ArticlesRamucirumab 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
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,
References (34)
- et al.
Cancer statistics 2012
CA Cancer J Clin
(2012) - et al.
Genotyping and genomic profiling of non-small cell-lung cancer: implications for current and future therapies
J Clin Oncol
(2013) Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, second-, and third-line
Curr Oncol
(2012)- et al.
Maintenance chemotherapy for advanced non-small cell lung cancer: new life for an old idea
J Clin Oncol
(2013) - et al.
Current treatments for advanced stage non-small cell lung cancer
Proc Am Thorac Soc
(2009) - et al.
A prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy
J Clin Oncol
(2000) - et al.
Erlotinib in previously treated non-small-cell lung cancer
N Engl J Med
(2005) - et al.
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy
J Clin Oncol
(2004) - et al.
Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials
J Thorac Oncol
(2007) - et al.
Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised trial
Lancet Oncol
(2014)
The hallmarks of cancer
Cell
Halting angiogenesis suppresses carcinoma cell invasion
Nat Med
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer
N Engl J Med
Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL)
Ann Oncol
Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2
J Clin Oncol
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial
Lancet
RAINBOW: a global, phase 3, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy IMCL CP12–0922 (I4T-IE-JVBE)
J Clin Oncol
Cited by (1037)
Anti–Vascular Endothelial Growth Factor/Programmed Cell Death Protein 1 Bispecific Antibodies: Using Nunchucks to Fight an Old Adversary
2024, Journal of Thoracic OncologyThe effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies
2024, Acta Pharmaceutica Sinica B