T he investigational monoclonal antibody ramucirumab improved overall survival (OS) when added to docetaxel versus chemotherapy alone in patients with stage IV non–small-cell lung cancer (NSCLC), according to a phase 3 trial highlighted in a press briefing at ASCO 2014.
“This is the first treatment to have shown a significant survival advantage over chemotherapy alone in second-line therapy of NSCLC, and the first treatment in approximately a decade to improve outcomes in the second-line setting,” said Maurice Pérol, MD, of the Département de Cancérologie Médicale, Centre Léon-Bérard, Lyon, France.
Ramucirumab, which was recently approved by the US Food and Drug Administration (FDA) for advanced gastric cancer, targets vascular endothelial growth factor receptor 2 and thus blocks the formation of new blood vessels to feed the tumor.
“This study met the primary end point of OS, reducing the risk of death by 14% and prolonging median survival by 1.4 months,” Dr Pérol reported. The combination reduced the risk of disease progression by 24%.
“Ramucirumab represents a potential new option for treatment in the second-line setting,” Dr Pérol suggested.
If further studies validate these findings, and the drug is approved by the FDA for this new indication, it would be the first antiangiogenic drug approved for the second-line treatment of patients with NSCLC.
The improvement in survival was demonstrated in patients with squamous histology and in patients with nonsquamous histology, but the median OS benefit, although significant, was quite modest. Nevertheless, Dr Pérol said that the drug could be useful in patients lacking a specific mutation (EGFR, ALK) that would make them candidates for targeted therapy.
In patients with NSCLC and EGFR mutation, the currently approved second-line chemotherapy agents include docetaxel, pemetrexed, and erlotinib, and the median OS with these drugs is between 7 months and 9 months.
REVEL Study Details
The double-blind, placebo-controlled, phase 3 REVEL clinical trial enrolled 1253 patients with stage IV NSCLC (26% of whom had squamous histology) whose disease progressed with standard platinum-based therapy. Patients were randomized to ramucirumab plus docetaxel or to docetaxel plus placebo.
The active combination significantly improved response rate, progression-free survival (PFS), and OS compared with docetaxel alone. The median PFS times were 4.5 months with ramucirumab versus 3 months without (P <.001), and the median OS times were 10.5 months versus 9.1 months (P = .0235), respectively.
The safety profile was in line with other angiogenesis inhibitors. No increase in pulmonary hemorrhage was observed with the combination.
“This combination shows good activity in the difficult-to-treat second-line setting of NSCLC,” said Gregory A. Masters, MD, Director, Medical Oncology Fellowship, Helen F. Graham Cancer Center, Newark, DE, who moderated the press briefing.
Dr Masters was asked whether 1.4 months of additional survival represented “value,” especially in light of ASCO’s recommendation that new NSCLC treatments (in the first-line setting) extend survival by at least 3 months.
Dr Masters responded that the drug may be a small step along the pathway that ultimately constitutes improvement. “Progress is slow and step-wise, and we build one step at a time. The cumulative progress is what we find encouraging….A study like REVEL may not change the way we treat NSCLC, but it can influence our design of further studies,” he said, adding that there is a mandate to “balance benefit with cost, and figure out how best to treat patients.”
Don S. Dizon, MD, Assistant in Medicine, Medical Gynecologic Oncology, Massachusetts General Hospital, Boston, commented that ASCO’s 3-month OS threshold is “guidance” but is not the “be all and end all” for investigational studies. “When we decide that a treatment has value, we consider 3 key things: efficacy, toxicity, and cost,” Dr Dizon noted.