ArticlesAfatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial
Introduction
EGFR tyrosine-kinase inhibitors (TKIs) such as gefitinib1 or erlotinib2 have high anti-tumour activity in patients with non-small-cell lung cancer (NSCLC) with tumours that harbour an activating EGFR mutation. High objective response rates and long progression-free survival with the use of EGFR-TKIs contribute to substantially improved overall survival compared with chemotherapy alone.3 However, all patients with NSCLC who are treated with EGFR-TKIs eventually develop acquired resistance4, 5—their disease subsequently progresses and leads to death.
Investigation of the EGFR sequence of tumour samples obtained from patients with acquired resistance to gefitinib showed that a second, so-called gatekeeper mutation, T790M (found in EGFR exon 20) is often present.4 The T790M mutation plays a major part in acquired resistance to gefitinib or erlotinib.5 Also, evidence suggests that low levels of T790M in the presence of common mutations might have a role in de-novo resistance and might reduce the effectiveness of reversible EGFR-TKIs for first-line treatment.6, 7, 8 Therefore, the development of drugs that inhibit specific gefitinib-resistant or erlotinib-resistant EGFR mutations or have the potential to prevent the development of resistance is important.
Afatinib (previously called BIBW2992; Boehringer-Ingelheim Pharma GmbH, Ingelheim, Germany)9 is a novel small-molecule ErbB-family blocker. It covalently binds and irreversibly blocks signalling from all homodimers and heterodimers formed by the ErbB-family members EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. Afatinib has shown preclinical activity against cancer cells harbouring activating EGFR mutations, including the common mutations (L858R and deletion 19) and also against the gatekeeper T790M mutation, albeit with a lower potency.9 In tumour xenograft models carrying the L858R or T790M mutations, afatinib, but not gefitinib or erlotinib, prevented tumour growth progression,9, 10 and in some cases even caused tumour regression.9 The findings from these preclinical studies prompted the investigation of afatinib in patients with NSCLC and EGFR mutations.
Phase 1 studies of afatinib were done in patients with solid tumours—the maximum tolerated dose was 50 mg once a day with the most common adverse events being diarrhoea and rash.11, 12 In a phase 1 study,12 three patients with NSCLC had durable partial response to afatinib, including two patients who were subsequently shown to have EGFR mutations. We therefore designed the LUX-Lung 2 phase 2 study to further assess the efficacy of afatinib in patients with lung adenocarcinoma containing EGFR mutations.
Section snippets
Study design and patients
LUX-Lung 2 was a single-arm, phase 2 study to explore the anti-tumour efficacy of afatinib in patients with lung adenocarcinoma whose tumours harbour activating EGFR mutations within exons 18–21 of the EGFR receptor, confirmed by direct DNA sequencing of tumour tissue. We included patients (from 30 centres—7 in Taiwan and 23 in the USA) if they had stage IIIB (with pleural effusion) or stage IV disease with Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. We judged tumour
Results
Between Aug 21, 2007, and June 4, 2009, we assessed 431 patients for eligibility, of whom 386 patients were successfully tested for EGFR mutations. 156 patients (41%) were positive, and of these, 129 (104 from Taiwan and 25 from the USA) were treated with afatinib (figure 1). Most patients were Asian, women, had good performance status, and were never-smokers, and almost all had stage IV disease (table 1). 61 patients received afatinib as first-line treatment, and 68 received afatinib after one
Discussion
Our results suggest that afatinib is active in the treatment of patients with lung adenocarcinoma harbouring EGFR mutations, irrespective of previous chemotherapy exposure, with an acceptable adverse event profile. Afatinib was more effective in patients with the common EGFR mutations—exon 19 deletions and L858R point mutations—than it was in patients with less common mutations. The starting dose of 40 mg provided a more favourable therapeutic index than did 50 mg.
The large proportion of
References (33)
- et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Lancet Oncol
(2010) - et al.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study
Lancet Oncol
(2011) - et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Lancet Oncol
(2012) - et al.
New CT response criteria in non-small cell lung cancer: proposal and application in EGFR tyrosine kinase inhibitor therapy
Lung Cancer
(2011) - et al.
Cetuximab monotherapy in patients with advanced non-small cell lung cancer after prior epidermal growth factor receptor tyrosine kinase inhibitor therapy
J Thorac Oncol
(2010) - et al.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
N Engl J Med
(2004) - et al.
Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors
Clin Cancer Res
(2006) - et al.
EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan
J Clin Oncol
(2008) - et al.
Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain
PLoS Med
(2005) Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors
Oncogene
(2009)