IASLC 2011 Report – Erlotinib with or without MetMAb in the management of lung cancer
by Dr Sunil Upadhyay – Increased Met signalling in tumours can occur from increased levels of Hepatocyte Growth Factor (HGF), activating mutations within Met, and/or receptor over expression with or without gene amplification. Binding of the Met ligand to its extracellular receptor results in Met activation leading to cell survival, migration and tumour growth. Therefore, inhibition of the ligand binding by targeting the extracellular domain of the Met receptor is an attractive option for tumour control. MetMAb a monovalent (1-armed) anti-Met antibody is designed to effectively bind to the extracellular domain of Met thus effectively competing with HGF binding and receptor activation. In preclinical studies, MetMAb has demonstrated anti-proliferative, anti-angiogenic and pro-apoptotic activity.
Met is associated with a poor outcome in many cancers, including non-small cell lung cancers. Met activation is a mechanism of resistance to EGFR inhibition, supporting dual inhibition hypothesis of Met/EGFR. Final efficacy results from a randomised Phase II study (OAM4558g) evaluating MetMAb or placebo in combination with erlotinib in advanced lung cancers were presented by David Spigel from the USA. Tissue collection was mandatory to assess c-Met IHC expression levels in this study. The co-primary endpoints were progression free survival in the Met Dx+population and intention to treat (ITT) population. Additional end points included safety and overall survival. The Met Dx- patients were removed from the Met-erlotinib group after the initial unblinding.
Patients were stratified according to their smoking history, ECOG performance status, and histology. Treatment was continued until progression. Crossover from placebo to MetMAb was allowed. The baseline characteristics were balanced between the two groups. Met Dx+ was present in 54% of the patients which is associated with worse results. After a median follow-up of 9.9 months, MetMAb + erlotinib resulted in a statistically and clinically significant improvement in both PFS and OS in the Met Dx+ patients. An Overall Survival benefit from MetMAb + erlotinib was observed in the Met FISH + as well as the FISH-/IHC+ group, suggesting that c-Met IHC is a more sensitive predictor of benefit from MetMAb. Removing the data from patients with EGFR mutation did not alter the results.
The result of this small, Phase II study is encouraging but needs further validation in a phase III trial. It provides convincing evidence of additional anti-tumour activity of MetMAb when added to erlotinib in a pre-specified population and that the Met pathway has prognostic as well as therapeutic importance. No other equivalent antibody reached this stage of clinical trials in Met positive lung cancer. One of the interesting observations from this study was that the lack of Met expression (Met negative) seems to be detrimental for treatment with MetMAb + erlotinib compared with erlotinib alone. Therefore, the idea that targeted agents might help but can not harm is not true. Therefore, accurate molecular testing to identify patients who are going to really benefit is essential. It is also not known if the advantage for MetMAb combination is limited to erlotinib. (Abstract O19.03).