CHICAGO – Final efficacy results from the phase II OAM4458g trial confirm that the success of MetMAb in previously treated advanced lung cancer lies in accurate biomarker testing.
While some patients gained a striking survival advantage when given the investigational monoclonal antibody as second-or third-line therapy for non–small cell lung cancer (NSCLC), the study group as a whole did not and others actually did worse. The difference appears to be driven by expression of the c-Met receptor.
Dr. David Spigel
MetMAb targets hepatocyte growth factor and its receptor, c-Met. Expression of c-Met is associated with a worse prognosis in many cancers, including NSCLC. Met activation by hepatocyte growth factor is also thought to decrease sensitivity to erlotinib (Tarceva). Hence the interest in combining MetMAb with erlotinib. In this trial patients received either a combination of the two drugs or erlotinib with a placebo.
In NSCLC patients whose tumors were classified as Met positive, the addition of MetMAb to erlotinib nearly doubled the median time that they were free of disease from 1.5 months to 2.9 months (hazard ratio, 0.53; log rank P = .04) and tripled median overall survival from 3.8 months to 12.6 months (HR, 0.37; log rank P = .002), Dr. David Spigel said at the annual meeting of the American Society of Clinical Oncology.
When MetMAb plus erlotinib was given to patients with Met-negative tumors, however, median progression-free survival was significantly lower at 1.4 months, compared with 2.7 months in the control arm given erlotinib plus placebo (HR, 1.82; P = .05).
Median overall survival was also shorter with the combination in the Met-negative group – 8.1 months vs. 15.3 months with erlotinib and placebo – although the difference did not reach statistical significance (HR, 1.78; P = .158), said Dr Spigel, director of lung cancer research at the Sarah Cannon Research Institute in Nashville, Tenn.
Invited discussant Dr. Tony Mok, with the Chinese University of Hong Kong, said there’s no doubt that MetMAb should move into phase III evaluation, but stressed the need for accurate biomarker testing in patients to determine Met status.
"This is the key to the success of this drug," he said. "Is this biomarker valid and trustworthy?"
The Met diagnostic test used in the phase II study was developed by Ventana Medical Systems, a tissue diagnostics company owned by Roche, the parent company of the study sponsor, Genentech. Met status was assessed after randomization and prior to unblinding, with 93% of all 137 patients having adequate tissue for evaluation of c-Met by immunohistochemistry. In all, 52% of patients with evaluable tissue were "Met diagnostic positive," defined by at least 50% of tumor cells with moderate or strong staining intensity, Dr. Spigel explained.
Patients were randomized to erlotinib 150 mg daily plus MetMAb 15 mg/kg IV every 3 weeks or the same dosing of erlotinib and placebo. Coprimary end points were progression-free survival in the Met diagnostic–positive and intention-to-treat populations.
In the latter, the combination of MetMAb and erlotinib failed to significantly improve median time to progression over erlotinib (2.2 months vs. 2.6 months; HR, = 1.09; P = .69) or overall survival (8.9 months vs. 7.4 months; HR, 0.80; P = .34), he said.
The researchers performed additional analyses in key subpopulations, suggesting that the benefit from MetMAb is not related to epidermal growth factor receptor mutation or fluorescence in situ hybridization (FISH) status.
Although the patient numbers were small, an overall survival advantage was observed with MetMAb for patients with high Met expression (at least 5 copies) by FISH (HR, 0.60; P = .35), and was maintained in FISH-negative/Met diagnostic–positive patients (HR, 0.37; P = .01), Dr. Spigel said. Patients who were Met diagnostic positive and did not have an epidermal growth factor receptor mutation also gained a survival advantage (HR, 0.42; P = .01).
"Outcomes in the diagnostic subpopulations highlight the importance of developing tools to identify patients who might best benefit from this treatment," he said, adding that immunohistochemistry appears to be more sensitive than FISH in determining benefit from combination MetMAb/erlotinib.
The study confirmed that Met expression by immunohistochemistry is associated with worse outcomes. An analysis of the 68 patients treated with erlotinib plus placebo confirmed that Met expression revealed that progression-free survival was worse among Met diagnostic–positive vs. Met diagnostic–negative patients (1.5 months vs. 2.7 months; HR, 1.71; P = .06), as was overall survival (3.8 months vs. 15.3 months; HR, 2.61; P = .004).
In response to audience questions, Dr. Spigel said it is unknown whether metastatic sites have different Met expression than primary tumor sites or why outcomes are worse in low Met tumors.