Expert Says Clinical Trials Are Essential for Progress in Metastatic CRC

Shubham Pant, MD

Third-line treatment options for patients with metastatic colorectal cancer (CRC) essentially boil down to regorafenib (Stivarga) and TAS-102 (Lonsurf), according to Shubham Pant, MD.

CRC is a malignancy that harbors many genetic mutations/aberrations, such as RAS, BRAF, microsatellite instability (MSI), and HER2/neu. These mutations serve as a road in which to develop targeted agents and, with the rapid progress of next-generation sequencing, the development of therapeutics in this arena is more of a possibility now than it has ever been, he adds.

During the 2017 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, Pant, an associate professor of The University of Texas MD Anderson Cancer Center, discussed therapeutic options for patients with metastatic CRC.

“We should consider profiling for these patients early when they are failing their second-line therapy, just to see if there are available therapies out there,” Pant explained. “Physicians should be clued into all of the clinical trials that are going on in CRC, because there are quite a few going on hitting different targets. We need to individualize treatment, because we truly need to figure out the actionable mutation[s], who can be helped, and in which patients we can make an impact.”

OncLive: Please provide an overview of your lecture on metastatic CRC.

How do you approach third-line treatment for a patient with metastatic CRC?

What regimens currently being explored in clinical trials look promising?

In an interview during the event, Pant stressed the importance of clinical trials as an avenue to establish more novel treatment decisions in this setting.Pant: We have [treatment options] in the first 2 lines but, in the third line, we do not have so many options. However, more options are being developed. We have 2 options essentially, regorafenib and TAS-102, but my whole talk focused on where we are going to go from here—the emerging therapies, targeted therapies, and immunotherapies for CRC in the third-line setting.Normally, before that, we try to get some profiling on the patient such as next-generation sequencing. We try to identify targets but, obviously, this depends on how the performance status is—it has to be really good. Then, we try to identify a clinical trial for them that we can use for targeted therapy. The “pie” of third-line CRC is a big pie, but if you break it down into specialties, such as BRAF-mutant disease, HER2/neu-positive, and MSI-high CRC, we can find new therapies in all categories. Immunotherapy works in some, targeted therapies work in others, and some [tumors require] a combination.

It is an exciting time in the field, because these patients with metastatic CRC, even in the third-line setting, are very robust in a way where they have excellent performance status—their liver and lungs work great—so we need to try to find more therapies for them.

What is the most pressing unmet need for these patients?

How do you see treatments progressing in the next 5 to 10 years?

What impact has next-generation sequencing had on this patient population?

One of my colleagues, Dr Scott Kopetz, presented data at the 2017 ASCO Annual Meeting of the combination of vemurafenib (Zelboraf), which is used in melanoma, plus cetuximab (Erbitux) and irinotecan in BRAF-mutant CRC. There were great response rates in patients who had been refractory to everything else prior.We need to develop new therapies and identify actionable targets, where we can go in and hit the mutation well so that they can get prolonged or stable disease control. Previously, we used to always look at response rate and, while that is still important, one of the things that we are trying to target is controlling the disease so that we see a longer progression-free survival. This is so the patient can live months and years without progressing and that, I believe, is the ultimate goal. [I see] combinations [that] work, such as for BRAF-mutant CRC, with the combination of vemurafenib plus cetuximab and irinotecan. However, there are good examples of single agents, such as in MSI-high CRC in which the single agents pembrolizumab (Keytruda) and nivolumab (Opdivo) are both showing promise. It has had a great impact. We can identify some targets; we can look for that needle in a haystack. Obviously, some of the data are still maturing, and we'll just go to where the data take us. It has made a big impact, but we need a lot more data to come in before we can say for sure how big the impact has been.