Future Directions in Later Line Therapy for mCRC

Axel Grothey, MD: Future drug development of active agents in the later-line setting will focus on 2 things. Number one, identifying patients molecularly to find subgroups for a targeted intervention. I’m looking at low-frequency mutations and alterations, like BRCA mutations, which do exist in colorectal cancer but at lower frequency, for instance, in than pancreatic cancer, prostate cancer, and breast cancer. I’m looking at other alterations like fusions, RET alterations, etc. Everything we know from other tumors should be tested in colorectal cancer. Even if we just identify 2% to 5% of patients with these selected mutations that are targetable, it helps these 2% to 5% of patients.

The other point is, of course, we want the immunotherapy to work because immunotherapy is a very powerful tool that can meet sustained response, really affect the clinical course of patients dramatically. I strongly believe that with further insights and escape mechanisms, immunosuppressive effects of cancers, we will find combination therapy. It is clearly not a single agent. It is combination therapies that will augment immune responses, will make immunotherapy work in MSS [microsatellite stable] colon cancer. It is not one agent that I would single out right now, so that’s the road forward. There are dozens of trials ongoing right now, and this shows me, with various combinations, that no one knows exactly the right answer because preclinical models are not perfect in predicting what’s happening in a host like a human body in terms of immunotherapy. But I have not given up hope.

Heinz-Josef Lenz, MD, FACP: I’m very excited about the future because I think you have just started to take advantage of the newest molecular technology profiling platforms, such as NGS [next-generation sequencing]. We will identify more unique targets and may potentially fragment out more colon cancer, which we have started with the BRAF, MSI [microsatellite instability], and KRAS. That will expand, and 1 of the major new strategies is that we are so focused on a single mutation—KRAS, BRAF, PI3 kinase or TP53—that we have not even learned to understand what it means when you have a KRAS and a TP53 mutation. Does that change the efficacy of certain target drugs? I think we are just in the beginning of understanding the complexity of genetic signatures because we have been stuck to 1 mutation or the other and have not moved on to that. Machine learning, artificial intelligence will help us understand it. I’m very excited about that.

There are a lot of new drugs coming, and the challenge is how can we select the patients? These molecular profiling technologies developing are very helpful. I’m also very excited about the use of liquid biopsies to monitor real-time molecular changes, identifying novel targets and potentially use better treatments, taking advantage of the activated mechanism resistant pathway you see in the liquid biopsies. I’m very optimistic. I’m sure we did push further the limit and increase overall survival for our patients.

We will see in the next couple of years improvements in the KRAS-mutant population. We now have SOS inhibitors. We have certain vaccines and Polo kinase inhibitors, which seemed to be promising in a subset of KRAS mutant. I’m very hopeful that this will move forward and we will finally have a more effective treatment for KRAS mutant. With the deep understanding of immune signaling, we will get better immunotherapy combinations, and we have now more sophisticated vaccines and the entrance of oncolytic viruses. I’m very optimistic that we will also make significant progress for the MSS patients, who at the moment are very limited to use clinical trials with immunotherapy combinations.

Fortunato Ciardiello, MD, PhD: Clearly, we have done a very important series of steps forward that better derive prognosis from a management of metastatic colorectal cancer. Twenty years ago we had very few drugs and the expected median survival was between 6 and 12 months for most patients. Now we have extended 3 or 4 times the expected survival time for most patients. What we need to do is understand more the tumor heterogeneity of metastatic colorectal cancer. We need to apply more chemotherapy, chemotherapy combinations, sequencing of therapy in different lines of treatment, and rechallenge with specific drugs and biologic agents against specific molecular targets and immunotherapy in a more selective way. Basically, the big challenge in the treatment of metastatic colorectal cancer is to apply the enormous knowledge that we are accruing on the genetics and epigenetics of this cancer at the individual patient level, so that it can be followed during evolution of disease by liquid biopsy testing. All this information is a big challenge because this should be applied to selecting specific therapies on an individual basis. The big challenge is really to apply precision medicine in the treatment of metastatic colorectal cancer.

Transcript Edited for Clarity