Epidermal Growth Factor Receptor Mutation-positive Patients Research Articles

Epidermal Growth Factor Receptor Mutational Status and Brain Metastases in Non-Small-Cell Lung Cancer.

IntroductionEpidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancers (NSCLC) may be more common in patients with brain metastases. Previous studies, however, did not adjust for effects of confounding variables.MethodsThis retrospective study included 1,522 consecutive patients with NSCLC, whose tumors were diagnosed and tested for EGFR mutations at the University of Nebraska Medical Center (Omaha, NE) and Tata Memorial Hospital (Mumbai, India). Multivariate logistic regression was used to identify any association between EGFR status and clinical factors.ResultsEGFR mutations were more common in females than males (38.7% v 24.8%), Asians than whites (31.3% v 13.4%), nonsmokers than smokers (40.2% v 14.6%), alcohol nonconsumers than users (32.4% v 15.8%), adenocarcinoma than other histology types (32.7% v 10.3%), and patients with brain metastases than extracranial or no metastases (39.4% v 29.8% v 15.1%; P < .001 for all comparisons). There was a higher likelihood of an EGFR mutation among patients with brain metastases (odds ratio, 1.8; P < .001). The median overall survival (OS) was 19.8 months. Patients with brain metastases had a shorter median OS (15 v 20.6 months; P = .02). However, in the cohort of EGFR mutation–positive patients, there was no difference in median OS between patients with and without brain metastases (20.8 v 25.1 months; P = .11).ConclusionThere is a nearly two-fold higher incidence of EGFR mutations in NSCLC among patients with brain metastases at diagnosis. EGFR mutations did not predict for outcomes from brain metastases.

A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy

ObjectivesRamucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC. Materials and methodsPatients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10mg/kg or placebo, followed by docetaxel 60mg/m2 (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints. ResultsIn the primary population (N=160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52–6.97] months; n=76) than with placebo-docetaxel (4.21 [2.83–5.62] months; n=81); hazard ratio 0.83 (95% CI 0.59–1.16). Median (95% CI) overall survival was 15.15 (12.45–26.55) months with ramucirumab-docetaxel and 14.65 (11.93–24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56–1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%). ConclusionSecond-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC.

Re-biopsy status among non-small cell lung cancer patients in Japan: A retrospective study

ObjectiveDisease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy. Patients and methodsThis was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed×100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed. ResultsOverall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax. ConclusionsSuccess rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs.

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

BackgroundPatients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs.MethodsThis study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples.ResultsThe ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone.ConclusionsAlthough this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination.Trial registration numberNCT01580735.

Hepatic metastasis is a poor predictive marker for erlotinib in lung adenocarcinoma

Lung cancer is the leading cause of cancer related death worldwide and most of lung cancer patients have had metastases when they are diagnosed. With respect to chemotherapy, target therapy is a more effective and less toxic treatments. The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, are one of the representatives of targeted therapy which have been widely used in first line, maintenance and 2nd/3rd line therapy among advanced non-small cell lung cancer (NSCLC). But those with hepatic metastases may insensitive to EGFR-TKIs due to MET activation by hepatocyte growth factor (HGF).In our retrospective analysis, 164 lung adenocarcinoma patients with known epidermal growth factor receptor (EGFR) mutation status who received the treatment of erlotinib as 2nd/3rd line setting were reviewed. The disease control rate (DCR) in patients without hepatic metastases group was higher than that in patients with hepatic metastases (66.1% vs 54.5%, p<0.001). In EGFR mutation-positive patients, median PFS was significantly longer in patients without hepatic metastases than that in those with hepatic metastases (9.9months 95% CI 7.74–12.06months vs. 7.9months 95% CI 5.88–9.92months; p=0.017). Therefore, we assume that hepatic metastasis may be a poor predictive marker for erlotinib in lung adenocarcinoma.

Prognostic factors analysis in EGFR mutation-positive non-small cell lung cancer with brain metastases treated with whole brain-radiotherapy and EGFR-tyrosine kinase inhibitors.

The survival time of non-small cell lung cancer (NSCLC) patients with brain metastases has been previously reported to be 6.5-10.0 months, even with systematic treatment. Patients that possess a certain epidermal growth factor receptor (EGFR) mutation alongside NSCLC with brain metastases also have a short survival rate, and a reliable prognostic model for these patients demonstrates a strong correlation between the outcome and treatment recommendations. The Cox proportional hazards regression and classification tree models were used to explore the prognostic factors in EGFR mutation-positive NSCLC patients with brain metastases following whole-brain radiation therapy (WBRT) and EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment. A total of 66 EGFR mutation-positive NSCLC patients with brain metastases were retrospectively reviewed. Univariate and multivariate analyses by Cox proportional hazards regression were then performed. The classification tree model was applied in order to identify prognostic groups of the patients. In the survival analysis, age, carcinoembryonic antigen (CEA) and status of the primary tumor were prognostic factors for progression free survival (P=0.006, 0.014 and 0.005, respectively) and overall survival (P=0.009, 0.013 and 0.009, respectively). The classification tree model was subsequently applied, which revealed 3 patient groups with significantly different survival times: Group I, age <65 years and CEA ≤10 µg/ml; Group II, age <65 years and CEA >10 µg/ml or age ≥65 years and CEA ≤10 µg/ml; and Group III, age ≥65 years and CEA >10 µg/ml. The major prognostic predictors for EGFR mutation-positive NSCLC patients with brain metastases following WBRT and EGFR-TKI were age and CEA. In addition, primary tumor control may be important for predicting survival.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Advanced Squamous Cell Lung Cancer

BackgroundThe efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in squamous cell carcinoma (SCC) of the lung remains controversial, and the role of EGFR testing in patients with SCC of the lung remains debatable. Patients and MethodsWe retrospectively identified patients with stage IIIB or IV SCC of the lung who had undergone EGFR testing at Shanghai Chest Hospital from January 2009 to December 2013. ResultsA total of 29 EGFR mutation-positive patients (22 patients had received TKI therapy and 7 had not) and 151 EGFR wild-type patients (27 patients had received TKI therapy and 124 had not) were available for an analysis of efficacy. The EGFR mutation-positive patients had significantly improved overall survival (OS) with EGFR TKI therapy compared with those who had not received EGFR TKIs (18.04 months [95% confidence interval (CI), 13.47-22.61 months] vs 13.18 months [95% CI, 5.22-21.13]; P = .015). Patients with wild-type EGFR did not have an improvement in OS with TKI therapy compared with those who had not received TKIs (14.03 months [95% CI, 11.11-16.9 months] vs. 13.63 months [95% CI, 11.91-15.36]; P = .927). The progression-free survival (PFS) for EGFR mutation-positive and EGFR wild-type patients was 3.94 months (95% CI, 2.73-5.15 months) and 1.94 months (95% CI, 0.89-2.99 months), respectively (P = .004). ConclusionEGFR TKIs could be an option for the treatment of SCC, and EGFR mutation detection can help to select a subgroup of patients who would have the best response to TKIs.

Prognostic impact of initial maximum standardized uptake value of 18F-FDG PET/CT on treatment response in patients with metastatic lung adenocarcinoma treated with erlotinib

PurposeTo investigate whether the initial maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has a prognostic significance in metastatic lung adenocarcinoma.Patients and methodsSixty patients (24 females, mean age: 57.9±12 years) with metastatic stage lung adenocarcinoma who used erlotinib and underwent 18F-FDG PET/CT at the time of diagnosis between May 2010 and May 2014 were enrolled in this retrospective study. The patients were stratified according to the median SUVmax value, which was found as 11. Progression-free survival (PFS) rates for 3, 6, and 12 months were examined for SUVmax values and epidermal growth factor receptor (EGFR) mutation status.ResultsThe number of EGFR-sensitizing mutation positive/negative/unknown was 26/17/17, respectively, and the number of patients using erlotinib at first-line, second-line, and third-line therapy was 15, 31, and 14 consecutively. The PFS rates of EGFR mutation positive, negative, and unknown patients for 3 months were 73.1%, 35.3%, and 41.2% (P=0.026, odds ratio [OR]=4.39; 95% confidence interval [CI]: 1.45–13.26), respectively. The PFS rates of EGFR positive, negative, and unknown patients for 6 months were 50%, 29.4%, and 29.4% (P=0.267, OR: 2.4; 95% CI: 0.82–6.96), respectively. The PFS rates of EGFR positive, negative, and unknown patients for 12 months were 42.3%, 29.4%, 23.5% (P=0.408, OR: 2.0; 95% CI: 0.42–5.26), respectively. Thirty-one of 60 patients had SUVmax values ≤11. The PFS rates for 3, 6, and 12 months were 70.5%/28% (P=0.001, OR=9.0; 95% CI: 2.79–29.04), 61.7%/8% (P<0.001, OR=28.35; 95% CI: 5.5–143), and 52.9%/8% (P<0.001, OR=18.69; 95% CI: 3.76–92.9) for low SUVmax (≤11) group/high SUVmax (>11) group, respectively.ConclusionInitial SUVmax value on 18F-FDG PET/CT is found to be a prognostic factor anticipating the response to erlotinib for 3, 6, and 12-month rates of PFS in both EGFR-sensitizing mutation and wild-type tumor group.

O1-10-3 - Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer

a b s t r a c t Objectives: Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. Materials and methods: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Results: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n = 457) received gefitinib, those in 5 trials (n = 513) received erlotinib, and those in 3 trials (n = 498) received afatinib. Rash and diarrhea of grade ≥3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade ≥3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade ≥3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Conclusion: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.

Genetic polymorphism in the epidermal growth factor receptor gene predicts outcome in advanced non-small cell lung cancer patients treated with erlotinib

Epidermal growth factor receptor (EGFR) mutations are important predictors of treatment response to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, some patients with mutations do not respond and some patients without mutations show response. We therefore need additional biomarkers to improve the selection of these patients for treatment. A promising candidate could be germline genetic variations in the EGFR gene that can alter protein expression or function and may influence the response to TKIs. Thus, the aim of this study was to evaluate the predictive role of genetic variations in the EGFR gene in advanced NSCLC patients treated with a TKI. Genotypes for -216G>T, -191C>A and 181946C>T in the EGFR gene were retrospectively evaluated by DNA sequencing and allele-specific PCR analysis in 331 Caucasian patients with advanced NSCLC. Genotypes were correlated with clinical characteristics, toxicity and outcome. A multivariate analysis was performed using Cox proportional hazards model while adjusting for clinically relevant factors including EGFR mutation status. 181946CT or TT genotypes showed an association with clinical outcome compared with patients with the 181946CC genotype (disease control rate (DCR), 68% versus 52%; P=0.049; progression-free survival (PFS), adjusted hazard ratio (HR)=0.74 (95% confidence interval (CI): 0.55-0.99); overall survival (OS), adjusted HR=0.73 (95% CI: 0.54-0.97)). Subgroup analysis demonstrated that the association may be most relevant in EGFR mutation-positive patients (PFS, adjusted HR=0.43 (95% CI: 0.22-0.82); OS, adjusted HR=0.47 (95% CI: 0.24-0.93)). The 181946C>T polymorphisms in the EGFR gene seems to be a potential predictor of higher DCR, longer PFS and OS in advanced NSCLC patients treated with erlotinib, especially in EGFR mutation-positive patients. Thus, this SNP may be a new potential tool for selection of patients for treatment. Prospective randomized studies are wanted to confirm our data.

Symptom and Quality of Life Improvement in LUX-Lung 6: An Open-Label Phase III Study of Afatinib Versus Cisplatin/Gemcitabine in Asian Patients With EGFR Mutation-Positive Advanced Non–small-cell Lung Cancer

In the phase III, LUX-Lung 6 trial, afatinib prolonged progression-free survival (PFS) versus cisplatin/gemcitabine in Asian patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). This article provides detailed assessments of patient-reported outcomes (PROs), a LUX-Lung 6 secondary end point, and explores the relationship between PFS and health-related quality of life (QoL) in these patients. Patients (n = 364) were randomized (2:1) to oral afatinib (40 mg/day) or up to six cycles of cisplatin/gemcitabine (21-day cycle; cisplatin 75 mg/m(2) [d1]; gemcitabine 1000 mg/m(2) [d1,8]). QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and its lung cancer-specific module. The relationship between PFS (investigator assessment and independent review) and QoL was evaluated using analysis of covariance and a longitudinal model. More patients treated with afatinib versus cisplatin/gemcitabine showed improvements in global health status/QoL (p < 0.0001) and physical (p < 0.0001), role (p = 0.013), and social (p < 0.001) functioning scales. Delayed symptom deterioration and better QoL over time was also observed with afatinib. QoL measured before tumor assessment was considerably poorer for patients with progression than those without progression, with significant differences in mean scores at multiple assessment time points. Results from the longitudinal analysis consistently demonstrated a significant negative impact of progression on QoL (p < 0.0001). Afatinib improved PFS and PROs versus chemotherapy in EGFR mutation-positive NSCLC patients. Progression was associated with statistically significant worsening in QoL measured before tumor assessment, underscoring the value of PFS as a clinically relevant end point.

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients.

Epidermal growth factor receptor (EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors (TKIs) efficacy in non-small cell lung cancer (NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations. A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system (ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS). Of all patients, EGFR mutation rate was 28.6% (60/210) by direct sequencing and 45.2% (95/210) by ARMS (P<0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR (48.0% vs. 80.9%, P=0.004) and shorter median PFS (7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods. Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.

Final Overall Survival Results from a Phase III, Randomized, Placebo-Controlled, Parallel-Group Study of Gefitinib Versus Placebo as Maintenance Therapy in Patients with Locally Advanced or Metastatic Non–Small-Cell Lung Cancer (INFORM; C-TONG 0804)

The results of the Iressa in NSCLC for maintenance study (NCT00770588; C-TONG 0804), which compared gefitinib and placebo as maintenance therapy in patients with advanced non-small-cell lung cancer without disease progression after first-line chemotherapy, were published previously. The objective of this report is to provide a mature analysis of overall survival (OS) for Iressa in NSCLC for maintenance study in intention to treat (ITT) population and in subgroups according to epidermal growth factor receptor (EGFR) mutation status. A total of 296 patients were randomly assigned. EGFR mutations were detected using an amplification mutation refractory system. Seventy-nine patients were assessable for EGFR mutations. OS was analyzed by a Cox proportional hazards model adjusted for the same covariates in ITT population and subgroups according to EGFR mutation status. OS was similar for gefitinib and placebo arm with no significant difference between treatments in ITT population (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.68-1.14; p = 0.335) and in subgroups with wild type EGFR (HR, 1.27; 95% CI, 0.7-2.3; p = 0.431) or unknown EGFR mutations (HR, 0.92; 95% CI, 0.68, 1.25; p = 0.603). In the EGFR mutation-positive subgroup, the gefitinib arm showed a higher OS than the placebo arm (HR, 0.39; 95% CI, 0.15, 0.97; p = 0.036). EGFR mutation was the strongest predictive biomarker for OS benefit of gefitinib as maintenance treatment. The analyses of OS showed that patients achieve a clear and significant survival benefit if they receive EGFR tyrosine kinase inhibitors as maintenance treatment in EGFR mutation-positive patients.

Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer.

Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n=457) received gefitinib, those in 5 trials (n=513) received erlotinib, and those in 3 trials (n=498) received afatinib. Rash and diarrhea of grade ≥3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade ≥3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade ≥3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.

Expression of insulin-like growth factor 1 receptor (IGF-1R) predicts poor responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer patients harboring activating EGFR mutations.

Expression of insulin-like growth factor 1 receptor (IGF-1R) in non-small cell lung cancer (NSCLC) is associated with poor prognosis. The IGF-1R pathway activates downstream targets that bypass dependency in signals from the epidermal growth factor receptor (EGFR), which mediates resistance to EGFR tyrosine kinase inhibitors (TKIs). The aim of the present study was to determine the predictive role of IGF-1R expression in the response to EGFR-TKIs of NSCLC patients harboring activating EGFR mutations. We retrospectively studied 62 NSCLC patients who had activating EGFR mutations and received TKIs. Protein expression of IGF-1R, vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) were measured by immunohistochemical staining. Univariate and multivariate analyses were performed to identify predictive factors associated with the responses to EGFR-TKIs. The relationship of progression-free survival (PFS) with IGF-1R expression and the presence of diabetes mellitus (DM) were examined. Of 62 EGFR mutation positive patients, 26 expressed IGF-1R, and 13 had DM. In the multivariate analysis, young age, squamous cell carcinoma, and IGF-1R expression were independently associated with a shorter PFS after treatment with EGFR-TKIs. Patients expressing IGF-1R showed a significantly shorter PFS in response to EGFR-TKIs compared with those lacking IGF-1R expression (9.1 vs. 20.1 months, p=0.005). The 13 patients with DM were more likely to express IGF-1R (p=0.001) and had shorter PFS times when treated with first-line EGFR-TKIs (7.6 vs. 18.6 months, p=0.005), compared with those without DM. IGF-1R expression was a negative predictive factor for a response to EGFR-TKIs in NSCLC patients harboring activating EGFR mutations. Moreover, patients with DM highly expressed IGF-1R in tumor tissues, which was associated with a poor response to first-line TKI therapy. Further studies aimed at overcoming EGFR-TKI resistance will need to also address IGF-1R pathways.

Intercalated chemotherapy and erlotinib for advanced NSCLC: high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutations.

BackgroundPharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC).Patients and methods.Eligible patients were treatment-naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never-smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance.ResultsFifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation-positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2–3 (11 patients - 21%) and brain metastases (15 patients -28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months.ConclusionsWhile patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations.

Egfr Ca Repeat Polymorphism Predict Clinical Outcome in Egfr Mutation Positive Nsclc Patients Treated with Erlotinib

Aim: Somatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). However, not all patients with EGFR mutations respond to erlotinib and the duration of the response varies markedly between patients. ACA repeat polymorphism in intron 1 of the EGFR gene influences the transcription of the EGFR gene. Here the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib is evaluated. Methods: The number of CA repeats in the EGFR gene was evaluated in 432 advanced NSCLC patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA ≤16 in any allele) or long alleles (CA > 16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based on the somatic EGFR mutation status. Results: We demonstrate a significant better median progression free survival (HR= 0.39 (0.22-0.70); p = 0.002) and overall survival (HR= 0.43, (0.23-0.78); p = 0.006) in EGFR mutation positive patients (N = 62) harboring a short allele versus a long allele (median follow-up time of 52.2 months). The result remained highlysignificant in a multivariate Cox proportional hazards model. This correlation was not seen in EGFR mutation negative patients. Further, there were an association between having a short allele and developing the L585R mutation in exon 21 and between long allele and exon 20 insertions. Conclusions: We demonstrate that in EGFR mutation positive NSCLC patients treated with erlotinib a low number of CA repeats in intron 1 of the EGFR gene is a predictor for longer progression free survival and overall survival. Disclosure: All authors have declared no conflicts of interest.

EGFR CA repeat polymorphism predict clinical outcome in EGFR mutation positive NSCLC patients treated with erlotinib

ObjectivesSomatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). A CA repeat polymorphism in intron 1 of the EGFR gene influences the transcription of the EGFR gene. This study evaluates the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib. Materials and methodsNumber of CA repeats in the EGFR gene was evaluated with PCR-fragment length analysis by capillary electrophoresis in 432 advanced NSCLC patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA≤16 in any allele) or long alleles (CA>16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based on the somatic EGFR mutation status. ResultsIn EGFR mutation positive patients (N=62) we demonstrate a significantly higher median progression free survival (HR=0.39 (0.22–0.70); p=0.002) and overall survival (HR=0.43 (0.23–0.78); p=0.006) in patients also harboring a short CA repeat length vs. a long (median follow-up time of 52.2 months). The result remained highly significant in a multivariate Cox proportional hazards model. This correlation was not seen in EGFR mutation negative patients. ConclusionOur study demonstrate that in EGFR mutation positive NSCLC patients treated with erlotinib a low number of CA repeats in intron 1 of the EGFR gene is a predictor for both longer progression free survival and overall survival.

Impact of the epidermal growth factor receptor mutation status on the post-recurrence survival of patients with surgically resected non-small-cell lung cancer.

The impact of epidermal growth factor receptor (EGFR) status and the use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy have not been well discussed only in recurrent non-small-cell lung cancer (NSCLC). The purpose of this study was to identify the prognostic factors associated with post-recurrence survival after surgical resection of NSCLC in terms of the EGFR mutation status and the use of EGFR-TKI therapy. From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence by the end of 2012. We reviewed the cases of recurrence and analysed the predictors and length of post-recurrence survival. The median post-recurrence survival time and the 5-year survival rate of all patients were 25 months and 20.8%, respectively. A multivariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (PS), brain metastasis, number of sites of recurrence and EGFR mutation status to be independent prognostic factors for post-recurrence survival. Among all cases, the median post-recurrence survival time according to the use of EGFR-TKI therapy was as follows: 49 months in the EGFR mutation-positive patients treated with EGFR-TKI therapy, 20 months in the EGFR wild or unknown cases treated with EGFR-TKI therapy and 17 months in the patients not treated with EGFR-TKI therapy. As to EGFR mutation-positive cases, the patients treated with EGFR-TKIs exhibited significantly longer post-recurrence survival time than the patients treated without EGFR-TKIs (49 vs 12 months). It is essential for recurrent NSCLC patients to be examined for the EGFR mutation status. Patients with a positive EGFR mutation status receive significant benefits from EGFR-TKI therapy.

Epidermal Growth Factor Receptor Mutations in 510 Finnish Non–Small-Cell Lung Cancer Patients

Among the driver gene mutations in non-small-cell lung cancer, mutations in epidermal growth factor receptor (EGFR) are the most important because of their predictive role in selecting patients eligible for targeted therapy. Our aim was to study EGFR mutations in a Finnish non-small-cell lung cancer cohort of 528 patients. Mutation testing was conducted on DNA extracted from paraffin-embedded, formalin-fixed tumor material using the following real-time polymerase chain reaction-based kits: Therascreen EGFR PCR Kit and cobas EGFR Mutation Test. EGFR mutation frequency was 11.4% and all positive cases were adenocarcinomas, of which a majority had an acinar predominant pattern. Mutations were seen significantly more often in females and never-smokers than in males and smokers. The most frequent mutations were L858R in exon 21 and deletions in exon 19. Overall survival of the patients, not treated with EGFR inhibitor, did not differ between EGFR mutation-positive and EGFR mutation-negative patients. EGFR mutation profile in this Finnish non-small-cell lung cancer cohort resembles in many respect with that of other Western European cohorts, even though the overall frequency of mutations is slightly higher. We show the occurrence of EGFR mutations in patients with occupational asbestos exposure and also in those diagnosed with chronic obstructive pulmonary disease who have not been often investigated before.