Selecting from available therapeutic options in the later-line metastatic colorectal cancer (mCRC) setting requires balancing modest efficacy and cumulative toxicities seen with these agents, as well as ample consideration of patient preferences, according to Tiago Biachi, MD, PhD.

 Biachi discussed how data from the phase 3 CORRECT (NCT01103323), SUNLIGHT (NCT04737187), and FRESCO/FRESCO-2 (NCT02314819; NCT04322539) trials have informed the use of regorafenib (Stivarga), trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin), and fruquintinib (Fruzaqla), respectively, across refractory disease settings, and how clinicians have navigate treatment decisions when there is a lack of head-to-head comparisons.

Bianchi explained that treatment selection in later-line mCRC often hinges on broad clinical considerations, such as cumulative hematologic toxicity and the need for disease control, rather than isolated response metrics.

“It’s always important to start educating [patients about] the real purpose of [later-line] treatment from the beginning, actually. This is a palliative treatment [that is] supposed to make [life] a little longer; that’s what matters. Sometimes, we might need to reduce the dose from the beginning. We might need to reduce the dose to keep [a patient] on track. I would say it doesn’t matter much if the lesion shrunk by 1 cm if the patient is experiencing a lot of toxicities,” Biachi explained.

Biachi is an associate member in the Department of Gastrointestinal Oncology at Moffitt Cancer Center in Tampa, Florida.

: In your practice, which patient characteristics and disease factors can help drive later-line treatment decisions in mCRC?

This is a scenario for which we have trials to support all these options, like regorafenib in the CORRECT trial, the SUNLIGHT [trial] for the combination of TAS-102 with bevacizumab, and then the FRESCO/FRESCO-2 [trials] for fruquintinib.

We don’t have head-to-head comparisons between those trials. The main thing [to consider] is the toxicity profile we [expect] with [a given] therapy.

Of course, there are always some points [in favor of a given agent; for example], fruquintinib is going to be [all] oral, so this patient doesn’t need to come in for intravenous infusions every 2 weeks. We have to remember that these patients have been on chemotherapy for sometimes more than 2 or 3 years, so if the patient is struggling with myelosuppression, [where] neutropenia or myelotoxicity has been an issue, [then] this patient [may benefit] from fruquintinib.

On the other hand, we know that response rates are a little bit higher in the SUNLIGHT trial. If the patient [needs] some kind of response, then I might [select], for example, the combination of TAS-102 with bevacizumab for that patient.

How do you interpret and communicate the magnitude of benefit observed with these agents in randomized trials when setting expectations with patients?

This is a conversation that I always have, even with my fellows. We’re sometimes so focused on the CT scan, and again, these patients are on chemotherapy for 2 or 3 years. If you keep just trying to track down those lesions on the CT, trying to measure those lesions, and trying to prove that you were still able to shrink those lesions for 2 or 3 years, at this point, the patient will be disappointed, because the response rate is very low here.

It’s always important to start educating [patients about] the real purpose of this treatment from the beginning. I would say it doesn’t matter much if the lesion shrinks by 1 cm if the patient is having a lot of toxicities. For example, if the patient understands the real purpose of this treatment when we get into the third line, it’s easier to explain that, ‘We’re going to change this treatment to something where it’s very unlikely we’re going to see [a] response. Response rates are going to be very low, but we can try to [maintain] your quality of life. We can try to prolong disease progression and, consequently, [extend your life] a little longer.’

Which starting dose, schedule, and dose-modification strategies do you use in routine care?

In the past, the [approved] dose of regorafenib was a really hard dose to start with. Then we had the phase 2 ReDOS trial [NCT02368886], starting with the lower dose and escalating. With TAS-102 sometimes, due to this myelotoxicity, we might prefer to do this treatment every other week instead of 2 weeks on and 2 weeks off.

With fruquintinib, I would say the challenging part here is that those pills come as a 5-mg or 1-mg dose. If we start with 4 mg—say we’re going to request this dose for insurance, for example—then later, if we need to change this to 5 mg, we might need to send another prescription. This can cause some delays.

Personally, what I prefer to do is start with the standard dose [of fruquintinib] for these patients [and follow] them closely, mainly during the first 1 or 2 cycles. Now we have the capacity to do this virtually. If we need to dose-reduce this patient, I might prefer to do, for example, something like [a dosing schedule that includes] weekends off, or 3 days on and then 1 day off. That is a bit off-label, but [these are ways] you can make things easier for patients. [That] dose reduction [strategy] has been working well.

What would you say are some of the most common adverse effects (AEs) that you typically see associated with these later-line agents? How do you tend to manage such toxicities, apart from dose modification?

Toxicity is the key [element] in later lines, and because the benefit with all these regimens is very modest, [toxicity management becomes critical]. With TAS-102 plus bevacizumab, we usually see more fatigue and myelotoxicity. We do have more hypertension with [regorafenib], which is usually something that we’re used to because of bevacizumab and other antiangiogenic drugs that we’ve been using for CRC.

Fatigue is real, and this is probably the hardest toxicity to manage, because again, we have drugs to help [manage] gastrointestinal toxicities [but not fatigue].

I would add that toxicity is not only about grade 3 or higher [AEs]; this is another conversation I have with my fellows. Sometimes those trials will focus on grade 3 or higher toxicity, but we may be talking about a daily treatment. If the median overall survival is approximately 8 to 10 months, then those patients will be on treatment for 4 to 8 months.

[A patient with] grade 1 diarrhea might [have] 4 or 5 episodes of diarrhea per day; that’s not easy for a patient. [It is] going to impact social life for this person. We have to be mindful about even lower-grade toxicities for [patients with later-line mCRC], and we might need to dose reduce accordingly.

Grothey A, Cutsem EV, 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

Prager GW, Taieb J, Fakih M, et al. Trifluridine–tipiracil and bevacizumab in refractory metastatic colorectal cancer. 

. 2023;388(18):1657-1667. doi: 10.1056/nejmoa2214963

Fruquintinib in less pretreated patients: Multivariate profile-matching analysis of FRESCO-2 to FRESCO. 

. 2025;227:115641. doi:10.1016/j.ejca.2025.115641

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