During a Targeted Oncology Case-Based Roundtable event, Alan Venook, MD, professor of medicine at the University of California, San Francisco, discussed the data related to regorafenib therapy for relapsed/refractory metastatic colorectal cancer.
Targeted OncologyTM: What are the triggers to switch therapy in metastatic colorectal cancer (CRC)?
VENOOK: Patients typically get about 6 to 8 months of benefit from first-line therapy, so [this case] is as expected. The algorithm from the NCCN [National Comprehensive Cancer Network] guidelines shows how to make decisions about therapy.1 Obviously, the triggers for switching therapy [in this case] are progression on CT scan, the rising CEA [carcinoembryonic antigen] level, and decrease in performance status. Each of us has a different threshold. I don’t favor switching therapy just because there’s progression on a CT scan. It can be very minimal progression, for example, in which case I’m not likely to change therapy, depending on how many therapies the patient has had and what I have left on the shelf.
Rising CEA may lead me in the direction of changing, but I would rarely make a decision just based on that. Decrease in performance status, of course, can be the result of disease progression, chemotherapy, or something else, but if it is from the cancer that would probably be the most likely reason to change therapy promptly. The choices [outlined in the NCCN guidelines] are different depending on the status. In this case, for example, we talk about possible irinotecan [Camptosar] plus an EGFR [inhibitor] even in right-sided tumors, although it’s not terribly likely the patient will get a response but they might the more therapies they get. Otherwise, it would be regorafenib [Stivarga] perhaps or TAS-102 [trifluridine and tipiracil (Lonsurf)], which is typically used with bevacizumab. Similarly, other therapies might be considered and this might be the time to use next-generation sequencing [NGS] to look for examples of their BRAF or HER2 status.1
What therapy are you most likely to recommend?
You could continue the therapy with no change, though the patient has new symptoms. You could switch to or reach for a chemotherapy regimen again as the patient has symptoms on maintenance therapy, or you could go for irinotecan plus an EGFR inhibitor, or you can go for regorafenib or TAS-102 plus or minus bevacizumab.
Again, this is a patient not on active therapy or on what we call maintenance therapy. I’m not so sure that’s very effective in colon cancer, but it’s commonly done.
Which data support the use of regorafenib in this patient with CRC?
The data for regorafenib are from the phase 3 CORRECT trial [NCT01103323], which were published 8 years ago. [The trial] looked at regorafenib vs placebo and used a 2:1 randomization in patients who failed multiple lines of prior therapy. There is a slight overall survival [OS] advantage of 6.4 months vs 5.0 months [HR, 0.77; 95% CI, 0.64- 0.94; P = .0052].2
This was at the recommended regorafenib dose [of 160 mg], which we practically don’t use because it is incredibly toxic, but it’s approved and is in the guidelines, so it is perfectly reasonable to use.
I don’t know what to make of the data from the REVERCE trial [UMIN000011294], which is a small data set. This was probably the scenario of oncology a couple of years ago, such as in this patient, [for whom] they used regorafenib followed by cetuximab [Erbitux], but the sequence [in the other arm] was cetuximab first and then regorafenib.3
Regorafenib first improved OS compared with cetuximab first. [The OS for regorafenib first was 17.4 months vs cetuximab first at 11.6 months (HR, 0.61; 95% CI, 0.39- 0.96; P = .0293)]. This was a big result, but the data set was small. I have questions, especially about right-sided disease, as most of the patients [in the data set] had left-sided disease. Furthermore, there was a disproportionate number of patients who started with cetuximab who had left-sided vs right-sided disease.3
In any case, there was a big difference, so is there some biological reason for perhaps stopping the bevacizumab treatment? If patients are coming off bevacizumab and then you give regorafenib, that’s like continuing a VEGF inhibitor, and perhaps there is no rebound from the absence of bevacizumab. This is not something I endorse particularly, but it’s in the data and it may be a curious result, but we can consider the sequence of therapy as the data suggest. Again, especially with right-sided disease, theoretically the patients could get benefit again, but I probably wouldn’t go there as these are European data and [they are what they are].
What dose and duration of therapy do you start at for regorafenib?
Regorafenib is not tolerable. As with any drug in development, if you pick a dose, you must go forward based on the study. Incredibly enough, the study [results were] favorable, but if you go back to the CORRECT data, many patients stopped the treatment even though they were not progressing. That’s because regorafenib, amongst other things, is poorly tolerated both short-term with a variety of toxicities as well as long-term with muscle wasting and poor performance status.
The phase 2 ReDOS study [NCT02368886] was a very interesting study that showed if a drug is approved, you can go back and retweak the dose. In this case, they started at 80 mg and worked their way up.4 With tyrosine kinase inhibitors [TKIs], and not infrequently with other drugs and other diseases, we know that starting low and going up often generates some toxicity tolerance and the drugs can keep working. In these patients they were able to escalate the dose.
The survival was favorable for patients who had the escalated dose as opposed to the standard dose.4 It is very hard to know how to interpret this other than to start at a low dose and work up and it’s hard to know exactly what the right dose is, as pills come in a certain size, and who is to say that 80 mg is better than 120 mg.
Maybe 100 mg would be the right amount but our knowledge is restricted, though clearly these data would suggest that starting lower and working up is a better strategy than starting high.
Especially as you get to patients down the road there is a lot of toxicity up front, and they are not going to like you very much and will not be keen on subsequent therapies that could help them because they find the toxicities unacceptable.
Do you take this approach when you treat patients?
I would start at 80 mg and not work my way up at all, because treating to toxicity is not good in patients on third- or fourth-line therapy.
There is a population of patients who responds for sure and of course I think that’s why we use [regorafenib], but if we look at the medians of all these drugs and subsequent lines it’s hard to justify use. Of course, medians are made up of some patients who might get a lot of benefit and that’s what you’re looking at in these patients.
I think certainly you can see some effect with regorafenib and if you don’t use it, you won’t see those positive effects. At UCSF [University of California, San Francisco], we generally offer patients a clinical trial before we go to regorafenib.
Do older or younger patients react differently to this treatment?
It’s not out of the question that some of the wear and tear or the beating up of regorafenib in these patients is from prior chemotherapy, although I confess using regorafenib in patients with GIST [gastrointestinal stromal tumors] is no picnic either. We also have to start low, but that is for all the TKIs from imatinib [Gleevec] to nilotinib [Tasigna] to lorlatinib [Lorbrena].
All of these are toxic in some patients and others will not tolerate it very well. It’s a mystery how some patients, for example, can get a year of oxaliplatin without any neuropathy. But that’s a good point, it’s true you never know—sometimes you are surprised by a patient’s tolerance. [Data from] the RECOURSE trial [NCT01607957] were published by Mayer RJ et al.5 [The study] was comparing TAS-102 vs placebo in [patients receiving] subsequent lines of therapy after having failed at least 2 prior lines of therapy. This study led to the approval of TAS-102. There was an OS advantage with TAS-102 and it was 7 months vs 5 months give or take [HR, 0.69; 95% CI, 0.59-0.81; P < .0001].6
TAS-102 and regorafenib would likely never be compared head-to-head, but I think each of these is an option and this certainly led to the use of TAS-102 in many settings. It’s interesting that it has not been able to move up front, because in the studies I have looked at it’s better tolerated than other drugs and one would think we would be using more of it. Whether one uses it with bevacizumab is a good question, obviously, as to the cost, but in our experience it’s as to the efficacy as well.
The adverse events [AEs] of TAS-102 in the RECOURSE study were mostly cytopenia and that’s not surprising.5 It’s sort of a different kind of fluoropyrimidine and patients have had a lot of fluoropyrimidine, so limiting factors are generally cytopenia.
A side-by-side comparison of 80 mg of regorafenib and TAS-102 would make it seem as if regorafenib is a better drug than TAS-102, but I think it’s a little deceptive compared that way, but it’s worth thinking about.7 Remember regorafenib at 80 mg is a pretty effective drug in some patients as we said.
Clearly, for patients, before you say there are no options, these are things you want to consider and you also want to make sure patients are treated enough in the course of their disease, so you don’t lose the opportunity to try 1 of these drugs, which…can have major favorable effects.
1. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 3.2021. Accessed December 8, 2021. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
2. Grothey A, Van Cutsem E, Sobrero A, et al; CORRECT Study Group. 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. Shitara K, Yamanaka T, Denda T, et al. REVERCE: a randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients. Ann Oncol. 2019;30(2):259-265. doi:10.1093/annonc/mdy526
4. 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
5. Mayer RJ, Van Cutsem E, Falcone A, et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi:10.1056/NEJMAoa1414325
6. Van Cutsem E, Mayer RJ, Laurent S, et al; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS- 102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018;90:63-72. doi:10.1016/j. ejca.2017.10.009
7. Sonbol MB, Benkhadra R, Wang Z, et al. A systematic review and network meta-analysis of regorafenib and TAS-102 in refractory metastatic colorectal cancer. Oncologist. 2019;24(9):1174-1179. doi:10.1634/ theoncologist.2019-0189