Fruquintinib Represents a Novel Therapeutic Approach in Advanced mCRC

Fruquintinib (Fruzaqla) has been integrated into the treatment landscape for patients with refractory metastatic colorectal cancer (mCRC) following its FDA approval in November 2023.¹ The oral agent, now available for use in patients following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and anti-VEGF therapy, may be ideal for those at high risk of myelosuppression or those looking to avoid the infusions required of treatment with trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin), according to Arvind Dasari, MD.

Data from the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) trials served as the basis for the approval, each demonstrating the efficacy of fruquintinib in refractory mCRC. In the FRESCO trial, patients treated with fruquintinib achieved a median overall survival (OS) of 9.30 months (95% CI, 8.18-10.45) compared with 6.57 months (95% CI, 5.88-8.11) for those who received placebo (HR, 0.56; 95% CI, 0.51-0.83; P <.001).² The subsequent FRESCO-2 trial, which was a global study involving more heavily pretreated patients, reaffirmed these findings, validating the use of fruquintinib in the third- and later-line settings.³

“Clinical use suggests that fruquintinib appears to be pretty well tolerated and provides a novel therapeutic approach for patients with mCRC who are truly refractory to all available therapies,” Dasari explained.

In an interview with OncLive®, Dasari discussed the factors influencing the choice of later-line therapy, including patient comorbidities, prior treatments, and adverse effect (AE) profiles, emphasizing the need for individualized decision-making, particularly in sequencing fruquintinib with other agents such as TAS-102 plus bevacizumab and regorafenib (Stivarga).

Dasari is an associate professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What factors do you consider when selecting a later-line treatment for patients with refractory mCRC?

Dasari: Most patients with unresectable mCRC will develop resistance to the therapies that they are on, and this includes cytotoxic therapies such as fluorouracil, irinotecan, and oxaliplatin [as well as] targeted therapies such as BRAF, HER2, and EGFR inhibitors. After [patients] experience disease progression on all these therapies we have a few salvage options.

[The choice of therapy depends on various clinical factors, including the patient’s comorbidities, previous treatments, and any residual AEs. It also involves assessing the disease burden and its impact on organ function. For instance, in CRC the liver is the most common site for metastasis, so liver function and health are crucial considerations.

Patient preferences play another significant role in treatment selection because although some may prefer intravenous therapies, others may opt for oral treatments to avoid frequent visits to an infusion center]. All these factors go into determining what the best therapy is for these patients.

How has fruquintinib, which was approved by the FDA in November 2023 for later-line treatment in mCRC, been integrated into the treatment paradigm?

Fruquintinib is a highly selective and potent inhibitor of VEGFR1, 2, and 3. It was first evaluated in the FRESCO trial, a placebo-controlled phase 3 study conducted in China, that enrolled patients with pretreated CRC. The trial demonstrated an improvement in the primary end point of OS, showing a median OS of 9.30 months in the fruquintinib group vs 6.57 months in the placebo group. However, patients included in this trial were not as heavily pretreated as those typically seen in current practice.

The FRESCO-2 trialis a global study that included more heavily pretreated patients and had a similar placebo-controlled design to the FRESCO trial. This trial also showed improved OS and progression-free survival [PFS] with fruquintinib. The median OS was 7.4 months vs 4.8 months with fruquintinib and placebo, respectively. The median PFS was 3.7 months vs 1.8 months, respectively. The FDA used data from both the original FRESCO trial and the FRESCO-2 trial to approve fruquintinib for use in the third- and later-line settings for patients with mCRC.

Where does fruquintinib fit in amongst other approved agents like TAS-102 and regorafenib?

Taking a step back, before we had the data from FRESCO-2 that led to the approval of fruquintinib and the phase 3 SUNLIGHT trial (NCT04737187) that led to the approval of TAS-102 plus bevacizumab, the only two agents in this setting were regorafenib and TAS-102 as monotherapy. [In these trials, we observed that the improvement in survival was incremental and use was somewhat limited because of the AE profile, especially in the case of regorafenib [where it became common practice to start treatment at a much lower dose]. There [had been] a huge unmet need, and [it was] exciting to see the approval of two new regimens in this space.

The SUNLIGHT trial was conducted in patients who were in more of that third-line setting, whereas FRESCO-2 was conducted in truly refractory patients who had progressed on all available therapies, including TAS-102 and regorafenib. FRESCO and FRESCO-2 together provide evidence for the use of fruquintinib in the third-line setting and beyond although there is some overlap between TAS-102 plus bevacizumab and fruquintinib in the third-line setting.

Are there any sequencing strategies that should be considered when selecting one of these therapies in the later-line setting?

[The choice of therapy would depend on the patient profile. TAS-102 tends to cause more myelosuppression, so if a patient has a higher risk of myelosuppression caution is needed]. Additionally, with TAS-102 plus bevacizumab patients need to come in for bevacizumab infusions. For patients who prefer to avoid infusions and opt for an oral regimen, fruquintinib would be a more suitable option.

Overall, the field seems to be guided by the data, with a tendency to use TAS-102 plus bevacizumab in the third-line setting before considering fruquintinib. [Even before the recent data emerged, regorafenib was falling out of favor due to its toxicity profile. Now, with the availability of another VEGF TKI like fruquintinib, the use of regorafenib is diminishing even further].

References

1. Takeda receives U.S. FDA approval of FRUZAQLA (fruquintinib) for previously treated metastatic colorectal cancer. Takeda. News release. November 8, 2023. Accessed August 30, 2024. https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Receives-US-FDA-Approval-of-FRUZAQLA-fruquintinib-for-Previously-Treated-Metastatic-Colorectal-Cancer/
2. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855
3. Dasari A, Lonardi S, Garcia-Carbonero R, et al. 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