A randomised, double-blind, phase III REVEL study demonstrated a statistically significant improvement in overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) for ramucirumab plus docetaxel vs. docetaxel in patients with stage IV non-small-cell lung cancer (NSCLC) as a second-line treatment after platinum-based therapy. Benefits were similar in patients with non-squamous and squamous tumours and no unexpected adverse events were identified, according to presentation by Dr Maurice Perol of the Léon-Bérard Cancer Centre, Lyon, France at American Society of Clinical Oncology (ASCO) 2014 Annual Meeting. The results were also published as an early online publication on 2 June in the Lancet.
Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. Patients were randomised 1:1 to receive docetaxel in combination with either ramucirumab or placebo in a 3-week cycle until disease progression, unacceptable toxicity, or death. The patients were stratified by sex, region, ECOG performance status and prior maintenance therapy.
The primary endpoint was OS; secondary efficacy endpoints included PFS and ORR.
The Study Results
Between December 2010 and February 2013, the study team randomised 1,253 patients (628 patients in the docetaxel/ramucirumab arm and 625 patients in docetaxel/placebo arm). Patient characteristics were balanced between arms and 26.2% had squamous NSCLC.
The REVEL study met its primary endpoint; the hazard ratio (HR) for OS was 0.857 (95% CI 0.751, 0.98; p = 0.0235); median OS was 10.5 months in docetaxel/ramucirumab vs. 9.1 months for docetaxel/placebo. The OS was longer for docetaxel/ramucirumab in most patient subgroups, including those with squamous and non-squamous histology.
In the docetaxel/ramucirumab arm, the ORR was 22.9% and 13.6% for docetaxel/placebo (p < 0.001).
The HR for PFS was 0.762 (p < 0.0001); median PFS was 4.5 months in the docetaxel/ramucirumab arm vs. 3.0 months for docetaxel/placebo.
Grade 5 adverse events were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all patients: 2.1% vs. 1.6%; patients with squamous tumours: 3.8% vs. 2.4%).
Grade ≥3 adverse events occurring in more than 5% of patients on docetaxel/ramucirumab were neutropaenia (34.9% vs. 28.0%), febrile neutropaenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopaenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%).
REVEL: Study Implications
During the session, the results triggered a debate if statistically significant improvement of 1,5 months is clinically meaningful. It should be emphasised that this study was performed in a second-line setting.
The study also aimed to identify plasma or tumour biomarkers associated with response to ramucirumab, but such analyses are yet to be released.
In an accompanied editorial article, Tony Mok and Herbert Loong from The Chinese University of Hong Kong wrote that implications of this positive randomised phase III trial should be appraised, as this publication might lead to the approval of ramucirumab as a standard second-line treatment.
The study discussants also noted that EGFR mutation status was incomplete for the patients and cautioned on possible bias in OS data due to exposure to EGFR tyrosine kinase inhibitors in subsequent lines of treatment.
Perol M, Ciuleanu T-E, Arrieta O, et al. REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA8006)
Garon EB, Ciuleanu T-E, Arrieta O, et al. 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. Lancet 2014; Early Online Publication 2 June. doi:10.1016/S0140-6736(14)60845-X