Onartuzumab Added No Benefit in MET-Amplified NSCLC

The addition of the MET-targeting antibody onartuzumab to erlotinib added no benefit, and may have been detrimental, to patients with MET-amplified stage IIIb/IV metastatic non–small-cell lung cancer (NSCLC), according to the results (abstract 8000) of a new phase III trial presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, held May 30–June 3 in Chicago.

“Dysregulation of the MET pathway in solid tumors is associated with poor prognosis,” said David R. Spigel, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee. “There is good rationale in targeting MET and EGFR.” Previous work showed that patients with high MET expression determined by immunohistochemistry did better with the combination of onartuzumab and erlotinib, which led to the phase III METLung trial.

A total of 499 patients with MET expression were randomized to either erlotinib plus onartuzumab (250 patients) or erlotinib plus placebo (249 patients). An interim analysis was planned when 67% of the overall survival events took place, and the trial was stopped at that point due to futility.

The median overall survival was 6.8 months in the study group and 9.1 months in the placebo group, for a hazard ratio of 1.27 (95% confidence interval [CI], 0.98–1.65; P = .07). “There really is no one subgroup where there is a suggestion of benefit,” Spigel added; those included MET expression, EGFR mutation status, race, prior lines of therapy, and others. Those with non-squamous histology and those with two prior lines of therapy actually showed small but significant improvements with the placebo treatment.

Similarly, progression-free survival was 2.7 months in the study group and 2.6 months in the control group, for a hazard ratio of 0.99 (95% CI, 0.81–1.2; P = .92). Response rates were “quite low,” Spigel said, at 8.8% in the placebo group and 6.4% in the onartuzumab group. The combination therapy was very well tolerated, though it did produce more peripheral edema and hypoalbuminemia, both expected side effects with MET-targeted drugs.

“Unfortunately for our patients, because we need more options, it was a negative trial,” said session discussant Federico Cappuzzo, MD, PhD, of the Ospedale Civile in Livorno, Italy. “Why did we have these negative results? Probably because the selection of patients was not optimal.” Immunohistochemistry is likely not the best way to evaluate MET expression, he said, since other work has shown that MET amplification and immunohistochemistry expression don’t always match up.

“MET remains a very important target in NSCLC, but unfortunately not in the vast majority of patients, just in a small subgroup of approximately 3% to 4% of them,” Cappuzzo said. “Immunohistochemistry is not the best method for allocating patients for treatment with anti-MET agents, and certainly, we need additional trials.”