Treating advanced non-small-cell lung cancer in Chinese patients: focus on icotinib

Icotinib hydrochloride is an orally administered small-molecule reversible tyrosine kinase inhibitor that has been independently researched and developed and has independent intellectual property rights in the People’s Republic of China. Clinical trials have demonstrated that the response to icotinib among advanced non-small-cell lung cancer (NSCLC) patients who received at least one platinum-based chemotherapy regimen was not inferior to gefitinib. Since being launched August 2011 in the People’s Republic of China, icotinib has been widely used in clinics, and has become an important treatment option for Chinese patients with advanced NSCLC. The present study presents the Phase I, II, and III clinical trials of icotinib and discusses current clinical applications in the People’s Republic of China and future research directions.

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title: Global cancer statistics
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title: Treatment of non-small-cell lung cancer with erlotinib or gefitinib.
abstract: A 64-year-old woman receives the diagnosis of metastatic non-small-cell lung cancer (NSCLC), which has progressed during treatment with carboplatin, paclitaxel, and bevacizumab. Erlotinib therapy is recommended.

title: Icotinib, a potent and specific EGFR tyrosine kinase inhibitor, inhibits growth of squamous cell carcinoma cell line A431 through negatively regulating AKT signaling.
abstract: Icotinib is a potent and specific epidermal growth factor receptor tyrosine kinase inhibitor. In this study, we reported that icotinib had the antitumor activity on human squamous cell carcinoma cell line A431 in vitro. Meanwhile, adhesion to fibronectin and expression of integrin α3 and β1 were significantly reduced in a dose-dependent manner after the treatment of icotinib. Moreover, icotinib induced cell cycle arrested and affected expression of various cell cycle related proteins in squamous cancer cell line A431, whereas it did not cause apoptosis. Furthermore, icotinib remarkably down-regulated phosphorylation of protein kinase B (AKT) though blocking the interaction between 3-phosphoinositide-dependent protein kinase-1 (PDK1) and AKT in A431 cells. Taken together, it is shown that the small molecular compound, icotinib, has an anti-squamous cell carcinoma activity in vitro and its antitumor mechanism is associated with the blockage of the interaction between PDK1 and AKT. These results provide a novel strategy for anti-squamous cell carcinoma therapy.

title: Effects of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in EGFR-mutated non-small cell lung cancer.
abstract: Epidermal growth factor receptor (EGFR) is one of the most promising targets for non-small cell lung cancer (NSCLC). Our study demonstrated the antitumor effects of icotinib hydrochloride, a highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), in two EGFR-mutated lung cancer cell lines compared to A549, a cell line without EGFR mutations. We incubated PC-9 and HCC827 human lung cancer cell lines both with (E746-A750) mutations with various concentrations of icotinib and gefitinib for 48 h. Cell proliferation and migration were determined using a real-time cell invasion and migration assay and cytotoxicity assay. Apoptosis was assessed by measuring Annexin V staining using flow cytometry. The antitumor effects of icotinib compared to gefitinib were similar and were most effective in reducing the proliferation of EGFR-mutated cells compared to non-mutated controls. Our results suggest the possibility of icotinib as a new therapeutic agent of EGFR-mutated cancer cells, which has the potential to be used in the first-line treatment of EGFR-mutated NSCLC.

title: Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies.
abstract: Icotinib, one of the leading compounds selected from our compound library, was found to be a potent and specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an IC(50) of 5 nM. When profiled with 88 kinases, Icotinib only showed meaningful inhibitory activity to EGFR and its mutants. Icotinib blocked EGFR-mediated intracellular tyrosine phosphorylation (IC(50)=45 nM) in the human epidermoid carcinoma A431 cell line and inhibits tumor cell proliferation. In vivo studies demonstrated that Icotinib exhibited potent dose-dependent antitumor effects in nude mice carrying a variety of human tumor-derived xenografts. The drug was well tolerated at doses up to 120 mg/kg/day in mice without mortality or significant body weight loss during the treatment. A head to head randomized, double blind phase III trial using Gefitinib as an active control for patients with advanced non-small cell lung cancer (NSCLC) was finished recently ( The data shows that Icotinib was non-inferior to Gefitinib in terms of median progression free survival (PFS) and safety superior favor to Icotinib compared to Gefitinib.

title: Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects
abstract: AbstractPurpose
Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has proved effectiveness in xenografted nude mice. Purpose of the present studies was to investigate tolerability and pharmacokinetics of Icotinib in healthy subjects for the first time, including dose proportionality, food effect, and tolerability. Two studies were conducted in total of 22 healthy subjects: a randomized, two-Latin-square crossover, dose proportional study (n = 12) and a randomized two-way crossover food-effect study (n = 10).Results
Plasma concentration of Icotinib reached peak at a median Tmax of 0.75–3.5 h after single dose and then declined with a mean t1/2β of 6.02–7.83 h. Over the dose range of 100–600 mg, AUC values were proportional to dose and Cmax showed a slight saturation when dose increases. Only 0.2 % of the dose was excreted through kidney in unchanged Icotinib. After dosing 400 mg of Icotinib with high-fat and high-calorie meal, mean Cmax and AUC were significantly increased by 59 and 79 %, respectively. Three subjects experienced four adverse events (rash, increase in AST and ALT, and external injury). Rash and increased levels of AST and ALT were considered as drug-related. No serious adverse events were reported.ConclusionThe current work demonstrated that Icotinib was well tolerated in healthy male subjects (n = 22) over the dose range of 100–600 mg with or without food. Icotinib exposure, expressed in AUC, was proportionally increased with dose over the above dose range. Food intake significantly increased the absorption and exposure of Icotinib in healthy subjects.

title: Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors.
abstract: The goal of this study was to assess the safety and tolerability of icotinib hydrochloride (BPI-2009H), a new selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and to explore its pharmacokinetics (PK) and clinical activity in patients with advanced solid tumors, mainly those with non-small-cell lung cancer (NSCLC) after the failure of the prior platinum-based chemotherapy.



Different doses of oral icotinib were administered once every 8 h (Q8H) for a 28-continuous-day cycle until disease progression and or undue toxicity was observed. PK studies of subjects' blood were performed during cycle one (day 1 through 28). Patients aged ≥18 and ≤70 years with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ functions eligible for the study. Tumor responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST). K-ras and EGFR mutations in the extracted DNA of fourteen specimens were examined using PCR-based direct sequencing assay.



Thirty-six patients were enrolled in the study. PK analysis demonstrated that the mean elimination half-life of icotinib was 6 h, and the T(max) was around 2 h. The steady-state concentration of icotinib administered at a dose of 125 mg once every 8 h (Q8H) was significantly higher than that achieved by a dose of 100mg Q8H. The most frequent treatment-related adverse events (TRAEs) were an acne-like (folliculitis) rash (16/36, 44.4%), diarrhea (8/36, 22.2%) and a decrease in white blood cells (4/36, 11.1%). The maximum-tolerated dose (MTD) was not reached. Among 33 patients with NSCLC, 7 patients exhibited a partial response, 7 showed stable disease at the 24 weeks. Among 14 patients undergoing DNA sequence for K-ras and EGFR mutations, 3 with K-ras mutation presented 2 stable disease (SD) and 1 partial response (PR), 5 with EGFR exon 19 or 21 mutation 2 PR and 3 SD within 4 weeks.



Oral icotinib was generally well tolerated, with manageable and reversible adverse events (AEs) and showed positive clinical anti-tumor activities in patients with advanced NSCLC. The recommended dose for phase II/III studies with icotinib is 125 mg or 150 mg Q8H.

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



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. 
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).



Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.

title: Short-term Response and Toxicity of Icotinib Hydrochloride in the Treatment for Advanced Non-small Cell Lung Cancer
abstract: To observe short-term response and toxicity of icotinib hydrochloride in the treatment for advanced non-small cell lung cancer(NSCLC).[Methods] Sixty-seven cases with NSCLC treated with icotinib hydrochloride alone taken orally for at least one month were enrolled in the study.Efficacy and toxicity were evaluated.[Results] Objective response rate(ORR)was 38.8%(26/67),and disease control rate(DCR)was 62.7%(42/67) in 67 cases,with complete response(CR),1 case;partial response(PR),25 cases;stable disease(SD),16 cases;and progressive disease(PD),25 cases.ORR and DCR were 59.5 %(22/37) and 73.0%(27/37) respectively in patients with CEA30μg/L,while those CEA30μg/L were 13.3%(4/30) and 46.7%(14/30) respectively,with significant difference between the two groups.The DCR of male was lower than that of female,and the DCR between genders showed significant difference after adjusting smoking status.Multivariate analysis showed that gender and CEA(30μg/L) were independent prognostic factors for short-term response.The major toxicities were skin rash(26.8%) and diarrhea(13.4%).[Conclusion] Monotherapy with icotinib hydrochloride is effective and tolerable for the patients with advanced NSCLC,especially for female patients or patients with CEA elevation.

title: Curative Effect Observation of Icotinib in the Treatment of Patients with Advanced Non- small Cell Lung Cancer and Epidermal Growth Factor Receptor( EGFR) Mutations
abstract: To observe curative effect,progression- free survival( PFS) and adverse reaction of icotinib in the treatment of patients with advanced non- small cell lung cancer( NSCLC) and epidermal growth factor receptor( EGFR)mutations.  From October 2011 to April 2012,38 patients with advanced NSCLC and EGFR mutations were admitted to our hospital,when their chemotherapy failed,these patients were treated with icotinib 125mg by mouth three times a day,then the short- term curative effect,PFS and adverse reaction were evaluated.  Among the 38 patients who received icotinib therapy,1 case had a complete response,and 1 case had progressive disease after 3 months. Median progression- free survival for 38 patients was 10 months〔95% CI( 8. 91,11. 09) 〕. Median progression- free survival for female patients was 10 months〔95%CI( 8. 34,11. 66) 〕,and median progression- free survival for male patients was 6 months〔95%CI( 1. 20,10. 80) 〕,the difference was statistically significant( P = 0. 01). Multivariable analysis of Cox model showed that PFS had no correlation with sex,smoking status,pathological type,age,performance status score,clinical stage,history of chemotherapy and the presence of skin rash. The most common adverse reactions were skin rashes( 24 patients,63. 2%) and diarrhea( 11 patients,28. 9%),no patien stopped treatment because of adverse reactions.  The curative effect of icotinib in the treatment of patients with advanced NSCLC and EGFR mutations is satisfactory,few patients have adverse reaction,and the extent of adverse reaction is light,therapy with icotinib is safety,the patients can tolerate therapy with icotinib.

title: Efficacy and safety of icotinib in Chinese patients with advanced nonsmall cell lung cancer after failure of chemotherapy
abstract: 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.  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.  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.  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.

title: Safety,toleration and therapeutic effect of the new drug icotinib hydrochloride in treating Chinese patients with non-small cell lung cancers
abstract: To observe the safety,toleration,dose-correlated efficacy and survival in treatment with icotinib for Chinese patients with non-small cell lung cancers(NSCLC).Methods: In a single center,open phase I clinical trial,Chinese NSCLC patients were selected,and they took various doses of icotinib till disease progression or intolerance of toxic reactions. Totally 40 NSCLC patients were selected in the trial.In 150 mg(bid) dose group,1 patient appeared complete remission(CR),6 partial remission(PD) and 8 stable disease(SD);other 8 patients appeared progressive disease(PD).Of 9 patients in 200 mg(bid) dose group,1 patient appeared PR,4 SD and 4 PD.Of 8 patients in 125 mg(tid) dose group,2 patients appeared PR and 6 SD.No significant difference was observed among the three dose groups(P=0.272 4).The total ORR and total DCR were 25% and 70%,respectively.The median progression free survival(PFS) and the median overall survival were 160 days(95%CI: 72～236 days) and 454 days(95%CI: 226～582 days),respectively.Adverse effects(AE) appeared in 35% patients,including skin rash(25%),diarrhea and etc. The efficacy of icotinib has reached the level of similar products.Icotinib is safe,and the common adverse effects are reversible skin rash and diarrhea.

title: Efficacy of icotinib hydrochloride in the treatment of 31 patients with advanced squamous cell lung carcinoma
abstract: To evaluate the efficacy and safety of icotinib hydrochloride in the treatment of patients with advanced squamous cell lung carcinoma.We retrospectively reviewed medical records of 31 patients with advanced squamous cell lung carcinoma receiving icotinib hydrochloride therapy from August 1,2011 to August 30,2012 in Zhejiang Cancer Hospital.The efficacy was analyzed based on the Kaplan-Meier method and Cox proportional-hazards model.The objective response rate(ORR) was 6.5%(2 patients),the disease control rate(DCR) was 38.7%(12 patients),the median progression-free survival(mPFS) was 2.1 months,and the median overall survival(mOS) was 21.8 months.The main toxic reactions were skin rash(38.7%),diarrhea(16.1%),and elevated transaminase level(6.5%);most of them were Grade I to Grade II,and 3.2% appeared skin rash with Grade III.Conclusion:Icotinib hydrochloride is effective for treating patients with advanced squamous cell lung carcinoma,and its toxicity can be tolerated.

title: Erlotinib in patients with advanced lung squamous cell carcinoma
abstract: PurposeErlotinib had proved efficacy in patients with advanced non-small cell lung cancer, especially adenocarcinoma. The aim of this study was to evaluate the efficacy of erlotinib in patients with advanced lung squamous cell carcinoma (LSQC).MethodsWe retrospectively reviewed medical records and serial chest images of consecutive patients who were diagnosed with advanced LSQC and had been treated with erlotinib monotherapy. The primary objective was to evaluate the treatment efficacy and to correlate with patients’ clinical characteristics.ResultsTotally 55 patients were analyzed (42 men and 13 women, median age of 71 years). In 37 patients who had measurable lesions, 6 had partial response and 13 had stable disease, yielding an overall response rate of 16.2 % and disease control rate of 51.4 %. In all patients, the median progression-free survival (PFS) and overall survival (OS) were 2.0 months (95 % confidence interval, 1.5–2.4 months) and 10.4 months (95 % confidence interval, 0.6–20.2 months), respectively. The PFS and OS were significantly longer in patients who had good clinical response (either the tumor achieved partial response or the patients had disease controlled for more than 6 months) than those who did not (median PFS, 13.0 vs. 1.6 months; median OS, 28.3 vs. 4.9 months; both P values <0.01). Patients who never smoked seemed to have better clinical response and longer survival than those who had smoking history (P = 0.077 and 0.086, respectively).ConclusionsErlotinib could provide some clinical benefit to patients with advanced LSQC.

title: Erlotinib for pretreated squamous cell carcinoma of the lung in Japanese patients.
abstract: Erlotinib has demonstrated survival benefit in patients with not only adenocarcinoma but also squamous cell carcinoma. Epidermal growth factor receptor-tyrosine kinase inhibitors are more effective in Asian populations, including the Japanese than in western populations. However, a higher incidence of interstitial lung disease has been reported as a fatal adverse event in the Japanese population. There is little data on erlotinib for Japanese patients with pretreated squamous cell carcinoma.



Between January 2004 and October 2010, we retrospectively evaluated the efficacy and toxicity of erlotinib administered as the first epidermal growth factor receptor-tyrosine kinase inhibitors for 41 Japanese patients with pretreated squamous cell carcinoma. Patients with pre-existing interstitial lung disease were carefully excluded by several examinations including high-resolution computed tomography.



The response rate and disease control rate were 9.7% [95% confidence interval: 2.7-23.1%) and 43.9% (95% confidence interval: 28.5-60.2%], respectively. Median time to treatment failure and overall survival were 2.2 months (95% confidence interval: 1.0-2.8 months) and 11.0 months (95% confidence interval: 5.7-15.7 months), respectively. Interstitial lung disease (Grade 5) was observed in one (2.4%) patient. Patients with Grade 0-1 skin rashes vs. patients with Grades 2-3 exhibited disease control rates of 28 vs. 83% (P = 0.0017), and median time to treatment failure of 1.2 months vs. 3.4 months (P = 0.0099).



Erlotinib has moderate efficacy for pretreated squamous cell carcinoma in Japanese patients. A higher grade of skin rash was associated with clinical benefit. Careful exclusion of pre-existing interstitial lung disease can minimize the occurrence of interstitial lung disease.

title: Retrospective study of erlotinib in patients with advanced squamous lung cancer.
abstract: The effective targeted therapy for lung squamous cell carcinoma (SCC) is needed. The epidermal growth factor receptor (EGFR) mutation rate is low in lung SCC. The aim of this study was to evaluate the status of erlotinib treatment and EGFR mutation in lung SCC patients.



We retrospectively enrolled lung cancer patients with SCC histology and history of erlotinib treatment. The primary objective was to assess overall response rate (ORR) and disease control rate (DCR) and the secondary objective was to assess progression-free survival (PFS) and overall survival (OS). EGFR mutations were assessed in parts of patients using both direct sequencing and protein nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp methods.



In total, 92 patients were analyzed (75 men and 17 women, median age 69 years, and 74 current or former smokers). Sixteen patients achieved partial response and 9 had stable disease. The ORR was 17.4% and the DCR was 27.2%. The PFS and OS were longer in patients with disease control than with progressive disease (PFS 7.8 versus 1.3 months and OS 20.7 versus 2.7 months, both p<0.0001). The 1-year survival rate was 21.7%. In 27 patients with adequate specimens for molecular analysis (including 4 PR and 4 SD), two (7.4%) had EGFR complex mutations. One patient experienced response to erlotinib and the other did not.



A significant proportion of lung SCC patients would derive a clinical benefit from erlotinib treatment. The relatively higher response rate than the EGFR mutation rate in present study needs further evaluation.

title: Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer.
abstract: To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC).



A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity.



A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (P<0.05). The symptom improvement rate was 57.3% (51/89), and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 (33.7%)] and diarrhea [15/89 (16.9%)]. The level of toxicity was typically low.



The use of icotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

title: Efficacy of Icotinib for Advanced Lung Adenocarcinoma
abstract: To evaluate the efficacy and safety of Icotinib for advanced lung adenocarcinoma.Sixty-seven patients with advanced lung adenocarcinoma were collected from July 2011 to March 2012 in our hospital.All of them received Icotinib (125mg) three times a day till disease progression or intolerable adverse events developed.Of 67 patients,16 patients were treated with Icotinib as the first-line therapy,other 51 patients accepted Icotinib as the second or over second-line therapy.The overall response rate was 35.8%(24/67),and the disease control rate was 74.6%(50/67).Of 15 patients with EGFR(Epidermal growth factor receptor) mutation-positive,the objective response rate was 60.0%(9/15 ),and the disease control rate was 93.3%(14/ 15 ).The analysis for the influencing factors of clinical efficacy showed that only the number of chemotherapy regimen was significantly relevant to the response rate and the disease control rate(P =0.034,P =0.044).About adverse events,skin rash,diarrhea and skin itching were observed most frequently,which happened on 20.9%,11.9%and 9.0%of patients respectively.But most of them were The treatment of Icotinib for advanced lung adenocarcinoma is safe and may get good efficacy as well as clinical benefit.

title: Efficacy and toxicity of icotinib hydrochloride in 66 patients with advanced non-small cell lung cancer
abstract: To evaluate the efficacy and toxicity of icotinib hydrochloride,and to analyze prognostic factors influencing curative effect in patients with advanced non-small cell lung cancer(NSCLC).Methods: A total of 66 patients with ⅢB or Ⅳ NSCLC were enrolled in this study from January 2011 to February 2013,and all of these patients had been confirmed by pathology or cytology.Of the patients,34 were newly diagnosed and received icotinib hydrochloride for the first-line treatment;16 received icotinib hydrochloride for second-line treatment and 16 for third and more than third-line treatment. Of the 66 patients,16 had received icotinib hydrochloride for more than one month,and 4 did not tolerate the side events to stop taking the medicine.There was none with complete response,24 patients had partial response,24 had stable disease and 14 had progressive disease.The objective response was 38.7%,and the disease control rate was 77.4%.In 7 patients,EGFR was detected and found to be mutant;among them 3 patients had partial response and 4 had stable disease.The total progressive free survival was 7 months.The progressive free survivals after first-line treatment,second-treatment, 1931 and third or more than third treatment were 11(1 ～ 16.3),6(0.3 ～ 11.5) and 5(1 ～ 14.7) months,respectively.The effect of icotinib hydrochloride did not relate to clinical characteristics statistically.Subgroup analysis showed that PFS significantly related to ECOG score,smoking status,pathological types and rash.The main clinically relevant toxicity in 66 patients was rash that occurred in 27 patients including grade I in 23 patients,grade II in 3 patients and grade III in 1 patient.Diarrhea occurred in 12 patients including grade I in 9 patients,grade II in 3 patients and grade III in 3 patients.Other toxic reactions included stomach discomfort,heart discomfort,ALT / AST elevation,vomiting,skin itch,dry skin,pain and anemia.Four patients did not continue the therapy because of adverse events,which included diarrhea(2 patients,one was grade I and one was grade II),vomiting(1 patient,grade I) and cardiac discomfort(1 patient,grade I).Conclusion: Treatment with icotinib hydrochloride shows satisfactory clinical efficacy,and is tolerable for patients with advanced NSCLC.Advanced NSCLC patients with a lower ECOG score or experiencing a skin rash after taking icotinib hydrochloride would achieve better efficacy.

title: [Clinical observation of icotinib hydrochloride in first-line therapy for pulmonary adenocarcinoma].
abstract: It has been proven that icotinib hydrochloride, as a molecule targeted drug, can be safely and efficiently used to treat advanced non-small cell lung cancer (NSCLC) for second-line or third-line. This research was aimed to investigate the efficacy and toxicity of icotinib hydrochloride as the first-line therapy for pulmonary adenocarcinoma.



Among the 56 patients, the tumor objective response rate (ORR) and disease control rate (DCR) was 46.4% (26/56) and 78.6% (46/56), respectively. Among the 20 patients with EGFR analyses, 18 patients were positive for a mutation, ORR was 66.7% (12/18), DCR was 94.4% (17/18) respectively. The ORR with no history of smoke. EGFR positive mutation and appearance of rash were significantly higher than those with smoker, wild type EGFR, no information about EGFR and no appearance of rash (P<0.05). The most common drug-related adverse events were mild skin rash (28.5%) and diarrhea (12%).



Single agent treatment with icotinib hydrochloride is effective and tolerable in first-line therapy for pulmonary adenocarcinoma, especially with EGFR mutation.

title: Clinical value in treatment with icotinib as first- line therapy in advanced non- small cell lung cancer
abstract: To observe the efficacy,safety in treatment with icotinib as first- line therapy with advanced non-small cell lung cancer(NSCLC).  Twenty- one patients with advanced NSCLC were enrolled in the study. All the patients treated with icotinib 125 mg,po,three times a day. The response rate,clinical symptom and toxicity were observed until progression or unacceptable toxicity.  No patient appeared complete response,nine patients appeared partial response,nine patients appeared stable disease and three patients had progressive disease. The objective response rate was42. 9 %,and the disease control rate was 85. 7 %. Median Time to Progress was 7. 2 months. The main toxicity were skin rash and diarrhea.  Icotinib as first- ling therapy is an effective in the treatmean of advanced non- small cell lung cancer. All of patients are well- tolerated.

title: A pilot study: sequential gemcitabine/cisplatin and icotinib as induction therapy for stage IIB to IIIA non-small-cell lung adenocarcinoma
abstract: BackgroundA phase II clinical trial previously evaluated the sequential administration of erlotinib after chemotherapy for advanced non-small-cell lung cancer (NSCLC). This current pilot study assessed the feasibility of sequential induction therapy in patients with stage IIB to IIIA NSCLC adenocarcinoma.MethodsPatients received gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 on day 1, followed by oral icotinib (125 mg, three times a day) on days 15 to 28. A repeatcomputed tomography(CT) scan evaluated the response to the induction treatment after two 4-week cycles and eligible patients underwent surgical resection. The primary objective was to assess the objective response rate (ORR), while EGFR and KRAS mutations and mRNA and protein expression levels of ERCC1 and RRM1 were analyzed in tumor tissues and blood samples.ResultsEleven patients, most with stage IIIA disease, completed preoperative treatment. Five patients achieved partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (ORR=45%) and six patients underwent resection. Common toxicities included neutropenia, alanine transaminase (ALT) elevation, fatigue, dry skin, rash, nausea, alopecia and anorexia. No serious complications were recorded perioperatively. Three patients had exon 19 deletions and those with EGFR mutations were more likely to achieve a clinical response (P= 0.083). Furthermore, most cases who achieved a clinical response had low levels of ERCC1 expression and high levels of RRM1.ConclusionsTwo cycles of sequentially administered gemcitabine/cisplatin with icotinib as an induction treatment is a feasible and efficacious approach for stage IIB to IIIA NSCLC adenocarcinoma, which provides evidence for the further investigation of these chemotherapeutic and molecularly targeted therapies.

title: Treatment with high-dose icotinib in a lung adenocarcinoma patient with epidermal growth factor receptor mutation
abstract: Epidermal growth factor receptor tyrosine kinase inhibitors have been a preferred selection for NSCLC patients with EGFR mutation as the first line therapy.Icotinib is a small molecular targeted drug which was independently developed in our country.An advanced lung adenocarcinoma patient with EGFR mutation took icotinib at the recommended dose of 125 mg three times per day.The patient's symptoms obviously alleviated 10 days after treatment,and the diffuse micronodular on both lungs began to disappear or diminish 1 month later.The patient continued to take icotinib and was estimated every three months.The tumors in both lungs began to progress slowly after 11 months from the start of the therapy.Then the patient continued to take icotinib for one month and was evaluated again.The lung tumors progressed slowly yet.We increased the dose of icotinib as alternate uses of 125 mg three times a day and 250 mg three times a day.Tumor evaluation was SD at 45 days after dose was increased.

title: Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.
abstract: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment.

title: Network Meta-Analysis of Erlotinib, Gefitinib, Afatinib and Icotinib in Patients with Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations
abstract: Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons.  We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments.  Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib.  The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.