Spigel D.R., et al. Final efficacy results from OAM4558g, a randomised phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol 2011 (suppl; abstr 7505)
The hepatocyte growth factor (HGF)–mesenchymal-epithelial transition factor (MET) molecular pathway affects cancer development at different stages, from initiation to metastatic behaviour, in many tumour types, among them lung cancer.
The epidermal growth factor receptor (EGFR), or ERBB, family is important in carcinogenesis. Among its’ members, EGFR and human epidermal growth factor receptor type 2 (ERBB2) are now successfully targeted by biological agents used in cancer therapeutics. However, their effectiveness is limited in some patients because of the development of intrinsic or acquired resistance, and there is a need to identify other molecular participants in ERBB-related cellular events. Lung carcinomas are also dependent on MET receptor as an absolute requirement for their development and progression. MET-related signal transduction is thought to be involved in the development of resistance to EGFR-targetting agents.
MET interacts with EGFR proteins in several ways. In tumour-cell lines, EGFR activation leads to MET-ligand-independent constitutive activation. It has been reported that MET amplification in lung-cancer cell lines treated with EGFR tyrosine-kinase inhibitors can circumvent the blocking activity of these agents by maintaining activation of EGFR downstream pathways. Specifically, HGF–MET activation leads to EGFR-independent activation of the PI3K–AKT pathway through the cross-activation of ERBB3. Treatment of resistant cells with a tyrosine-kinase inhibitor specific for MET or EGFR can not affect cell viability or ERBB3-related phosphorylation events. However, the combined targeting of MET and EGFR can stop the growth of resistant cells and inhibit ERBB3–PI3K–AKT signalling. Furthermore, such a combinatorial strategy in patients with lung cancer can also circumvent resistance to EGFR tyrosine-kinase inhibitors mediated by the Thr790Met.
Various strategies are currently in development to disrupt the HGF–MET signal transduction pathway. Most are being assessed in preclinical animal models or are entering early clinical testing. Before these treatments proceed to large-scale clinical trials, their antitumour activity as a single therapeutic strategy or in combination with other molecularly targeted agents (mainly EGFR inhibitors) should be established, and concerns regarding toxic effects in healthy tissues (eg, liver regeneration) need to be adequately addressed. HGF inhibitors include biological antagonists and neutralising monoclonal antibodies (MAbs).
OAM4558g is a randomised phase II trial that was presented in the recent congress of American Society of Clinical Oncology in Chicago. In this trial 128 previously-treated patients with advanced and/or metastatic non-small cell lung cancer (NSCLC) were randomised to receive erlotinib with placebo or a Met MAb. In most of the patients tissue was available for c-Met immunohistochemistry (IHC) (95%), MET FISH (75%) and EGFR / KRAS mutation analysis (88%).
A statistically significant improvement in both progression-free survival (PFS) and overall survival (OS) was reported in the combination arm. Interestingly enough, this benefit was not exclusive to EGFR mutant or MET FISH+ lung carcinomas and was also observed in MET FISH- / IHC+ lung carcinomas. The toxicity profile was comparable in both treatment arms.
The HGF–MET pathway is a promising target for the development of novel agents. The heterogeneity that characterises MET-related carcinogenesis, along with the documented cross reactions with other membrane-initiated molecular routes, warrants well designed preclinical strategies for finding the best methods of HGF–MET inhibition in lung carcinomas. The concept of targeting HGF–MET pathway as a strategy to overcome resistance to EGFR-targetting agents seems clinically feasible. The role of the ERBB3 and PI3K–AKT molecular cascades as a dominant mechanism in resistance to anti-EGFR protein-targeting agents is of paramount importance, although it is part of a multifactorial, and possibly tissue-specific, process of resistance development.