MET INHIBITORS FOR NSCLC

A novel agent that blocks MET activation, onartuzumab (under development by Genentech), has shown promise in a phase 2 trial in patients with non-small cell lung cancer (NSCLC).

The results, published online October 7 in Journal of Clinical Oncology, show benefits from onartuzumab in combination with erlotinib (Tarceva) in NSCLC patients who tested positive for MET (using immunohistochemistry).

As a result, onartuzumab is now being investigated in a phase 3 study in combination with, and without, erlotinib in patients with MET-positive NSCLC.

Targeting MET Activation

MET is a transmembrane tyrosine kinase that is frequently dysregulated in tumor cells, explain the researchers, headed by David Spigel, MD, from the Sarah Cannon Research Institute in Nashville, Tennessee.

Elevated MET expression is commonly observed in NSCLC tumor tissue (in 76% of samples in one study [Cancer Res.2005;65:1479-1488]), and it has been associated with a worse prognosis, the researchers note.

In addition, MET appears to cooperate with epidermal growth-factor receptor (EGFR) in driving tumorigenesis, and MET activation has been implicated as a mechanism of erlotinib resistance in tumors with EGFR-activating mutations.

Hence, blocking MET activation could be beneficial for patients with MET-positive NSCLC, they reasoned, and it may also overcome some of the resistance that develops to erlotinib.

The theory was put to the test in a phase 2 trial, which involved 137 patients with NSCLC, randomly assigned to receive a combination of onartuzumab with erlotinib or placebo with erlotinib. Overall, there was no difference between the 2 groups in either progression-free survival (2.2 vs 2.6 months with placebo) or overall survival (8.9 vs 7.4 months with placebo).

However, there was a significant difference in a subset of patients (n = 66) who were found to have MET-positive NSCLC (128 patients had tumor tissue tested, and 52% were found to be MET-positive).

In this subset of 66 MET-positive NSCLC patients, the overall survival was nearly tripled, the researchers report. Median overall survival with the onartuzumab/erlotinib combination was 12.6 months vs 3.8 months with placebo/erlotinib (hazard ratio [HR], 0.37; P = .002). In addition, progression-free survival was nearly doubled to 2.9 months vs 1.5 months with placebo (HR, 0.53; P = .04).

Conversely, in the 62 patients who tested negative for MET, clinical outcomes were worse with onartuzumab plus erlotinib than with the placebo/erlotinib combination, the researchers note.

These results highlight the importance of diagnostic testing in drug development, they comment.

Adverse effects more commonly reported with onartuzumab include peripheral edema, pyrexia, asthenia, insomnia, and pneumonia.

Different Mechanism of Action?

Dr. Spigel and colleagues comment that the results are consistent with previous reports that MET expression is associated with a worse prognosis. However, the improvement in overall survival and progression-free survival seen with onartuzumab and erlotinib suggests that the combination "abrogated the negative prognostic effect of MET expression."

Interestingly, the magnitude of gain in overall survival was much greater than in progression-free survival, the researchers note. "Low response rates, together with this disproportionate progression-free survival to overall survival improvement, suggest that blockade of MET signaling in MET-positive disease may be acting through a mechanism distinctly different from other receptor tyrosine kinase inhibitors," they comment.

"MET has been implicated in the spread of metastases, and therefore the therapeutic benefit of onartuzumab may derive from inhibition of cancer-cell migration and invasion rather than direct inhibition of existing tumor growth," they suggest.

Reports accompanying the publication of this study explore the development of resistance to tyrosine kinase inhibitors (such as erlotinib and crizotinib) in lung cancer, and discuss signaling control by EGFR and MET and rationale for cotargeting strategies in lung cancer.

The trial was funded By Genentech, the developer of onartuzumab. Dr. Spiegel reports having an unpaid consultancy agreement with Genentech, and several authors are employees of Genentech.

J Clin Oncol. Published online October 7, 2013. Abstract