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

J. C.H. Yang, L. V. Sequist, C. Zhou, M. Schuler, S. L. Geater, T. Mok, C. P. Hu, N. Yamamoto, J. Feng, K. O'Byrne, S. Lu, V. Hirsh, Y. Huang, M. Sebastian, Isamu Okamoto, N. Dickgreber, R. Shah, A. Märten, D. Massey, S. WindY. L. Wu

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Abstract

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.

Original languageEnglish
Pages (from-to)2103-2110
Number of pages8
JournalAnnals of Oncology
Volume27
Issue number11
DOIs
Publication statusPublished - Jan 1 2016

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Safety
Lung
Mutation
Disease-Free Survival
Non-Small Cell Lung Carcinoma
Adenocarcinoma of lung
BIBW 2992
Therapeutics
Republic of Korea
Incidence
Thailand
Drug-Related Side Effects and Adverse Reactions
China
Pharmacokinetics
Drug Therapy
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

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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. / Yang, J. C.H.; Sequist, L. V.; Zhou, C.; Schuler, M.; Geater, S. L.; Mok, T.; Hu, C. P.; Yamamoto, N.; Feng, J.; O'Byrne, K.; Lu, S.; Hirsh, V.; Huang, Y.; Sebastian, M.; Okamoto, Isamu; Dickgreber, N.; Shah, R.; Märten, A.; Massey, D.; Wind, S.; Wu, Y. L.

In: Annals of Oncology, Vol. 27, No. 11, 01.01.2016, p. 2103-2110.

Research output: Contribution to journalArticle

Yang, JCH, Sequist, LV, Zhou, C, Schuler, M, Geater, SL, Mok, T, Hu, CP, Yamamoto, N, Feng, J, O'Byrne, K, Lu, S, Hirsh, V, Huang, Y, Sebastian, M, Okamoto, I, Dickgreber, N, Shah, R, Märten, A, Massey, D, Wind, S & Wu, YL 2016, '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', Annals of Oncology, vol. 27, no. 11, pp. 2103-2110. https://doi.org/10.1093/annonc/mdw322
Yang, J. C.H. ; Sequist, L. V. ; Zhou, C. ; Schuler, M. ; Geater, S. L. ; Mok, T. ; Hu, C. P. ; Yamamoto, N. ; Feng, J. ; O'Byrne, K. ; Lu, S. ; Hirsh, V. ; Huang, Y. ; Sebastian, M. ; Okamoto, Isamu ; Dickgreber, N. ; Shah, R. ; Märten, A. ; Massey, D. ; Wind, S. ; Wu, Y. L. / 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. In: Annals of Oncology. 2016 ; Vol. 27, No. 11. pp. 2103-2110.
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abstract = "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-na{\"i}ve 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.",
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TY - JOUR

T1 - Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma

T2 - Post hoc analyses of the randomized LUX-Lung 3 and 6 trials

AU - Yang, J. C.H.

AU - Sequist, L. V.

AU - Zhou, C.

AU - Schuler, M.

AU - Geater, S. L.

AU - Mok, T.

AU - Hu, C. P.

AU - Yamamoto, N.

AU - Feng, J.

AU - O'Byrne, K.

AU - Lu, S.

AU - Hirsh, V.

AU - Huang, Y.

AU - Sebastian, M.

AU - Okamoto, Isamu

AU - Dickgreber, N.

AU - Shah, R.

AU - Märten, A.

AU - Massey, D.

AU - Wind, S.

AU - Wu, Y. L.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

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-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.

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U2 - 10.1093/annonc/mdw322

DO - 10.1093/annonc/mdw322

M3 - Article

C2 - 27601237

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VL - 27

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EP - 2110

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 11

ER -