Retrospective Data Demonstrates Efficacy of Regorafenib in mCRC


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.

Madappa Kundranda, MD, PhD

Madappa Kundranda, MD, PhD

Gastrointestinal Medical Oncologist

Banner MD Anderson Cancer Center Clinic

Gilbert, AZ

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

MADAPPA KUNDRANDA, MD, PHD: 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.1

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.2,3 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].1

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.4 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.4 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). J Clin Oncol. 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. Lancet. 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. Lancet Oncol. 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. Ann Oncol. 2023;34(suppl_2):S442. doi:10.1016/j.annonc.2023.09.1807
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