Small but Statistically Significant Improvement in Overall Survival With Second-Line Addition of Ramucirumab to Docetaxel in Stage IV NSCLC
In the phase III REVEL trial reported in The Lancet, Garon et al found that the addition of the antiangiogenic VEGFR-2 inhibitor ramucirumab (Cyramza) to docetaxel produced a statistically significant improvement in overall survival as second-line treatment in patients with non–small cell lung cancer (NSCLC) after progression on platinum-based therapy.
Study Details
In this double-blind trial, 1,253 patients with squamous or nonsquamous stage IV NSCLC from academic medical centers and community clinics in 26 countries on six continents were randomly assigned between December 2010 and January 2013 to receive docetaxel at 75 mg/m² and either ramucirumab at 10 mg/kg (n = 628) or placebo (n = 625) on day 1 of 21-day cycles until disease progression, unacceptable toxicity, withdrawal, or death. Patients had to have progressed during or after a single platinum-based chemotherapy regimen, with or without bevacizumab (Avastin) or maintenance therapy.
Randomization was stratified by sex, region, performance status, and previous maintenance therapy. The primary endpoint was overall survival in the intent-to-treat population.
The ramucirumab and control groups were generally balanced for age (median, 62 and 61 years), sex (67% and 66% male), race (84% and 80% white, 12% and 14% Asian), Eastern Cooperative Oncology Group performance status (0 in 33% and 32%, 1 in 67% and 68%), measurable disease (96% in both), smoking history (ever for 82% and 77%), histology (nonsquamous in 74% and 72%, squamous in 25% and 27%), EGFR status (mutant in 2 % and 3%, unknown in 65% and 66%), best response to platinum-based chemotherapy (response or stable disease in 67% in both), previous maintenance treatment (21% and 23%), previous taxane (24% in both), previous bevacizumab (14% and 15%), and time since previous therapy (< 9 months in 64% and 60%).
Improved Overall Survival
After median follow-up of 9.5 months in the ramucirumab group and 8.8 months in the control group, median overall survival was 10.5 months (interquartile range = 5.1–21.2 months) vs 9.1 months (interquartile range = 4.2–18.0 months), yielding a hazard ratio (HR) of 0.86 (P = .023). Median progression-free survival was 4.5 vs 3.0 months (HR = 0.76, P < .0001). Investigator-assessed objective response was observed in 23% vs 14% of patients (odds ratio [OR] = 1.89, P < .0001) and the disease control rate was 64% vs 53% (OR = 1.60, P < .0001, with the ramucirumab benefit being similar in nonsquamous and squamous subgroups.
The trial was not powered for subgroup analysis. However, subgroup analysis showed consistent numerical benefit of ramucirumab on overall survival, including among patients with nonsquamous disease (11.1 vs 9.7 months, HR = 0.83, 95% confidence interval [CI] = 0.71–0.97), those with squamous disease (9.5 vs 8.2 months, HR = 0.88, 95% CI = 0.69–1.13), those with response to first-line platinum treatment (11.2 vs 10.3 months, HR = 0.84, 95% CI = 0.71–0.99), and those without response to first-line platinum treatment (8.3 vs 6.3 months, HR = 0.86, 95% CI = 0.68–1.08).
Toxicity
The most common grade ≥ 3 adverse events in the ramucirumab group were neutropenia (49% vs 40% in the control group), febrile neutropenia (16% vs 10%), fatigue (14% vs 10%), leukopenia (14% vs 12%), and hypertension (6% vs 2%). An increased incidence of neutropenia and febrile neutropenia in east Asia (Taiwan and South Korea) led to a reduction in docetaxel dose to 60 mg in 27% of patients, with the reduction being associated with a reduction in neutropenia rate to that observed in other regions. Patients in the ramucirumab group had more bleeding or hemorrhage events of any grade (29% vs 15%). Grade ≥ 3 pulmonary hemorrhage occurred in 1% of both groups.
Serious adverse events occurred in 43% vs 42% of patients. Adverse events led to dose adjustment in 33% of ramucirumab patients and 23% of control patients, with the most common reasons being neutropenia (12% vs 9%), fatigue (9% vs 6%), and febrile neutropenia (7% vs 5%). Death due to adverse events occurred in 5% vs 6% of patients.
Data on global quality of life, measured using the Lung Cancer Symptom Scale, were available at baseline for 77% of patients in the ramucirumab group and 79% in the control group and for 47% and 49% at 30-day follow-up. There was no difference between groups in time to deterioration of quality of life (stratified HR = 1.00, P = .99).
The investigators concluded: “Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.”
Edward B. Garon, MD, of David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, is the corresponding author for The Lancet article.
The study was funded by Eli Lilly. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
