New ALK Agents: Lung Cancer's 'Second Miracle'?

Giorgio V. Scagliotti, MD, PhD; D. Ross Camidge, MD, PhD


October 07, 2013

In This Article

Dual Inhibition: EGFR and cMET

I made a presentation[16] about a large phase 3 study that we did in second-line in nonsquamous histology (mainly stage IV nonsquamous patients) investigating the role of the coinhibition of the EGFR and mesenchymal-epithelial transition (cMET) pathways in genotypic "all-comers." There was stratification for the EGFR genotype and the KRAS genotype, but the treatment was delivered to all patients with nonsquamous cell lung cancer. We found no improvement in survival, a significant improvement in progression-free survival in the overall patient population, and a higher objective response rate. When we were selecting according to the cMET status, as has been done before, we found that there was an improvement in progression-free survival as well as in overall survival in the cMET-positive population, whereas the data from the cMET-low population was a bit confused. I would like to get your opinion on the meaning of this and the potential of the coinhibition of 2 different pathways in the cancer cell.

Dr. Camidge: I was going to ask you that question because you were the principal investigator of the study. Do you think the study was designed correctly? Why have these 2 targeted agents and give them to essentially an unselected population?

Dr. Scagliotti: It was mainly driven by the data generated in the phase 2 study in which they found that when all-comers were treated (including squamous cell), the progression-free survival was significantly improved in those with nonsquamous cell cancer. The molecular characteristics that were analyzed in that study were minimal, so they didn't get enough strong signals.

For example, the KRAS-mutated patients showed more benefit from the combination than from single-agent erlotinib, but the analysis was done only in 15 tumor samples. The same was done for the gene amplification and for EGFR wild-type vs EGFR mutants. The benefit of cMET inhibition combined with the EGFR inhibition was stronger in the EGFR wild-type patients than the EGFR-mutant patients. Furthermore, the follow-up for the EGFR mutant is still relatively short. We haven't had enough events to make a final statement about that, but it is still up in air; the jury is still out. We need to put these data in the context of ongoing studies.

Dr. Camidge: What led you to combine the 2 drugs? Why didn't you explore a monotherapy signal with the drug on its own?

Dr. Scagliotti: They did. The drug came from a small biotech company that did the single-agent study in just a few patients, and they saw marginal single-agent activity. That was not unexpected because we have preclinical data saying that the MET inhibitors work only in cell lines that are gene-amplified, but at the clinical level there is no such strong correlation. Consequently, all the studies have been done with immunohistochemistry. I believe that the coinhibition of 2 different pathways can potentially generate much better data than the inhibition of each pathway alone. I am not certain of the value of inhibiting the EGFR pathway in the EGFR wild-type mutation.

Dr. Camidge: My take would be that we know that MET on its own can be a primary driver, and the best evidence is for a gene amplification. The issue is where we put the cut-off to say that the patient is MET gene-amplified. If you look at the lung cancer mutation consortium, their 2% MET-amplified figure is using as a cut-off a ratio of the gene to the centromere of 2.2. That is probably not high enough to truly identify MET as a driver, and the 1 case report of a MET-amplified patient who responded to crizotinib (which is also a MET inhibitor) had a ratio of more than 5, so very highly amplified. There might be a monotherapy signal. In terms of MET being a second driver, the only evidence that we have is in the EGFR-mutated patients, so I agree that the EGFR wild-type population in this study is interesting, but I worry that it is diluting out any true signal that might be in there.

Dr. Scagliotti: It is important to me because people are misunderstanding the meaning of MET, and it is probably interfering not only with the tumor but also with the host. This is much more complicated that just hitting 1 target, as we are used to doing in the EGFR mutants, and probably is a more complex interplay.

Thank you, Ross -- and you, our audience -- for joining me for this edition of Medscape Oncology Insights. This is Giorgio Scagliotti reporting from the ECC 2013.


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