Table 3. Qualitative analyses of trials according to the CONSORT criteria
CONSORT checklistStudy [ref.]
NEJ002 [12, 23]WJTOG3405 [13, 25]IPASS# [8, 14]EURTAC [9]LUX-Lung 3 [15]OPTIMAL [10, 11]LUX-Lung 6 [16]ENSURE [17]
2b: Specific objectives or hypothesesSuperiority of gefitinib over carboplatin/paclitaxelSuperiority of gefitinib over cisplatin/docetaxelNon-inferiority of gefitinib over carboplatin/paclitaxelSuperiority of erlotinib over standard chemotherapySuperiority of afatinib over cisplatin-pemetrexedSuperiority of erlotinib over standard chemotherapySuperiority of afatinib over gemcitabine/cisplatinSuperiority of erlotinib over gemcitabine/cisplatin
3a: Allocation ratioTwo-arm parallel groupsTwo-arm parallel groupsTwo-arm parallel groupsTwo-arm parallel groupsTwo-arm parallel groupsTwo-arm parallel groupsTwo-arm parallel groupsTwo-arm parallel groups
1:1 randomised1:1 randomised1:1 randomised1:1 randomised2:1 randomised1:1 randomised2:1 randomised1:1 randomised
3b: Important changes after trial commencementNot reportedChange of inclusion criteria; site for EGFR testing; sample sizeNot reportedNot reportedNot reportedNot reportedNot reportedNot reported
4a: Eligibility criteriaStage IIIb/IVInitially recurrence after surgery (n = 71); amended to stage IIIb/IV (n = 101)Stage IIIb/IV adenocarcinoma plus BACStage IIIb/IVStage IIIb/IV adenocarcinomaStage IIIb/IVStage IIIb/IV adenocarcinomaStage IIIb/IV
Measurable disease (RECIST)Measurable or non-measurable disease (RECIST)Measurable disease (RECIST)Measurable or evaluable disease (Not specified)Measurable disease (RECIST v1.1)Measurable disease (RECIST v1.0)Measurable disease (RECIST v1.1)Measurable disease (not specified)
EGFR mutant and absence of T790MDel 19 and L8585RNonsmokers or former light smokers (no EGFR status required)Del19 or L858REGFR mutation-positiveDel19 or L858REGFR mutation-positiveDel19 or L858R
ECOG 0-1WHO 0–1WHO 0–2ECOG 0–2ECOG 0–1ECOG 0–2ECOG 0–1ECOG 0-2
Age ≤75 yearsAge up to 75 years
4b: Settings and locations where the data were collected43 sites in Japan36 sites in Japan87 sites in East Asia42 sites in Spain, Italy and France133 sites in 25 countries globally22 sites in China36 sites in Asia28 sites in Asia
5: Interventions250 mg gefitinib or paclitaxel 200 mg·m-2 + carboplatin AUC6 three times per week250 mg gefitinib or cisplatin 80 mg·m-2 + docetaxel 60 mg·m-2 three times per week250 mg gefitinib or paclitaxel 200 mg·m-2 + carboplatin AUC5-6 three times per week150 mg erlotinib three times a week or either: cisplatin 75 mg·m-2 + docetaxel 75 mg·m-2; or cisplatin + gemcitabine 1250 mg·m-2; or, for patients ineligible for cisplatin, carboplatin AUC6 + docetaxel or + gemcitabine (1000 mg·m-2 and carboplatin AUC5)40 mg afatinib or cisplatin 75 mg·m-2 + 500 mg·m-2 pemetrexed three times a week150 mg erlotinib or carboplatin AUC5 + gemcitabine 1000 mg·m-2 three times a week40 mg afatinib or cisplatin 75 mg·m-2 + 1000 mg·m-2 gemcitabine three times per week150 mg erlotinib or cisplatin 75 mg·m-2 + gemcitabine 1250 mg·m-2 three times per week
At least three cycles3–6 cyclesUp to 6 cyclesUp to 4 cyclesUp to 6 cyclesUp to 4 cyclesUp to 6 cyclesUp to 4 cycles
6a: Pre-specified primary and secondary end-points including assessmentPrimary: PFS by two monthly CTPrimary: PFS by 2 monthly CT/MRIPrimary: PFS every 6 weeksPrimary: PFS every 6 weeks by CTPrimary: PFS every 6 weeks by CT/MRIPrimary: PFS every 6 weeks by CT/MRI/bone scanPrimary: PFS every 6 weeks by CT/MRIPrimary: PFS
Investigator review RECIST 1.0Investigator review RECISTMethod and assessment not described RECISTInvestigator review Confirmation by central review board. RECIST 1.0Independent central review RECIST 1.1Investigator review with input from radiologist RECIST 1.0Independent central review RECIST 1.1Investigator review with Independent Review Committee assessment for sensitivity analysis [17]
Secondary: OS, ORR, QoL, safetySecondary OS, ORR, DCR, mutation type specific survival, safetySecondary: OS, ORR, QoL, correlation of efficacy to baseline status of EGFR, safetySecondary: OS, ORR, EGFR mutation analysis in serumSecondary: OS, ORR, QoL, PK, safetySecondary: OS, ORR, TTP, doR, QoL, safetySecondary: OS, ORR, QoL, safetySecondary: OS, ORR, safety
7a: Sample sizeSample size: 230 based on a PFS of 9.7 versus 6.7 months to achieve a power of 80% and a two-sided significance level of 5Sample size: 146 to achieve a HR of 0.5 with 90% power to show superiority α 0.05 two-sided; HR amended to 0.48With 944 progression events, the study would have 80% power to demonstrate non-inferiority, with a two-sided 5% probability of an erroneous demonstration of non-inferioritySample size 135 events (174 patients) to show PFS of 10 months versus 6 months with 80% power to show superiority α 0.05 two-sidedSample size: 330 to show a HR of 0.64, equating to an increase in median PFS from an expected 7 months for chemotherapy to 11 months for afatinib to provide 90% power with a two-sided 5% significance levelSample size: 152 patients based on PFS 11 months versus 6 months for a HR of 0.54 with a power of 80% and an α of 0.025Sample size: at least 217 events reported by independent review needed to detect a HR of 0.64 (or median increase in PFS from 7 to 11 months) at two-sided 5% significance level with 90% powerSample size: 217 patients randomised
7b: Interim analysesOne interim analysis after enrolment of 200 patients resulting in premature closureInitially planned but not done; prematurely stopped after a DMC recommendationOne interim analysis was planned The purpose of this analysis was to detect inferiority of gefitinib compared with carboplatin/paclitaxel in terms of PFS, DMC recommended to continue with the trialOne planned interim analysis at 88 events The DMC recommended halting enrolmentNo interim analysisNo interim analysisNo interim analysisOne planned interim analysis was conducted after 73% of PFS events (cut-off July 20, 2012) An additional exploratory updated analysis (cut-off November 19, 2012), included all planned PFS events
8-10: Methods of randomisationRandomisation not describedCentral Fax randomisationRandomisation not describedComputer-generated central randomisation by CROComputer-generated central randomisation by IVRSCentral randomisation via telephone or emailComputer-generated central randomisation by IVRSNot reported
Strata: sex, stage, siteStrata: site, adjuvant chemotherapy, interval between surgery and recurrence, stage, sexDynamic balancing: WHO performance status, smoking status, sex, siteStrata: ECOG performance status and mutation typeStrata: ethnicity, mutation typeStrata: histology, smoking status, mutation typeStrata: mutation typeStrata: ECOG performance status, mutation type, sex, country
12a: Statistical methods for primary and secondary outcomesKaplan–Meier using log-rank test, HR using Cox proportional hazard model ORR and safety were compared between the two groups with Fisher's exact test and the Wilcoxon test, respectively Each analysis was performed with the use of a two-sided, 5% significance level and a 95% CIKaplan–Meier using log-rank test, HR using Cox proportional hazard model The Chi-squared test was used to compare proportions Differences were considered significant at a two-sided p-value of ≤0.05Cox proportional hazards model in the ITT, ORR and QoL were assessed with the use of a logistic regression model with the same covariates as those considered for PFS to calculate ORs and 95% CIs Adverse events were compared with the use of Fisher’s exact test; adjustment for multiple comparisons was performed with the use of the method of Westfall and YoungKaplan–Meier curves using the log-rank test HR (95% CI) by Cox proportional hazards analysis Prespecified adjustment factors included ECOG performance status and type of mutation (exon 19 deletion versus L858R) Response rates were compared between the two groups using the Chi-squared testStratified log-rank test, using the same stratification factors used in randomisation Cox proportional hazard models were used to compare PFS between arms, and Kaplan–Meier estimates were calculated PFS analysis in patients with common EGFR mutations (L858R and exon 19 deletions) was prespecified Logistic regression models were used to compare armsSurvival was estimated with Kaplan-Meier methodology A two-sided log-rank test was used to compare survival between the two treatment groups Exploratory and pre-planned subgroup analyses of PFS were performed with the Cox proportional hazards model and included the stratification factors from randomisationStratified log-rank and Cox proportional hazard for PFS comparisons (ITT for all randomised patients) Prespecified subgroup analyses included sex, age, mutation type, performance status and smoking statusNot reported
12b: Methods for additional analyses including subanalysesOne interim analysis was planned to analyse the primary end-point (significance level, p = 0.003) The Lan–DeMets method was used to adjust for multiple comparisons The O’Brien–Fleming type α-spending function was also usedHRs in the overall population and in patient subsets were calculated using the Cox proportional hazards model The Chi-squared test was used to compare proportionsTests to determine interactions of treatment with covariates were used to identify predictive factors by assessing whether there was a significant difference in the treatment effect for PFS (HR for progression or death) between subgroupsA Lan–DeMets α-spending function with a Pocock stopping boundary was used to maintain the significance level at 5% with a 0.037 significance level at interim and 0.025 for the final analysis based on 135 eventsNANANANA
13a: Participant flow for primary outcomeScreened: not reported Enrolled: 230 Excluded: 2Screened: 337 Enrolled 118 + 71 (detected at commercial clinical laboratory, not central laboratory) Excluded: 12Screened 1329 Enrolled: 1217 Excluded: 0Screened: 1227 Enrolled: 174 Excluded: 42 for change in target lesionScreened: 1269 Enrolled: 345 Excluded: 0Screened; 549 Enrolled: 165 Excluded: 11Screened: 910 Enrolled 364 Excluded 0NA
13b: Participant flow for losses and exclusionsNo protocol violations, six patients were excluded from the PFS analysisNo protocol violations, five randomised patients were excluded from efficacy analysesNo protocol violationsTwo protocol violations: two patients less than stage IIIb in erlotinib arm Not excluded from analyses 1 patient received treatment before randomisation (protocol violation)One protocol violation: ECOG 2Four protocol violations (patients allocated to chemotherapy received an EGFR TKI) were excluded from analysesNo protocol violationsNA
14a: Recruitment datesMarch 2006 to May 2009March 2006 to June 2009March 2006 to October 2007February 2007 to January 2011August 2009 to February 2011August 2008 to July 2009April 2010 to November 2011April 2010 to November 2011
Median follow-up >17 monthsMedian (range) follow-up was 81 (74–1253) daysMedian follow-up for OS 17 monthsMedian follow-up 14.4 months for chemotherapy and 18.9 months for erlotinibMedian follow-up 16.4 monthsMedian follow-up 15.6 monthsMedian follow-up not reportedMedian follow-up 10.3 months for chemotherapy and 11.7 months for erlotinib
16: Numbers analysed224 for PFS 228 in ITT172261 EGFR mutation positive173 (131 for change in target lesion)345154364217
  • CONSORT: Consolidated Standards of Reporting Trials; NEJ002: North East Japan 002; WJTOG: West Japan Thoracic Oncology Group; IPASS: Iressa Pan-Asia Study; EURTAC: European Randomised Trial of Tarceva versus Chemotherapy. RECIST: Response Evaluation Criteria In Solid Tumours; EGFR: epidermal growth factor receptor; ECOG: Eastern Cooperative Oncology Group; AUCn: target area under the free carboplatin plasma concentration versus time curve of n× (glomerular filtration rate + 25) mg·m−2; PFS: progression-free survival; CT: computed tomography; OS: overall survival; ORR: overall response rate; QoL: quality of life; HR: hazard ratio; ITT: intention-to-treat; WHO: World Health Organization; MRI: magnetic resonance imaging; DCR: disease control rate; DMC: data monitoring committee; BAC: bronchoalveolar carcinoma; PK: pharmacokinetics; CRO: contract research organisation; IVRS: contract research organisation; NA: not available; TTP: time to progression; doR: duration of response; TKI: tyrosine kinase inhibitor. #: all patients.