ESMO 2012, Vienna, Austria
MET inhibitors for non-small cell lung cancer
Professor Georgio Scagliotti – University of Torino, Italy
Dr Scagliotti, we’re here at ESMO 2012 and yesterday you presented some interesting new data on a MET inhibitor for non-small cell lung cancer.
Yes, they are not totally new because, as I said, the data had been already presented at other meetings. What is the most important information that came from the data that has been presented is the fact that a huge phase III study has been already closed down and finished accruing in May 2012. That specific phase III study was generated on the basis of the outcome of the phase II data. So the phase II study was looking at patients who were previously exposed to at least one line of therapy, maximum two lines of therapy, excluding the exposure to EGFR TKIs. Patients were randomly allocated to receive erlotinib plus tivantinib, that is an oral tyrosine kinase inhibitor against MET, versus erlotinib alone; that is one of the indications for erlotinib, the second line indication is an approved indication for this drug. So in total 154 patients were included in this study and the primary endpoint was the progression free survival in the intent to treat population. After the adjustment of the progression free survival data as well the overall survival data for prognostic factors, the difference in terms of progression free survival and overall survival was marginally statistically significant. The benefit was statistically significant in the non-squamous population and that specific population was the population that was considered for the phase III study. The phase II study included also a lot of molecular analysis, the most important one was the assessment of the c-MET status originally through c-MET amplification, that is a relatively rare event, and subsequently also through immunohistochemistry. In addition to that, the other added value for that specific study was the mandatory tissue collection for every patient. The mandatory tissue collection was requested at the time of the inclusion into the study so we were not working on archive material. Obviously, as anything in medicine, it’s almost impossible to collect 100% of the samples and to analyse 100% of the samples but it was possible to generate a lot of molecular data in the vast majority of the patients. What was of some scientific interest was the fact that the combination of tivantinib and erlotinib was much more effective in KRAS positive patients than in KRAS naïve patients, but again this information is based on a limited number of positive patients because obviously you don’t have too much information with the incidence of KRAS mutation only 20% of the patients with non-squamous, non-small cell lung cancer.
So how does KRAS link to MET?
This is a totally unexpected finding, as I said. We need to carefully follow this information in the phase III because it could be that we don’t know completely, for instance, the co-inhibition of two pathways it’s leading to. There are preclinical models telling us that also in the wild type EGFR cell lines the co-inhibition of the EGFR pathway and consequently in the cell line that is not addicted to EGFR, but the inhibition of the EGFR pathway, together with the inhibition of the c-MET pathway, they are leading to a KRAS inhibition, they are leading to a better inhibition. Obviously KRAS is playing an important role in the transmission of the signal and consequently we need to carefully follow the larger cohort, hopefully, that we will get from the phase III study.
So would the idea be that the drug will be tested on selected patients that have this mutation?
We need to put this data into a more general context also with the data that are coming out from other MET inhibitors, including monoclonal antibodies and other TKIs. There is a general trend across several studies that there is a much better benefit for those patients who are c-MET positive at the immunohistochemistry, being defined in positivity for those tumours having more than 50% positive cells. So this is true for another experimental compound as well as for the MetMAb monoclonal antibody and it was also true for tivantinib in the hepatocellular carcinoma study that has been presented at ASCO 2012. So this is something that, again, I’m not making any final statement, I’m saying that the fact that you have much more expression of the protein makes sense; that probably you are getting a much better activity through the inhibition of the MET pathway at the different levels. But this is something that we need to validate prospectively in the context of a phase III clinical trial.