Adding onartuzumab to erlotinib therapy improved progression-free survival and overall survival in patients whose advanced non–small cell lung cancers showed elevated expression of the MET tyrosine kinase receptor.
In contrast, compared with control subjects given erlotinib alone, patients with MET-negative tumors had earlier disease progression and poorer overall survival with onartuzumab and erlotinib in this randomized phase II trial, reported Dr. David R. Spigel of Sarah Cannon Research Institute, Nashville, Tenn., and his associates.
Dr. David Spigel
The findings of this industry-sponsored, preliminary study must be confirmed, and a randomized phase III trial is now underway. Meanwhile, the results indicate that adding onartuzumab to erlotinib may eventually benefit a large proportion of patients with non–small cell lung cancer (NSCLC), the investigators noted in an article published in the Journal of Clinical Oncology (2013 Oct. 7, published online before print [doi: 10.1200/JCO.2012.47.4189]).
MET is a transmembrane tyrosine kinase receptor involved in cellular proliferation, survival, motility, and invasion. Elevated MET expression is common in NSCLCs and previously has been associated with a worse prognosis. In addition, elevated MET has been implicated as a mechanism of the resistance to erlotinib that eventually develops in most NSCLC patients who take that drug.
Onartuzumab is a monoclonal antibody thought to block some MET activity. Dr. Spigel and his colleagues performed their double-blind phase II study in 137 patients with recurrent NSCLC who were randomly assigned to receive daily oral erlotinib plus either IV-infused onartuzumab (69 patients) or placebo (68 patients) every 3 weeks until the disease progressed, toxicity became unacceptable, or the patient died.
The median follow-up was 10.4 months (range, 0.1-18.4 months).
Tumor tissue from 66 patients in the active-treatment group and from 62 patients in the placebo group was available for immunohistochemical assessment of MET status.
The coprimary end points were progression-free survival in the intention-to-treat population and progression-free survival in the subgroup of 66 patients with MET-positive tumors.
In the intention-to-treat analysis, progression-free survival was not significantly different between patients who received erlotinib plus onartuzumab (2.2 months) and those who received erlotinib plus placebo (2.6 months).
However, when the data were categorized by tumor MET status, the risk of disease progression was nearly halved in patients with MET-positive tumors by the addition of onartuzumab (median progression-free survival, 2.9 months) compared with placebo (median progression-free survival, 1.5 months).
The opposite trend was noted in patients with MET-negative tumors, in whom the addition of onartuzumab markedly shortened the median progression-free survival (1.4 months), compared with placebo (2.7 months).
A similar pattern occurred with overall survival. In the intention-to-treat analysis, overall survival was not significantly different between patients given erlotinib plus onartuzumab (8.9 months) and those given erlotinib plus placebo (7.4 months).
But overall survival was nearly three times longer in patients with MET-positive tumors given erlotinib plus onartuzumab (12.6 months) than in those given erlotinib plus placebo (3.8 months). In contrast, among patients with MET-negative tumors overall survival was markedly better for those given erlotinib plus placebo (15.3 months) than for those given erlotinib plus onartuzumab (8.1 months).
The proportion of patients who discontinued treatment because of adverse events was higher with onartuzumab (11.6%) than with placebo (4.4%). The adverse events that developed more often with onartuzumab than with placebo were peripheral edema, pyrexia, asthenia, insomnia, and pneumonia.
Serious adverse events also were more frequent with the addition of onartuzumab (42%) than with the addition of placebo (33%). However, serious adverse events were impossible to distinguish from the underlying disease (pneumonia, dyspnea, hemoptysis, pulmonary embolism, and respiratory distress) or from the concomitant erlotinib therapy (interstitial lung disease and rash).
The reason for the differential response between MET-positive and MET-negative NSCLCs is not yet fully understood, Dr. Spigel and his associates said.
This study was sponsored by Genentech, which also provided the study drugs. Dr. Spigel and his associates reported ties to Genentech and numerous other industry sources.