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Spotlight

This roundtable series looks at therapies available for patients with colorectal cancer after prior lines of treatment, as discussed by key opinion leaders and participants at virtual live events.

Inhibition Options in Advanced CRC After Prior Treatment

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

: 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 

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.

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. 

. 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. 

. 2024;42(suppl_3):47. doi:10.1200/JCO.2024.42.3_suppl.47

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.

Retrospective Data Highlight Impact of Dose Escalation of Regorafenib in mCRC

Targeted Oncology: What recent data have been presented related to the use of regorafenib (Stivarga) in patients with recurrent colorectal cancer?

: There were 2 abstracts presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. One was the OSERO study [UMIN000040586], which was an observational study in a Japanese patient population that looked at regorafenib and TAS-102 [trifluridine-tipiracil; Lonsurf] and observed them. They separated patients into 3 different arms: regorafenib followed by TAS-102 [with or without] bevacizumab [Avastin], TAS-102 followed by regorafenib, and the combination [of TAS-102 plus bevacizumab], followed by regorafenib.

The eligibility criteria, as with any observational study, are standard, and the end point that was looked at in this study was the overall survival [OS]. What we saw, and this is typical, was the deepest decline in the Kaplan-Meier curve in most of these would be with the first and second set of scans. Then you see the separation of the curves at the midpoint between the second and third scans.

The study had a relatively large number of patients, approximately 450 patients who were seen on this, and what was observed was that the median PFS [progression-free survival] was 7.1 months for the TAS-102, approximately 12 months for regorafenib, and then the combination of the TAS-102 plus bevacizumab was 10.3 months, [which was] on the higher side.

One thing to also keep in mind is this was an Asian patient population. Even when we looked at the CORRECT study [NCT01103323], which got us the FDA approval for regorafenib, followed by the CONCUR study [NCT01584830], which was more of an Asian patient population, survival had increased.

Some of the other studies where we looked at the survival [demonstrated] further increased survival with regorafenib, and it could be [because of] the patient selection in terms of the demographics. The second thing was that we had speculated [that this was likely because] we were managing these toxicities better. But nevertheless, this is what was seen in this observational study for all of the nuances that go with that. In essence, when we looked at the [PFS], there was not a lot of difference seen within this with the HR [when] each of these were compared with each other. The HR was [0.72 comparing regorafenib vs TAS-102, 0.73 comparing TAS-102 plus bevacizumab with TAS-102, and 1.03 comparing TAS-102 plus bevacizumab with regorafenib].

In essence, when we looked at these 3 combinations, they have a similar OS. There may be a little bit of a difference but it was not statistically significant in the context of the PFS. The adverse events [AEs] were not surprising. [We saw] the typical AEs that we see with TAS-102, which are the hematological toxicities, the typical AEs that we see with regorafenib, and nothing surprising with regard to that…in the Asian patient population.

What other retrospective data investigated the sequencing of regorafenib and TAS-102?

At that same time, we looked at Flatiron Health’s database; this was a retrospective cohort [STAR-T (NCT05839951)] that asked the same question of these patients who were treated between 2015 to 2023. Patients first got regorafenib followed by TAS-102, and [other] patients got TAS-102 followed by regorafenib. The question asked was, is there an [optimal] sequence with these 2 drugs? This was before we even had the data on fruquintinib [Fruzaqla]. What was seen was…the median OS was [13.1] months with regorafenib followed by TAS-102, and the [OS with TAS-102 followed by] regorafenib was [11.5] months.

 It was similar, and not statistically significant [unadjusted HR, 0.94; 95% CI, 0.74-1.19; adjusted HR, 0.99; 95% CI, 0.75-1.29]. It didn’t give us anything to say that one was better than the other from [either of] these studies, when we looked at it. The median OS [for patients treated in the fourth line was 11.6 months with regorafenib first and 10.4 months with TAS-102 first].

When we look at the unadjusted HR and the adjusted HR [for time to discontinuation], it aligns together; whether it’s in the third line or in the fourth line, it doesn’t seem to make a difference. When you’re looking at it statistically, which one is initiated first or next, knowing that this is a retrospective analysis, it still balances out. So if your survival isn’t different from a statistical standpoint, then what are you going to use to make a determination [for sequencing] therapy?

What other guidance on the use of these therapies do these retrospective data provide?

In terms of toxicities, there was nothing surprising. However, one of the things that was observed and is not surprising was the increase of growth factor [use]; granulocyte colony–stimulating factor use was 14% with the regorafenib vs 18% with TAS-102. These are relatively small numbers, and it needs to be kept in perspective. The use of growth factors with oral agents is not completely [accepted] in this context. If you have dose-reduced a patient, and you have an absolute neutrophil count [ANC] of 800/μL or so, do you use growth factors or give them a break and then start them on treatment? If the counts recover, [giving a break] typically has been the practice because when you think about the rationale of using growth factors, it doesn’t make sense when you’re using oral agents such as these, to use growth factors to bump their counts up prior to treating them on it. That was surprising, but this was a database and a reflection in terms of the patient population.

 Although if you do have someone who [has declining ANC] and doesn’t recover the counts even after a dose reduction in a couple of weeks, it may be reasonable to consider that.

The other part of this is the subsequent use of therapies.… The fact that after the third line of therapy, close to 10% of patients received more than 3 subsequent lines of therapy, [up to] 6 lines of therapy is certainly impressive in its own way. A lot of it might be related to how lines of therapy were calculated. But nevertheless, I think this is truly the reality of the world we live in. Five years ago, patients getting a third line of therapy were just few and far between. Usually when we look at every line of therapy to the next line of therapy, we [see] about a 50% of patients who drop off. But to have even a quarter of patients getting 4 to 6 lines of therapy is what we are going to be seeing in some way or form. That’s something to be aware of, and more importantly, something to factor in, especially when you’re choosing lines of therapy, when you’re trying to treat them, and trying to preserve your marrow as much as possible—that is a key part of it.

1. Chida A, Kawakami T, Hamano T, et al. Prospective observational study investigating the impact of treatment sequence using regorafenib and FTD/TPI for metastatic colorectal cancer on overall survival (OSERO study). 

. 2024;42(suppl_3):103. doi:10.1200/JCO.2024.42.3_suppl.103

2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. 

. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X

3. Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2015;16(6):619-629. doi:10.1016/S1470-2045(15)70156-7

4. Bekaii-Saab T, Ahn D, Yuan C, et al. Sequential treatment with regorafenib (REG) and trifluridine/tipiracil (TAS) +/- bevacizumab (Bev) in refractory metastatic colorectal cancer (mCRC) in community clinical practice in the USA. 

. 2023;34(suppl_2):S442. doi:10.1016/j.annonc.2023.09.1807

During a Case-Based Roundtable® event, Madappa Kundranda, MD, PhD, discussed recent retrospective studies that compared outcomes between the available treatment options in patients with relapsed/refractory advanced colorectal cancer in the first article of a 2-part series.

Retrospective Data Demonstrates Efficacy of Regorafenib in mCRC

Daniel H. Ahn, DO, discusses treatment with regorafenib for patients with advanced CRC.

Regorafenib Continues to Benefit Patients With Advanced CRC

Daniel H. Ahn, DO, medical director of the clinical cancer research office, oncologist, and associate professor at the Mayo Clinic in Phoenix, Arizona, discusses the ongoing use of regorafenib (Stivarga) for patients with metastatic colorectal cancer (CRC). Regorafenib is the first small-molecule multikinase inhibitor to show a survival benefit for this patient population and continues to demonstrate effectiveness even with dose modifications.

Regorafenib was approved based on the randomized phase 3 CORRECT trial (NCT01103323), which showed the drug significantly improved overall survival (OS) for patients with metastatic CRC who progressed after standard treatments. The trial investigators recruited 760 patients and randomly assigned them 2:1 to receive regorafenib (n = 505) vs placebo (n = 255) and observed a median OS of 6.4 months compared with 5.0 months (HR, 0.77; 95% CI, 0.64-0.94; 

Following the CORRECT trial, a post hoc analysis of a cohort of Japanese patients on this trial explored if radiological imaging markers could predict clinical outcomes with regorafenib. The analysis, called RadioCORRECT, still showed an improvement in OS and progression-free survival (PFS) for these patients regardless of biomarkers.

Ahn also highlights how the approach to dosing this therapy has changed based on results from the phase 2 ReDOS trial (NCT02368886). Initially, a daily dose of 160 mg for 3 weeks followed by a 1-week break was the standard approach to treatment with regorafenib, but the trial looked at a dose-escalation method of starting at 80 mg of the drug given daily with a weekly escalation of 40 mg until reaching 160 mg.

The randomized, multicenter, open-label study looked at 116 patients randomly assigned to either a dose-escalation group (n = 54) or standard-dose group (n = 62). Forty-three percent (95% CI, 29%-56%) of patients in the dose-escalation group met the primary end point of initiating their 3rd cycle of treatment without stopping compared with 26% (95% CI, 15%-37%) in the standard-dose group (

 = .043). This demonstrated the benefits of a personalized approach to treatment with regorafenib focusing on treatment duration rather than intensity, according to Ahn.

 | Regorafenib has been around for several years now, and that [approval] was based off the randomized phase 3 CORRECT trial. Subsequently, there was a Japanese study called RadioCORRECT, which showed an improvement in OS and PFS in patients with treatment-refractory metastatic CRC irrespective of the genomic mutation present in their tumor.

 A lot has changed in terms of how we prescribe regorafenib. In the past, the recommendations were to give it at a full dose of 160 mg daily for 3 weeks on followed by a 1-week break. But based off the more recent randomized phase 2 trial from the ReDOS trial, led by Dr. Tanios S. Bekaii-Saab, we know that the appropriate treatment strategy for using regorafenib is in a dose-escalation fashion where the study showed that it's more about...the duration rather than dose intensity. And when we see patients who receive regorafenib based off their dose tolerability, [they] have actually a better median OS compared to what was initially projected on the CORRECT trial.

Daniel H. Ahn, DO, discusses how regorafenib continues to benefit patients with advanced colorectal cancer as researchers look to modify treatment strategies with the therapy. 