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.
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.



Treatment-naïve 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.



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)}.



Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy.



Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.
National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
J C-H
JC
Yang
Massachusetts General Hospital and Harvard Medical School, Boston, USA.
L V
LV
Sequist
Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
C
C
Zhou
West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
M
M
Schuler
Prince of Songkla University, Songkhla, Thailand.
S L
SL
Geater
State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong.
T
T
Mok
Xiangya Hospital, Central South University, Changsha, China.
C-P
CP
Hu
Wakayama Medical University, Wakayama, Japan.
N
N
Yamamoto
Jiangsu Province Cancer Hospital, Nanjing, Jiangsu, China.
J
J
Feng
Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia.
K
K
O'Byrne
Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
S
S
Lu
McGill University, Montreal, Canada.
V
V
Hirsh
Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan Province, China.
Y
Y
Huang
Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany.
M
M
Sebastian
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
I
I
Okamoto
Thoracic Oncology and Respiratory Care Medicine, Mathias Spital Rheine, Rheine, Germany.
N
N
Dickgreber
Kent Oncology Centre, Maidstone Hospital, Kent, UK.
R
R
Shah
Boehringer Ingelheim GmbH & Co. KG, Ingelheim am Rhein, Germany.
A
A
Märten
Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
D
D
Massey
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
S
S
Wind
Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China syylwu@live.cn.
Y-L
YL
Wu
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002681:China; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D056910:Republic of Korea
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors
EGFR; NSCLC; afatinib; dose; first-line; phase III