Elsevier

The Lancet Oncology

Volume 17, Issue 5, May 2016, Pages 577-589
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(16)30033-XGet rights and content

Summary

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.

Introduction

Non-small-cell lung cancer (NSCLC) with EGFR mutations represents a molecularly distinct type of lung cancer with established first-line treatment options; these include the EGFR-targeting tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib.1, 2, 3 All three drugs have been approved on the basis of randomised trials showing superior progression-free survival, objective responses, and more favourable safety profiles when compared with standard first-line platinum-based doublet chemotherapy in patients with EGFR-mutant NSCLC.4, 5, 6, 7, 8, 9, 10, 11 In the absence of prospective randomised head-to-head comparisons of these EGFR tyrosine kinase inhibitors, a series of meta-analyses were done to identify the most efficacious drug. These studies did not identify any significant differences in efficacy between gefitinib, erlotinib, or afatinib, but indicated differences in adverse event profile.12, 13, 14

Research in context

Evidence before this study

We searched the literature published from Jan 1, 2009, to Jan 5, 2016, using PubMed and of trials presented as abstracts at major oncology meetings (annual meetings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the World Conference of Lung Cancer). Using the search terms “NSCLC” and “randomised”, and “erlotinib” or “gefitinib”, or “afatinib”, we reviewed manuscripts and abstracts reporting phase 2 and 3 trials investigating EGFR-targeted drugs in patients with EGFR mutation-positive NSCLC in a first-line setting. Based on this review, we confirmed that to the best of our knowledge, apart from LUX-Lung 7, only one other first-line head-to-head trial has been completed to date (gefitinib vs erlotinib in Chinese patients; completed in 2014, NCT01024413). Therefore, at the onset of LUX-Lung 7, there were no prospective data to guide the selection of the most appropriate tyrosine kinase inhibitor in patients with EGFR mutation-positive NSCLC. A search of ClinicalTrials.gov showed that several randomised trials comparing EGFR tyrosine kinase inhibitors are ongoing, including: a phase 2 trial comparing erlotinib and gefitinib (NCT01955421); a phase 3 trial comparing dacomitinib (a second-generation tyrosine kinase inhibitor) versus gefitinib (NCT01774721); and two phase 3 trials comparing the third-generation tyrosine kinase inhibitors, osimertinib and ASP8273, versus gefitinib or erlotinib (NCT02296125 and NCT02588261, respectively).

Added value of this study

To our knowledge, this study is the first randomised multicentre trial comparing two EGFR-targeting drugs in a setting in which both are approved, providing efficacy and safety evidence in a head-to-head comparison. This study showed that afatinib has improved efficacy compared with gefitinib over a range of clinically relevant endpoints including progression-free survival, time-to-treatment failure, and the proportion of patients achieving an objective response. The improvement in efficacy was noted both in patients with exon 19 deletion and Leu858Arg mutations. The adverse event profile was predictable and manageable; the discontinuation rate due to treatment-related adverse events was the same as with gefitinib.

Implications of all the available evidence

LUX-Lung 7 indicates that irreversible ErbB blockade with afatinib could be more effective than reversible EGFR inhibition in the treatment of EGFR mutation-positive NSCLC. The results suggest that first-generation and second-generation tyrosine kinase inhibitors are not interchangeable and imply that the broader and irreversible mechanism of action of afatinib compared with gefitinib could have led to better tumour control.

There are inherent differences in the method of action of the first-generation EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, which reversibly bind to and inhibit EGFR signalling, and the second-generation ErbB family blocker afatinib, which irreversibly blocks signalling from all relevant homo-dimers and hetero-dimers of the ErbB family of receptors (EGFR/ErbB1, HER2/ErbB2, ErbB3, and ErbB4).15, 16 The broad spectrum of activity and irreversible mechanism of action of afatinib has been postulated to be associated with improved inhibition of EGFR-dependent tumour growth compared with first-generation EGFR tyrosine kinase inhibitors. We aimed to address this question, and to prospectively estimate the effect of a first-generation versus a second-generation EGFR tyrosine kinase inhibitor, by assessing the efficacy and safety of gefitinib and afatinib in patients with NSCLC harbouring common (exon 19 deletions or Leu858Arg) EGFR mutations.

Section snippets

Study design and participants

LUX-Lung 7 was a multicentre, international, randomised, open-label, phase 2B trial, done at 64 sites in 13 countries (appendix pp 4–6). Eligible patients were aged 18 years or older with treatment-naive pathologically confirmed stage IIIB (ineligible for curative intent surgery or local radiotherapy) or IV (recurrent or metastatic) adenocarcinoma of the lung (American Joint Committee on Cancer version 7) with a documented, locally or centrally assessed, common activating EGFR mutation (exon 19

Results

Between Dec 13, 2011, and Aug 8, 2013, 571 patients were screened and 319 were randomly assigned and treated with afatinib (n=160) or gefitinib (n=159; figure 1). Baseline demographics and disease characteristics were similar between the treatment group, except for a slight imbalance in sex (table 1).

Median duration of treatment was 13·7 months (IQR 7·4–24·3) for afatinib and 11·5 months (6·2–18·8) for gefitinib. Nine (6%) of 160 patients had afatinib dose escalations to 50 mg per day, 63 (39%)

Discussion

To the best of our knowledge, LUX-Lung 7 is the first prospective head-to-head trial to assess an irreversible ErbB family blocker, afatinib, and a reversible EGFR tyrosine kinase inhibitor, gefitinib, as first-line treatment of patients with EGFR mutation-positive NSCLC in both Asians and non-Asian patients. Afatinib significantly improved progression-free survival and time-to-treatment failure. The proportion of patients treated with afatinib who achieved an objective response was also

References (33)

  • JG Paez et al.

    EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy

    Science

    (2004)
  • SV Sharma et al.

    Epidermal growth factor receptor mutations in lung cancer

    Nat Rev Cancer

    (2007)
  • M Maemondo et al.

    Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR

    N Engl J Med

    (2010)
  • TS Mok et al.

    Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma

    N Engl J Med

    (2009)
  • LV Sequist et al.

    Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

    J Clin Oncol

    (2013)
  • YL Wu et al.

    First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study

    Ann Oncol

    (2015)
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