Lancet Oncol 2012; 13: 528–38 Vincent A Miller, Vera Hirsh, Jacques Cadranel, Yuh-Min Chen, Keunchil Park, Sang-We Kim, Caicun Zhou, Wu-Chou Su, Mengzhao Wang, Yan Sun, Dae Seog Heo, Lucio Crino, Eng-Huat Tan, Tsu-Yi Chao, Mehdi Shahidi, Xiuyu Julie Cong, Robert M Lorence, James Chih-Hsin Yang Journal conference R2 Seon-Hye Kim, Prof. Jae-Heon Jeong

EGFR  a member of the ErbB family of receptors  receptor tyrosine kinase : EGFR(ErbB-1), Her2/c-neu (ErbB-2), Her3(ErbB-3) & Her4 (ErbB-4) *EGFR tyrosine kinase inhibitor  Iressa (gefitinib)  Tarceva (erlotinib)

Advanced lung adenocarcinoma + EGFR mutation (+) - the first-line erlotinib or gefitinib - high objective response rate & long progression-free survival and overall survival  All patients’ treatment eventually fails. - resistance to EGFR tyrosine-kinase inhibitors (TKIs) - characterised by the so-called gatekeeper mutation, T790M

Irreversible ErbB-family blocker : Afatinib : M/C mutations, L858R and deletion-19 & the exon 20 gatekeeper T790M mutation. EVALUATION : to assess its efficacy in patients with advanced lung adenoca. with previous treatment failure on EGFR tyrosine kinase inhibitors.

LUX-lung 1 study Randomized, double-blind, multicenter phase 2b/3 trial Afatinib + best supportive care or placebo group + best supportive care Pathologically confirmed stage IIIB (with pleural effusion) or stage IV adenoca. failed one or two lines of chemotherapy & had disease progression after at least 12 weeks of previous treatment with erlotinib or gefitinib. Study duration : Between May 26, 2008, and Sept 21, centres in 15 countries (from three continents: Asia [China, Hong Kong, Korea, Singapore, Taiwan, Thailand], Europe [Belgium, Germany, France, Italy, The Netherlands, UK, Spain], and North America [Canada, USA])

Inclusion criteria  Age : 18 yrs or older  ECOG performance status : 0-2  Life expectancy ≥ 3 months Exclusion criteria  active brain metastases pregnant or nursing women heart disease or dysfunction serious GI disorders, serious active infection abnormal liver, renal, and haematological function ECOG performance status Grade 0Fully active 1Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 2Ambulatory & capable of all selfcare but unable to carry out any work activities. >50% of waking hrs 3Capable of only limited selfcare confined to bed or chair >50% of waking hrs 4Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5Dead

Primary end point  overall survival Secondary end point  progression free survival  objective response rate  response duration, safety, and health-related QoL

2 : 1

The lack of effective therapies in pts with EGFR(+) NSCLC after the development of acquired resistance to erlotinib or gefitinib is a major clinical problem. Afatinib had a clear biological effect confirmed partial responses seen in about 7–11% of patients prolonged median progression-free survival Improvements in lung cancer related symptoms

Subsequent cancer therapies are believed to be potential confounders of an overall survival endpoint. chemotherapy and EGFRTKIs, both of which were given to a greater proportion of patients in the placebo group than those in the afatinib group, although these differences were not statistically significant.

No benefit in terms of overall survival with afatinib. 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.