// Yue-Lun Zhang 1, 2 , Jin-Qiu Yuan 1, 2 , Kai-Feng Wang 3 , Xiao-Hong Fu 1, 2 , Xiao-Ran Han 1, 2 , Diane Threapleton 1 , Zu-Yao Yang 1, 2 , Chen Mao 1, 2 , Jin-Ling Tang 1, 2 1 Division of Epidemiology, The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China 2 Shenzhen Municipal Key Laboratory for Health Risk Analysis, Shenzhen Research Institute of The Chinese University of Hong Kong, Shenzhen, Guangdong Province, China 3 Division of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China Correspondence to: Chen Mao, email: maochen@cuhk.edu.hk Jin-Ling Tang, email: jltang@cuhk.edu.hk Keywords: non-small cell lung cancer, epidermal growth factor receptor, prevalence, systematic review, meta-analysis Received: May 17, 2016     Accepted: September 25, 2016     Published: October 12, 2016 ABSTRACT Objectives: Estimate the epidermal growth factor receptor ( EGFR ) mutation prevalence in all non-small cell lung cancer (NSCLC) patients and patient subgroups. Results: A total of 456 studies were included, reporting 30,466 patients with EGFR mutation among 115,815 NSCLC patients. The overall pooled prevalence for EGFR mutations was 32.3% (95% CI 30.9% to 33.7%), ranging from 38.4% (95% CI: 36.5% to 40.3%) in China to 14.1% (95% CI: 12.7% to 15.5%) in Europe. The pooled prevalence of EGFR mutation was higher in females (females vs. males: 43.7% vs. 24.0%; OR: 2.7, 95% CI: 2.5 to 2.9), non-smokers (non-smokers vs. past or current smokers: 49.3% vs. 21.5%; OR: 3.7, 95% CI: 3.4 to 4.0), and patients with adenocarcinoma (adenocarcinoma vs. non-adenocarcinoma: 38.0% vs. 11.7%; OR: 4.1, 95% CI: 3.6 to 4.8). Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched to June 2013. Eligible studies reported EGFR mutation prevalence and the association with at least one of the following factors: gender, smoking status and histology. Random-effects models were used to pool EGFR mutation prevalence data. Conclusion: This study provides the exact prevalence of EGFR mutations in different countries and NSCLC patient subgroups.

/pdf/the-prevalence-of-egfr-mutation-in-patients-with-non-small-2zch4vyl3c.pdf

The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis

Summary Background Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. Methods In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18–75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. Findings 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67–1·05; median progression-free survival 4·6 months [95% CI 3·5–6·3] vs 3·4 months [2·3–3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033). Interpretation Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer. Funding Zhejiang Beta Pharma (China), the Chinese National Key Special Program for Innovative Drugs, the 863 Project, and Zhejiang Provincial Key Special Program.

/pdf/icotinib-versus-gefitinib-in-previously-treated-advanced-non-n4p4t32r29.pdf

Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial

Lung cancer is the leading cause of cancer related deaths in Canada with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Tumor characterization can identify cancer-driving mutations as treatment targets. One of the most successful examples of cancer targeted therapy is inhibition of mutated epidermal growth factor receptor (EGFR), which occurs in ~10-30% of NSCLC patients. While this treatment has benefited many patients with activating EGFR mutations, almost all who initially benefited will eventually acquire resistance. Approximately 50% of cases of acquired resistance (AR) are due to a secondary T790M mutation in exon 20 of the EGFR gene; however, many of the remaining mechanisms of resistance are still unknown. Much work has been done to elucidate the remaining mechanisms of resistance. This review aims to highlight both the mechanisms of resistance that have already been identified in patients and potential novel mechanisms identified in preclinical models which have yet to be validated in the patient settings.

Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review.

Prognostic role of pretreatment blood neutrophil-to-lymphocyte ratio in advanced cancer survivors: A systematic review and meta-analysis of 66 cohort studies

Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung cancer (NSCLC) with proven efficacy. We undertook a systematic review and meta-analysis to synthesize existing studies with direct comparisons of EGFR TKIs in NSCLC in terms of both efficacy and safety. Eight randomized trials and 82 cohort studies with a total of 17,621 patients were included for analysis. Gefitinib and erlotinib demonstrated comparable effects on progression-free survival (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.95 to 1.04), overall survival (HR, 0.99; 95% CI, 0.93 to 1.06), overall response rate (risk ratio [RR], 1.05; 95% CI, 1.00 to 1.11), and disease control rate (RR, 0.98; 95% CI, 0.96 to 1.01), which did not vary considerably with EGFR mutation status, ethnicity, line of treatment, and baseline brain metastasis status. Gefitinib was associated with more grade 3/4 liver dysfunction, but tended to cause lower rates of dose reduction, treatment discontinuation, total grade 3/4 adverse events (RR, 0.78; 95% CI 0.65 to 0.94), and a number of specific adverse events such as rash and diarrhea. No solid evidence was found that afatinib had greater efficacy than gefitinib or erlotinib in first-line treatment of EGFR-mutant NSCLC. However, afatinib was more effective than erlotinib as second-line treatment of patients with advanced squamous cell carcinoma. The grade 3/4 adverse events rate of afatinib was comparable to that of erlotinib but higher than that of gefitinib.

/pdf/comparison-of-gefitinib-erlotinib-and-afatinib-in-non-small-476cz2irte.pdf

Comparison of gefitinib, erlotinib and afatinib in non‐small cell lung cancer: A meta‐analysis

Background

The outcomes of patients with metastatic nasopharyngeal carcinoma (NPC) differ between individuals. The purpose of this study was to examine the impact of neutrophil-to-lymphocyte ratio (NLR) on survival in patients with metastatic NPC.



Methods

A total of 229 patients with disseminated NPC were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte, and NLR on survival were examined using the proportional hazards regression model to estimate hazard ratio (HR). The relationship between short-term treatment efficacy and pretreatment NLR was analyzed using the chi-square test.



Results

The pretreatment elevated neutrophil count (p = .020), percentage of neutrophil (p < .001), and NLR (p = .002) were statistically significantly associated with a poor prognosis. The cutoff value selected for NLR was 3.6. The median survival time was 15.3 months for the high-NLR group and was 23.5 months for the low-NLR group (p < .001).



Conclusion

NLR is a prognosticator in patients with metastatic NPC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 69–75, 2015

Pretreatment neutrophil-to-lymphocyte ratio as predictor of survival for patients with metastatic nasopharyngeal carcinoma.

Preoperative elevation of serum C-reactive protein (CRP) is reportedly associated with poor prognosis in several types of cancer. This study investigated the role of serum CRP as a prognostic factor in early-stage esophageal squamous cell carcinoma (ESCC). The preoperative serum CRP levels were measured in 156 newly diagnosed pT1–2N0M0 patients using an enzyme-linked immunosorbent assay. Correlations between serum CRP levels and other clinical parameters were analyzed. Multivariate analyses were performed to find prognostic markers using Cox's proportional hazards model. CRP concentrations were within the normal range in 117 (75%) individuals, but were elevated in 39 (25%) patients. Serum CRP levels were significantly correlated with the tumor length ( p  = 0.032), depth (T classification, p  = 0.0157), or histologic grade ( p  = 0.034). The overall 5-year survival rates were 76.3% and 50.2% in the low- and high-CRP groups, respectively ( p  = 0.005). By multivariate analyses, the elevated serum CRP level was found to be an independent prognostic factor for poor survival (hazard ratio = 2.131; p  = 0.007), regardless of tumor classification or other prognostic factors. In conclusion, preoperative, high serum CRP is an independent determinant of poor prognosis in early-stage ESCC.

Preoperative elevation of serum C-reactive protein as an indicator of poor prognosis for early-stage esophageal squamous cell carcinoma

Objective: Few treatment options are available for advanced non-small cell lung cancer (NSCLC) patients who have failed of gefitinib or erlotinib treatment in second/third-line treatment. The aim of this study was to investigate the efficacy of re-administration of the same TKI after failure of gefitinib or erlotinib.
 Patients and methods: The clinical data of 33 patients with advanced NSCLC were retrospectively analyzed. All of the patients were given the same TKI treatment after the failure of gefitinib or erlotinib. Survival analysis was evaluated by Kaplan-Meier method.
 Results: Twenty patients (60.6%) were re-administration with gefitinib as the 2 nd EGFR-TKI, and thirteen patients (39.4%) received erlotinib. One patient (3.0%) showed partial response (PR), 14 (42.4%) achieved stable disease (SD), and 18 (54.5%) had progressive disease (PD). The disease control rate was 45.5% and the median progression-free survival was 1.5 months (95% CI: 0.6-2.3 months). The PFS in patients who got disease control in the prior TKI was 2.2 and 1.2 months in the progression disease cases (P=0.29), the DCR was 54.5% and 27.3% in two group, respectively (P=0.26).
 Conclusions: Re-administration of TKI seems to be a potential therapeutic option for treatment of selected advanced NSCLC patients after failure of gefitinib or erlotinib, especially for the patients with NSCLC who once responded from the prior TKI treatment.

Re-administration after the failure of gefitinib or erlotinib in patients with advanced non-small cell lung cancer.

BACKGROUND The preclinical experiments and several clinical studies showed icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in Chinese patients with advanced non-small cell lung cancer (NSCLC) who failed previous chemotherapy. We performed a retrospective study of the efficacy and safety of icotinib monotherapy in a different and more recent sample of Chinese patients. METHODS The clinical data of 149 patients with advanced NSCLC who were admitted to Zhejiang Cancer Hospital from August 1, 2011 to July 31, 2012 were retrospectively analyzed. All patients were given icotinib treatment after the failure of previous chemotherapy. Univariate and multivariate analyses were conducted based on the Kaplan Meier method and Cox proportional hazards model. RESULTS The objective response rate was 33/149 and disease control rate was 105/149. No complete response occurred. Median progression free survival (PFS) with icotinib treatment was 5.03 months (95% CI: 3.51 to 6.55). Median overall survival was 12.3 months (95% CI: 10.68 to 13.92). Multivariate analysis showed that the mutation of EGFR and one regimen of prior chemotherapy were significantly associated with longer PFS. At least one drug related adverse event was observed in 65.8% (98/149) of patients, but mostly grade 1 or 2 and reversible and none grade 4 toxicity. CONCLUSIONS Icotinib monotherapy is an effective and well tolerated regimen for Chinese patients with NSCLC after the failure of chemotherapy. It is a promising agent and further study with icotinib in properly conducted trials with larger patient samples and other ethnic groups is warranted.

Efficacy and safety of icotinib in Chinese patients with advanced non-small cell lung cancer after failure of chemotherapy.

Background and objective As the first epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in China, icotinib shows promising anticancer activity in vitro and vivo. The phase III clinical study (ICOGEN) showed that icotinib has a good efficacy and tolerability in Chinese patients with advanced non-small cell lung cancer (NSCLC) compared with gefitinib. This retrospective study aims to evaluate the efﬁcacy and tolerability of icotinib monotherapy for advanced NSCLC patients with EGFR mutation and wild-type patients in our hospital. Methods Patients with advanced NSCLC who were treated with icotinib in Zhejiang Cancer Hospital were retrospectively analyzed from August, 2011 to August, 2012. Survival was estimated using Kaplan-Meier analysis and Log-rank tests. Results The clinical data of 49 patients (13 with wild-type and 36 with EGFR mutation) with NSCLC were enrolled in the current study. The patients’ overall objective response rate (ORR) was 58.3% and the disease control rate (DCR) in 36 EGFR mutation patients was 88.9%. The ORR was 7.7% and DCR was 53.8% in the wild-type patients. Median progression-free survival (PFS) with icotinib treatment in EGFR mutation patients was 9.5 months and 2.2 months in wild-type patients (P<0.001). Nineteen patients with EGFR mutation received icotinib as first-line and 17 in further-line treatment. The PFS was 9.5 months in the first-line and 8.5 months for second-line or further-line patients (P=0.41). Median overall survival (OS) in EGFR mutation patients was not reached, but was 12.6 months in wild-type patients. Most of the drug-related adverse events were mild (grade I or II) and reversible with no grade IV toxicity. Conclusion Icotinib monotherapy showed signiﬁcant antitumor activity in advanced NSCLC EGFR mutation patients. The toxicity was well tolerated and acceptable.
	
	DOI: 10.3779/j.issn.1009-3419.2013.03.04

[Efficacy of icotinib for advanced non-small cell lung cancer patients with EGFR status identified].

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