Afatinib versus placebo for patients with advanced, metastatic non-small-cell
lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines
of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.
Author(s): Miller VA(1), Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang
M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang
JC.
Affiliation(s): Author information:
(1)Memorial Sloan-Kettering Cancer Center, New York City, NY, USA; Weill Cornell
Medical College, New York City, NY, USA.
Publication date & source: 2012, Lancet Oncol. , 13(5):528-38
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.
Erratum in
Lancet Oncol. 2012 May;13(5):e186.
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