The Optimal Dosing Strategy for Regorafenib in mCRC

Tanios Bekaii-Saab, MD, FACP:The decisions on overall survival [OS], the tyrosine kinase inhibitors [TKI] and how to dose them has been one of our biggest challenges in oncology. That doesn’t only pertain to regorafenib. It’s also sorafenib, sunitinib, lenvatinib. I mean, you name it, any “-ib”, cabozantinib, all these agents that we’ve been working with for many years, we’ve always had the same challenge. What is the correct dose to start with? And with regorafenib, at least in the refractory metastatic colorectal cancer, that patient population is already challenging as it is. And starting at 160mg for all patients had been even a bigger challenge. Because most patients at 2 to 3 weeks start having significant toxicities—hand and foot syndrome reaction, diarrhea, a little bit of diarrhea, and fatigue.

And so with that said, the challenge when you actually see your patient in clinic, first time you use it, you say, “Wow, this is tough.” Second patient is going to come to your clinic and you’re going to think, can I start this patient on 160mg? They’re tired of their chemotherapy, their disease burden is significant. Perhaps I should consider a lower dose. So dosing was all over the place. Some physicians start at 80mg, some physicians give the patient 120mg, 30% to 40% start at 160mg and de-escalate. So there was no standard.

So we brought this study called ReDOS: regorafenib dose optimization study, which essentially tried to ask the question in a rational way. Can we essentially create a strategy where patients start at the lowest dose, 80mg, and then escalate them to 120mg and then to 160mg on a weekly basis, so 40mg a day for a week, every week as tolerated versus starting the patients at 160mg and then de-escalate. And the rationale for that was that we hit a lot of toxicities in the first 2 or 3 weeks, so hopefully we will know very quickly what is the optimal dose for the patient.

The other theoretical benefit from all this is with all these TKIs [tyrosine kinase inhibitors], there is a theoretical benefit of continuous exposure versus chopped exposure. Meaning, if patients stop and go, stop the treatment because they have toxicities, they get very little exposure, we know that the first 2 months are very critical for the treatment, that a lesser exposure may actually get less patients to benefit from the drug. And that was the other reason why we did this.

So the primary endpoint of the study was a composite endpoint of efficacy and toxicity. There was a question about how many patient or what % of patients will be able to reach cycle 3, being able to continue on the drug because lack of toxicity or significant toxicities, because we figured out the right dose, and they haven’t progressed on their disease. Our goal was to see 15% extra for the dose escalation strategy versus the 160. And the study was positive for its primary endpoint. Meaning more patients were able, 24% to 43% were able to actually make it on the dose escalation strategy, so 80mg, 120mg, 160mg, were able to make it to cycle 3 than the 160 mg.

Very intriguing. The survival of those patients on the dose escalation strategy was about 10 months, a little bit less than 10 months, whereby on the 160mg was 6 months which is very consistent with what we’ve seen with the CORRECT study. And that was very intriguing. I can’t really explain why this was not powered for survival, but that’s an interesting observation. The other thing that we’ve observed is the quality of life of the patients on the dose escalation strategy was preserved. So there was no dip, there was no loss of quality of life, and the toxicities were lesser. And the hand and foot syndrome reaction, fatigue, everything was lesser. So, overall, this study suggested that the best strategy for regorafenib is perhaps to start with 80mg, then 120mg, then 160mg for patients that has tolerated. The goal remains to get to 160mg as about 20% of the patients were able to get to 160mg and continue through beyond cycle 3.

This was a practice-changing study. ReDOS was a practice-changing study. The NCCN guidelines adopted the ReDOS schedule as one of the schedules, proposed schedules for regorafenib. The FDA actually did issue a little guidance on it as well, allowing exposure to it. So there was an uptake about the understanding that this will change the way we treat patients with metastatic colorectal cancer. In my clinic, of course, it’s the only way I give regorafenib now. The PK [population pharmacokinetic] studies are underway, so we can learn a little bit more about the exposures on the short and long-term. We haven’t completed those. We also are looking at the effects of preemptive steroid, clobetasol versus reactive. These results will hopefully be presented at ASCO [American Society of Clinical Oncology]. So there will be much more to come regarding these options.

We recently presented a meta-analysis and a systemic review on a systematic meta-analysis at ASCO GI [Gastrointestinal] which looked essentially at all the studies with regorafenib and TAS-102 [trifluridine/ tipiracil]. And that study was interesting, at least the results of the study is interesting. And we’re writing this up now as a manuscript. It suggests that in the comparisons of regorafenib with 80 mg going to 120mg, 160mg would be superior to best supportive care or placebo in an historical fashion. But, interestingly, again, it confirmed that regorafenib dose escalation strategy would likely be a superior strategy. Although, again, we didn’t reach quite the statistical significance. But at least numerically it seems to be superior to both regorafenib at 160mg and TAS-102.

Now, both regorafenib and TAS-102, regorafenib at 160mg and TAS-102 seemed to perform equally well in that meta-analysis. But REGO [regorafenib] 80mg is going to 160mg seemed to actually have a better trend than either. So more to come. We’re learning more and more about how to optimize the strategies. But, at this point of time, at least from the clinical standpoint, I think it would be preferable if you choose to treat your patients with regorafenib to go with the dose escalation strategy based on the results of ReDOS trial and what followed in terms of the meta-analysis we presented at ASCO GI.

When we look at the real-world data from the CORRELATE study and others that tell us about how physicians practically use regorafenib in their own clinics, certainly aligns with our concern with a lack of adherence to the standard dosing and also wide array of different dosing patterns and dosing strategies. I think now that we have ReDOS and soon we’ll have the results of RE-ARRANGE study that are asking these questions of how to dose optimize regorafenib in the setting of a prospective randomized clinical trial, that we go back and start standardizing a little bit better how we treat our patients without just randomly assigned dosing strategies.

Transcript edited for clarity.

Case: A 60-Year-Old Male With mCRC

Initial presentation

April 2015

• A 60-year—old man was referred to gastroenterology after complaining of general malaise and alternating constipation with bloody diarrhea.
• PE: Showed left-sided lower abdominal pain
• Carcinoembryonic antigen (CEA); 8.1 mg/L
• Colonoscopy revealed a left-sided adenocarcinoma of the colon
• Surgery: left hemicolectomy
• Pathology: well-differentiated adenocarcinoma
• PET/CT: 15/15 lymph nodes tested negative
• Staging: IIIA
• ECOG PS 0
• Patient received adjuvant mFOLFOX4

April 2018

• 24 months later, the patient complained of mild abdominal distension and his stools were pencil-shaped with some presence of blood
• PET/CT scan showed widespread small liver lesions
• CEA; 14.7 mg/L
• Biopsy was CK2-positive
• Molecular testing; allRAS&BRAFWT
• ECOG PS 1
• Patient began treatment with FOLFIRI + bevacizumab

February 2019

• PET/CT scan showed evidence of new liver lesions and a 2-cm mass in the right lung
• CEA; 31.7 mg/L
• Patient started on regorafenib 80 mg/day