Modern Testing and Treatment for Rare Genomic Alterations in Colorectal Cancer

Michael J. Overman, MD

Research looking at subsets of colorectal cancer (CRC) has identified targets for rare genomic alterations in recent years. But the expanding space still has much room for grow, according to Michael Overman, MD.

In CRC, there are gene fusions, polymerase epsilon mutation, BRAF V600E mutation, and KRAS mutations. Although there have been FDA-approved drugs for some mutations, there is still a treatment gap for these patients in comparison with biomarkers like mismatch repair deficiency and microsatellite instability. Further, there is more that can be done with testing for these rare genomic alterations.

In an interview with Targeted Oncology™, Overman, a professor in the Department of Gastrointestinal Medical Oncology, at the University of Texas MD Anderson Cancer Center, discussed targeted rare genomic alterations in CRC.

TARGETED ONCOLOGY™: Can you provide an overview of what you discussed during your ESMO GI presentation?

Overman: In metastatic colon cancer, we've had recent success in looking at subsets of colon cancer based on genomic alterations. These tend to be smaller subsets of overall CRC. So, during my talk, I mentioned some of those, and then I'd say even more kind of some of the rarer ones that are potentially more evolving and of interest.

In particular, fusions is one area that I spent a fair amount of time talking about. Targeting fusions and their presence in colon cancer and kind of the context of that, and then talking about some of the drugs that are out there targeting these various fusions and have shown great activity. I also discussed how many of the patients with CRC were in some of those studies, and it tends to be rare numbers, but I think it’s kind of a rare subset where we have it’s one worth trying to identify. Then, I talked about genomic alterations that rare and not ones we necessarily think of targeting as much. Those include polymerase epsilon mutations, which are mutations that can lead to defects in DNA replication. You get a lot of mutations in their immune therapy responses.

There are also BRAF nonV600E mutations. Many think of V600E as having FDA-approved drugs for targeting V600E, but the nonV600E mutations are different and there is some preclinical research looking at them. The other that I would mention in this category is KRAS G12C. Overall, I think that's a space where we'll see more work in the future.

As for the alterations that are more established, I would say, there’s microsatellite instability, high, deficiency in mismatch repair, HER2, and then BRAF V600E.

What advances have we seen recently around testing and treatment guidance for some of these genomic alterations?

We've kind of expanded over the years. Historically, we were talking about KRAS status related to the use of anti EGFR therapies. But we've kind of grown that and now it's KRAS, RAS, BRAF, HER2, a deficiency in mismatch repair. We increased the number of ones that I would say are mandated for every metastatic CRC patient. And then there are some of these other ones that I think are interesting. This fusion category is really rare but clearly, there are some excellent agents out there if somebody has those fusions, so, I think we're just seeing an increasing number of alterations that we need to know about.

In metastatic colon cancer, the space where we need to be thinking more, I also think this moves us to broad next-generation sequencing panels for testing. Historically, we did single gene sequencing some immunocytochemical testing to capture the different alterations. As we grow the number that we need, it speaks to the fact we need to probably be transitioning more to next-generation sequencing panels. I think we see that in other tumor types. Lung cancer would be a classic example where the number of alterations has increased and that speaks to having to do panel-based testing. That’s where we're getting to in CRC.

One of the things that's nice about that approach is that you get these additional alterations that are so rare. I think they're a little bit hard to justify testing independently, so fusions, for example, in a microsatellite stable metastatic hyper cancer patient is probably down around the point 1.2 percent range, right. That biomarker is seen in 1 in 1500. So, it’s really rare, and the money to test just for that, one could ask, does that make sense?

If you're getting a big panel for all your alterations, then you can capture some of these rare ones, and when you find it, then you can engage on it. I think we're moving towards that, and that's a real benefit.

I also think that we need to be more aware of some of these rare things as we start seeing them more. Since we're doing a broader panel, I think it behooves us to understand them and talk about them more, not just the alterations we have defined approvals for.

Which genomic alterations are most challenging to treat, in your opinion? How would you typically approach treatment for these alterations?

KRAS G12C I think is interesting, because they're these new drugs that target this specific alteration in KRAS, and early data with single-agent activity in CRC is fairly limited. I think this speaks to the need for combination therapy, but we're still optimizing how to use those agents. So that's one where I think clinical trials are just critical because I think the prediction is that combination-based therapies where you fully inhibit the KRAS signaling MAP kinase pathway may be the way to success.

The other challenging alteration is the BRAF V600E, where single-agents targeting is fantastically active in melanoma and CRC. You need dual targeting or triplet targeting where you fully inhibit the MAP kinase pathway with combination therapies and I think that's probably what we're going to see soon with KRAS G12C as well.

I think trials to define that are critical right now.

The other one, I think, is the BRAF nonV600E space. There's a lot of BRAF mutations that we see that are not V600E and all of the approvals when we talk about BRAF, we're always talking about BRAF V600E-specific targeting like vemurafenib [Zelboraf] or dabrafenib [Taflinar]. Those agents target that specific molecular alteration, and so there are a number of these nonV600E mutations in BRAF, and we categorize those as class 2 or class 3 agents. The classifications depend on signaling and dependency on upstream signaling activity drives that kind of mutation to function. There's an improved understanding of the different mutations in the non V600E BRAF space and how they function. That's improved our sense of what the approach should be. It’s based on these categorizations of those in class 2 and class 3.

What research is ongoing in rare genomic alterations of CRC that appear promising for the future?

An interesting area is trying to move different agents in a more kind of fundamental practice, which would probably be the deficiency and mismatch repair or microsatellite instability-high space. In this space, we’ve had approvals of immune therapy agents, recently. In December of 2020, we had the publication of the KEYNOTE-177 study [NCT02563002], which is pembrolizumab [Keytruda] versus chemotherapy, and pembrolizumab was superior to chemotherapy for progression-free survival. The study defined pembrolizumab as the standard and best systemic therapy for metastatic colon cancer that's deficient mismatch repair. It was an amazing paradigm shift of how to treat that subset. And other clinical trials are building on that right now.

The other area I think about is the HER2 space. There's a lot of different agents. We went from having nothing to now a plethora of combinations and options, which is great. One of the more recent ones is this antibody-drug conjugate which is trastuzumab deruxtecan [Enhertu]. It has a high level of activity and there's also tucatinib [Tukysa] that has a trial in progress.

I think we're going to see several trials trying to help us define what line to use all the agents in and how best to use them.

LISTEN to the full interview with Overman in the July special episode of Targeted Talks. >>