Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial

Keunchil Park, Eng Huat Tan, Ken O'Byrne, Li Zhang, Michael Boyer, Tony Mok, Vera Hirsh, James Chih Hsin Yang, Ki Hyeong Lee, Shun Lu, Yuankai Shi, Sang We Kim, Janessa Laskin, Dong Wan Kim, Catherine Dubos Arvis, Karl Kölbeck, Scott A. Laurie, Chun Ming Tsai, Mehdi Shahidi, Miyoung Kim & 3 others Dan Massey, Victoria Zazulina, Luis Paz-Ares

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Abstract

Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding: Boehringer Ingelheim.

LanguageEnglish (US)
Pages577-589
Number of pages13
JournalThe lancet oncology
Volume17
Issue number5
DOIs
StatePublished - May 1 2016

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
Randomized Controlled Trials
Mutation
Therapeutics
gefitinib
BIBW 2992
Treatment Failure
Disease-Free Survival
Safety
Survival
Acne Vulgaris
Liver Failure
Random Allocation
Exanthema
Drug-Related Side Effects and Adverse Reactions
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Population
Renal Insufficiency

ASJC Scopus subject areas

  • Oncology

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Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7) : A phase 2B, open-label, randomised controlled trial. / Park, Keunchil; Tan, Eng Huat; O'Byrne, Ken; Zhang, Li; Boyer, Michael; Mok, Tony; Hirsh, Vera; Yang, James Chih Hsin; Lee, Ki Hyeong; Lu, Shun; Shi, Yuankai; Kim, Sang We; Laskin, Janessa; Kim, Dong Wan; Arvis, Catherine Dubos; Kölbeck, Karl; Laurie, Scott A.; Tsai, Chun Ming; Shahidi, Mehdi; Kim, Miyoung; Massey, Dan; Zazulina, Victoria; Paz-Ares, Luis.

In: The lancet oncology, Vol. 17, No. 5, 01.05.2016, p. 577-589.

Research output: Contribution to journalArticle

Park, K, Tan, EH, O'Byrne, K, Zhang, L, Boyer, M, Mok, T, Hirsh, V, Yang, JCH, Lee, KH, Lu, S, Shi, Y, Kim, SW, Laskin, J, Kim, DW, Arvis, CD, Kölbeck, K, Laurie, SA, Tsai, CM, Shahidi, M, Kim, M, Massey, D, Zazulina, V & Paz-Ares, L 2016, 'Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial', The lancet oncology, vol. 17, no. 5, pp. 577-589. https://doi.org/10.1016/S1470-2045(16)30033-X
Park, Keunchil ; Tan, Eng Huat ; O'Byrne, Ken ; Zhang, Li ; Boyer, Michael ; Mok, Tony ; Hirsh, Vera ; Yang, James Chih Hsin ; Lee, Ki Hyeong ; Lu, Shun ; Shi, Yuankai ; Kim, Sang We ; Laskin, Janessa ; Kim, Dong Wan ; Arvis, Catherine Dubos ; Kölbeck, Karl ; Laurie, Scott A. ; Tsai, Chun Ming ; Shahidi, Mehdi ; Kim, Miyoung ; Massey, Dan ; Zazulina, Victoria ; Paz-Ares, Luis. / Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7) : A phase 2B, open-label, randomised controlled trial. In: The lancet oncology. 2016 ; Vol. 17, No. 5. pp. 577-589.
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abstract = "Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95{\%} CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95{\%} CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95{\%} CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95{\%} CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13{\%}] of 160 patients given afatinib vs two [1{\%}] of 159 given gefitinib) and rash or acne (15 [9{\%}] patients given afatinib vs five [3{\%}] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9{\%}] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11{\%}) patients in the afatinib group and seven (4{\%}) in the gefitinib group. Ten (6{\%}) patients in each group discontinued treatment due to drug-related adverse events. 15 (9{\%}) fatal adverse events occurred in the afatinib group and ten (6{\%}) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding: Boehringer Ingelheim.",
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T1 - Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7)

T2 - The Lancet Oncology

AU - Park, Keunchil

AU - Tan, Eng Huat

AU - O'Byrne, Ken

AU - Zhang, Li

AU - Boyer, Michael

AU - Mok, Tony

AU - Hirsh, Vera

AU - Yang, James Chih Hsin

AU - Lee, Ki Hyeong

AU - Lu, Shun

AU - Shi, Yuankai

AU - Kim, Sang We

AU - Laskin, Janessa

AU - Kim, Dong Wan

AU - Arvis, Catherine Dubos

AU - Kölbeck, Karl

AU - Laurie, Scott A.

AU - Tsai, Chun Ming

AU - Shahidi, Mehdi

AU - Kim, Miyoung

AU - Massey, Dan

AU - Zazulina, Victoria

AU - Paz-Ares, Luis

PY - 2016/5/1

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N2 - Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding: Boehringer Ingelheim.

AB - Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding: Boehringer Ingelheim.

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