Expert Commentary on the Product Profile of Fruquintinib in Metastatic CRC

Jagoda Misniakiewicz, PharmD

Clinical Pharmacy Specialist, Medical University of South Carolina

ONCOLOGY spoke with Jagoda Misniakiewicz, PharmD, about the recent approval of fruquintinib for patients with metastatic colorectal cancer. The conversation focused on the mechanism of action of the agent and how it compares with other available treatment options in the space.

The product profile of fruquintinib.

Q / What is the mechanism of action of fruquintinib?

Misniakiewicz / Fruquintinib is a highly selective and potent oral small-molecule kinase inhibitor of VEGFR-1, -2, and -3, which are key regulators of angiogenesis associated with tumor growth and metastasis. Fruquintinib inhibits VEGF-mediated endothelial cell proliferation, tubular formation, VEGF receptor phosphorylation, and tumor growth. Fruquintinib prevents VEGF receptor structural change and dimerization, therefore preventing the phosphorylation of the intracellular kinase domain that impacts downstream signaling cascades. It directly affects tumor cell function by inhibiting new blood vessel growth and results in vascular regression, normalization, and construction. It’s known that angiogenesis inhibition has been proven to be an effective treatment strategy throughout the continuum of care in metastatic colorectal cancer, which led to the [approval] of fruquintinib in this setting. Notably, fruquintinib is a weak inhibitor of RET, FGFR1, and CK kinases, which contributes to decrease in tumor growth.

Q / Are there any specific biomarkers or tumor characteristics that might help identify patients who are most likely to benefit from fruquintinib?

Misniakiewicz / Today, little is known about the pattern of response to fruquintinib. In the FRESCO-2 study, the subgroup analysis showed consistent results having a benefit in the majority of the prespecified subgroups, which had previously used TAS-102 [trifluridine, tipiracil, and hydrochloride; Lonsurf], regorafenib [Stivarga], RAS status, and duration of metastatic disease. It showed a benefit for patients who had liver metastases; however, it would be helpful to have more data on patients with lung metastases. Right now, anyone who has progressed on prior lines of therapy would ideally benefit from fruquintinib therapy. There just needs to be more research into what is that specific [patient population] that could show more benefit.

There is some literature looking at the efficacy of fruquintinib in patients who may have become resistant to bevacizumab [Avastin]. That would be an interesting population. Right now, there are no specific biomarkers or tumor characteristics that we are looking at. Most patients would be appropriate candidates, and we would expect them to receive some benefit from fruquintinib therapy. The only exception to that would be patients whose [diseases] express DNA mismatch repair or are microsatellite instability-high [MSI–high], as they would receive benefit from immunotherapy first, but that probably isn’t even relevant at this time since fruquintinib is used in later settings.

Q / How significant was the progression-free survival (PFS) improvement in the FRESCO-2 trial compared with other treatment options available for this population?

Misniakiewicz / The data that came out of FRESCO-2 were exciting. The forest plot was something that everyone was excited by; it showed a novel treatment for patients with relapsed/refractory colorectal cancer. When we look at what the PFS is compared with the agents that we would be grouping it with, so regorafenib and TAS-102, there is a difference. There are no head-to-head studies looking at that but there is a meta-analysis of 5 clinical trials that showed no difference in the efficacy analysis of overall survival and that fruquintinib was superior in PFS compared with TAS-102.⁴ Overall, I would say that this is significant when we look at this improvement, and it does show a promising treatment option for patients with refractory colorectal cancer.

Q / Were there any common or significant adverse effects (AEs) associated with this treatment? How do they compare with other agents in the space?

Misniakiewicz / According to the results from FRESCO-2 and the package insert, the most common AEs of fruquintinib are hypertension and asthenia, which makes sense based on its mechanism of action. It is comparable with what we would expect with other tyrosine kinase inhibitors (TKIs) used for colorectal cancer and that specific TKI is regorafenib.

Clinically, we can see some differences in AEs. Fatigue has been very significant in our patients who are treated with fruquintinib. This may be associated with the significant and rapid change in their thyroid function tests that we’re seeing. Within 2 weeks of starting therapy, patients are expressing rapid changes in their thyroid-stimulating hormone, and that could be contributing to the fatigue that they’re feeling. We’re seeing a lot of voice changes in hoarseness, which is also to be expected with regorafenib.

Due to fruquintinib’s mechanism of action, one would expect AEs related to the VEGF pathway, so hypertension, proteinuria, bleeding, impaired wound healing, and arterial thromboembolism. Those are the same AEs that I would be on the lookout for in patients treated with regorafenib. The big difference that we see is that patients treated with regorafenib experience more hand-foot syndrome and diarrhea than we have seen in patients with fruquintinib. Hand-foot syndrome has a high incidence in the FRESCO-2 trial; we just are not seeing as much as we see in patients who have been treated with regorafenib.

Q / What are some known potential resistance mechanisms associated with fruquintinib?

Misniakiewicz / The mechanisms of resistance to anti-VEGF therapies are not exactly clear. To date, there are 3 main theorized mechanisms that include activation of compensatory pathways, redundancy and angiogenic pathways, and MET upregulation and hepatocyte growth factor/c-MET activation. It’s also important to consider that factors such as hypoxia and limited blood supply can decrease drug delivery leading to resistance. Interestingly, some strategies have been explored to overcome these potential resistance mechanisms, including targeting alternative angiogenic pathways and combining VEGF targets with PD-1 and MET. It will be interesting to see if fruquintinib has a role in patients who may develop resistance to bevacizumab therapies and then differentiate what is the known resistance mechanism to bevacizumab. How does that compare with fruquintinib, especially since we’ll be using it in later lines?

Q / Where do you see this agent headed?

Misniakiewicz / There are currently a lot of clinical trials looking at fruquintinib in combination with chemotherapy. That will be an avenue to be explored. It’s being studied with chemotherapy as well as other targeted agents and immunotherapy. Seeing the outcomes of these trials will be interesting and then seeing it navigate its place in the treatment algorithm will also be interesting to see what comes of that. I can see fruquintinib making its way into other gastrointestinal malignancies. There’s some studies in the gastric cancer setting, and we will see if it will make its way into those guidelines in the coming years. Then we will see if fruquintinib will continue to move its way up in terms of lines of treatment. The FRESCO-2 trial studied it as a fourth- or fifth-line setting. Right now, in the guidelines, it could be a third-line treatment option. There are some clinical trials looking at fruquintinib in combination with FOLFOX [leucovorin calcium, fluorouracil, and oxaliplatin] in the first-line setting, so I’m interested to see what will come of that.

Q / Is there anything else you want to highlight?

Misniakiewicz / Treatment options for metastatic colorectal cancer are limited, and the approval of fruquintinib will hopefully bridge that gap a little bit. Oral agents have changed the landscape of treatment for patients with cancer. Furthermore, targeted agents allow us to tailor therapy with the goal of improving clinical outcomes while minimizing off-target toxicities. Fruquintinib hopefully allows us to do this and for patients with metastatic colorectal cancer, oral anticancer therapies are an area where we oncology pharmacists can play a big role in patient care. There’s a lot of opportunities to help with AE management and help with being able to keep these patients on therapy longer, helping patients have access to therapies, and then being able to provide patients with a therapy where they don’t need to come into the clinic for long treatment days and trying to optimize their quality of life. Fruquintinib’s approval has been very exciting in this space, and I hope to continue to see great outcomes with it as we have more patients started on it. It’s a big area for oncology pharmacists to help manage these toxicities.

References

1. Takeda receives U.S. FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. News release. Takeda. November 8, 2023. Accessed June 6, 2024. https://bit.ly/3SwkD8U
2. Fruzaqla. Prescribing information. Takeda; 2023. Accessed June 6, 2024. https://shorturl.at/yMXXP
3. Dasari A, Lonardi S, Garcia-Carbonero R, et al; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9
4. Chen J, Wang J, Lin H, Peng Y. Comparison of regorafenib, fruquintinib, and TAS-102 in previously treated patients with metastatic colorectal cancer: a systematic review and network meta-analysis of five clinical trials. Med Sci Monit. 2019;25:9179-9191. doi:10.12659/MSM.918411