A combination of the investigational agent MetMAb plus erlotinib appears to improve both progression-free and overall survival rates in patients with non-small cell lung cancer (NSCLC) and high MET expression, according to the results of a Phase II trial reported at the ESMO Congress.
David R. Spigel, MD, Director of Lung Cancer Research at the Sarah Cannon Research Institute, who reported the findings, explained that MetMAb is a monoclonal antibody that binds specifically to the MET receptor on cancer cells.
Added ESMO press officer Fortunato Ciardiello, MD, PhD, Professor of Medical Oncology at the Second University of Naples: “It has been shown that MET can be overexpressed or amplified in these patients, and this has been correlated with resistance to epidermal growth factor receptor inhibitors such as erlotinib. As such, MET is an important switch in cancer cells. MetMAb helps target this switch and turn it off.”
The randomized, double-blind study, which was sponsored by Genentech, involved 128 patients with advanced non-small cell lung cancer who were randomly assigned to treatment with either erlotinib plus placebo, or erlotinib plus MetMAb (given at 15 mg/kg intravenously). Overall, about 20% of NSCLC patients have MET overexpression or amplification, said Dr. Ciardello.
All the patients had disease that had progressed after one or two prior therapies.
Patients in the control arm had the option of being unblinded and crossing over to receive MetMab, and 23 patients chose to do so.
Among patients who received MetMab, 57% were MET-positive, 23% had a KRAS mutation, and 13% were positive for EGFR mutation. Among patients in the erlotinib and placebo group, the figures were similar—51%, 23%, and 11%, respectively.
After randomization, immunohistochemistry was performed, and patients who had 2% or 3% stains were defined as MET high, while those with either no expression or 1% expression were defined as MET low.
MET-High Patients Benefit
Among the entire intent-to-treat population, the progression-free survival rates were nearly identical in the two arms, indicating no advantage to MetMab, and this was also the case for survival, Dr. Spigel reported.
However, in the predefined population with MET overexpression, the progression-free survival time was 12.4 weeks in the MetMab arm vs only 6.4 weeks in the erlotinib-plus-placebo group— “resulting in a dramatic hazard ratio of 0.56,” he said.
There was also an overall survival rate benefit for MET-high patients who received the experimental treatment, with a hazard ratio of 0.55. Patients with low MET expression who received MetMab, however, were twice as likely to have disease progression and more than three times more likely to die.
“In those patients who were found to express the MET protein, MetMAb appeared to improve the treatment benefit when added to erlotinib compared with erlotinib alone,” Dr. Spigel said.
Conversely, patients whose tumors did not express the MET protein appeared to do worse when treated with the MetMAb/erlotinib combination, he said.
No Other Subgroups Benefit
Dr. Ciardiello said he wouldn't expect the drug to work well in patients with low MET expression, since MET is the target of MetMab.
The combination therapy did not appear to benefit any other subgroup, including patients with nonsquamous cell cancer and those with EGFR or KRAS mutations.
Overall adverse events, including rash, diarrhea, and fatigue, were similar among the two groups in both MET-positive and MET-negative subpopulations.
In the MET-negative patients who received the experimental therapy, however, the incidence of Grade 3 and higher events were substantially higher. In the MET-positive arm, they were similar in both treatment groups (54% vs 53%).
Larger Trial Warranted
Dr. Ciardeiello said that the trial is still exploratory, so it is not possible to draw any firm conclusions, but that given the signal in patients with high MET expression, a larger Phase II or Phase III trial is warranted.