BACKGROUND: Afatinib, an irreversible ErbB-family blocker, has shown preclinical 
activity when tested in EGFR mutant models with mutations that confer resistance 
to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients 
with advanced lung adenocarcinoma with previous treatment failure on EGFR 
tyrosine-kinase inhibitors.
METHODS: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV 
adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) 
performance score of 0-2 who had received one or two previous chemotherapy 
regimens and had disease progression after at least 12 weeks of treatment with 
erlotinib or gefitinib. We used a computer-generated sequence to randomly 
allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all 
patients received best supportive care. Randomisation was done in blocks of 
three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). 
Investigators, patients, and the trial sponsor were masked to treatment 
assignment. The primary endpoint was overall survival (from date of 
randomisation to death), analysed on an intention-to-treat basis. This study is 
registered with ClinicalTrials.gov, number NCT00656136.
FINDINGS: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 
585 of whom were randomly allocated to treatment (390 to afatinib, 195 to 
placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the 
afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 
1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in 
the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo 
group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No 
complete responses to treatment were noted; 29 (7%) patients had a partial 
response in the afatinib group, as did one patient in the placebo group. 
Subsequent cancer treatment was given to 257 (68%) patients in the afatinib 
group and 153 (79%) patients in the placebo group. The most common adverse 
events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] 
were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). 
These events occurred less often in the placebo group (18 [9%] of 195 patients 
had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related 
serious adverse events occurred in 39 (10%) patients in the afatinib group and 
one (<1%) patient in the placebo group. We recorded two possibly 
treatment-related deaths in the afatinib group.
INTERPRETATION: Although we recorded no benefit in terms of overall survival 
with afatinib (which might have been affected by cancer treatments given after 
progression in both groups), our findings for progression-free survival and 
response to treatment suggest that afatinib could be of some benefit to patients 
with advanced lung adenocarcinoma who have failed at least 12 weeks of previous 
EGFR tyrosine-kinase inhibitor treatment.
FUNDING: Boehringer Ingelheim Inc.