups, both LMR ≥ 1.97 and mGPS 0 - 1, either LMR ≥ 1.97 or mGPS 0 - 1 and both LMR < 1.97 and mGPS 2. The OS of both LMR < 1.97 and mGPS 2 was significantly shorter than the other two groups. After adjustment for age, sex, ECOG PS, sodium, alkaline phosphatase and NLR, multivariate analysis found both LMR < 1.97 and mGPS 2 as an independent poor prognostic combination in comparison with both LMR ≥ 1.97 and mGPS0-1 (HR 5.98, 95% CI: 2.64 - 13.5; P < 0.01). CONCLUSIONS: LMR and mGPS are independent prognostic markers for pulmonary adenocarcinoma with wild-type EGFR. Combination of LMR and mGPS can stratify patients according to prognosis.

Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild-type epidermal growth factor receptor.

Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor (EGFR) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B (FAM83B) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated. Matched tumor and adjacent normal tissue samples were obtained from 216 patients who underwent complete lung resection for primary lung ADC and were examined for FAM83B expression using cDNA microarray analysis. The associations between FAM83B expression and clinicopathological parameters, including patient survival, were examined. FAM83B was highly expressed in tumors from males, smokers and in tumors with wild-type EGFR. Multivariate analyses further confirmed that wild-type EGFR tumors were significantly positively associated with FAM83B expression. In survival analysis, FAM83B expression was associated with poor outcomes in disease-free survival and overall survival, particularly when stratified against tumors with wild-type EGFR. Furthermore, FAM83B knockdown was performed to investigate its phenotypic effect on lung ADC cell lines. Gene silencing by FAM83B RNA interference induced growth suppression in the HLC-1 and H1975 lung ADC cell lines. FAM83B may be involved in lung ADC tumor proliferation and can be a predictor of poor survival. FAM83B is also a potential novel therapeutic target for ADC with wild-type EGFR.

Which treatment is preferred for advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor in second-line therapy? A meta-analysis comparing immune checkpoint inhibitor, tyrosine kinase inhibitor and chemotherapy.

BACKGROUND: The recommendations regarding the optimum treatment for advanced non-small-cell lung cancer (NSCLC) patients with wild-type (WT) epidermal growth factor receptor (EGFR) tumors remain unclear. This meta-analysis was conducted to assess the efficacy among programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) antibody, EGFR-tyrosine kinase inhibitors (TKI) and chemotherapy in second-and third-line therapy. PATIENTS AND METHODS: Randomized trials investigating two of the three treatments were searched and included. Multiple treatments comparison and pairwise comparison were performed to assess overall survival (OS) and progression-free survival (PFS), expressed as hazard ratios (HRs). The effect of prespecified study-level characteristics was assessed by subgroup analysis and meta-regression. RESULTS: 12 randomized trials accruing 3341 advanced patients with WT EGFR tumors were analyzed. PD-1/PD-L1 antibody was associated with significantly longer OS and PFS than chemotherapy (OS: HR 0.67, 95% CrI 0.60-0.75; PFS: HR 0.83, 95% CrI 0.73-0.95) and TKI (OS: HR 0.59, 95% CrI 0.50-0.70; PFS: HR 0.75, 95% CrI 0.66-0.84) , while chemotherapy was associated with significantly longer OS (HR 0.88, 95% CrI 0.77-0.99) and PFS (HR 0.75, 95% CrI 0.66-0.84) than TKI. CONCLUSIONS: For advanced NSCLC patients with WT-EGFR tumors in second- or third-line therapy, PD-1/PD-L1 antibody appeared to be the most efficacious treatment, which was followed by chemotherapy. EGFR-TKI was worse than chemotherapy.