CONSORT checklist | Study [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 hypotheses | Superiority of gefitinib over carboplatin/paclitaxel | Superiority of gefitinib over cisplatin/docetaxel | Non-inferiority of gefitinib over carboplatin/paclitaxel | Superiority of erlotinib over standard chemotherapy | Superiority of afatinib over cisplatin-pemetrexed | Superiority of erlotinib over standard chemotherapy | Superiority of afatinib over gemcitabine/cisplatin | Superiority of erlotinib over gemcitabine/cisplatin |
3a: Allocation ratio | Two-arm parallel groups | Two-arm parallel groups | Two-arm parallel groups | Two-arm parallel groups | Two-arm parallel groups | Two-arm parallel groups | Two-arm parallel groups | Two-arm parallel groups |
1:1 randomised | 1:1 randomised | 1:1 randomised | 1:1 randomised | 2:1 randomised | 1:1 randomised | 2:1 randomised | 1:1 randomised | |
3b: Important changes after trial commencement | Not reported | Change of inclusion criteria; site for EGFR testing; sample size | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
4a: Eligibility criteria | Stage IIIb/IV | Initially recurrence after surgery (n = 71); amended to stage IIIb/IV (n = 101) | Stage IIIb/IV adenocarcinoma plus BAC | Stage IIIb/IV | Stage IIIb/IV adenocarcinoma | Stage IIIb/IV | Stage IIIb/IV adenocarcinoma | Stage 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 T790M | Del 19 and L8585R | Nonsmokers or former light smokers (no EGFR status required) | Del19 or L858R | EGFR mutation-positive | Del19 or L858R | EGFR mutation-positive | Del19 or L858R | |
ECOG 0-1 | WHO 0–1 | WHO 0–2 | ECOG 0–2 | ECOG 0–1 | ECOG 0–2 | ECOG 0–1 | ECOG 0-2 | |
Age ≤75 years | Age up to 75 years | |||||||
4b: Settings and locations where the data were collected | 43 sites in Japan | 36 sites in Japan | 87 sites in East Asia | 42 sites in Spain, Italy and France | 133 sites in 25 countries globally | 22 sites in China | 36 sites in Asia | 28 sites in Asia |
5: Interventions | 250 mg gefitinib or paclitaxel 200 mg·m-2 + carboplatin AUC6 three times per week | 250 mg gefitinib or cisplatin 80 mg·m-2 + docetaxel 60 mg·m-2 three times per week | 250 mg gefitinib or paclitaxel 200 mg·m-2 + carboplatin AUC5-6 three times per week | 150 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 week | 150 mg erlotinib or carboplatin AUC5 + gemcitabine 1000 mg·m-2 three times a week | 40 mg afatinib or cisplatin 75 mg·m-2 + 1000 mg·m-2 gemcitabine three times per week | 150 mg erlotinib or cisplatin 75 mg·m-2 + gemcitabine 1250 mg·m-2 three times per week |
At least three cycles | 3–6 cycles | Up to 6 cycles | Up to 4 cycles | Up to 6 cycles | Up to 4 cycles | Up to 6 cycles | Up to 4 cycles | |
6a: Pre-specified primary and secondary end-points including assessment | Primary: PFS by two monthly CT | Primary: PFS by 2 monthly CT/MRI | Primary: PFS every 6 weeks | Primary: PFS every 6 weeks by CT | Primary: PFS every 6 weeks by CT/MRI | Primary: PFS every 6 weeks by CT/MRI/bone scan | Primary: PFS every 6 weeks by CT/MRI | Primary: PFS |
Investigator review RECIST 1.0 | Investigator review RECIST | Method and assessment not described RECIST | Investigator review Confirmation by central review board. RECIST 1.0 | Independent central review RECIST 1.1 | Investigator review with input from radiologist RECIST 1.0 | Independent central review RECIST 1.1 | Investigator review with Independent Review Committee assessment for sensitivity analysis [17] | |
Secondary: OS, ORR, QoL, safety | Secondary OS, ORR, DCR, mutation type specific survival, safety | Secondary: OS, ORR, QoL, correlation of efficacy to baseline status of EGFR, safety | Secondary: OS, ORR, EGFR mutation analysis in serum | Secondary: OS, ORR, QoL, PK, safety | Secondary: OS, ORR, TTP, doR, QoL, safety | Secondary: OS, ORR, QoL, safety | Secondary: OS, ORR, safety | |
7a: Sample size | Sample 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 5 | Sample size: 146 to achieve a HR of 0.5 with 90% power to show superiority α 0.05 two-sided; HR amended to 0.48 | With 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-inferiority | Sample size 135 events (174 patients) to show PFS of 10 months versus 6 months with 80% power to show superiority α 0.05 two-sided | Sample 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 level | Sample 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 0.025 | Sample 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% power | Sample size: 217 patients randomised |
7b: Interim analyses | One interim analysis after enrolment of 200 patients resulting in premature closure | Initially planned but not done; prematurely stopped after a DMC recommendation | One 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 trial | One planned interim analysis at 88 events The DMC recommended halting enrolment | No interim analysis | No interim analysis | No interim analysis | One 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 randomisation | Randomisation not described | Central Fax randomisation | Randomisation not described | Computer-generated central randomisation by CRO | Computer-generated central randomisation by IVRS | Central randomisation via telephone or email | Computer-generated central randomisation by IVRS | Not reported |
Strata: sex, stage, site | Strata: site, adjuvant chemotherapy, interval between surgery and recurrence, stage, sex | Dynamic balancing: WHO performance status, smoking status, sex, site | Strata: ECOG performance status and mutation type | Strata: ethnicity, mutation type | Strata: histology, smoking status, mutation type | Strata: mutation type | Strata: ECOG performance status, mutation type, sex, country | |
12a: Statistical methods for primary and secondary outcomes | Kaplan–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% CI | Kaplan–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 ≤0.05 | Cox 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 Young | Kaplan–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 test | Stratified 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 arms | Survival 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 randomisation | Stratified 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 status | Not reported |
12b: Methods for additional analyses including subanalyses | One 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 used | HRs in the overall population and in patient subsets were calculated using the Cox proportional hazards model The Chi-squared test was used to compare proportions | Tests 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 subgroups | A 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 events | NA | NA | NA | NA |
13a: Participant flow for primary outcome | Screened: not reported Enrolled: 230 Excluded: 2 | Screened: 337 Enrolled 118 + 71 (detected at commercial clinical laboratory, not central laboratory) Excluded: 12 | Screened 1329 Enrolled: 1217 Excluded: 0 | Screened: 1227 Enrolled: 174 Excluded: 42 for change in target lesion | Screened: 1269 Enrolled: 345 Excluded: 0 | Screened; 549 Enrolled: 165 Excluded: 11 | Screened: 910 Enrolled 364 Excluded 0 | NA |
13b: Participant flow for losses and exclusions | No protocol violations, six patients were excluded from the PFS analysis | No protocol violations, five randomised patients were excluded from efficacy analyses | No protocol violations | Two 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 2 | Four protocol violations (patients allocated to chemotherapy received an EGFR TKI) were excluded from analyses | No protocol violations | NA |
14a: Recruitment dates | March 2006 to May 2009 | March 2006 to June 2009 | March 2006 to October 2007 | February 2007 to January 2011 | August 2009 to February 2011 | August 2008 to July 2009 | April 2010 to November 2011 | April 2010 to November 2011 |
Median follow-up >17 months | Median (range) follow-up was 81 (74–1253) days | Median follow-up for OS 17 months | Median follow-up 14.4 months for chemotherapy and 18.9 months for erlotinib | Median follow-up 16.4 months | Median follow-up 15.6 months | Median follow-up not reported | Median follow-up 10.3 months for chemotherapy and 11.7 months for erlotinib | |
16: Numbers analysed | 224 for PFS 228 in ITT | 172 | 261 EGFR mutation positive | 173 (131 for change in target lesion) | 345 | 154 | 364 | 217 |
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.