Testing, Trials, and Treatments

Heather Greene

Hi, Kevin. I wanted to start off by talking about biomarkers. Since you work at a National Comprehensive Cancer Network (NCCN)-designated cancer center, how does your team approach ordering biomarker testing in patients with colorectal cancer?

Kevin Krise

It’s certainly become more widely used with the in-house testing that’s being done. In-house testing continues to expand, and we continue to send out testing. Whether it’s additional tissue profiling or liquid biopsies for biomarker testing, it continues to increase. Patients with metastatic colon cancer will undoubtedly have an expanded set of biomarker testing. Even now with patients who are having their initial surgeries, there’s more expanded testing being done, which is helpful if they experience recurrence.

Heather Greene

Oh yes, that would be beneficial. At Northwestern, are you able to perform next-generation sequencing or molecular profiling in-house?

Kevin Krise

Some of that can be done in-house, but we are still sending it out as well. The hospital is trying to expand what we’re capable of doing in-house.

Heather Greene

When you send out for testing, do your physicians or your centers use one platform or is it physician-dependent on what they prefer in terms of the product they use?

Kevin Krise

It varies. I believe some physicians use multiple platforms. Other physicians use the platform that comes back the fastest. But as far as speed, I think they’ve all aligned more uniformly over the last couple of years and they’re trying to get their results to us as quickly as possible.

Heather Greene

What is your typical turnaround time for in-house tissue-based testing?

Kevin Krise

It’s usually within a couple of weeks, which is pretty quick.

Heather Greene

Here at West Cancer Center, we have in-house pathology, but we don’t have the ability to do in-house next-generation sequencing or fully expanded molecular profiling. It’s our standard for any patient with metastatic colorectal cancer to do tissue testing, either in de novo metastatic disease or when they recur. This is pretty universal across all tumor types but particularly in the gastrointestinal (GI) setting. If they progress down the road and we’re looking for a new biomarker to try and target, time is of the essence. Sometimes these patients are debilitated, or don’t progress in an area that really lends to tissue-based testing. It’s not ideal to have to get another biopsy and wait an additional 3 to 4 weeks to get those results back, so liquid-based testing works better in these situations.

Kevin Krise

There’s been a shift toward liquid-based testing the last couple of years due to being able to expedite these results. There’s that fine balance–do you start treatment or do you wait for the results of biomarker testing? Obviously, the patients and we, the medical oncology team, look for this information as quickly as possible so we can provide the best care to our patients and open up any opportunities, whether it’s standard-of-care treatment options or looking at different biomarkers and potential clinical trial participation, for example.

Heather Greene

The liquid-based testing really does help expedite that process and helps to ease patients’ concerns. They hear they’ve progressed and they’re ready to get started and move on to that next line of therapy.

Kevin Krise

Yes, I think patients often have a lot of hope with next-generation sequencing biomarker testing, and oftentimes we don’t find anything that’s groundbreaking for them. It’s important to build reasonable expectations about what the testing can do when we have those discussions with patients because, with all the information out there, they’re becoming super savvy on the different platforms of testing, including what’s available and what it might mean to them.

Heather Greene

That’s an excellent point. With molecular profiling, we outlined a couple of markers to test on, like HER2, BRAF, and RAS mutations. When you have a patient who comes back with any one of these mutations, how do you talk through that with your patients?

Kevin Krise

Biomarker treatment is driven by NCCN guidelines. When patients ask for a particular treatment, having this information is helpful when educating them on why they are or aren’t a candidate for a particular therapy that is targeted at one of these biomarkers. Having that discussion of the pertinent positives and the negatives that relate to their treatment is made easier with the guidelines there.

Heather Greene

I’d like to touch on HER2, one of the less common mutations in colorectal cancers, although we do see it. I have some patients who, like you said, are very savvy in browsing the internet and looking for mutations, and they have access to their molecular profile results in the patient portal. HER2 mutations in this setting are not as common as in the breast cancer world. Only about 3% to 5% of metastatic colorectal cancer patients have them.¹ Sometimes, we see a slightly higher percentage of it in RAS-RAF wild-type patients. This means we have the ability to use HER2-targeted treatments, which are still mainly trastuzumab-based. Even though we see this mutation, we typically reserve that for the second-line setting and still use first-line standard of care.

Kevin Krise

Exactly. I think we have that same experience. Interestingly, since HER2 has come into play, I have seen very few patients with this mutation or variant that leads to that as a treatment option. But the important part of doing this testing is that we can find those very specific targets that would benefit that patient. That’s why we have to do this testing.

Heather Greene

What if you come upon a BRAF mutation in a patient? What are you looking at there?

Kevin Krise

I think this is a bit more common. The literature says about 8% to 12% of colorectal cancer patients have the BRAF mutation.² It’s tough because these patients often have a poor prognosis, although there are targeted therapies available. It’s a tricky disease to treat and can become refractory to a lot of the treatments, unlike other patients without that mutation who often have better outcomes. Are you seeing the same?

Heather Greene

Yes, I think sometimes it’s a bit of a catch-22. We’re used to seeing mutations and saying, “This is actionable, and we can do something with it.” But on the flip side, you’re right—it can correspond with a poor prognosis of only about 4 to 6 months of survival after they fail initial therapy, which at some point they will. Of course, these patients don’t benefit from EGFR inhibitors unless we co-target using the BEACON regimen (encorafenib plus cetuximab with or without binimetinib),³ which we reserve usually for second-line or greater.

Kevin Krise

So, regarding KRAS mutations, what do you see in patients and how would you approach this at your center?

Heather Greene

This is one of the most common mutations in colorectal cancer, with 30% to 45% of patients having it.⁴ Unfortunately, it’s also a poor prognostic indicator with poor progression-free survival and overall survival vs. RAS wild type. We know that these patients do not benefit from EGFR inhibitors, and NCCN cautions us about potential harm that can be caused by using them because of the toxicities and side effects to those medications.⁵ Only the RAS wild type can get EGFR inhibitors. There is emerging data for some specific KRAS mutations that may be a little bit more targetable, such as KRAS G12C. A recent study in the New England Journal of Medicine showed a response greater than 6 months when using the combination of adagrasib and cetuximab.⁶

This was a heavily pre-treated population. Unfortunately, it doesn’t look to be a dominant driver, like we see in patients with non–small cell lung cancer, but there’s hope because it wasn't too terribly long ago when non–small cell lung cancer didn’t have all of the dominant driver mutations that we see today.

Kevin Krise

Regarding clinical trials, we’ve been treating colorectal cancer patients for a long time now and haven’t seen much change. It's these very specific populations, a small subset of patients, who are benefiting from these biomarkers and the targeted treatments. We need more clinical trials to help find other biomarkers that might be targetable, and to help find more treatments that are going to benefit everyone, not just these small populations. I think that’s just the nature of oncology, and with colorectal cancer, we need to find those clinical trials that are going to push the needle a bit.

Speaking of trials, data from the SUNLIGHT trial showed that there’s an efficacy benefit of trifluridine-tipiracil plus bevacizumab treatment in refractory patients, in patients of all ages. Are you familiar with that trial?

Heather Greene

Trifluridine-tipiracil was FDA-approved for third-line or greater in metastatic colorectal cancer after the RECOURSE trial demonstrated significant benefit.⁷ The trifluridine-tipiracil plus bevacizumab regimen is also used in the third-line or greater setting, but the SUNLIGHT trial showed us that trifluridine-tipiracil should be used in combination with bevacizumab in patients with metastatic colorectal cancer given the better overall survival and progression-free survival. Plus, we know bevacizumab does not add a lot of extra toxicity when used with trifluidine-tipiracil.⁸

Kevin Krise

Which is great news.

Heather Greene

Yes, it is. As far as you know, is there anything that we need to keep in mind when we’re considering trifluridine-tipiracil plus bevacizumab for treating these patients with metastatic colorectal cancer?

Kevin Krise

Good question. In the SUNLIGHT trial, neutropenia was observed as the most common grade 3 to 4 adverse effect of trifluridine-tipiracil plus bevacizumab.⁹ It’s important to follow the package insert recommendations on dose reductions to avoid complications of neutropenia. The schedule for taking the medication is also important. Creating a calendar or having patients take it Monday through Friday makes it easier for them to remember to take the trifluridine-tipiracil treatment on days 1–5 and 8–12 of a 28-day cycle.

Heather Greene

The more treatment options we have, especially for metastatic colorectal cancer, the better.

Kevin Krise

Absolutely. Thanks for sharing that information with me.

Heather Greene

You’re welcome and same to you. I’m looking forward to our next conversation.