The other important data that came out of this study which corroborated other data but put us on the radar screen, is that the left- and right-sided colons are not the same. The tumors that arise from the left side of the colon have a far better prognosis and they are the ones that may potentially benefit from frontline EGFR
-targeted therapy. Whereas, tumors on the right side have a worse prognosis and there was no evidence that the EGFR
-targeted therapies offered anything there. My personal style is that I don’t use the EGFR
-targeted therapies upfront [unless] one wishes to consider it. It is only in RAS
wild-type, left-sided tumors.
How have you seen the wave of PD-1 inhibitors impact patients with MSI-high patients?
The issue of MSI is a somewhat complicated one; about 15% of all patients who develop CRC will have MSI-high tumors, and we can look for that either by doing the PCR for MSI or immunohistochemistry for MMR deficiency. However, we know that that is a relatively good prognosis for stage II and III patients, and they have a lower [chance] to go stage IV disease. Whereas, only somewhere between 2% and 4% with mCRC will have MMR deficiency and that is the subset for whom the checkpoint inhibitors appear to be useful.
Specifically, the PD-1 inhibitors, which are far easier to tolerate than the CTLA-4 inhibitors, are the ones that are now approved for treatment. Therefore, it has been appropriate to do genetic screening to screen all patients with MMR deficiency. The patients with metastatic disease who have MMR deficiency have a high likelihood of benefitting from either pembrolizumab or nivolumab. For patients who are microsatellite stable (MSS), we don’t have evidence that any of the commercially available checkpoint inhibitors are useful at this time. There is an active investigation underway to try to figure out how to change that, to see what other immunomodulatory agents might be useful in MSS CRC. However, outside of a clinical trial, we don’t have anything right now.
TRK fusions can be found in patients with CRC. If entrectinib gets approved by the FDA, how might this affect clinical practice?
That is going to be a complicated question because TRK
fusions occur in 1 in 5000 patients, so we are going to get into a very complicated question: how do we go about justifying screening everybody for TRK? Is that the right thing to do? That is a question that society is going to have to wrestle with.
There are emerging data suggesting that TRK
fusions are virtually nonexistent in the presence of RAS
mutations, so there may be a subset of patients for whom it is a more rational thing to look for. This is investigational right now; we don’t have TRK
fusion–targeting drugs available commercially.
It creates a real challenge in terms of determining how are we going to figure out which patients have these specific rare mutations that may benefit from precision-type applications of medicine. It is an example of where precision medicine does have a substantial impact, as long as we can find the right patients.
What ongoing clinical trials in mCRC are you excited about?
It is hard to say what is exciting, because a lot of [studies] are in progress and they are very widely spread out across the world; no one site is developing a tremendous amount of experience. We are hopeful that some of the preliminary data that were presented with the combination of MEK inhibitors and PD-1/PD-L1 inhibitors will turn out to be useful. There were very preliminary data 2 years ago, and there hasn’t been much that we have heard from since, so we are going to have to wait on that.