PMID- 27601237 OWN - NLM STAT- MEDLINE DCOM- 20171226 LR - 20220330 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 27 IP - 11 DP - 2016 Nov TI - Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. PG - 2103-2110 AB - BACKGROUND: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade >/=3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. PATIENTS AND METHODS: Treatment-naive patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. RESULTS: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00). CONCLUSIONS: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393. CI - (c) The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Yang, J C-H AU - Yang JC AD - National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan. FAU - Sequist, L V AU - Sequist LV AD - Massachusetts General Hospital and Harvard Medical School, Boston, USA. FAU - Zhou, C AU - Zhou C AD - Shanghai Pulmonary Hospital, Tongji University, Shanghai, China. FAU - Schuler, M AU - Schuler M AD - West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. FAU - Geater, S L AU - Geater SL AD - Prince of Songkla University, Songkhla, Thailand. FAU - Mok, T AU - Mok T AD - State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong. FAU - Hu, C-P AU - Hu CP AD - Xiangya Hospital, Central South University, Changsha, China. FAU - Yamamoto, N AU - Yamamoto N AD - Wakayama Medical University, Wakayama, Japan. FAU - Feng, J AU - Feng J AD - Jiangsu Province Cancer Hospital, Nanjing, Jiangsu, China. FAU - O'Byrne, K AU - O'Byrne K AD - Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia. FAU - Lu, S AU - Lu S AD - Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. FAU - Hirsh, V AU - Hirsh V AD - McGill University, Montreal, Canada. FAU - Huang, Y AU - Huang Y AD - Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan Province, China. FAU - Sebastian, M AU - Sebastian M AD - Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany. FAU - Okamoto, I AU - Okamoto I AD - Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Dickgreber, N AU - Dickgreber N AD - Thoracic Oncology and Respiratory Care Medicine, Mathias Spital Rheine, Rheine, Germany. FAU - Shah, R AU - Shah R AD - Kent Oncology Centre, Maidstone Hospital, Kent, UK. FAU - Marten, A AU - Marten A AD - Boehringer Ingelheim GmbH & Co. KG, Ingelheim am Rhein, Germany. FAU - Massey, D AU - Massey D AD - Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK. FAU - Wind, S AU - Wind S AD - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. FAU - Wu, Y-L AU - Wu YL AD - Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China syylwu@live.cn. LA - eng SI - ClinicalTrials.gov/NCT00949650 SI - ClinicalTrials.gov/NCT01121393 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial DEP - 20160906 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Quinazolines) RN - 41UD74L59M (Afatinib) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adenocarcinoma/*drug therapy/genetics/pathology MH - Adenocarcinoma of Lung MH - Adult MH - Afatinib MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects MH - China MH - Disease-Free Survival MH - Dose-Response Relationship, Drug MH - Drug-Related Side Effects and Adverse Reactions/pathology MH - ErbB Receptors/*genetics MH - Female MH - Humans MH - Lung Neoplasms/*drug therapy/genetics/pathology MH - Male MH - Middle Aged MH - Mutation MH - Protein Kinase Inhibitors/administration & dosage MH - Quinazolines/*administration & dosage/adverse effects MH - Republic of Korea OTO - NOTNLM OT - EGFR OT - NSCLC OT - afatinib OT - dose OT - first-line OT - phase III EDAT- 2016/10/30 06:00 MHDA- 2017/12/27 06:00 CRDT- 2016/09/08 06:00 PHST- 2016/04/07 00:00 [received] PHST- 2016/07/29 00:00 [accepted] PHST- 2016/10/30 06:00 [pubmed] PHST- 2017/12/27 06:00 [medline] PHST- 2016/09/08 06:00 [entrez] AID - S0923-7534(19)35839-9 [pii] AID - 10.1093/annonc/mdw322 [doi] PST - ppublish SO - Ann Oncol. 2016 Nov;27(11):2103-2110. doi: 10.1093/annonc/mdw322. Epub 2016 Sep 6.