Regorafenib as a Metastatic Colorectal Cancer Therapy Option


Dr Marshall discusses the impact regorafenib has had in the treatment of metastatic colorectal cancer and describes data from the CORRECT and ReDOS clinical trials.

John Marshall, MD: As oncologists, a lot of us don’t understand the principle that regorafenib, or STIVARGA, brings to the table. We must first remember that we have been trying to find drugs with a survival benefit in metastatic colon cancer for a long time. Regorafenib broke through after many years of not having anything new. We can’t forget that the CORRECT clinical trial is a positive clinical trial. We also must remember what kind of disease we’re treating. If you know about regorafenib, you know it hits 19 different targets, and these targets are signal pathway targets that are commonly abnormal in metastatic colorectal cancer.

The way I like to think about metastatic colon cancer is that some cancers are strongly driven by 1 pathway. If I get a big, supertanker stuck in the Suez Canal—1 single pathway and no way around it—the whole world knows it happened. If I get a supertanker stuck in, I don’t know, the Mississippi River Delta down in New Orleans, it’s not that big of a deal because there are other ways around that pathway. In many ways, that’s the signaling of metastatic colon cancer. It’s messy. There are multiple pathways. If you block 1, it simply goes around. One of the fundamental principles of regorafenib is that we are going to carpet bomb a bunch of those pathways and see if we can shut down more than 1 and, with that, see if we can slow the growth of colorectal cancer. Basically, the CORRECT clinical trial showed that clearly happened.

Remembering the design, it was a big study, with 2:1 randomization in refractory third line, but these patients had to have a good PS [performance status] of 0 or 1. These are not patients who are refractory who are in the hospital considering hospice. These are people showing up in your clinic, feeling and looking good saying, “What next, Doc?” These are patients with good PS, which was randomized 2:1 to a placebo arm, starting at 160 mg daily, 3 weeks on, 1 week off. You should know this data by heart. Half of the people who got treatment showed some benefit with improvement in progression-free survival [PFS] with a nice hazard ratio. About 25% of patients had stable disease at roughly 6 months. One in 4 patients had stable disease at about 6 months, which is a good number for patients in the refractory setting. The problem has always been the fact that the toxicity was difficult, starting at the 160-mg dose. You had this PFS and overall survival [OS] benefit, but it felt like it was hard to get there because if you gave patients 160 mg, 4 tablets daily, they would get early hand-foot syndrome, fatigue, and other adverse effects. There were a lot of patients who said, “Forget it, I don’t want to do this.”

A follow-up study done by Tanios S. Bekaii-Saab, MD, basically said, “Let’s look at this a different way. What if we started at 80 mgs, or 2 pills? If they do OK for a week, we’ll go up to 120 mg. If they’re still OK, we‘ll go up to 160 mg, then keep that as our dose.” So there is an escalation scheme, instead of when they’re sick, then de-escalate. They randomized patients between these 2 strategies. What the ReDOS study essentially showed was that it was better to start low and go high. More people made it into third line. The overall toxicity was the same because you eventually got there, but your patient compliance and the opportunity to benefit from the treatment was greater. Now some people are saying, “I’ll just start them at 120 mg and see.” Well that’s not the right answer either, so what I typically do with all patients is see them once a week for this first cycle, by video or in person, and start off with 2 pills. If they’re fine and their liver functions are OK, we go up to 3. If they’re still fine, we go up to 4. They get the week off, then start back with whatever dose we finished out in that first cycle.

This was a good lesson for us all in how best to use this medicine. I have used it more and more in those earlier maintenance phase settings, or for patients with small progression for whom I was not eager to start some more intensive treatment or recycle chemotherapy. It has given me a stronger handle on this. Between the CORRECT study showing us the clear OS and PFS advantage and the ReDOS study, which teaches us how to give it, it has become much easier to use regorafenib in the metastatic setting.

This transcript has been edited for clarity.

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