Elsevier

The Lancet

Volume 384, Issue 9944, 23–29 August 2014, Pages 665-673
The Lancet

Articles
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial

https://doi.org/10.1016/S0140-6736(14)60845-XGet rights and content

Summary

Background

Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy.

Methods

In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m2 and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973.

Findings

Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1–21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2–18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75–0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3–8·3) for the ramucirumab group compared with 3·0 months (1·4–6·9) for the control group (0·76, 0·68–0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care.

Interpretation

Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.

Funding

Eli Lilly.

Introduction

Lung cancer is the leading cause of death from cancer in the world.1 Advanced non-small-cell lung cancer (NSCLC) is responsible for most of these cases, and although therapy directed against driver mutations has led to impressive gains in many regions, most patients do not have mutations associated with approved targeted drugs.2 Initial therapy usually entails four to six cycles of platinum-based chemotherapy,3 and some patients subsequently receive maintenance therapy.4 Although 30–40% of patients initially respond to cytotoxic therapy, all patients eventually have disease progression on or after treatment.5

Clinically approved second-line therapies for NSCLC include docetaxel, erlotinib, and pemetrexed.3, 6, 7, 8 Treatment with docetaxel led to improved overall survival compared with best supportive care6 and erlotinib led to improved overall survival compared with placebo.7 Pemetrexed did not differ in efficacy from docetaxel and is approved in non-squamous NSCLC.8 Clinical outcomes in this second-line population are poor with objective response rates (ORR) of less than 10%, median progression-free survival (PFS) of less than 4 months, and median overall survival of 7–9 months.9 Several phase 3 studies have assessed addition of a cytotoxic or targeted agents in previously treated patients, but outside of subset analyses, none of these studies showed an improvement in overall survival.10 Treatment of patients with squamous tumour histology is especially challenging because of a lack of driver mutations associated with response to approved agents, and the frequent central location of the tumour in proximity to large blood vessels and airways, haemoptysis, and worse overall prognosis.2

One hallmark of cancer is angiogenesis, the multistep formation of new capillaries and blood vessels.11 Blockade of VEGFR-2 signalling inhibits formation, proliferation, and migration of new blood vessels.12 Addition of bevacizumab, a recombinant humanised monoclonal antibody against VEGF, to carboplatin-paclitaxel first-line chemotherapy led to a significant improvement in overall survival in eligible patients with non-squamous NSCLC;13 however, the addition of bevacizumab to first-line cisplatin plus gemcitabine did not improve overall survival.14

Ramucirumab (IMC-1121B, ImClone Systems, Bridgewater, NJ, USA) is a fully human IgG1 monoclonal antibody that specifically binds to the VEGFR-2 extracellular domain with high affinity, preventing binding of all VEGF ligands and receptor activation.15 In second-line treatment of advanced gastric cancer, two positive phase 3 studies16, 17 showed ramucirumab significantly improved survival as a single agent and in combination with paclitaxel.

We aimed to assess efficacy and safety of ramucirumab plus docetaxel versus placebo plus docetaxel as second-line therapy in patients with stage IV NSCLC whose disease had progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment.

Section snippets

Study design and patients

In this randomised, double-blind, placebo-controlled phase 3 REVEL study, we enrolled adults (aged ≥18 years) at academic medical centres and community clinics in 26 countries on six continents.18 Eligible patients had pathologically confirmed, squamous or non-squamous stage IV NSCLC that had progressed during or after a single platinum-based chemotherapy regimen, with or without bevacizumab or maintenance therapy. We included patients with recurrent disease who had received adjuvant or

Results

We enrolled patients between Dec 3, 2010, and Jan 24, 2013 (figure 1, table 1). By data cutoff on of Dec 20, 2013, 884 patients had died (29% censoring rate). Four patients on each arm did not receive treatment, and three patients in the placebo group received one dose of ramucirumab inadvertently; thus for safety analyses, 627 patients were included in the ramucirumab group and 618 patients were included in the placebo group. Baseline characteristics were much the same for patients in the

Discussion

To our knowledge, ramucirumab is the first new therapy for previously treated NSCLC to improve overall survival compared with an active comparator (panel). Other therapies have been approved on the basis of non-inferiority or comparisons with placebo and best supportive care. Our data analysis plan was straightforward and was maintained throughout the study. Improvement of overall survival is regarded as the gold standard in NSCLC, especially for second-line therapy.23 Other endpoints,

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