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In Halting METLung, Roche Evaluating How to Proceed with Other Lung Cancer Trials of Onartuzumab

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Originally published March 3.

Roche's announcement this week that it is halting a Phase III trial of its investigational non-small cell lung cancer drug onartuzumab in combination with Tarceva (erlotinib) in previously treated patients with MET-positive tumors may have implications for other trials the company is running that are exploring a similar molecularly targeted treatment strategy in lung cancer patients.

Evaluation by an independent data monitoring committee recently found that the METLung study failed to show "clinically meaningful efficacy" of the combination regimen over just Tarceva. As a result, Roche has decided to stop the trial, which had aimed to enroll nearly 500 pretreated NSCLC patients.

Now, Roche is evaluating what to do about other lung cancer studies involving the investigational drug, including one called METDriver, in which researchers are planning to enroll 300 previously untreated NSCLC patients with unresectable stage IIIB or IV disease. Patients enrolled in this Phase III, double-blind, randomized trial will have to have EGFR mutations and be MET positive. Like METLung, this study will compare an onartuzumab/Tarceva regimen against Tarceva, but involve patients who are earlier in their treatment trajectory.

"We are evaluating the implications of the METLung study results across the ongoing onartuzumab clinical program, including METDriver," a Roche spokesperson said.

In METLung, only patients whose tumors were MET positive were enrolled. A tumor was deemed MET positive when there were high levels of the protein as assessed by an immunohistochemistry test developed by subsidiary Ventana.

When the MET protein binds to another protein, called HGF, it dimerizes and signals cells to multiply and spread. Earlier studies have suggested that MET activation drives patients' resistance to EGFR inhibitors, such as Tarceva. Pre-clinical studies have also shown that dual inhibition of EGFR and MET may be a more potent strategy than targeting a single pathway.

Roche has said that it plans to report results from METLung at a future medical meeting. The company spokesperson said it was too early to determine why METLung yielded disappointing results. The Phase III results came out different than the company was expecting, based on a Phase II study of the same design.

In 2011, Roche reported that onartuzumab (then called MetMAb) in combination with Tarceva did not show a statistically significant improvement in progression-free survival in the overall patient cohort, including those with high and low MET expression. However, in those with high MET expression, onartuzumab/Tarceva doubled median progression-free survival compared to Tarceva (2.9 months versus 1.5 months), and tripled median overall survival (12.6 months versus 3.8 months).

"These results were consistent with the scientific hypothesis of the interaction of the MET and EGFR pathways that drives the growth of lung cancer tumors," the company spokesperson said. "The decision and the design of the study were informed by discussions with leading oncologists."

The METLung trial, now may have implications for METDriver and other studies involving onartuzumab. Outside of the lung cancer setting, Roche is also studying onartuzumab in combination with the chemotherapy regimen mFOLFOX6 (5-fluorouracil, folinic acid, and oxaliplatin) versus just mFOLFOX6 in patients with HER2-negative, MET-positive patients with adenocarcinoma of the stomach or the gastroesophageal junction.

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