Retrospective Data Highlight Impact of Dose Escalation of Regorafenib in mCRC


During a Case-Based Roundtable® event, Madappa Kundranda, MD, PhD, discussed recent retrospective studies that looked at outcomes of dose optimization of regorafenib for patients with relapsed/refractory advanced colorectal cancer in the first article of a 2-part series.

Madappa Kundranda, MD, PhD

Madappa Kundranda, MD, PhD

Gastrointestinal Medical Oncologist

Banner MD Anderson Cancer Center Clinic

Gilbert, AZ

TARGETED ONCOLOGY: How did investigators optimize the dose of regorafenib (Stivarga) in patients with refractory metastatic colorectal cancer?

MADAPPA KUNDRANDA, MD, PHD: This was [shown in] the ReDOS trial [NCT02368886]…. In essence, there were 2 arms. [One] was the dose escalation arm [giving regorafenib] from 80 mg to 120 mg to 160 mg [daily]. [The other arm] was a standard group [who received 160 mg of regorafenib daily]. Within that, there were these subgroups of patients wherein they received the steroid cream preemptively vs those who were reactively treated [for a hand-foot skin reaction]. Although the primary end point of the study was the number of patients getting to the third [cycle of treatment], and it was not powered to look for overall survival, [benefit to dose escalation] was seen in the small subset of patients [HR, 0.72; 95% CI, 0.47-1.10; log-rank P = .12].1 This is to be taken with a grain of salt, when you look at the number [of patients], because this wasn’t powered for this, and was not statistically significant. But what it did establish was the fact that with ReDOS, we realized that starting with 160 mg of regorafenib was not the way to dose these patients.

The other thing we realized with ReDOS, and that the subsequent [studies] will indicate, is that getting the 160 mg as the total cumulative dose is not the optimal dose, and we realized that…keeping patients on treatment for longer [leads to] having a prolonged exposure to a lower dose, and the sweet spot is probably somewhere between 120 mg to 140.

The toxicities were significantly higher with the standard dose as opposed to the dose escalation across the board, whether it was the skin toxicities, or whether it was the diarrhea. This is not surprising, but this was one of the studies that first demonstrated that.

What did the presentation on the European patient population at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium [ASCO GI] show about the use of regorafenib?

In terms of looking at this real-world evidence of the European patient population at 3 years [2019-2022] of looking at the patients who received regorafenib, the key part of this to remember is that when these patients were looked at, [it was] all of these patients who [received] regorafenib irrespective of the line of therapy. It wasn’t a line of therapy study; when they looked at it, it was just the European experience with any line of therapy, and this was presented at ASCO GI this year.2

Within this patient population, they looked at the ‘ReDOs-like’ [regimen]: dose adjusted [vs] the standard regimen of 160 mg. The ‘dose-adjusted’ [regimen] for patients who started off at 160 mg had dose reductions based on toxicities and how they did. The ‘ReDOS-like’ was exactly what [the study did], which was the 80 mg and 120 mg [dose escalation]. That’s why they call it ‘ReDos-like’, and the standard was still the 160 mg dose.

When we look at these 2 parameters, in terms of the patients who had more lines [of therapy] and at least got past the third cycle of treatment, the ones who did the best were the ones who were dose adjusted. And to a certain degree it reflects what we saw even prior to the ReDOS data, [which was] we stopped them at a dose and then dose deescalated very quickly. This goes to the point of saying that the exposure to a certain degree makes a lot more difference than trying to push for a higher dose. The [mean] duration of treatment across the board is in the magnitude of [2.2 months in the overall population, 2.0 months for ‘ReDos-like’, 2.0 months for dose-adjusted, and 1.7 months for the standard]. This reiterated what we’ve always seen with these drugs, [which was] getting that exposure for a prolonged period of time helps in getting these patients to have a better outcome.

In terms of the reasons for discontinuation, most of it is because of disease progression, which is not unusual.2 But I’m impressed with the fact that quite a few of the patients within the standard arm made [disease progression], whereas, the patients who discontinued within the European population was not as high as I thought it would be.

1. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4
2. Peeters M, Chibaudel B, Barzi A, et al. Real world (RW) use and outcomes of regorafenib (REG) flexible dosing in patients (pts) with metastatic colorectal cancer (mCRC) in Europe. J Clin Oncol. 2024;42(suppl_3):47. doi:10.1200/JCO.2024.42.3_suppl.47
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