Adding Ramucirumab to Pemetrexed and Chemotherapy Does Not Appear to Improve Progression-Free Survival in NSCLC
In a study of patients with nonsquamous non–small cell lung cancer (NSCLC), the addition of ramucirumab (Cyramza) to pemetrexed (Alimta) and platinum chemotherapy did not significantly improve progression-free survival, according to a study by Doebele et al in Cancer. However, the investigators did suggest a possible clinical benefit of adding ramucirumab to established pemetrexed/platinum chemotherapy in patients with stage IV nonsquamous NSCLC not previously treated with chemotherapy.
Studies have shown that patients with nonsquamous NSCLC who are treated with a combination of the platinum-containing agents pemetrexed and cisplatin have an overall survival of just 9 to 11 months. More recent studies in NSCLC have focused on the addition of targeted biologic agents, such as bevacizumab (Avastin), to platinum-containing chemotherapy to improve clinical outcomes. Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor ligand, is currently the only antiangiogenic agent approved for nonsquamous NSCLC. A correlation between VEGF receptor 2 (VEGFR2) expression and tumor microvessel density has been associated with a poor prognosis and lower relapse-free survival.
With that in mind, Doebele and colleagues conducted a phase II study of the addition of ramucirumab to pemetrexed and platinum chemotherapy. Ramucirumab, a fully human immunoglobulin G1 monoclonal antibody, specifically binds to the extracellular domain of VEGFR2 with high affinity. The investigators wanted to determine whether the addition of ramucirumab to a standard first-line platinum-based combination chemotherapy regimen would result in prolonged progression-free survival.
Study Details
In total, 140 patients with nonsquamous NSCLC received pemetrexed plus carboplatin (or cisplatin) or ramucirumab plus pemetrexed and carboplatin (or cisplatin). Patients received the induction combination treatment for a minimum of four 21-day cycles. Ramucirumab was administered intravenously at a dose of 10 mg/kg over 60 minutes on day 1 of each cycle. Patients were followed for survival up to 2 years from randomization.
In the pemetrexed/platinum cohort, 66.7% and 44.9% of patients completed four and six cycles, respectively. Exposure to pemetrexed in the ramucirumab-pemetrexed-platinum cohort was higher than that in the pemetrexed-platinum group. In the ramucirumab/pemetrexed/platinum group, 74.6% and 61.2% of the patients completed four and six cycles, respectively.
The most common reasons for treatment discontinuation were progressive disease (43.7% for the pemetrexed/platinum cohort and 37.7% for the ramucirumab/pemetrexed/platinum cohort) and adverse events (18.3% for the pemetrexed/platinum group and 23.2% for the ramucirumab/pemetrexed/platinum group).
Progression-Free Survival Not Significantly Improved With Ramucirumab
Final analysis indicated that progression-free survival was not significantly different between the two treatment groups (hazard ratio [HR] = 0.75; 90% confidence interval [CI] = 0.55–1.03; P = .132). The median progression-free survival was 7.2 months (90% CI = 5.8–8.4 months) for the ramucirumab/pemetrexed/platinum patient group and 5.6 months (90% CI = 4.0–5.7 months) for the pemetrexed/platinum patient group.
The overall response rate was 49.3% in patients in the ramucirumab/pemetrexed/platinum cohort (90% CI = 39.4%–59.2%) and 38.0% in the pemetrexed/platinum cohort (90% CI = 28.6%–47.5%; P = .180).
The percentages of patients who experienced at least one treatment-emergent adverse event of any grade were similar for the two patient groups. Grade 3 or higher adverse events occurred in 80.6% of patients in the ramucirumab/pemetrexed/platinum group and in 76.8% of patients in the pemetrexed/platinum group. The most commonly reported adverse events among patients in the ramucirumab/pemetrexed/platinum cohort included fatigue, neutropenia, thrombocytopenia, decreased appetite, peripheral edema, headache, epistaxis, back pain, dyspnea, and insomnia.
Closing Thoughts
The results of this study indicate the addition of ramucirumab did not significantly prolong progression-free survival in patients with nonsquamous NSCLC. In addition, the overall response rate was not significantly improved for patients receiving ramucirumab vs those receiving only pemetrexed and platinum-based therapy. However, the investigators did suggest a possible clinical benefit of adding ramucirumab to established pemetrexed/platinum chemotherapy for the first-line treatment of nonsquamous NSCLC.
The investigators noted, “The results of this phase II study warrant further exploration of the suggested clinical activity of adding ramucirumab to such chemotherapy doublets.”
Robert C. Doebele, MD, PhD, of the Medical Oncology/Department of Medicine, University of Colorado, Aurora, Colorado, is the corresponding author of this article in Cancer.
This trial was funded by ImClone Systems, LLC, a wholly owned subsidiary of Eli Lilly and Company. For full disclosures from the study authors, see the article at onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291097-0142.
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®.
