Bekaii-Saab Shares Insight on Regorafenib Updates in mCRC


Tanios Bekaii-Saab, MD, discusses the ReDOS and IMblaze370 trials with regorafenib trials in metastatic colorectal cancer.

Tanios Bekaii-Saab, MD

A weekly dose-escalation strategy of regorafenib (Stivarga) is clearly the new standard approach for the agent, as it was found to be superior than the previously average dose of 160 mg in patients with metastatic colorectal cancer (mCRC), said Tanios Bekaii-Saab, MD.

In the phase II ReDOS study, led by Bekaii-Saab, patients were randomized to either the dose-escalation arm—which began at 80 mg daily and increased every week up to 160 mg daily if no dose-limiting toxicities occurred—or the standard 160-mg dose of regorafenib.

Results showed that the median overall survival (OS) was improved in the dose-escalation arm compared with the standard arm at 9.0 months versus 5.9 months, respectively (P = .0943). The dose-escalation arm also had a slight improvement in progression-free survival (PFS) and quality-of-life data.1 Bekaii-Saab added that nearly double the number of patients made it to cycle 3 of treatment on the dose-escalation arm.

Based on these findings, the National Comprehensive Cancer Network (NCCN) incorporated the dose-escalation approach into their guidelines for regorafenib in this patient population.

Additional data with the multikinase inhibitor were presented at the 2018 World Congress on Gastrointestinal Cancer with the IMblaze370 trial. In the phase III study, the combination of atezolizumab (Tecentriq) and cobimetinib (Cotellic) or atezolizumab alone were not found to be superior to regorafenib in patients with chemorefractory mCRC.2

OncLive: Please provide some background to the ReDOS trial.

In an interview with OncLive®, Bekaii-Saab, a professor of medicine at Mayo Clinic, discussed the ReDOS and IMblaze370 with regorafenib trials in mCRC.Bekaii-Saab: We wanted to test how effective the standard dose of 160 mg daily was for regorafenib. It worked for a few patients. For the majority of the patients—let's say 70% to 80%— they were not able to receive the full 160 mg. A lot of the toxicity started to appear in the first 2 to 3 weeks, and it also met its highest severity at that time. That certainly was one of the biggest challenges. Therefore, in the community, a lot of people started using their own schedule and started cutting down on the dose. Some people started with 80 mg and then made their way up to 120 mg. A lot of different alterations were made, but there were absolutely zero data saying that you could alter the dose and keep the same benefit.

This was the premise for ReDOS, which essentially was a randomized phase II study that looked at patients who would be eligible for regorafenib. The experimental arm was a dose-escalation strategy from 80 mg, to 120 mg, to 160 mg on a weekly basis as tolerated. Then you would get a week-long break. Whatever the highest-tolerated dose level was for the first cycle, we would move on to the second cycle. This was compared with the standard 160 mg daily for 1 week on/1 week off. We thought that, for this study, we should have a primary endpoint capturing 2 elements: toxicity and efficacy.

What we did was look at the patients who made it through the 2 cycles and then put them into cycle 3. We're assuming that the dose-escalation arm would be superior because more patients will be able to make it to cycle 3 with that strategy. Our study of 120 patients met its primary endpoint, meaning the dose-escalation strategy of 80 mg, to 120 mg, to 160 mg was superior to the 160 mg daily dose. Almost double the number of patients made it to cycle 3 and continued throughout.

Are there any toxicity issues that are unique to regorafenib?

Has your use of regorafenib changed at all since ReDOS was added to the NCCN guidelines?

What was learned from the negative IMblaze370 trial?

Interestingly, we also found that the OS was superior in the dose-escalation arm. This was the secondary endpoint, and it wasn't statistically significant, but the difference was about 3 months. There was also a hint in improvement for PFS; it was numerically at least, but not that significant. The quality of life for patients were not compromised under the dose-escalation strategy, but it did in week 2 for patients treated with 160 mg. When we looked at these patients, the main reason why they couldn't move on to cycle 3 was because of progression on both arms. There were more progressions on the 160-mg arm than with the dose-escalation strategy. Between both arms, for the patients who made it to cycle 3, the survival data were very similar.This whole class of agents has its own set of side effects. We primarily see fatigue, some gastrointestinal toxicities, and sometimes with regorafenib we see hand-foot syndrome. The unique part for regorafenib is that these toxicities start very early in the game. Within 2 weeks, you could start seeing hand-foot syndrome. You usually wouldn't see something like this until after 4 weeks. That has been one of the biggest issues in terms of managing this agent. Overall, the side effects themselves aren't unique; it's the quickness of it that's unique.In my practice, it hasn't changed because we've worked with regorafenib quite a bit. We're very comfortable with the agent and with the dose-escalation strategy. Ultimately, this is an option that becomes very important to consider for patients with mCRC. Having a dosing strategy creates a more standardized way to deliver the agent. For now, we use this agent in the third-line setting, and in the fourth-line setting for a few patients.The whole premise that we can turn a “cold” tumor—what we call a tumor that is invisible to the immune system—to a “hot” tumor, and then take a group of patients with mCRC who do not respond to immunotherapy and make them respond better, was the idea behind this study. We know that only about 4% of patients with mCRC will demonstrate high levels of microsatellite instability (MSI-H). These are the patients who are most likely to respond to PD-1 inhibition; the other 96% do not. The focus [of this study] was that 96% of patients. Can we take the benefit we've seen in MSI-H patients and apply this to microsatellite stable patients?

The FDA granted a breakthrough designation for the novel triplet combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux). Where could this fit into practice?

When do you use TAS-102 (Lonsurf) to treat a patient with mCRC?

We did a phase Ib study taking cobimetinib, a MEK inhibitor, along with atezolizumab, a PD-L1 inhibitor. Preclinical data suggested these 2 types of agents would work well in these types of patients. The first 20 or 30 patients we had enrolled showed some promising activity—we saw a 17% to 20% response rate. It was exciting enough data to move this into the phase III arena. We compared this combination to regorafenib and atezolizumab alone. Unfortunately, there was no survival advantage to the combination versus regorafenib. It was also more toxic.This would be for the BRAF V600E-mutated patients, which is about 5% of patients with mCRC. This would be a second-line therapy, and an even smaller percentage of patients make it to the second line setting with these tumors. It's exciting news, but I don't think it's going to affect the landscape too much. However, this is one of the worst subgroups of patients in terms of outcomes, so to see high response rates is exciting.This is an active agent, which historically has very similar activity to the 160-mg dose of regorafenib. It hasn't been compared with the dose-escalation strategy yet. This does have a role in my clinic, although it falls after regorafenib for most patients. I would give this to patients in the fourth-line setting. For some patients, we choose TAS-102 before regorafenib if they have minor liver dysfunction or if they previously had hand-foot syndrome, and they don’t want to risk getting it again as a regorafenib side effect.

At the 2018 World Congress on Gastrointestinal Cancer, we saw an interesting study showing TAS-102 plus bevacizumab (Avastin) had a slight advantage over capecitabine and bevacizumab. We would like to see larger trials looking at this, so we can see what this means to our overall practice.


  1. Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36(suppl 4S; abstr 611).
  2. Bendell J, Ciardiello F, Tabernero J, et al. Efficacy and safety results from IMblaze370, a randomised phase III study comparing atezolizumab plus cobimetinib and atezolizumab monotherapy vs. regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol. 2018;29 (suppl 5; abstr LBA-004).
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