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 RAS wild-type and medically appropriate, an anti-EGFR therapy.1 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.2
“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 OncLive®. “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.
OncLive: How does fruquintinib fit into the treatment paradigm for mCRC following its FDA approval?
Raghav: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; P < .001].1,3 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.3
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].
References
- 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
