In the phase III REVEL trial reported in Lancet, Edward B. Garon, MD, of the David Geffen School of Medicine at UCLA/Translational Research in Oncology–US Network, Los Angeles, and colleagues found that the addition of the antiangiogenic vascular endothelial growth factor receptor (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) who had disease progression on or after platinum-based therapy.¹ The findings indicate a role of VEGFR-2 inhibition in this setting.

Ramucirumab is a human IgG1 monoclonal antibody that binds to the VEGFR-2 extracellular domain with high affinity and thus prevents binding of VEGF ligands and receptor activation.

Study Details

This double-blind trial included 1,253 patients with squamous or nonsquamous stage IV NSCLC from academic medical centers and community clinics in 26 countries on six continents. Patients 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 shown disease progression 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 a 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). Treatment after study discontinuation was received by 51% of patients in the ramucirumab group and 55% of the control group.

Median progression-free survival was 4.5 vs 3.0 months (HR = 0.76, P < .0001). Investigator-assessed objective response occurred in 23% vs 14% of patients (odds ratio [OR] = 1.89, P < .0001) and the disease control rate was 64% vs 53% (odds ratio [OR] = 1.60, P < .0001), with the ramucirumab benefit being similar in nonsquamous and squamous cell disease subgroups.

The trial was not powered for subgroup analysis. However, subgroup analysis showed consistent numeric 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 clinical adverse events of any grade in the ramucirumab group were fatigue (55% vs 49% in the control group) and diarrhea (32% vs 27%). The most common grade ≥ 3 clinical adverse events occurring in > 5% of either group were fatigue (14% vs 10%), hypertension (6% vs 2%) and dyspnea (4% vs 8%). The most common grade ≥ 3 hematologic adverse events were neutropenia (49% vs 40%, grade 4 in 37% vs 28%), febrile neutropenia (16% vs 10%), and leukopenia (14% vs 12%).

An increased incidence of neutropenia and febrile neutropenia in patients from East Asia (Taiwan and South Korea) led to a reduction in docetaxel dose to 60 mg in 27% of East Asian patients, with the reduction being associated with a reduction in the neutropenia rate compared with that observed in other regions. Overall, granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was used in 42% vs 37% of patients and 13% vs 8% were admitted to hospital for febrile neutropenia. Anemia of any grade occurred in 21% vs 28% of patients (grade ≥ 3 in 3% vs 6%. Transfusion was required in 10% vs 12%.

Patients in the ramucirumab group had more bleeding or hemorrhage events of any grade (29% vs 15%, grade ≥ 3 in 2% vs 2%), including significantly more epistaxis (19% vs 6%, grade ≥ 3 in < 1% vs < 1%). Other bleeding events included pulmonary hemorrhage (8% vs 7%, grade ≥ 3 in 1% vs 1%), hemoptysis (6% vs 5%, grade ≥ 3 in 1% vs 1%), and gastrointestinal hemorrhage (3% vs 2%, grade ≥ 3 in 1% vs < 1%).

“Although the incidence of bleeding was higher in the ramucirumab arm, it was almost exclusively secondary to events such as epistaxis, while more concerning events such as pulmonary and gastrointestinal hemorrhages were not increased,” Dr. Garon commented to The ASCO Post.

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.

Quality of Life

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:

Our study shows that, in patients with advanced non-small-cell lung cancer with disease progression during or after first-line platinum-based therapy, ramucirumab plus docetaxel can significantly prolong survival compared with docetaxel, providing evidence for the role of a VEGFR-targeted therapy and offering patients with non-squamous and squamous recurrent disease a potential option for treatment. ■

Disclosure: The study was funded by Eli Lilly. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. 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 384:665-673, 2014.