Elsevier

The Lancet Oncology

Volume 13, Issue 5, May 2012, Pages 539-548
The Lancet Oncology

Articles
Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial

https://doi.org/10.1016/S1470-2045(12)70086-4Get rights and content

Summary

Background

Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations.

Methods

In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0–2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148.

Findings

129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease).

Interpretation

Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC.

Funding

Boehringer Ingelheim Inc.

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

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