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Introduction: In LUX-Lung 3 and LUX-Lung 6, afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with tumors harboring common epidermal growth factor receptor (EGFR) mutations (Del19/L858R) and significantly improved overall survival (OS) in patients with tumors harboring Del19 mutations. Patient-reported outcomes stratified by EGFR mutation type are reported., Patients and Methods: Lung cancer symptoms and health-related quality of life (QoL) were assessed every 21 days until progression using the EORTC Quality of Life Core Questionnaire C30 and its lung cancer-specific module, LC13. Analyses of cough, dyspnea, and pain were prespecified and included analysis of percentage of patients who improved on therapy, time to deterioration of symptoms, and change over time. Global health status (GHS)/QoL was also assessed. Analyses were conducted for all patients with tumors harboring Del19 or L858R mutations and were exploratory., Results: Compared with chemotherapy, afatinib more commonly improved symptoms of, delayed time to deterioration for, and was associated with better mean scores over time for cough and dyspnea in patients with Del19 or L858R mutations. All three prespecified analyses of pain showed a trend favoring afatinib over chemotherapy. In both Del19 and L858R mutations, afatinib was also associated with improvements in GHS/QoL. Longitudinal analyses demonstrated statistically significant improvements in GHS/QoL for afatinib over chemotherapy for patients with tumors harboring Del19 mutations or L858R mutations., Conclusions: These exploratory analyses suggest first-line afatinib improved lung cancer-related symptoms and GHS/QoL compared with chemotherapy in patients with non-small-cell lung cancer with tumors harboring common EGFR mutations, with benefits in both Del19 and L858R patients. When considered with OS (Del19 patients only) and PFS benefits, these findings substantiate the value of using afatinib over chemotherapy in these patient groups.

Background: We performed an individual patient data meta-analysis to examine the impact of first-generation epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor (TKI) therapy on overall survival (OS) in advanced non-small cell lung cancer (NSCLC)., Methods: Data from trials comparing EGFR-TKI against chemotherapy in exon 19 deletion (del19) or exon 21 L858R (L858R) EGFR mutations patients were used. We performed Cox regression to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). Impact of postprogression therapies was examined in exploratory analyses. All statistical tests were two-sided., Results: Six eligible trials (gefitinib = 3, erlotinib = 3) included 1231 patients; 632 received EGFR-TKI and 599 received chemotherapy. At a median 35.0 months follow-up, there were 780 deaths and 1004 progressions. There was no difference in OS between EGFR-TKI and chemotherapy (HR = 1.01, 95% CI = 0.88 to 1.17, P =  .84). There was also no difference in OS for Del19 (n = 682, HR = 0.96, 95% CI = 0.79 to 1.16, P =  .68) and L858R (n = 540, HR = 1.06, 95% CI = 0.86 to 1.32, P =  .59) subgroups ( P interaction = .47), or according to smoking status, sex, performance status, age, ethnicity, or histology. However, EGFR-TKI statistically significantly prolonged progression-free survival (PFS) overall (HR = 0.37, 95% CI = 0.32 to 0.42, P <  .001) and in all subgroups. Following progression, 73.8% from the chemotherapy arm received EGFR-TKI, and 65.9% from the EGFR-TKI arm received chemotherapy. Nine percent from the EGFR-TKI arm received no further treatment vs 0.6% from the chemotherapy arm. Following disease progression, patients randomly assigned to EGFR-TKI had shorter OS than those randomly assigned to chemotherapy (12.8 months, 95% CI = 11.4 to 14.3, vs 19.8 months, 95% CI = 17.6 to 21.7)., Conclusions: Despite statistically significant PFS benefit, there is no relative OS advantage with frontline gefitinib or erlotinib vs chemotherapy in EGFR -mutated NSCLC. This finding is likely due to the high rate of crossover at progression., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data., Patients and Methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases., Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib., Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib., Clinicaltrials.gov Identifier: NCT01466660., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials., Patients and Methods: Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not., Results: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}., Conclusions: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy., Clinical Trial Registration: Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting., Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660., Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure., Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population., Funding: Boehringer Ingelheim., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Metastatic spread to the brain is common in patients with non-small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article., Methods: For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81)., Results: In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports., Conclusions: These findings lend support to the clinical activity of afatinib in EGFR mutation-positive patients with NSCLC and asymptomatic brain metastases., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials., Methods: Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393., Findings: Median follow-up in LUX-Lung 3 was 41 months (IQR 35-44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31-37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28.2 months (95% CI 24.6-33.6) in the afatinib group and 28.2 months (20.7-33.2) in the pemetrexed-cisplatin group (HR 0.88, 95% CI 0.66-1.17, p=0.39). In LUX-Lung 6, median overall survival was 23.1 months (95% CI 20.4-27.3) in the afatinib group and 23.5 months (18.0-25.6) in the gemcitabine-cisplatin group (HR 0.93, 95% CI 0.72-1.22, p=0.61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33.3 months (95% CI 26.8-41.5) in the afatinib group versus 21.1 months (16.3-30.7) in the chemotherapy group (HR 0.54, 95% CI 0.36-0.79, p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI 24.2-35.3) versus 18.4 months (14.6-25.6), respectively (HR 0.64, 95% CI 0.44-0.94, p=0.023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 months (24.3-not estimable) in the chemotherapy group (HR 1.30, 95% CI 0.80-2.11, p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI 17.0-22.1) versus 24.3 months (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). In both trials, the most common afatinib-related grade 3-4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3-4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3-4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%])., Interpretation: Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials., Funding: Boehringer Ingelheim., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study., Methods: In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554., Findings: Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib., Interpretation: Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations., Funding: Pfizer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: In the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population., Methods: In this open-label, randomised, phase 3 trial, eligible patients were ⩾18 years, chemonaïve, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500 mg/m(2)) plus cisplatin (75mg/m(2)) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250 mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874., Findings: Between 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N=114) and gefitinib monotherapy (N=118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p=0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63-1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p=0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3-4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p=0.002)., Interpretation: In the intention-to-treat (ITT) population, PFS was not significantly different. In the biomarker-assessable population, front-line EGFR tyrosine kinase inhibitor monotherapy was not efficacious in patients with wild-type EGFR. Identification of EGFR mutation status is key in the management of advanced non-squamous non-small cell lung cancer., Funding: Eli Lilly and Company., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA)., Materials and Methods: A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods., Results: The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eight trials performed in an EGFR mutation-positive population. The estimated PFS HR (95% credible interval, CrI) for afatinib compared with gefitinib was 0.70 (0.40-1.16) and compared with erlotinib was 0.86 (0.50-1.50) in the total population. The estimated probability of being best for afatinib over all other treatments for PFS was 70% versus 27% for erlotinib and 3% for gefitinib; the estimated probability of chemotherapy being the best treatment was 0%. Estimated HR (95% CrI) in patients with common mutations was 0.73 (0.42-1.24) for afatinib compared with erlotinib and 0.60 (0.34-0.99) for afatinib compared with gefitinib. OS findings were not significantly different between treatments., Conclusions: In the absence of direct head-to-head trial data comparing efficacy between the three EGFR TKIs, our analysis suggests that afatinib is a viable treatment alternative to erlotinib or gefitinib in terms of PFS. A direct trial-based comparison of the efficacy of these agents is warranted to clarify their relative benefits., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies., Patients and Methods: Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR)., Results: One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin., Conclusion: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS)., Patients and Methods: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs)., Results: A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain., Conclusion: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC., (Copyright © 2012. Published by Elsevier Inc.)

Aim: In the IRESSA Pan-Asia Study (IPASS), 1217 patients in East Asia with pulmonary adenocarcinoma who were never-smokers or ex/light-smokers received first-line gefitinib (250 mg/day) or carboplatin/paclitaxel (area under the curve 5/6; 200 mg/m(2) ). Efficacy analyses were pre-planned in patients in China., Methods: In China, 372 patients (30.6% of the overall group) were randomized. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), health-related quality of life (HRQoL), symptom improvement, safety and tolerability., Results: For patients in China, PFS did not significantly differ from the overall IPASS population (interaction test P= 0.427). PFS was numerically longer (hazard ratio [HR] 0.79; 95% CI 0.62-1.01; P= 0.065; median PFS 6.8 months for both treatments) and ORR significantly higher (ORR 44.6 vs 29.8%; odds ratio 1.88; 95% CI 1.22-2.89; P= 0.004) for gefitinib than carboplatin/paclitaxel. OS (mature data) was similar for both treatments (HR 0.92; 95% CI 0.73-1.17; P= 0.511; median OS gefitinib 18.1 months vs 18.3 months carboplatin/paclitaxel). HRQoL improvement rates favored gefitinib; symptom improvement rates were similar for both treatments. Gefitinib had a more favorable tolerability profile than carboplatin/paclitaxel. Efficacy by epidermal growth factor receptor biomarker status (exploratory analyses) was difficult to interpret due to low patient numbers with known biomarker status., Conclusion: For the Chinese subgroup of IPASS, gefitinib demonstrated improved PFS and ORR, similar OS, higher HRQoL, similar symptom improvement rates and a more favorable tolerability profile than carboplatin/paclitaxel, generally consistent with the overall IPASS population., (© 2012 Wiley Publishing Asia Pty Ltd.)

Background: Epidermal growth factor receptor (EGFR) testing and first-line therapy with gefitinib for patients with activating mutations is quickly becoming the standard option for the treatment of advanced lung adenocarcinoma. Yet, to date, little is known about the cost-effectiveness of this approach., Methods: A decision-analytic model was developed to determine the cost-effectiveness of EGFR testing and first-line treatment with gefitinib for those patients who harbor activating mutations versus standard care, which includes first-line treatment with chemotherapy followed by gefitinib as second-line treatment. The model uses clinical and outcomes data from randomized clinical trials and societal costs from Singapore cancer centers. Health effects were expressed as quality-adjusted life-years. All costs and cost-effectiveness ratios were expressed in 2010 Singapore dollars. Sensitivity and different scenarios analyses were conducted., Results: EGFR testing and first-line treatment with gefitinib is a dominant strategy (with lower costs and greater effectiveness) compared with standard care. Because the primary savings result from not providing gefitinib to those who are not likely to benefit, this finding holds regardless of the prevalence of activating mutations. In a secondary analysis, first-line treatment with gefitinib was also dominant when compared with first-line chemotherapy in patients with activating EGFR mutations., Conclusions: This strategy can be considered a new standard of care and should be of great interest for health care payers and decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs., (Copyright © 2011 American Cancer Society.)

Randomized trials comparing gefitinib with chemotherapy as first-line treatment in patients with EGFR mutated advanced NSCLC support gefitinib as a new, highly effective treatment option in this setting. However, its use in clinical practice has several relevant implications and open issues. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures. Every effort should be made in order to obtain sufficient tissue. If a clinical enrichment has to be performed for selecting patients to test for EGFR mutation, a reasonable proposal is to test all non-squamous tumors, and patients with squamous tumors only if never smokers. In patients with EGFR mutated tumor, one major issue is the decision about immediate use of gefitinib as first-line, or after failure of standard chemotherapy. First-line gefitinib, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life, and its administration as first-line warrants that all patients have the chance of receiving an EGFR inhibitor. Evidence about the efficacy of erlotinib in the same setting will be soon available, however, at the moment, there are no direct comparisons between gefitinib and erlotinib in EGFR mutated patients. Treatment with gefitinib is usually well tolerated. Typical side effects in most cases are of mild to moderate intensity, and usually manageable with temporary interruption of treatment. When indicated gefitinib appears feasible also in special populations, like elderly or unfit patients, characterized by a significantly poorer risk/benefit ratio with standard chemotherapy. Personalized medicine for patients with lung cancer is now a reality, and patients with EGFR mutation should be treated with first-line EGFR tyrosine kinase inhibitor., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Gefitinib is a small molecule tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR). Since 2004, it was clear that a substantial proportion of non-small-cell lung cancers (NSCLC) obtaining objective response when treated with gefitinib harbour activating mutations in the EGFR gene. Consequently, EGFR mutation has been widely studied, together with other molecular characteristics, as a potential predictive factor for gefitinib efficacy. As of August 2010, four East Asian randomized phase III trials comparing gefitinib to platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) eligible for first-line treatment have been reported or published. Two of these trials were conducted without a molecular selection in patients with clinical characteristics (adenocarcinoma histology, never or light smoking) characterized by higher prevalence of EGFR mutation. In patients selected for the presence of tumor harbouring EGFR mutation, the administration of first-line gefitinib, as compared to standard chemotherapy, was associated with longer progression-free survival, higher objective response rate, a more favourable toxicity profile and better quality of life. The relevant improvement in progression-free survival with first-line administration of gefitinib has been confirmed in the other two randomized trials, dedicated to cases with EGFR mutation. In July 2009, European Medicines Agency granted marketing authorization for gefitinib for the treatment of locally advanced or metastatic NSCLC with sensitizing mutations of the EGFR gene, across all lines of therapy. Gefitinib currently represents the best first-line treatment option for this molecularly selected subgroup of patients., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Importance of the Field: Erlotinib, a potent inhibitor of EGFR activity, is approved as a monotherapy for the treatment of advanced NSCLC and in combination with gemcitabine for advanced pancreatic cancer. The oral administration and manageable toxicity of erlotinib, along with its similar efficacy to chemotherapy, make it an important option as either maintenance therapy or in second-/third-line for patients with NSCLC who have previously received first-line chemotherapy. It is also an emerging option in other treatment settings in NSCLC., Areas Covered in This Review: This review summarizes safety data from major clinical trials of erlotinib in patients with advanced NSCLC, as well as post-marketing data obtained in the 5 years since this drug was first approved., What the Reader Will Gain: An understanding of the common toxicities expected with erlotinib in patients with advanced NSCLC., Take Home Message: Erlotinib is a well-tolerated treatment option for patients with advanced NSCLC. The main adverse events of rash and diarrhea are typically mild or moderate in severity, and rarely lead to treatment withdrawal. When necessary, rash and diarrhea can be easily managed prophylactically, by active intervention or through dose reduction.

Introduction: Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor that significantly increases survival for patients with previously treated advanced non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be particularly effective in Asian patients and may have a distinct safety profile in this population compared with non-Asian patients. We report safety and efficacy data from a subpopulation of East/South-East (E/SE) Asian patients enrolled in a global, open-label, phase IV trial of erlotinib (Tarceva Lung Cancer Survival Treatment study)., Methods: Patients who had previously failed on chemotherapy or radiotherapy, or were unsuitable for these treatments, were treated with oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity., Results: Best response data were available for 1118 E/SE Asian and 4276 non-E/SE Asian patients. The overall response rates were 27% versus 10%, respectively (p < 0.0001). The disease control rates were 78% versus 66%, respectively (p < 0.0001). Survival data were available for 1242 E/SE Asian and 5338 non-E/SE Asian patients. The median progression-free survival times were 5.78 months versus 2.92 months, respectively (hazard ratio = 0.66, p < 0.0001). The median overall survival times were 14.7 months versus 6.8 months, respectively (hazard ratio = 0.57, p < 0.0001). One-year survival rates were 58.3% and 32.7%, respectively. Safety data were available for 1242 E/SE Asian patients. Seventeen percent of these patients experienced one or more erlotinib-related adverse event (AE) (other than the most frequently occurring AEs prespecified in the protocol) and 2% experienced an erlotinib-related serious AE. Dose reductions were reported for 171 (14%) patients., Conclusion: Erlotinib is an effective and well-tolerated treatment for Asian patients with advanced non-small cell lung cancer.

PURPOSE In the phase III INTEREST trial, 1,466 pretreated patients with advanced non-small cell lung cancer (NSCLC) were randomly assigned to receive gefitinib or docetaxel. As a preplanned analysis, we prospectively analyzed available tumor biopsies to investigate the relationship between biomarkers and clinical outcomes. METHODS Biomarkers included epidermal growth factor receptor (EGFR) copy number by fluorescent in situ hybridization (374 assessable samples), EGFR protein expression by immunohistochemistry (n = 380), and EGFR (n = 297) and KRAS (n = 275) mutations. Results For all biomarker subgroups analyzed, survival was similar for gefitinib and docetaxel, with no statistically significant differences between treatments and no significant treatment by biomarker status interaction tests. EGFR mutation-positive patients had longer progression-free survival (PFS; hazard ratio [HR], 0.16; 95% CI, 0.05 to 0.49; P = .001) and higher objective response rate (ORR; 42.1% v 21.1%; P = .04), and patients with high EGFR copy number had higher ORR (13.0% v 7.4%; P = .04) with gefitinib versus docetaxel. CONCLUSION These biomarkers do not appear to be predictive factors for differential survival between gefitinib and docetaxel in this setting of previously treated patients; however, subsequent treatments may have influenced the survival results. For secondary end points of PFS and ORR, some advantages for gefitinib over docetaxel were seen in EGFR mutation-positive and high EGFR copy number patients. There was no statistically significant difference between gefitinib and docetaxel in biomarker-negative patients. This suggests gefitinib can provide similar overall survival to docetaxel in patients across a broad range of clinical subgroups and that EGFR biomarkers such as mutation status may additionally identify which patients are likely to gain greatest PFS and ORR benefit from gefitinib.

Background: Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy., Methods: We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (>/=one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m(2) intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00076388., Findings: 1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio [HR] 1.020, 96% CI 0.905-1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1.09, 95% CI 0.78-1.51; p=0.62; median survival 8.4 vs 7.5 months). In the gefitinib group, the most common adverse events were rash or acne (360 [49%] vs 73 [10%]) and diarrhoea (255 [35%] vs 177 [25%]); whereas in the docetaxel group, neutropenia (35 [5%] vs 514 [74%]), asthenic disorders (182 [25%] vs 334 [47%]), and alopecia (23 [3%] vs 254 [36%]) were most common., Interpretation: INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer.

Background: The epidermal growth factor receptor (EGFR) is commonly overexpressed in nasopharyngeal carcinoma (NPC) and gefitinib inhibits NPC growth in vitro., Method: Patients who progressed after prior platinum-based chemotherapy for recurrent NPC were given gefitinib orally at 500 mg/day at a 28-day cycle. Plasma Epstein-Barr virus (pEBV) DNA levels were obtained at specific intervals., Results: Sixteen patients enrolled and 15 were evaluable for response. The median age was 49 years (range 34-64 years), and most patients were males with metastatic NPC. No objective response was seen and three patients had stable disease (SD) for 2.8 to 8.5 months. Radiological progression of disease coincided with rising levels of pEBV DNA in most patients, while the level of a patient with the longest duration of SD fell to an undetectable level at study completion. The mean time to progression and overall survival was 2.7 (standard error, SE +/- 0.5 months) and 12 months (SE +/- 1.7 months), respectively. No unexpected drug-related toxicities were seen. The study was prematurely terminated because there was insufficient activity to warrant progression to the second stage of accrual., Conclusion: This study found limited activity of gefitinib in recurrent NPC. Further evaluation of pEBV DNA as a biomarker of response in clinical trials of target-based agents is warranted.

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

Background: Convincing data on epidermal growth factor receptor (EGFR) mutations in Chinese patients with non-small-cell lung cancer (NSCLC) remain limited. We investigated the relevance of demographic characteristics and EGFR mutations, correlations between the efficacy of gefitinib and EGFR mutations in NSCLC, and to identify individuals who would likely benefit from gefitinib., Methods: We conducted a meta-analysis based on updated individual patient data from six medical centers in mainland China. Outcome measures included the EGFR mutation status, demographic characteristics, response, and survival., Results: Among 506 patients with NSCLC who received EGFR mutation analysis, the EGFR mutation rate was 30.04%. Patients with adenocarcinoma had a higher mutation rate than those with non-adenocarcinoma (44.1% vs 9.2%; p < 0.00001). The EGFR mutation rate for smokers was 15.1%, lower than that for non-smokers (45.5%) (p < 0.00001). Male patients had a lower mutation rate than female patients (23.1% vs 42.9%; p < 0.0001). Multivariate analysis showed that "adenocarcinoma" and "non-smoker" were independent predictors of EGFR mutations. In a subgroup of 57 patients with complete treatment data, the response rate to gefitinib in the EGFR mutant group was 60.7%, significantly higher than that in the wild-type EGFR group (17.2%) (odds ratio, 5.78; 95% CI, 1.95-17.13; p = 0.002). "EGFR mutation", "adenocarcinoma," and "non-smoker" were independent predictors of response. Overall survival in the EGFR mutant group and the wild-type group did not differ significantly (hazard ratio, 0.60; 95% CI, 0.32-1.12; p = 0.110). "Adenocarcinoma status" was an independent prognostic factor for survival., Conclusions: In mainland China, "adenocarcinoma" and "non-smoker" are independent predictors for EGFR mutations. Response to gefitinib favors patients with EGFR mutations. The clinical selected populations for gefitinib are non-smokers with adenocarcinoma.

Purpose: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) confer a strong sensitivity to gefitinib, a selective tyrosine kinase inhibitor of EGFR., Experimental Design: We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non-small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non-small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers., Results: Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant)., Conclusions: The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.

Purpose: A multi-centre randomized phase II study of single agent nolatrexed dihydrochloride versus doxorubicin was undertaken in Chinese patients with advanced hepatocellular carcinoma (HCC) to study and compare the clinical efficacy of the two drugs., Methods: Fifty-four patients with clinical or histological diagnosis of HCC were randomized in a 2:1 ratio to receive nolatrexed or doxorubicin. Nolatrexed 725 mg/m(2)/day was given by continuous infusion via a central venous device for 5 days and doxorubicin 60 mg/m(2) was given as a rapid intravenous infusion every 3 weeks., Results: No objective responses were observed in either treatment arm. Two patients in the nolatrexed arm and none in the doxorubicin arm had >50% decline in serum alpha-fetoprotein. The median survival for the patients in the nolatrexed and doxorubicin arms was 139 days and 104 days, respectively. Moderate toxicities including leukopenia, thrombocytopenia, mucositis and skin rash were observed in both treatment arms., Conclusion: Nolatrexed and doxorubicin are minimally active in the treatment of advanced HCC. Given the small sample size, no difference is observed between the two drugs.