Case Study: MET and ALK Targeted Therapies in NSCLC

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Novel agents that target MET are currently under investigation in non-small cell lung cancer (NSCLC), explains moderator Corey J. Langer, MD. These agents are commonly being combined with erlotinib for patients with non-squamous histology.

The two leading MET inhibitors under investigation are onartuzumab (MetMAb) and tivantinib, explains Karen L. Reckamp, MD, MS. At this point, the phase III MetLung trial is exploring the efficacy and safety of onartuzumab in combination with erlotinib for patients with MET-positive NSCLC by IHC. In this study, patients are randomized to receive erlotinib with onartuzumab or placebo following prior treatment with chemotherapy. The primary endpoint of the trial is overall survival.

The phase III MARQUEE trial explored erlotinib with or without tivantinib in previously treated patients with advanced non-squamous NSCLC. However, an independent review in September 2012 resulted in the early discontinuation of this trial due to futility. This trial did not select patients for treatment based on MET status. Results from this trial will be presented at the 2013 ECCO-ESMO meeting held in the Netherlands.

At this point, Langer decides to adjust the example, stating that the patient tested positive for an EML4-ALK translocation. Regardless of the setting, if a test returns positive for the ALK translocation treatment with crizotinib is warranted, explains Anne S. Tsao, MD. Based on its broad biologically based efficacy, crizotinib is approved in all lines of therapy for patients with EML4-ALK alterations. For patients who are resistant to crizotinib, second-generation ALK inhibitors are currently under investigation.

In the phase III PROFILE 1007 trial crizotinib was compared to docetaxel or pemetrexed in previously treated patients with ALK-positive NSCLC. This trial showed a significant advantage in the primary endpoint of progression-free survival in favor of crizotinib. Observationally, Langer notes, there also appeared to be a slight advantage for pemetrexed over docetaxel, although these agents were not directly compared in the study.