Date: 2014-03-03
Type of information:
phase: 3
Announcement: interim results
Company: Roche (Switzerland)
Product: MetMAb (onartuzumab)
Action mechanism: Many cancers are the result of abnormal growth, replication and survival of cells. These factors are controlled by signalling pathways that relay information from the outside to the inside of cells, via receptors. Met is a receptor, expressed on the surface of epithelial and endothelial cells, which is activated by a protein, called hepatocyte growth factor (HGF). Signalling through the HGF/Met pathway can become abnormal and cause healthy cells to become cancerous. By preventing the binding of HGF to Met, the ability of cancerous cells to grow, replicate, survive and spread is inhibited. MetMAb is a unique, monovalent (one-armed), monoclonal antibody designed to block Met signalling in cancer cells by binding specifically to the cell surface Met receptor, blocking HGF-mediated activation.
Disease: previously-treated advanced non-small cell lung cancer
Therapeutic area: Cancer - Oncology
Country: Argentina, USA
Trial
details: *METLung is a Phase III, randomised, double-blind study evaluating the efficacy and safety profile of onartuzumab in combination with Tarceva® in patients with previously treated (second- or third-line) advanced NSCLC identified to be MET-positive. The METLung study included a companion diagnostic immunohistochemistry (IHC) test that was co-developed with Ventana Medical Systems, Inc., a member of the Roche Group.• Four hundred and ninety-nine patients were randomized to receive 150 mg of Tarceva taken daily plus either:o Intravenous 15 mg/kg of onartuzumab every three weekso Intravenous placebo every three weeks• The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate and safety profile. (NCT01456325)* OAM4558g is a global randomised, double-blind Phase II study comparing MetMAb plus Tarceva® to placebo plus Tarceva® in people with previously treated advanced NSCLC. One hundred and thirty-seven patients were randomised equally between the two arms between March 2009 and August 2010. Eligible patients in the placebo plus Tarceva® arm were allowed to receive MetMAb following progression. Patients’ tumours were classified as Met diagnostic-positive (high Met) or Met diagnostic-negative (low Met) depending on the results of the investigational companion diagnostic test. The primary endpoint of the study was PFS in the high Met and overall populations. Additional endpoints included OS and the safety profile.
Latest
news: * On March 3, 2014, Roche has announced that an independent data monitoring committee has recommended that the phase III METLung study be stopped due to a lack of clinically meaningful efficacy. The study evaluated if onartuzumab in combination with Tarceva® (erlotinib) helped patients with previously treated, advanced non-small cell lung cancer whose tumours were identified as MET-positive live longer compared to Tarceva® alone. Overall adverse event rates were generally similar between the two groups. Data will be submitted for presentation at a forthcoming medical meeting. Roche is evaluating the implications of the METLung study results across the ongoing onartuzumab clinical programme.* On May 19, 2011, Roche has announced final results from a randomised, multicentre, double-blind Phase II study with its investigational personalised medicine, MetMAb, in people with previously-treated advanced non-small cell lung cancer (NSCLC). MetMAb is a unique one-armed investigational antibody designed to target Met, a protein (or receptor) associated with a poor outcome in many cancers. The study showed that people whose tumours had high levels of Met, as determined by a companion diagnostic, lived twice as long without their disease getting worse (progression-free survival, [PFS]) when they received MetMAb plus Tarceva® (erlotinib) compared to Tarceva® alone. Overall survival (OS) was evaluated as an exploratory endpoint and the study showed MetMAb plus Tarceva® tripled the time people with this form of advanced NSCLC lived compared with Tarceva® alone. There were no unexpected safety signals from the combination of MetMAb with Tarceva and the safety profile of Tarceva® was consistent with previous studies of the medicine in people with solid tumours. In the Phase II MetMAb study, people with previously-treated NSCLC had their tumours analysed for Met protein levels using an immunohistochemistry (IHC) test developed by Roche’s Tissue Diagnostics Company, Ventana Medical Systems. Tumours with high Met protein levels were classified as Met diagnostic-positive, and with low Met protein levels as Met diagnostic-negative. In the overall population of patients with high and low Met expression, the combination of MetMAb and Tarceva did not show a statistically significant improvement in PFS compared to Tarceva alone (HR=1.09, p=0.687, median PFS: 2.2 months vs. 2.6 months). In people with high Met tumours, those who received MetMAb plus Tarceva had a statistically significant doubling of PFS compared to those who received Tarceva alone (HR=0.53, p=0.04). The median PFS was improved from 1.5 months to 2.9 months. The addition of MetMAb to Tarceva also led to a statistically significant improvement in OS compared to Tarceva alone (HR 0.37, p=0.002) in people with high Met tumours. The improvement in median OS was tripled from 3.8 months to 12.6 months.
Although PFS and OS were improved in people classified as having high Met tumours, those with low Met tumours had worse outcomes when given MetMAb plus Tarceva as compared to Tarceva alone (PFS: HR=1.82, p=0.050, median PFS 1.4 months vs. 2.7 months; OS: HR=1.78, p=0.158, median OS=8.1 months vs. 15.3 months). This result highlights the importance of a companion diagnostic in evaluating the efficacy of experimental therapeutics to distinguish between the people who may potentially benefit from a new medicine as well as those who may not. A phase III study should start later this year.
