You are here
Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials
Lancet Oncol 2015 http://dx.doi.org/10.1016/S1470-2045(14)71173-8
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.
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 .
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%]).
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.
Patients with lung adenocarcinoma harbouring EGFR mutations are highly responsive to treatment with EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, or afatinib. 1 Findings from seven randomised phase 3 studies done in this genetically selected subset of patients with lung cancer have shown better progression-free survival and responses with gefitinib or erlotinib than with platinum-based chemotherapy.2, 3, 4, 5, 6, 7, and 8However, differences in overall survival were not reported in these studies, irrespective of EGFR mutation type,8, 9, 10, 11, 12, 13, 14, and 15presumably because most patients randomly assigned to first-line chemotherapy were subsequently treated with EGFR tyrosine kinase inhibitors. Findings from a meta-analysis of 13 randomised studies examining first-line gefitinib or erlotinib (monotherapy or combined with chemotherapy) compared with chemotherapy or placebo in patients with EGFR mutation-positive lung cancer showed that overall survival did not differ (hazard ratio [HR] 1·01, 95% CI 0·87–1·18) despite the large progression-free survival advantage among patients receiving EGFR tyrosine kinase inhibitors (HR 0·43, 95% CI 0·38–0·49, p<0·001). 16
Afatinib, a second-generation irreversible tyrosine kinase inhibitor that inhibits signalling from all homodimers and heterodimers formed by ERBB receptor family members (including EGFR, HER2, ERBB3, and ERBB4), has shown clinical activity in patients with EGFR mutation-positive lung adenocarcinoma previously untreated with EGFR tyrosine kinase inhibitors.17, 18, and 19First-line afatinib was compared with standard chemotherapy in two large, randomised phase 3 trials in previously untreated patients with EGFR mutation-positive advanced lung adenocarcinoma.18 and 19These two studies, designed to meet the regulatory requirements of different regions, were nearly identical in design with the exception of the platinum-based comparator regimen: pemetrexed-cisplatin was used in LUX-Lung 3, and gemcitabine-cisplatin in LUX-Lung 6. Findings from both studies showed improved progression-free survival (the primary endpoint), objective responses, and patient-reported outcomes for patients receiving first-line afatinib.18, 19, and 20These studies also demonstrated differences in progression-free survival with afatinib on the basis of EGFR mutation type; progression-free survival was most improved in patients with tumours harbouring exon 19 deletion (del19) followed by the exon 21 substitution (Leu858Arg) mutation.18 and 19
Here, we report mature overall survival results from the individual LUX-Lung 3 and LUX-Lung 6 studies. Additionally, to provide more accurate estimates of the overall effect of afatinib treatment in these patients (particularly in prespecified subgroups), we combined individual patient data from the two studies for an exploratory analysis of overall survival.
Study design and participants
Detailed study designs, inclusion and exclusion criteria, and methods of the primary analyses of both trials have been previously published.18 and 19In brief, each trial was a randomised, open-label, phase 3 study done either globally 18 or in China, South Korea, and Thailand. 19 Eligible patients were aged 18 years or older, had previously untreated stage IIIB or IV lung adenocarcinoma (measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a life expectancy of at least 3 months. In addition, tumour tissue had to be EGFR mutation-positive at screening based on central laboratory analysis of biopsy tissue with a validated test kit (Therascreen EGFR 29; Qiagen, Manchester, UK).
Exclusion criteria included the presence of any other cancer diagnosed within the past 5 years or at screening (other than non-melanomatous skin cancer and in-situ cervical cancer); active brain metastases; pre-existing interstitial lung disease; clinically significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom; history or presence of clinically relevant cardiovascular abnormalities (eg, uncontrolled hypertension, congestive heart failure of New York Heart Association classification of 3, unstable angina, or poorly controlled arrhythmia) or myocardial infarction within 6 months of randomisation; cardiac left ventricular function with resting ejection fraction of less than 50%; active hepatitis B or C infection or known HIV carrier. Additionally, patients were excluded if they had: an absolute neutrophil count less than 1500 cells per μL, platelet count less than 100 000 cells per μL, creatinine clearance less than 60 mL/min or serum creatinine more than 1·5 × upper limit of normal (ULN), bilirubin more than 1·5 × ULN, and aspartate aminotransferase or alanine aminotransferase more than 3 × ULN (if related to liver metastases, >5 × ULN).
Both studies were done in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practice, and the protocols were approved by local ethics committees at each participating centre. Written informed consent was obtained for each patient.
Patients enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364) were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy and stratified by EGFR mutation type (del19vsLeu858Argvsother uncommon mutations) and by ethnic origin (Asianvsnon-Asian; LUX-Lung 3 only); a block size of three was used within each of the strata. Randomisation was done with a validated random-number generating system at Boehringer Ingelheim, verified by a trial-independent statistician, and implemented centrally via an interactive voice-web response system; individuals directly involved in the conduct and analysis of the trials did not have access to the randomisation schedule.
Patients received either continuous oral afatinib (40 mg/day) or up to six cycles of intravenous pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) once every 21 days in LUX-Lung 3 or gemcitabine (1000 mg/m2; days 1 and 8) plus cisplatin (75 mg/m2; day 1) once every 21 days in LUX-Lung 6. Patients receiving afatinib were permitted to increase their dose to 50 mg/day after the first 21 day cycle if they did not have treatment-related adverse events greater than grade 1. Afatinib dose reduction by 10 mg decrements down to 20 mg/day was allowed for treatment-related grade 3 or selected lengthy grade 2 adverse events, as previously described.18 and 19Dose reductions for patients receiving chemotherapy were in accordance with guidance provided in the current summary of product characteristics and institutional guidelines.
Tumour assessments were done by CT or MRI every 6 weeks for the first 48 weeks, and then every 12 weeks thereafter until disease progression or start of new anticancer therapy. Adverse events were categorised and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. After the last scheduled follow-up visit for the primary endpoint, patients were contacted every 2 months to collect information about subsequent therapies and survival until patient death, loss to follow-up, or withdrawal of consent.
In both studies, the primary endpoint was progression-free survival, defined as time from randomisation to progression (as determined by independent review). Key secondary endpoints in both studies were objective response (complete response and partial response), disease control (objective response and stable disease), and overall survival; other secondary endpoints included patient-reported outcomes and safety.
Each study was powered (90%) at a two-sided 5% significance level to detect a progression-free survival improvement from 7 months (combination chemotherapy) to 11 months (afatinib) after a minimum of 217 progression events by independent review, with estimated samples sizes of at least 330 patients for each study.18 and 19Efficacy endpoints were assessed for the intention-to-treat population, including all patients who met eligibility criteria and were randomly assigned to treatment. Safety was assessed for all randomly assigned patients who received at least one dose of study medication.
Primary and key secondary endpoints were analysed following a hierarchical testing strategy to minimise the overall risk of type I error (5%). Overall survival analyses were planned for two timepoints. The first analysis of overall survival was concurrent with the primary analysis of progression-free survival; a Haybittle-Peto stopping boundary was used (p<0·0001) to preserve the overall 5% type I error. The second overall survival analysis was planned after 209 deaths in LUX-Lung 3 and 237 deaths in LUX-Lung 6, when the investigators estimated that the data would be mature. Neither trial was purposefully designed with sufficient power to detect differences in overall survival because none of the previous studies comparing first-line erlotinib or gefitinib with chemotherapy showed benefits in overall survival.8, 9, 10, 11, 12, 13, 14, and 15Similar to the primary analysis of progression-free survival, stratification by EGFR mutation type (del19, Leu858Arg, or other) and ethnic origin (Asianvsnon-Asian; LUX-Lung 3 only) was applied for the overall survival analysis. For each trial, preplanned analyses of subgroups of special interest (sex, age, baseline ECOG performance status, EGFR mutation category [common—ie, del19 and Leu858Arg—and uncommon], smoking history, and ethnic origin [LUX-Lung 3 only]) were also defined. Because these analyses did not form part of the confirmatory analysis strategy, no adjustment for multiplicity was done, and p values are descriptive in nature. We did a post-hoc exploratory analysis of overall survival based on the combined individual patient data from both trials; heterogeneity was evaluated by testing the study-by-treatment interaction.
For each study, we compared overall survival between treatment groups using a stratified log-rank test, adjusting for EGFR mutation type (both trials) and ethnic origin (LUX-Lung 3 only); the combined analysis of overall survival was adjusted by study (LUX-Lung 3 or LUX-Lung 6) and EGFR mutation type. We used Cox proportional hazard models to derive HRs and 95% CIs comparing the two treatment groups, and to examine patient subgroups of interest. The proportional hazards assumption was checked via a test for proportionality 21 along with visual checks of the log-cumulative hazard plots. We used Kaplan-Meier estimates to construct survival curves and calculate median overall survival. Median follow-up was calculated with the reverse Kaplan-Meier method. 22 We did statistical analyses with SAS (version 9.2).
Role of the funding source
Boehringer Ingelheim was responsible for each of the trial designs, managed the clinical trial database, and coordinated the development of the Article. JC-HY, Y-LW, LVS, and the Boehringer Ingelheim study team were responsible for the collection, analysis, and interpretation of the data, and decided on exploratory analyses. JC-HY had full access to the study data and prepared the Article draft, and all authors participated in the Article development and made the final decision to submit the manuscript for publication.
In LUX-Lung 3, 1269 patients were screened between Aug 17, 2009, and Feb 28, 2011, and 345 patients were randomly assigned to study treatment ( figure 1 ). Of these patients, 340 received at least one dose of study medication. In LUX-Lung 6, 910 patients were screened between April 27, 2010, and Nov 16, 2011, and 364 patients were randomly assigned to study treatment ( figure 1 ). Of these patients, 352 received at least one dose of study medication. Reasons for patient ineligibility for randomisation are shown in figure 1 . Reasons for randomly assigned patients not receiving study medication included not meeting eligibility criteria (four [80%] of five patients in LUX-Lung 3; three [25%] of 12 patients in LUX-Lung 6) and refusal to take study medication (one [20%] in LUX-Lung 3; nine [75%] in LUX-Lung 6). All randomly assigned patients were included in the overall survival analyses; randomly assigned patients receiving at least one dose of study medication were included in the safety analyses.
Table 1 shows patient characteristics at baseline. In both studies, most patients were women, never smokers, had stage IV disease, and had an ECOG performance status of 1 ( table 1 ). In LUX-Lung 3, 249 (72%) of 345 patients were Asian. Most patients in each study had tumours harbouring common EGFR mutations (del19 or Leu858Arg); roughly half of patients had EGFR del19-positive tumours ( table 1 ). Because patients with lung adenocarcinoma harbouring uncommon EGFR mutations represent a heterogeneous population with variable responses to treatment, analysis of outcomes in these patients will be reported separately.
|LUX-Lung 3||LUX-Lung 6||Combined analysis|
|Afatinib (n=230)||Cisplatin-pemetrexed (n=115)||Afatinib (n=242)||Cisplatin-gemcitabine (n=122)||Afatinib (n=472)||Chemotherapy (n=237)|
|Men||83 (36%)||38 (33%)||87 (36%)||39 (32%)||170 (36%)||77 (32%)|
|Women||147 (64%)||77 (67%)||155 (64%)||83 (68%)||302 (64%)||160 (68%)|
|Age (years)||62 (28–86)||61 (31–83)||58 (29–79)||58 (27–76)||60 (28–86)||59 (27–83)|
|Asian||166 (72%)||83 (72%)||242 (100%)||122 (100%)||408 (86%)||205 (86%)|
|Non-Asian||64 (28%)||32 (28%)||0||0||64 (14%)||32 (14%)|
|IIIB with pleural effusion||20 (9%)||17 (15%)||16 (7%)||6 (5%)||36 (8%)||23 (10%)|
|IV||210 (91%)||98 (85%)||226 (93%)||116 (95%)||436 (92%)||214 (90%)|
|Baseline ECOG performance status|
|0||92 (40%)||41 (36%)||48 (20%)||41 (34%)||140 (30%)||82 (35%)|
|1||138 (60%)||74 * (64%)||194 (80%)||81 (66%)||332 (70%)||155 * (65%)|
|Common mutations||203 (88%)||104 (90%)||216 (89%)||108 (89%)||419 (89%)||212 (89%)|
|Exon 19 deletion||112 (49%)||57 (50%)||124 (51%)||62 (51%)||236 (50%)||119 (50%)|
|Leu858Arg||91 (40%)||47 (41%)||92 (38%)||46 (38%)||183 (39%)||93 (39%)|
|Uncommon mutations †||27 ‡ (12%)||11 (10%)||26 (11%)||14 (11%)||53 ‡ (11%)||25 (11%)|
|Never||155 (67%)||81 (70%)||181 (75%)||99 (81%)||336 (71%)||180 (76%)|
|Former||70 (30%)||32 (28%)||44 (18%)||13 (11%)||114 (24%)||45 (19%)|
|Current||5 (2%)||2 (2%)||17 (7%)||10 (8%)||22 (5%)||12 (5%)|
* Includes one patient with an ECOG performance status of 2.
† Including Thr790Met, exon 20 insertions, Gly719X (Gly719Ser, Gly719Ala, or Gly719Cys), Ser768Ile, and Leu861Gln, alone or as complex mutations in two or more exons.
‡ Includes one patient with wild-type EGFR who was randomly assigned in error.
Data are n (%) or median (range). ECOG=Eastern Cooperative Oncology Group.
At the data cutoff for this analysis (Nov 14, 2013, for LUX-Lung 3 and Dec 27, 2013, for LUX-Lung 6), the median duration of follow-up was 41 months (IQR 35–44) in LUX-Lung 3 and 33 months (IQR 31–37) in LUX-Lung 6; 213 (62%) patients in LUX-Lung 3 and 246 (68%) patients in LUX-Lung 6 had died. Because 21 (9%) of 230 patients in LUX-Lung 3 and 23 (10%) of 242 patients in LUX-Lung 6 were still receiving afatinib at the data cutoff, follow-up for overall survival and data on subsequent therapies are not final.
Overall survival in both studies did not significantly differ between treatment groups (LUX-Lung 3: HR 0·88, 95% CI 0·66–1·17, p=0·39; LUX-Lung 6: HR 0·93, 95% CI 0·72–1·22, p=0·61; figure 2 ). Likewise, in patients with tumours harbouring common EGFR mutations (del19 and Leu858Arg), overall survival did not differ significantly between treatment groups (LUX-Lung 3: HR 0·78, 95% CI 0·58–1·06, p=0·11; LUX-Lung 6: HR 0·83, 95% CI 0·62–1·09, p=0·18; figure 3 ). However, in subgroup analyses examining different EGFR mutations in both trials, we noted a significant improvement in overall survival with afatinib compared with chemotherapy in patients with tumours harbouring the EGFR del19 mutation (LUX-Lung 3: HR 0·54, 95% CI 0·36–0·79, p=0·0015; LUX-Lung 6: HR 0·64, 95% CI 0·44–0·94, p=0·023; figure 4 ). By contrast, we noted no significant differences in overall survival by treatment group for patients with EGFR Leu858Arg-positive tumours in either LUX-Lung 3 (HR 1·30, 95% CI 0·80–2·11, p=0·29) or LUX-Lung 6 (HR 1·22, 95% CI 0·81–1·83, p=0·34; figure 4 ).
Complete safety analyses—including incidence and severity of adverse events, dose reductions, discontinuations, and fatalities—in both trials have been previously reported (data cutoff for adverse events: Jan 11, 2012, for LUX-Lung 3; Dec 29, 2012, for LUX-Lung 6).18 and 19Briefly, in LUX-Lung 3, the most common treatment-related grade 3 or 4 adverse events were rash or acne (37 [16%] of 229 patients), diarrhoea (33 [14%]), and paronychia (26 [11%]) with afatinib, and neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]), and leucopenia (9 [8%]) with pemetrexed-cisplatin. Treatment-related serious adverse events occurred in 33 (14%) patients in the afatinib group and 16 (14%) patients in the pemetrexed-cisplatin group. In LUX-Lung 6, the most common treatment-related grade 3 or 4 adverse events were rash or acne (35 [15%] of 239 patients), diarrhoea (13 [5%]), and stomatitis or mucositis (13 [5%]) with afatinib, and neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]) with gemcitabine-cisplatin. Treatment-related serious adverse events occurred in 15 (6%) patients in the afatinib group and nine (8%) patients in the gemcitabine-cisplatin group. Patients with disease progression or intolerable adverse events discontinued assigned study medication (first-line afatinib or chemotherapy) and received subsequent standard treatment at their physician's discretion. In LUX-Lung 3, drug-related adverse events leading to treatment discontinuation in more than one patient included diarrhoea (three [1%]), paronychia (two [1%]) and interstitial lung disease (two [1%]) in 229 afatinib-treated patients, and fatigue (three [3%]) in 111 pemetrexed-cisplatin-treated patients. Drug-related adverse events leading to discontinuation in LUX-Lung 6 included rash (five [2%]) in 239 afatinib-treated patients, and vomiting (16 [14%]), nausea (11 [10%]), neutropenia (10 [9%]), leucopenia (eight [7%]), adverse events related to platelet and white blood cell count (five [4%]), anaemia (four [4%]), thrombocytopenia (four [4%]), fatigue (four [4%]), abnormal hepatic function (two [2%]), and renal failure (two [2%]) in 113 gemcitabine-cisplatin-treated patients.
Subsequent treatment regimens for the patients with common EGFR mutations are shown in table 2 . Subsequent treatment with chemotherapy or an EGFR tyrosine kinase inhibitor after first-line therapy was balanced across treatment groups within each study. Among patients who discontinued study medication in LUX-Lung 3, 78 (75%) of 104 chemotherapy-treated patients with tumours harbouring common EGFR mutations subsequently received an EGFR tyrosine kinase inhibitor, and 131 (71%) of 184 afatinib-treated patients received subsequent chemotherapy. Among patients who discontinued study medication in LUX-Lung 6, 61 (56%) of 108 chemotherapy-treated patients and 114 (59%) of 194 afatinib-treated patients received subsequent therapy with EGFR tyrosine kinase inhibitors or chemotherapy, respectively. Additionally, we noted no differences in the proportion of patients receiving subsequent treatment with chemotherapy or an EGFR tyrosine kinase inhibitor after first-line therapy by EGFR mutation type ( table 2 ). Of note, patients randomly assigned to first-line chemotherapy typically received erlotinib or gefitinib as later-line EGFR tyrosine kinase inhibitor treatment because afatinib was not clinically available at the time.
|Afatinib||Cisplatin combination||Afatinib||Cisplatin combination|
|Number of patients||112||57||91||47|
|Discontinued study treatment||100||57||84||47|
|Received subsequent systemic therapy *||76 (76%)||49 (86%)||68 (81%)||39 (83%)|
|Chemotherapy||69 (69%)||29 (51%)||62 (74%)||20 (43%)|
|EGFR TKI therapy||41 (41%)||43 (75%)||40 (48%)||35 (74%)|
|Erlotinib||32 (32%)||27 (47%)||29 (35%)||19 (40%)|
|Gefitinib||14 (14%)||26 (46%)||14 (17%)||18 (38%)|
|Afatinib||1 (1%)||6 (11%)||1 (1%)||1 (2%)|
|AZD9291||1 (1%)||1 (2%)||1 (1%)||0|
|EGFR TKI combinations||2 (2%)||8 (14%)||3 (4%)||3 (6%)|
|Other||2 (2%)||1 (2%)||3 (4%)||1 (2%)|
|Radiotherapy||18 (18%)||13 (23%)||14 (17%)||8 (17%)|
|Number of patients||124||62||92||46|
|Discontinued study treatment, n||110||62||84||46|
|Received subsequent systemic therapy *||79 (72%)||39 (63%)||44 (52%)||31 (67%)|
|Chemotherapy||72 (65%)||16 (26%)||42 (50%)||13 (28%)|
|EGFR TKI therapy||36 (33%)||33 (53%)||14 (17%)||28 (61%)|
|Gefitinib||15 (14%)||19 (31%)||4 (5%)||20 (43%)|
|Erlotinib||15 (14%)||11 (18%)||6 (7%)||11 (24%)|
|Icotinib||8 (7%)||3 (5%)||3 (4%)||0|
|EGFR TKI combinations||4 (4%)||2 (3%)||1 (1%)||1 (2%)|
|Other||2 (2%)||2 (3%)||1 (1%)||2 (4%)|
* Percentages based on the number of patients who discontinued treatment. Collection of data on subsequent therapies is still ongoing.
TKI=tyrosine kinase inhibitor.
We combined individual patient data from LUX-Lung 3 and LUX-Lung 6 for exploratory analyses. Because the two studies had very similar designs and were done simultaneously, heterogeneity in this combined analysis was insignificant (p=0·92). Median overall survival in the combined overall population was not significantly different between treatment groups (HR 0·91, 95% CI 0·75–1·11, p=0·37; figure 2 ). Among patients with tumours harbouring common EGFR mutations, overall survival was significantly improved with afatinib compared with chemotherapy (HR 0·81, 95% CI 0·66–0·99, p=0·037; figure 3 ). Consistent with individual study findings, subgroup analyses suggested that the overall survival benefit of afatinib was driven mainly by patients with EGFR del19-positive tumours (HR 0·59, 95% CI 0·45–0·77, p=0·0001; figure 4 ), whereas in patients with EGFR Leu858Arg-positive tumours, there was no difference between groups (HR 1·25, 95% CI 0·92–1·71, p=0·16; figure 4 ). Of note, HRs favoured afatinib for all but two of the subgroups analysed ( figure 3 ). In the subgroup of non-Asian patients with tumours harbouring common EGFR mutations (n=83) in LUX-Lung 3, median overall survival was 28·1 months (22·1 to not estimable) with afatinib versus 20·7 months (16·7–33·5) with chemotherapy (HR 0·68, 95% CI 0·39–1·20, p=0·18), with a significant improvement in non-Asian patients harbouring EGFR del19-positive tumours (n=46; 33·6 months [24·6 to not estimable]vs20·0 months [11·2–33·5]; HR 0·45, 95% CI 0·21–0·95, p=0·03) but not Leu858Arg-positive tumours (n=37; 19·8 months [14·5–41·8]vs21·2 months [14·2 to not estimable]; HR 1·22, 95% CI 0·50–2·99, p=0·67).
We also did exploratory combined analyses of patients in both trials treated in countries with or without a universal health-care reimbursement policy to examine whether regional and systematic access to subsequent therapies might affect overall survival in these studies. These results are shown in the appendix .
Findings from randomised studies comparing first-line EGFR tyrosine kinase inhibitors with standard chemotherapies suggest that patients with lung adenocarcinoma harbouring EGFR mutations have improved responses, progression-free survival, and quality of life, although no improvements in overall survival have been reported ( panel ).2, 3, 4, 5, 6, 7, 8, 18, and 19To our knowledge, our analysis of these two independent phase 3 studies shows for the first time that first-line afatinib significantly improved overall survival compared with chemotherapy, specifically in patients with lung adenocarcinoma harbouring the EGFR del19 mutation but not in patients with Leu858Arg-positive tumours or in the EGFR mutation-positive patient population overall. Of note, although most patients in LUX-Lung 3 and the entire population of LUX-Lung 6 were Asian, a significant improvement in overall survival with afatinib in the del19 subgroup was also noted in the smaller subpopulation of non-Asian patients in LUX-Lung 3, supporting the applicability of the findings to all patients with EGFR mutation-positive disease, irrespective of ethnic origin.
We did a systematic review of the scientific literature (English only) published up to Sept 30, 2014, using PubMed to identify phase 3, randomised trials assessing first-line EGFR tyrosine kinase inhibitor therapy versus standard platinum-based chemotherapy regimens in previously untreated patients with EGFR mutation-positive advanced lung adenocarcinoma. Using the search terms “phase 3”, “advanced” or “metastatic lung adenocarcinoma”, and “EGFR”, we identified seven trials done with the reversible EGFR tyrosine kinase inhibitors gefitinib (four trials2, 3, 4, 8, 9, 10, 11, 12, and 15) and erlotinib (three trials5, 6, 7, 13, and 14), and two trials done with the second-generation irreversible tyrosine kinase inhibitor afatinib (LUX-Lung 3 and LUX-Lung 618 and 19). In each of these studies, significant improvements in progression-free survival and objective response were reported with EGFR tyrosine kinase inhibitor therapy versus chemotherapy.2, 3, 4, 5, 6, 7, 8, 18, and 19None of the studies were designed to detect a difference in overall survival in the overall population or in EGFR exon 19 deletion (del19) or Leu858Arg mutation subgroups. In this context, overall survival benefit compared with chemotherapy was not reported in the gefitinib or erlotinib studies.8, 9, 10, 11, 12, 13, 14, and 15Only the IPASS, NEJ002, and EURTAC trials examined overall survival with reversible EGFR tyrosine kinase inhibitors specifically in EGFR del19 or Leu858Arg mutation subgroups; no differences in overall survival were reported.9, 10, 11, and 13
Results from LUX-Lung 3 and LUX-Lung 6 previously corroborated the findings of other randomised trials in this setting with regards to understanding of EGFR mutation-positive lung adenocarcinoma and response to EGFR tyrosine kinase inhibitors based on assessments of tumour response and progression-free survival.18 and 19To our knowledge, this is the first time that an overall survival benefit has been demonstrated in patients with tumours that contain the EGFR del19 mutations, although no such benefit was observed in patients with Leu858Arg-positive tumours, or when common EGFR mutations were pooled. This finding suggests that among standard first-line EGFR tyrosine kinase inhibitors, afatinib should be the preferred option for patients with EGFR del19-positive lung adenocarcinoma. The difference in outcomes for patients with EGFR del19 and Leu858Arg-positive disease suggests that these populations should be studied separately in future trials.
EGFR del19 and Leu858Arg mutations make up around 90% of all EGFR mutation-positive lung adenocarcinomas, 23 and are strongly associated with robust responses to EGFR tyrosine kinase inhibitors. 24 Patients with EGFR del19-positive tumours have consistently show improved outcomes with EGFR tyrosine kinase inhibitors compared with patients with Leu858Arg-positive disease.25, 26, 27, and 28The cause of this difference in response to EGFR tyrosine kinase inhibitors by EGFR mutation subtype is not known. Within this context, our analysis now suggests that afatinib significantly improves overall survival compared with chemotherapy among patients with EGFR del19-positive tumours but not for patients with Leu858Arg-positive disease, where clinical benefit of afatinib over chemotherapy was demonstrated in terms of progression-free survival and objective response.18 and 19One should note, however, that although subgroups and their analyses were preplanned, no adjustment for multiplicity was done, thus increasing the chance of a false positive finding.
Previous reports of reversible EGFR tyrosine kinase inhibitors erlotinib and gefitinib have not shown an overall survival benefit compared with chemotherapy in overall study populations or by EGFR mutation type.8, 9, 10, 11, 12, 13, 14, and 15Because EGFR tyrosine kinase inhibitor sensitivity among EGFR-mutant tumours is not adversely affected by chemotherapy pretreatment, 23 any overall survival benefit of first-line EGFR tyrosine kinase inhibitors in these studies was thought to be offset by subsequent treatment with second-line EGFR tyrosine kinase inhibitors after progression on chemotherapy. Because afatinib was not clinically available at the time of the LUX-Lung 3 and LUX-Lung 6 studies, very few patients received afatinib as later-line EGFR tyrosine kinase inhibitor treatment; the majority received erlotinib or gefitinib after chemotherapy. The clinically meaningful difference in median overall survival observed with afatinib compared with chemotherapy in patients with EGFR del19-positive tumours in both studies could be attributed to mechanistic differences between the irreversible ERBB family blocker afatinib and first-generation reversible EGFR tyrosine kinase inhibitors. Further, preclinical studies have shown tha tEGFR del19 and Leu858Arg mutants have distinct biological properties that might affect response to different EGFR tyrosine kinase inhibitors.29 and 30
In LUX-Lung 3, the proportion of patients receiving subsequent therapies after study discontinuation was consistent with reports of similar randomised trials.5, 6, 9, 11, and 12In LUX-Lung 6, fewer patients were followed up at the time of data cutoff (ie, the follow-up was shorter), and the proportion of patients receiving subsequent therapies was lower in both groups, potentially resulting from disparities in access to treatments in different countries. Of note, the group of patients who did not receive subsequent treatments in both studies included those who died early, withdrew consent, or were lost to follow-up. Additionally, we noted no differences in the proportions of patients receiving subsequent therapies in the EGFR del19 and Leu858Arg subgroups within each study, suggesting that the overall survival benefit seen with afatinib in del19-positive disease is unlikely to be attributable to follow-up treatment.
In summary, findings from the LUX-Lung 3 and LUX-Lung 6 trials showed no benefit in overall survival for all patients or the Leu858Arg-positive subgroup with the use of afatinib, but the drug did result in significant improvements in overall survival compared with platinum-doublet chemotherapy in patients with EGFR del19-positive lung adenocarcinoma. To the best of our knowledge, these are the only two studies to date to suggest an overall survival advantage for EGFR del19-positive disease treated with a first-line EGFR tyrosine kinase inhibitor. Further, these findings suggest that patients with lung adenocarcinoma harbouring EGFR del19 and Leu858Arg mutations should be stratified and analysed separately in future clinical trials.
JC-HY, Y-LW, KO'B, VH, TM, DM, MSh, and LVS were involved in conception and design of the study. JC-HY was involved in the literature search. MSc was involved in the provision of study material. JC-HY, Y-LW, MSc, MSe, SP, NY, CZ, C-PH, KO'B, JF, SL, YH, SLG, KYL, C-MT, VG, VH, JB, SO, TM, MB, W-CS, KHL, TK, and LVS were involved in patient enrolment, recruitment, and treatment. JC-HY, Y-LW, MSc, MSe, NY, CZ, C-PH, JF, YH, SLG, KYL, C-MT, VG, VH, JB, SO, TM, MB, W-CS, KHL, TK, and VZ were involved in data collection. JC-HY, Y-LW, MSc, MSe, SP, NY, CZ, KO'B, JF, SL, YH, SLG, KYL, C-MT, VH, SO, TM, MB, KHL, DM, MSh, VZ, and LVS were involved in data analysis and interpretation. JC-HY, Y-LW, and LVS were involved in study oversight and supervision. All authors were involved in the drafting and reviewing of the manuscript, and approved the final manuscript for submission.
Declaration of interests
JC-HY has received honoraria for presentations and advisory board participation from Boehringer Ingelheim, AstraZeneca, Roche, Genentech, Pfizer, Novartis, MSD, Merck Serono, Clovis Oncology, and Bayer. MSc has received personal fees from Novartis, AstraZeneca, Pfizer, GlaxoSmithKline, and Lilly, and grants from Novartis and Boehringer Ingelheim. MSe has received honoraria for lectures from Boehringer Ingelheim, Pfizer, Roche, Novartis, BMS, and Eli Lilly. He reports advisory board participation for Boehringer Ingelheim, Roche, Novartis, Pfizer, BMS, Eli Lilly, and Teva. SP has received reimbursement of travel expenses as a non-compensated consultant from Boehringer Ingelheim and Eli Lilly. KO'B has received advisory board and speaker honoraria from Boehringer Ingelheim. SLG has received fees from Boehringer Ingelheim for accommodation and travel to an international congress. VH reports advisory board participation for Boehringer Ingelheim. JB has received honoraria from Boeringher Ingelheim and Roche, and also Novartis for advisory board participation. TM has received personal fees from AstraZeneca, Roche, Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Boehringer Ingelheim, Novartis, GlaxoSmithKline, Clovis Oncology, Amgen, Janssen, BioMarin Pharmaceuticals, and Threshold Pharmaceuticals. MB has received grants from Boehringer Ingelheim and grants and personal fees from Pfizer, and reports non-financial support from Roche. TK has received fees from Boehringer Ingelheim, Eli Lilly, Chugai Pharmaceuticals, AstraZeneca, Pfizer, Taiho Pharmaceuticals, Takeda Pharmaceuticals, Kirin-Kyowa Pharmaceuticals, Shionogi, and BMS for research funding. He also reports advisory board participation for Eli Lilly, AstraZeneca, and Ono Pharmaceuticals. DM is an employee of Boehringer Ingelheim. MSh is an employee of Boehringer Ingelheim. VZ is an employee of Boehringer Ingelheim. LVS reports that her institution received funding from Boehringer Ingelheim to support the study and also reports non-compensated consulting for Boehringer Ingelheim, Clovis Oncology, AstraZeneca, Novartis, Merrimack, Taiho, and Genentech. All other authors declare no competing interests.
We thank the patients, their families, and all of the investigators who participated in these studies. Medical writing assistance was provided by Katie McClendon, of GeoMed, part of KnowledgePoint360, an Ashfield Company, and was supported financially by Boehringer Ingelheim during the preparation of this manuscript. SP acknowledges NHS funding to the Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre.
- 1 T Mok, JJ Yang, KC Lam. Treating patients with EGFR-sensitizing mutations: first line or second line-is there a difference?. J Clin Oncol. 2013;31:1081-1088
- 2 TS Mok, YL Wu, S Thongprasert, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957
- 3 M Maemondo, A Inoue, K Kobayashi, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388
- 4 T Mitsudomi, S Morita, Y Yatabe, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-128
- 5 R Rosell, E Carcereny, R Gervais, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239-246
- 6 C Zhou, YL Wu, G Chen, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735-742
- 7 Y-L Wu, C-K Liam, C Zhou, et al. First-line erlotinib versus cisplatin/gemcitabine (GP) in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC): Interim analyses from the Phase 3, open-label, ENSURE study. J Thorac Oncol. 2013;8:S603 (abstr).
- 8 JY Han, K Park, SW Kim, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30:1122-1128
- 9 M Fukuoka, YL Wu, S Thongprasert, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29:2866-2874
- 10 J Yang, YL Wu, S Saijo, et al. Efficacy outcomes in first-line treatment of advanced NSCLC with gefitinib (G) vs carboplatin/paclitaxel (C/P) by epidermal growth factor receptor (EGFR) gene-copy number score and by most common EGFR mutation subtypes—exploratory data from IPASS. Eur J Cancer. 2011;47:S633 (abstr).
- 11 A Inoue, K Kobayashi, M Maemondo, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24:54-59
- 12 T Mitsudomi, S Morita, Y Yatabe, et al. Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol. 2012;30(suppl):7521 (abstr).
- 13 TARCEVA (erlotinib) tablets, for oral use [prescribing information] 2014. http://www.gene.com/download/pdf/tarceva_prescribing.pdf (accessed Aug 14, 2014).
- 14 C Zhou, YL Wu, X Liu, et al. Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2012;30(suppl):7520 (abstr).
- 15 H Yoshioka, T Mitsudomi, S Morita, et al. Final overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol. 2014;32(suppl):8117 (abstr).
- 16 CK Lee, C Brown, RJ Gralla, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst. 2013;105:595-605
- 17 JC Yang, JY Shih, WC Su, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012;13:539-548
- 18 LV Sequist, JC Yang, N Yamamoto, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334
- 19 YL Wu, C Zhou, CP Hu, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213-222
- 20 JC Yang, V Hirsh, M Schuler, et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3342-3350
- 21 D Collett. Modelling Survival Data in Medical Research Second Edition (Chapman & Hall/CRC CRC Press LLC, USA, 2003)
- 22 JJ Shuster. Median follow-up in clinical trials. J Clin Oncol. 1991;9:191-192
- 23 R Rosell, T Moran, C Queralt, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958-967
- 24 SV Sharma, DW Bell, J Settleman, DA Haber. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7:169-181
- 25 DM Jackman, BY Yeap, LV Sequist, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:3908-3914
- 26 DM Jackman, VA Miller, LA Cioffredi, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15:5267-5273
- 27 GJ Riely, W Pao, D Pham, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:839-844
- 28 PN Ding, R Gralla, A Inoue, et al. Exon 19 deletions, smoking history and gender as additional predictive factors for treatment benefit with EGFR tyrosine kinase inhibitors in patients harbouring activating EGFR mutations: a meta-analysis of 1432 patients in six randomised trials. J Thorac Oncol. 2013;8 P1.11-003 (abstr).
- 29 T Okabe, I Okamoto, K Tamura, et al. Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res. 2007;67:2046-2053
- 30 JQ Zhu, WZ Zhong, GC Zhang, et al. Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals. Cancer Lett. 2008;265:307-317
a National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan
b Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
c West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
d Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, and University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
e Royal Marsden Hospital, London, UK
f Wakayama Medical University, Wakayama, Japan
g Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
h Xiangya Hospital, Central South University, Changsha, China
i Princess Alexandra Hospital and Queensland University of Technology, Australia
j Jiangsu Province Cancer Hospital, Nanjing, Jiangsu, China
k Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
l Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan Province, China
m Prince of Songkla University, Songkhla, Thailand
n Department of Internal Medicine, Konkuk University Medical Center, Seoul, South Korea
o Taipei Veterans General Hospital, Taipei, Taiwan
p FSBI “N N Blokhin Russian Cancer Research Centre”, Russian Academy of Medical Sciences, Moscow, Russia
q McGill University, Montreal, Canada
r Institut de Cancérologie de l'Ouest-site René Gauducheau, Nantes, France
s Pavlov State Medical University, St Petersburg, Russia
t State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, China
u Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
v National Cheng Kung University Hospital, Tainan, Taiwan
w Chungbuk National University Hospital, Cheongju, South Korea
x Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan
y Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK
z Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
* Correspondence to: Prof James Chih-Hsin Yang, National Taiwan University Hospital, Taipei 100, Taiwan
† Contributed equally
© 2015 Elsevier Ltd, All rights reserved.
T: +44 (0)20 7424 4422
F: +44 (0)20 7424 4433
The Lancet Oncology is a monthly subscription journal. For further information on how to subscribe please contact our Subscription Department
T: +44 (0) 1865 843077
F: +44 (0) 1865 843970
T: +1 (800) 462 6198
F: +1 (800) 327 9021
Elsevier España, S.L.U.
(A member of Elsevier)
Josep Tarradellas, 20-30, 1ª pl.
Tel. 93 2000711
Fax 93 2091136
This e-print is distributed with the support of Boehringer Ingelheim.
© 2015 Elsevier Ltd. All rights reserved. This journal and the individual contributions contained in it are protected under copyright by Elsevier Ltd, and the following terms and conditions apply to their use.
Publication information The Lancet Oncology (ISSN 1470-2045) is published monthly by Elsevier (The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK). Periodicals postage paid at Rahway, NJ, USA. POSTMASTER: send address corrections to The Lancet Oncology c/o Mercury International, 365 Blair Road, Avenel, NJ 07001, USA.
Photocopying Single photocopies of single articles may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier Global Rights Department, The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK, tel: +1 215 239 3804 or +44 (0)1865 843830, fax: +44 (0)1865 853333, email firstname.lastname@example.org In the USA, users may clear permissions and make payments through the Copyright Clearance Center Inc, 222 Rosewood Drive, Danvers, MA 01923, USA; tel: +1 (978) 7508400, fax: +1 (978) 646-8600. Other countries may have a local reprographic rights agency for payments.
Derivative works Subscribers may reproduce tables of contents or prepare lists of articles including abstracts for internal circulation within their institutions. Permission of the Publisher is required for resale or distribution outside the institution.
Permission of the Publisher is required for all other derivative works, including compilations and translations.
Electronic storage or usage Permission of the Publisher is required to store or use electronically any material contained in this journal, including any article or part of an article. Except as outlined above, no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier Health Sciences Rights Department, at the mail, fax, and email addresses noted above.
Notice No responsibility is assumed by Elsevier for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. The views expressed in this journal are not necessarily those of the Editor, the International Advisory Board, or Elsevier Ltd.