Final results from a randomized, multicenter, double-blind Phase II study with MetMAb, Genentech‘s investigational personalized medicine, in people with previously treated advanced non-small cell lung cancer (NSCLC)seems to indicate that the treatment may offer a beneficial treatment.
MetMAb is a unique monovalent or one-armed investigational antibody designed to target Met, a protein (or receptor) associated with a poor outcome in many cancers. MetMab blocks Met signaling in cancer cells by binding specifically to the cell surface Met receptor, blocking HGF-mediated activation.
The study showed that people whose tumors had high levels of Met, as determined by a companion diagnostic, lived twice as long without their disease getting worse (progression-free survival or PFS) when they received MetMAb plus erlotinib (Tarceva?, OSI Pharmaceuticals, LLC) compared to erlotinib alone.
Overall survival (OS) was evaluated as an exploratory endpoint and the study showed MetMAb plus erlotinib tripled the time people with this form of advanced NSCLC lived compared with erlotinib alone. There were no unexpected safety signals from the combination of MetMAb with erlotinib and the safety profile of erlotinib was consistent with previous studies of the medicine in people with solid tumors.
“The unique design of MetMAb and the development of a companion diagnostic test allowed us to target a specific pathway that may be driving cancer growth,” said Hal Barron, M.D., chief medical officer and head, Global Product Development. “These results support further investigation of MetMAb as a potential personalized medicine for people with lung cancer and we plan to start a Phase III study later this year.”
In the Phase II MetMAb study, people with previously treated NSCLC had their tumors analyzed for Met protein levels using an immunohistochemistry (IHC) test developed by Roche’s Tissue Diagnostics Company, Ventana Medical Systems. Tumors 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 erlotinib did not show a statistically significant improvement in PFS compared to erlotinib alone (hazard ratio [HR]=1.09, p=0.687, median PFS: 2.2 months for the combination vs. 2.6 months for erlotinib alone).
In people with high Met tumors, those who received MetMAb plus erlotinib had a statistically significant doubling of PFS compared to those who received erlotinib 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 erlotinib also led to a statistically significant improvement in OS compared to erlotinib alone (HR=0.37, p=0.002) in people with high Met tumors. The improvement in median OS was tripled from 3.8 months to 12.6 months.
The most common adverse events (AEs) of any grade (?15 percent in any subgroup or study arm, regardless of Met diagnostic status) included rash, diarrhea, fatigue, decreased appetite, nausea, shortness of breath, cough, acne-like rash, infections, dry skin, anemia (low red blood cell count), vomiting, fever, pain, chest pain, back pain and peripheral edema (swelling of the hands and feet). Of these AEs, only peripheral edema was seen at a higher rate (more than 10%) in the combination group compared with the erlotinib only group (23.2% vs. 7.5%).
Although PFS and OS were improved in people classified as having high Met tumors, those with low Met tumors had worse outcomes when given MetMAb plus erlotinib as compared to erlotinib alone (PFS: HR=1.82, p=0.050, median PFS: 1.4 months for the combination vs. 2.7 months for erlotinib alone; OS: HR=1.78, p=0.158, median OS: 8.1 months for the combination vs. 15.3 months for erlotinib alone). 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.
Full results of the OAM4558g study will be presented during an oral abstract session at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 5, 2011, by David R. Spigel, M.D., the principal investigator and program director of Lung Cancer Research at the Sarah Cannon Research Institute in Nashville, Tenn. (Abstract #7505, Sunday, June 5, 10:00 – 10:15 a.m. CDT, Hall D1).
Phase II Study Design
OAM4558g is a global, randomized, double-blind Phase II study comparing MetMAb plus erlotinib to placebo plus erlotinib in people with previously treated advanced NSCLC. One hundred and thirty-seven patients were randomized equally between the two arms between March 2009 and August 2010. Eligible patients in the placebo plus erlotinib arm were allowed to receive MetMAb following progression.
Patients’ tumors 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.
The Met Pathway
Many cancers are the result of abnormal growth, replication and survival of cells. These factors are controlled by signaling 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). Signaling 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.