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

Ann Oncol. 2016 Nov;27(11):2103-2110. doi: 10.1093/annonc/mdw322. Epub 2016 Sep 6.


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-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.

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.

Trial registration: ClinicalTrials.gov NCT00949650 NCT01121393.

Keywords: EGFR; NSCLC; afatinib; dose; first-line; phase III.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Adult
  • Afatinib
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • China
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • ErbB Receptors / genetics*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation
  • Protein Kinase Inhibitors / administration & dosage
  • Quinazolines / administration & dosage*
  • Quinazolines / adverse effects
  • Republic of Korea


  • Protein Kinase Inhibitors
  • Quinazolines
  • Afatinib
  • EGFR protein, human
  • ErbB Receptors

Associated data

  • ClinicalTrials.gov/NCT00949650
  • ClinicalTrials.gov/NCT01121393