FDA approval of fruquintinib (Fruzaqla) for the treatment of patients with previously treated metastatic colorectal cancer (mCRC) 

and ongoing efforts to expand patient access to the therapy, the later-line mCRC treatment paradigm has been bolstered by the inclusion of this VEGFR TKI, according to Kanwal P.S. Raghav, MBBS, MD.

Fruquintinib is indicated for the treatment of adult patients with mCRC who have previously received fluoropyrimidine (5FU)–, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if 

 wild-type and medically appropriate, an anti-EGFR therapy.

The FDA approval of this agent was supported by data from the phase 3 FRESCO-2 (NCT04322539) and FRESCO (NCT02314819) trials.

Moreover, in July 2025, Takeda Oncology announced that fruquintinib was covered on CVS Caremark National Template Formularies. This update means that 93% of commercial lives are now covered for the agent.

“Fruquintinib is a highly selective oral TKI that [targets] all 3 receptors in the VEGF pathway. As a result, its major implication is anti-angiogenesis, and it also affects lymphogenesis that occurs through VEGF3,” Raghav explained in an interview with 

®. “Since its approval, most of the use of this drug has been in the third- and fourth-line settings, as was designed by the study, depending on how you are defining your lines of therapy in mCRC.”

Raghav is a professor in the Department of Gastrointestinal (GI) Medical Oncology in the Division of Cancer Medicine, the associate vice president of the Department of Ambulatory Medical Operations, and the executive medical director of the Department of Ambulatory Treatment Centers at the University of Texas MD Anderson Cancer Center in Houston.

In the interview, Raghav discussed the current standing of fruquintinib in the mCRC treatment armamentarium, the data that led to its approval, patient selection considerations, and potential future roles for the agent.

How does fruquintinib fit into the treatment paradigm for mCRC following its FDA approval?

:The approval of fruquintinib was based on [findings from] FRESCO and FRESCO-2. These were 2 randomized trials. FRESCO was done primarily in China, but FRESCO-2 was a global trial. This trial randomly assigned patients to receive fruquintinib vs best supportive care and placebo. There was a median overall survival [OS] benefit [with fruquintinib] seen in FRESCO-2, as well as in FRESCO.

The median OS in the placebo arm [of FRESCO-2] was 4.8 months [95% CI: 4.0-5.8], and this was improved with fruquintinib to 7.4 months [95% CI, 6.7-8.2], [representing an] HR of 0.66 [95% CI, 0.55-0.80; 

 Owing to the results of this study, fruquintinib was approved in a treatment-refractory CRC population. The eligibility criteria [for FRESCO-2] were that patients should have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF therapy, and anti-EGFR agents, wherever indicated. One of the critical points of this trial was that patients had to have progression on the then standard of care trifluridine plus tipiracil [TAS-102; Lonsurf], regorafenib [Stivarga], or both. It was a highly treatment-refractory population.

Is there potential for fruquintinib to move into earlier lines of therapy?

That’s a burning question in the field. We have all these agents in the salvage setting, but there are 2 things we lack with many of these agents. The first is optimal sequencing, because there is no head-to-head comparison for these trials. The second is predictive biomarkers.

Putting that aside, the basis of many of these agents is that the VEGF axis is an important axis in CRC. [Findings from] the [phase 3] VELOUR [NCT00561470], RAISE [NCT01183780], and TML [NCT00700102] studies all showed convincingly that VEGF continuation, even after progression on prior VEGF inhibition, is effective in patients with CRC. I [believe] that there is a significant role in trying to learn how to best sequence these agents, because all these agents—aflibercept [Zaltrap], ramucirumab [Cyramza], bevacizumab [Avastin], regorafenib, and now fruquintinib—which are all primarily VEGF-targeted agents, work mechanistically in a different manner. There is a question of sequencing that we have yet to answer. However, there are evolving data with combination therapies, as well as single-agent treatment, bringing fruquintinib up in the first-line maintenance setting or to the second-line setting in combination with chemotherapy. There are also emerging data on combinations with immune checkpoint inhibitors and other drugs.

What quality-of-life and safety data have been reported with fruquintinib?

This agent, in the setting it was studied in [in FRESCO and FRESCO-2], was well tolerated. Most of the toxicities are predictable and manageable. The key area where one has to pay attention is hypertension, because any-grade hypertension occurred in nearly [61%] of patients [in FRESCO], and grade 3 or 4 hypertension was reported in [23%] of patients.

Another [toxicity] that you need to watch out for is the classic constitutional class effect of all TKIs, which is hand-foot syndrome. [In FRESCO], this occurred at any grade in [49%] of patients and [at a rate of] 11% for grade 3 or 4. You have to watch out for these toxicities, but these are manageable, especially if you can select your patients appropriately. [A patient] with uncontrolled hypertension is probably not a great candidate for this drug, but otherwise, compared with the toxicity profile of other drugs, [that of fruquintinib] is different but manageable, and that results in improved quality of life [QOL] in these patients.

Patients with CRC at this stage are not always looking for tumor shrinkage. [Fruquintinib is] a drug that is easily available, accessible, oral, and [allows] a patient to manage the toxicities well. The QOL is also dependent on the stability of disease and the disease control rate, which can be as high as 50% to 60% with these drugs. All those factors result in a maintained QOL.

What factors do you consider when deciding whether a patient in the later-line setting should receive fruquintinib?

The [FRESCO and FRESCO-2] trials define the types of patients who should receive this agent. Usually, first- or second-line [therapy] is combination cytotoxic and biologic agents, provided [the patient is] not in one of the [selected] molecular subsets in CRC. Then there is the question of whether you would treat a patient with TAS-102 plus bevacizumab because of the benefits seen [with fruquintinib and regorafenib] over TAS-102.

There is no optimal sequencing, so you have to take into consideration patient preferences [and] toxicities that they have had. For example, if [a patient] has received multiple lines of chemotherapy and are now drowning under the pressure of bone marrow suppression from treatment toxicity, it may not be feasible to continue a cytotoxic therapy such as TAS-102. But those are cases where VEGF inhibition is effective and acts as a chemotherapy-free treatment regimen. A variety of patient factors, including preference of administration and toxicity profile, should be considered. It is a multifaceted decision; [there is] not a clear-cut indication [for fruquintinib].

FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2023. Accessed October 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer

Now on formulary: Fruzaqla (fruquintinib) is covered on CVS Caremark National Template Formularies. News release. Takeda Oncology. July 1, 2025. Accessed October 8, 2025. https://msho.org/aws/MSHO/asset_manager/get_file/927883

Fruzaqla. Prescribing information. Takeda; 2023. Accessed October 8, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217564s000lbl.pdf

Articles

Kanwal P.S. Raghav, MBBS, MD, discusses the role of fruquintinib for the treatment of patients with later-line colorectal cancer.

Fruquintinib Represents Viable Later-Line Option for mCRC As Access Expands for Patients

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, we had the pleasure of speaking with Kanwal P. S. Raghav, MBBS, MD, about the role of fruquintinib (Fruzaqla) in the treatment of adult patients with pretreated, metastatic colorectal cancer (CRC). Dr Raghav is a professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine, associate vice president of the Department of Ambulatory Medical Operations, and executive medical director of the Department of Ambulatory Treatment Centers at The University of Texas MD Anderson Cancer Center in Houston.

In our exclusive interview, Dr Raghav discussed the mechanism of action of fruquintinib, key efficacy data from the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) trials, the treatment settings where this agent is most frequently administered, and adverse effects to be aware of. He also noted how the role of fruquintinib in earlier lines of therapy has yet to be defined due to a lack of optimal predictive biomarkers. Dr Raghav concluded by emphasizing the importance of clinical trials for improving outcomes for patient with CRC.

That’s all we have for today! Thank you for listening to this episode of 

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Podcasts

Dr Raghav discusses the role of fruquintinib in the treatment of adult patients with pretreated, metastatic colorectal cancer.

Sequencing, Efficacy, and Safety Data May Further Evolve the Role of Fruquintinib in CRC: With Kanwal P. S. Raghav, MBBS, MD

MArshahll

“You want to use this drug at some point in your patients, because it [offers a] survival advantage, so don’t leave it on the table. The one mistake oncologists make with this drug is holding off on it too long until the patient is too sick.”

John L. Marshall, MD, clinical director of oncology at Georgetown University Hospital, as well as chief of Hematology and Oncology, a professor of medicine and oncology, and director of the Otto J Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown Lombardi Comprehensive Cancer Center, discussed the role of fruquintinib (Fruzaqla) in the treatment paradigm for metastatic colorectal cancer (mCRC).

Findings from pivotal randomized trials established the efficacy of fruquintinib—a highly selective oral tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3—in patients with refractory disease. The agent demonstrated a survival advantage compared with placebo and has been approved for use in the third-line setting and beyond, where it primarily achieves disease stabilization rather than objective tumor regression, Marshall explained.

According to Marshall, the oral formulation of fruquintinib offers a practical advantage in later lines of therapy, allowing patients to transition from intravenous chemotherapy to a maintenance-oriented regimen. He emphasized that the key clinical consideration is timing, noting that one of the most frequent clinical mistakes is delaying fruquintinib initiation until patients are too ill to derive meaningful benefit. Used appropriately, the therapy provides a survival benefit that should not be left unused in eligible patients, he stated.

Regarding sequencing, Marshall highlighted the ongoing clinical question of whether fruquintinib should be considered before trifluridine/tipiracil (Lonsurf; TAS-102), with or without bevacizumab (Avastin). He explained that this decision is highly patient-specific, depending on tumor burden, prior lines of therapy, and overall clinical status. Although TAS-102 plus bevacizumab remains a strong option in many cases, fruquintinib provides a distinct mechanism of action and oral convenience, making it a viable alternative, he stated. Marshall compared treatment sequencing to making a chess move, where the best option is determined by the patient’s overall clinical context rather than a fixed treatment algorithm.

At present, clinical data support the use of fruquintinib primarily in the later-line setting, and there is insufficient evidence to recommend its routine incorporation earlier in the treatment continuum ahead of TAS-102, according to Marshall. However, Marshall suggested that fruquintinib’s tolerability and mechanism raise the possibility that future studies could explore the earlier integration of this agent in the therapeutic sequence. For now, sequencing decisions should remain individualized, guided by patient characteristics and prior treatment history, he concluded.

Videos

John L. Marshall, MD, discusses the use of fruquintinib in the treatment of patients with metastatic colorectal cancer.

Dr Marshall on the Role of Fruquintinib in the Treatment Paradigm for mCRC

Positive overall survival (OS) and quality of life (QOL) data with fruquintinib (Fruzaqla) in patients with advanced colorectal cancer (CRC) have positioned the agent as a valuable later-line therapy. The agent also serves as an important option to use as maintenance therapy as early as possible in each patient’s personalized treatment sequence, according to John Marshall, MD.

“You want to use this drug at some point in your patients [with CRC], because it [offers a] survival advantage,” Marshall said about fruquintinib in an interview with 

®. “Don’t leave it on the table.”

 for the treatment of adult patients with metastatic CRC (mCRC) who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; VEGF-directed therapy, and, if 

 wild-type and medically appropriate, an anti-EGFR therapy.

 The regulatory decision was backed by data from 2 pivotal clinical trials. In the phase 3 FRESCO-2 trial (NCT04322539), the median OS was 7.4 months (95% CI, 6.7-8.2) with fruquintinib plus best supportive care (BSC; n = 461) vs 4.8 months (95% CI, 4.0-5.8) with placebo plus BSC (n = 230; HR, 0.66; 95% CI, 0.55-0.80; 

 In the phase 3 FRESCO trial (NCT02314819), the median OS was 9.3 months (95% CI, 8.2-10.5) in the fruquintinib arm (n = 278) vs 6.6 months (95% CI, 5.9-8.1) in the placebo arm (n = 138; HR, 0.65, 95% CI, 0.51-0.83; 

In the interview, Marshall contextualized these fruquintinib data in the mCRC treatment paradigm, which also includes trifluridine/tipiracil (Lonsurf; TAS-102) plus bevacizumab (Avastin) for the same indication as fruquintinib. This regimen 

 based on data from the phase 3 SUNLIGHT trial (NCT04737187), in which TAS-102 plus bevacizumab (n = 246) elicited a median OS of 10.8 months (95% CI, 9.4-11.8) compared with 7.5 months (95% CI, 6.3-8.6) with TAS-102 alone (n = 246; HR, 0.61; 95% CI, 0.49-0.77; 

In the interview, Marshall also explained the agent’s efficacy in later lines of CRC therapy based on clinical trial data, advocated for the agent’s use as maintenance therapy to avoid overtreatment, and stressed the importance of molecular profiling in patients at diagnosis in conjunction with robust multidisciplinary care during treatment.

Marshall is chief of Hematology and Oncology, a professor of medicine and oncology, and director of the Otto J Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

: What is the mechanism of action of fruquintinib?

: Fruquintinib targets VEGF receptors. A lot of drugs do that. This [drug] targets VEGF receptors 1, 2, and 3. The whole VEGF receptor pathway is important for angiogenesis, and maybe immunotherapy, [although the field is] skeptical on that end. [Fruquintinib has] tight binding to the receptor, blocking signaling, [similar to a] TKI.

Where does fruquintinib currently fit into the CRC treatment paradigm?

We know fruquintinib works because of the big, randomized studies that were done.

We know that some patients [will have] minor responses, but mostly a stable disease [SD] benefit is what you see from the drug. It’s oral, which makes for a nice break from intravenous [IV] therapy. [The data with this agent support the] VEGF [inhibition] beyond progression idea. [Fruquintinib is] approved in the third- or later-line settings.

What might be the role of fruquintinib earlier in the treatment paradigm?

I am a big believer in the concept of maintenance therapy. There are only a few drugs in the CRC treatment continuum that cause a regression: [certain chemotherapy regimens] and sometimes EGFR-directed therapies. Almost everything else is maintenance [therapy], or [treatments that elicit] SD.

Every chance I get to switch from the more intensive IV approaches to oral maintenance, I do it. I make sure to use fruquintinib before the patient is too burnt out. The one mistake oncologists make with this drug is holding off on it too long until the patient is too ill.

Which [regimen] you use first between TAS-102/bevacizumab and fruquintinib has a lot to do with the patient in front of you. There are patients in whom TAS-102/bevacizumab is the right [subsequent treatment], [and other times it’s] fruquintinib. [This decision is related to] tumor burden and the last treatment the patient received. There is no one right answer for that.

What clinical trial data help you decide when to use fruquintinib?

[In the FRESCO and FRESCO-2 trials], fruquintinib was tested against placebo [in patients with mCRC] and proved positive. [In the SUNLIGHT trial], TAS-102/bevacizumab was [tested] against TAS-102 alone [in patients with mCRC], and the TAS-102/bevacizumab combination showed positive data as well. We have these 2 strong choices for patients in the more refractory setting.

Do [patients] want to avoid coming into the clinic? How bad is their bone marrow? The adverse effects [AEs] associated with these medicines are different [from each other]. I try to pick the optimal treatment for the patient in front of me.

What QOL data have been reported with fruquintinib that may play a role in your treatment decision-making?

With all these drugs, we give high doses. The recommended phase 2 dose is often the maximum tolerated dose. At 5 mg daily with fruquintinib, most patients [tolerate the agent] well.

[AEs like] hypertension and fatigue happen [with fruquintinib]. Often, as with many drugs, some patients start at a lower dose [of fruquintinib] and inch their way up vs starting high and de-escalating. When you’re dosing this medicine, you want [to schedule a] quick follow-up with that patient [to make sure] you get the dose right.

Based on the available efficacy, safety, and QOL data with fruquintinib, how do you explain treatment goals to patients and approach shared decision-making with patients who may be eligible for this agent?

By the time you’re making these kinds of decisions, you know the patient well. You know their family. You know their priorities. They know your style. You know theirs.

Describe this treatment [the same way] you’ve already [described other treatments] before with them. Sometimes they’ve already done the research themselves. Sometimes you’re the first one to introduce it. Take your time. Give them the best information available. There are web-based resources as well. The patient [should become] the best consumer.

What unmet needs persist for patients with CRC?

The biggest new development in CRC is we have to perform molecular profiling in all patients from the beginning. We have [biomarkers including] BRAF, HER2, and microsatellite instability, and soon we may have RAS. We have to know [the patient’s] molecular profiling from the start.

A high percentage of patients don’t have a targetable lesion or will eventually need some of these serious [treatments] we’re talking about that are not targeted to a precision medicine target. You have to know what’s going on there. You have to [see whether] the patient has a surgical option, even in the metastatic setting. Different centers have different levels of expertise and comfort about [treating] and removing [tumors]. You want good, solid, multidisciplinary care.

Importantly, there is nothing magical. You don’t get an award for giving 12 cycles of chemotherapy. That’s a completely made-up number, and yet we feel like we have to give 12 cycles. All 12 cycles [results in] is [more] toxicity. Stop [chemotherapy] sooner. You’re not going to get an ongoing response; the response is going to stay stable. Switch to one of these other medicines. Use maintenance therapies more.

FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2025. Accessed August 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer

Fruzaqla. Prescribing information. Takeda; 2025. Accessed August 19, 2025. https://www.fruzaqlahcp.com/sites/default/files/resources/fruzaqla-prescribing-information.pdf

FDA approves trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer. FDA. August 2, 2023. Accessed August 19, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-trifluridine-and-tipiracil-bevacizumab-previously-treated-metastatic-colorectal-cancer

Lonsurf. Prescribing information. Taiho Oncology; 2023. Accessed August 19, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/207981s012lbl.pdf

John Marshall, MD, discusses fruquintinib’s efficacy in later-line CRC, advocating for the agent’s use as maintenance therapy to avoid overtreatment.

Optimizing and Individualizing Third-Line and Later Therapies for Metastatic CRC | Supplements and Featured Publications

Fruquintinib Represents Viable Later-Line Option for mCRC As Access Expands for Patients

Sequencing, Efficacy, and Safety Data May Further Evolve the Role of Fruquintinib in CRC: With Kanwal P. S. Raghav, MBBS, MD

Dr Marshall on the Role of Fruquintinib in the Treatment Paradigm for mCRC

Fruquintinib Efficacy Data Support Its Use in the Third-Line Advanced CRC Setting