Elsevier

The Lancet Oncology

Volume 15, Issue 11, October 2014, Pages 1236-1244
The Lancet Oncology

Articles
Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study

https://doi.org/10.1016/S1470-2045(14)70381-XGet rights and content

Summary

Background

With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease.

Methods

In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390.

Findings

Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9–18·1) with erlotinib plus bevacizumab and 9·7 months (5·7–11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36–0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group).

Interpretation

Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted.

Funding

Chugai Pharmaceutical Co Ltd.

Introduction

Lung cancer is a leading cause of death worldwide; it is the primary cause of cancer deaths in men and the secondary cause in women.1 Most patients with lung cancer have non-small-cell lung cancer (NSCLC) and a clinically significant proportion of patients have activating mutations of EGFR.2 In this subgroup of patients, EGFR tyrosine-kinase inhibitors have consistently led to better outcomes than has standard chemotherapy.3, 4, 5, 6 Erlotinib and gefitinib have been shown to prolong progression-free survival compared with chemotherapy in several phase 3 trials.7, 8, 9, 10 Unfortunately, most patients with NSCLC with activating EGFR mutations who are given EGFR tyrosine-kinase inhibitors eventually develop resistance and relapse within about 1 year of initiation of treatment.5, 7, 8, 9, 10, 11 To improve outcomes, the foundation treatment of EGFR tyrosine-kinase inhibitors should be built on through investigation of biologically synergistic combinations.

The anti-angiogenic monoclonal antibody bevacizumab targets the VEGF signalling pathway and has been shown to provide additional efficacy when used in combination with first-line platinum-based chemotherapy in several trials in non-squamous NSCLC.12, 13, 14 The combination of erlotinib and bevacizumab has the potential to prolong progression-free survival in unselected populations of patients with NSCLC.15, 16 In a subgroup analysis of EGFR mutation-positive participants in the phase 3 BeTa study of second-line treatment of NSCLC (12 patients treated with erlotinib and bevacizumab and 18 with erlotinib alone), median progression-free survival with erlotinib plus bevacizumab in patients with EGFR mutation-positive disease was substantially higher than with erlotinib alone (17·1 months vs 9·7 months).16, 17 However, this analysis was post-hoc and EGFR mutation status was not a prespecified stratification factor in this trial. Because of this limitation, we undertook this phase 2 trial to examine the combination of erlotinib and bevacizumab in patients with EGFR mutation-positive NSCLC.

Section snippets

Study design and patients

JO25567 was a randomised, open-label, multicentre, phase 2 study in patients with stage IIIB/IV (according to the 7th edition of the General Rule for Clinical and Pathological Record of Lung Cancer18) or recurrent NSCLC with activating EGFR mutations. Patients were enrolled from 30 centres across Japan.

Eligible patients had histologically or cytologically (excluding sputum cytology) confirmed stage IIIB/IV or postoperative recurrent non-squamous NSCLC with activating EGFR mutation (either exon

Results

Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled, of whom 77 were randomly assigned to receive erlotinib plus bevacizumab and 77 to erlotinib alone. Two patients withdrew before treatment started and were excluded (one had multiple thrombosis and the other had increased pleural effusion). Thus, data from 152 patients (75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group) were included in the analysis population (figure 1). The cutoff date

Discussion

In this study, the addition of bevacizumab to erlotinib significantly prolonged progression-free survival in patients with NSCLC with activating EGFR mutation-positive disease compared with erlotinib alone. To our knowledge, this is the first randomised study to show a clinically significant treatment effect of combining an EGFR tyrosine-kinase inhibitor with another biological drug in patients with activating EGFR mutation-positive NSCLC (panel). We noted clear separation of the Kaplan-Meier

References (32)

  • YL Wu et al.

    Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non–small-cell lung cancer (FASTACT-2): a randomised, double-blind trial

    Lancet Oncol

    (2013)
  • 10 facts about cancer

  • TJ Lynch 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)
  • NCCN Drugs & Biologics Compendium (NCCN Compendium)

  • EGFR-TK mutation positive)—erlotinib (1st line) (TA258)

  • 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)
  • Cited by (672)

    View all citing articles on Scopus
    View full text