Expert Discusses CRC Developments, Importance of Molecular Profiling

Pashtoon M. Kasi, MD, MBBS, MS

Liquid biopsies may not be ready for prime time use in colorectal cancer (CRC), but they stand to show the importance of identifying clinically relevant mutations that can direct future treatment decisions, said Pashtoon M. Kasi, MD, MBBS, MS.

“There are many subsets of CRC, including RAS, RAF, HER2, NTRK, microsatellite instability-high (MSI-H), and high tumor mutational burden. Previously, some of these mutations were only prognostic. Now, we have options for patients with BRAF V600E mutations,” said Kasi. “Additionally, we have anti-HER2 drugs or trials, as well as drugs [targeted against] NTRK fusions. As you can see, it is a very heterogenous disease in which sidedness also plays a role, but we're moving towards individualizing therapy for patients.”

OncLive: Where do liquid biopsies stand in CRC?

In an interview with OncLive, Kasi, an assistant professor of oncology and senior associate consultant in the Division of Hematology/Oncology at Mayo Clinic, provided an overview of the potential for liquid biopsies in CRC and advances being made in the treatment landscape. Kasi: Liquid biopsies are done through circulating tumor DNA testing; it’s something that has rapidly made its way into research and is now making its way into practice. The most recent guidelines that came from the 2018 ASCO [Board of Directors] meeting in March 2018 are showing promise; however, they’re not ready for prime time. The only FDA-approved indication for liquid biopsies is in the sphere of lung cancer.

If you look at all the papers and abstracts that came from the 2018 ASCO Annual Meeting, and now, the 2019 ASCO Gastrointestinal Cancers Symposium, there is a great enthusiasm for the approach because of its sensitivity and specificity—at least in the metastatic setting. For early-stage cancers, it's still early in research. In the metastatic setting, these biopsies are able to pick up HER2, or clinically relevant mutations, such as BRAF or RAS.

This approach is helpful in patients where you may not have the tissue biopsy available. If the tissue biopsy is not sufficient, the liquid biopsy can help complement it. It's not meant to replace the solid tumor tissue testing, but it is an adjunct to tissue biopsy.

Could you elaborate on ongoing research efforts in this area?

Liquid biopsies help us identify acquired mechanisms of resistance, including RAS, and RAF wild-type tumors that acquire RAS mutations or EGFR mutations. Those are things you can pick up on a liquid biopsy that you wouldn't be able to pick up on [standard] tissue testing. It’s not feasible to do [tissue] biopsies again and again. HER2 is also an acquired mechanism of resistance that can be picked up by a liquid biopsy; it’s found in approximately 4% of patients in the acquired setting. We recently had the agnostic approval of NTRK inhibitors for NTRK fusion—positive patients, which constitute about 1% to 2% of CRCs as well. One of the most exciting things, in terms of the use of this approach in the metastatic setting, is in a clinical trial setting. One of the clinical trials that is being developed as we speak is going to be a master protocol, where each treatment arm may be determined by the patient’s liquid biopsy results. The study is being led by many academic institutions.

Could you discuss the BEACON trial?

As of right now, different arms are being developed based on the aberration found in each patient. We already have the HER2 arm open, in which there will be matched therapy based on circulating tumor DNA testing. Ongoing research is testing its use earlier on to determine which patients will benefit from chemotherapy and who may not need it.The BEACON trial is one of the most exciting trials that we had updates for at the 2019 ASCO Gastrointestinal Cancers Symposium. The trial is focused on patients with BRAF V600E-mutated CRC led by Scott Kopetz, MD, PhD, FACP, of The University of Texas MD Anderson Cancer Center, and Axel Grothey, MD, of West Cancer Center. These patients comprise an unmet need; their survival in the second-line setting is about 4 to 6 months; [outcomes in these patients are] up to 3 times worse than those of patients who don’t have the BRAF V600E mutation. These patients really don't have too many options. Historically, BRAF inhibitors didn't work. The combination of BRAF inhibitors with MEK inhibitors did not show much promise.

Their work showed that we had to block the pathway at 3 levels due to the upregulation of EGFR and overactivation of that pathway, and doing so [with encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux)] has demonstrated remarkable results. The median overall survival (OS) is now 15 months, and the response rate is approximately 48%. In this subset, even stable disease is an important clinical endpoint because these patients would otherwise die of their disease. Even the progression-free survival (PFS) is outperforming some of the historical OS rates.

How might the potential approval of this regimen impact this patient population?

How can pharmacogenomics be used to guide treatment?

Many patients who respond tend to show durable responses. ]The regimen is] also well tolerated. [The triplet regimen] received an FDA breakthrough therapy designation in August 2018 [for the treatment of patients with BRAF V600E—mutant mCRC following 1 or 2 prior lines of treatment in the metastatic setting]. Hopefully, this will become an option for our patients this year. This is going to become yet another treatment option for these patients. For patients with mCRC, there hasn't been 1 “wonder” drug or combination that has led to improvement in survival. We have many drugs and many combinations that can be used one after another. For these patients, I see this regimen being brought into earlier lines of therapy. For the subsets of those who receive only 1 line of chemotherapy, the responses and durability were better. Studies are being designed to move it up into earlier lines of therapy as well. Genetic testing is underutilized in CRC; it can help guide treatment dosing and adjustment based on the mutations or variations a patient may have. For a patient with GI cancer, specifically CRC, we know that there are genes that metabolize 5-fluorouracil or capecitabine. We also know the drugs that metabolize irinotecan chemotherapy [if a patient has the UGT1A1 gene]. Historical analyses have shown that these patients do far worse in terms of side effects when they get chemotherapy and harbor an aberration in one of these genes. It's underestimated how many patients have this aberration.

How do you see that testing impacting the field?

What are the next steps?

Incorporating this testing into practice is feasible. Now, you can get the results back within 3 to 5 days and make a treatment decision in real time; that was one of the previous barriers. The other barrier was figuring out how to interpret these results. Now, there are guidelines available that tell you how much chemotherapy should be considered if a patient has an aberration in a certain gene.By using this, we could avoid severe side effects in patients. It's going to help bridge that gap in terms of individualizing care. That will be very helpful because chemotherapy is still the mainstay for first-line therapy for all of our patients. To be able to give them treatment in a way that is safe without compromising the efficacy would impact the care of these patients.We're trying to conduct a prospective trial where we can show how much benefit this provides. Historically, every other study that has looked at this focuses on the increased side effects in these patients. However, there are very few studies that incorporate this concept in a purely randomized setting.

What is the ongoing research in the HER2 space?

Also, there are [limited] studies that go beyond more than 1 gene. A patient with CRC or another GI cancer is often getting combination therapy and supportive care drugs, which include pain medications such as anti-nausea medications and anti-depressants. If all of those things are factored into in a trial setting, it will improve the quality of life (QoL) of these patients. If the Qol on therapy is better, we may be able to administer the therapy longer. One of the key advances in CRC is looking at these [aberrations] at baseline and what happens to these tumors over time. One of the classic examples is the evolving recognition of HER2-positive CRC. At baseline, it confers resistance to some anti-EGFR therapies. Even though it's not part of the guidelines, HER2 may be another aspect to check for in patients. If found, we may not consider an anti-EGFR therapy for them. HER2 is an acquired mechanism of resistance; you can pick it up later either through liquid biopsy or tissue testing. For those 3% to 4% of patients, you can [enroll them in] anti-HER2-based therapy trials. Some trials have already completed, and some data have been presented.

Data with lapatinib (Tykerb) and trastuzumab (Herceptin) look promising. There are data with the combination of trastuzumab and pertuzumab (Perjeta). These are studies where it is important to know HER2 status at baseline and also at progression, so that we can pick the right trials for patients. It won’t be long before a biologic becomes available for these patients, in addition to anti-VEGF and anti-EGFR agents.

What is being done to address the incidence of CRC in younger patients?

There is also the newly diagnosed subset of NTRK fusion—positive CRC. The NTRK inhibitor larotrectinib (Vitrakvi) is the second drug of its kind in terms of a tumor agnostic approval; the first approval [from the FDA] was for [pembrolizumab (Keytruda)] for patients with MSI-H tumors, regardless of tumor type.It has led to some guideline changes. The screening age has gone from 50 years to 45 years, and even younger for select populations. Some studies show a higher and earlier incidence in certain races as well. If individuals are in their 20s, 30s, or 40s, they wouldn’t necessarily have met the screening guidelines. By the time their disease is diagnosed, it’s often advanced or metastatic.

We don't know why this rise is happening. We've done comprehensive germline testing in young patients if there is a family history. Lynch syndrome is one of the most common CRC- causing hereditary diseases, but even that doesn't explain the whole story.

One common emerging pattern is that tumors in younger individuals tend to be more rectal and left-sided as opposed to right-sided. It’s an early observation. As we know, these tumors have different embryologic origins. The fact that we're seeing a preponderance on left-sided tumors in many of these large cohort studies is a starting point. It's probably a combination of both environmental and genetic events that are causing these tumors in young individuals. That is one place where identifying the driver is extremely important.