Fruquintinib Combo Exhibits Manageable Safety Profile in Pretreated mCRC

Hypertension, asthenia, PPE syndrome, and diarrhea were the most common TRAEs with fruquintinib in pretreated metastatic colorectal cancer.

Fruquintinib (Fruzaqla) plus best supportive care exhibited a manageable and expected safety profile in the treatment of patients with pretreated metastatic colorectal cancer (CRC), according to a safety analysis of the phase 3 FRESCO-2 trial (NCT04322539).¹

The most common any-grade treatment-related adverse events (TRAEs) with fruquintinib were hypertension (28.9%), asthenia (24.6%), palmar-plantar erythrodysesthesia (PPE) syndrome (18.6%), diarrhea (18.0%), and decreased appetite (16.0%).

Treatment with fruquintinib plus best supportive care led to treatment-related AEs of special interest (AESIs) in 64.9% of patients vs 23.0% with placebo plus best supportive care. In patients who received fruquintinib, the most common treatment-related AESIs of any grade and grade 3 or higher were hypertension (28.9% and 10.7%, respectively), dermatologic toxicity (28.3% and 6.4%), thyroid dysfunction (19.1% and 0.4%), PPE syndrome (18.6% and 6.1%), and hypothyroidism (15.6% and 0.4%). In those who received placebo, they were dermatologic toxicity (7.4% and 0.0%), hypertension (5.2% and 0.9%), abnormal hepatic function (3.9% and 1.3%), and proteinuria (3.5% and 0.4%).

Treatment-related thrombotic and embolic events occurred in a total of 7 patients who received fruquintinib, 6 of which were grade 3 or 4 events; treatment-related gastrointestinal perforation events occurred in 6 patients, all of which were grade 3 or higher. AESIs leading to death occurred in 1.8% of the fruquintinib group and 1.3% of the placebo group.

The median time to first occurrence of hypertension was 21.0 days (IQR, 5.0-33.0) with fruquintinib and 20.0 days (IQR, 2.0-29.5) with placebo; of hypothyroidism was 58.0 days (IQR, 35.0-113.0) and 27.0 days (IQR, 27.0-27.0), respectively; of PPE syndrome was 21.0 days (IQR, 12.0-49.0) and 13.0 days (IQR, 7.0-24.0); and of proteinuria was 42.0 days (IQR, 29.0-91.0) and 29.0 days (IQR, 24.5-44.0).

Dose reductions occurred in 10.3% of patients who received fruquintinib and 0.4% of those who received placebo, and dose interruptions occurred in 15.8% and 2.2%, respectively, due to treatment-related AESIs. PPE syndrome (5.0% and 6.1%), hypertension (2.9% and 2.6%), and proteinuria (1.3% and 4.6%) were the most common AESIs that led to dose reductions and dose interruptions, respectively, in the fruquintinib group.

“This safety analysis of FRESCO-2 demonstrates that fruquintinib plus [best supportive care] is well tolerated in pretreated patients with [metastatic] CRC,” stated study author Josep Tabemero, MD, PhD, head of the Medical Oncology Department at Vall d’Hebron Barcelona Hospital Campus and director of Vall d’Hebron Institute of Oncology, in the paper with coauthors.¹ “Fruquintinib is a novel oral treatment option for patients with [metastatic] CRC, is well tolerated, and enriches the continuum of care for these patients by prolonging survival.”

The FRESCO-2 trial enrolled a total of 691 patients; 461 received fruquintinib plus best supportive care, and 230 received placebo plus best supportive care. Patients were 18 years or older with histologically or cytologically documented metastatic CRC who received all standard therapies with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and anti-VEGF therapy, and if they had RAS wild-type disease, anti-EGFR therapy. Those with microsatellite instability-high, mismatch repair deficient, or BRAF V600E-mutated disease were required to have received a BRAF inhibitor or an immune checkpoint inhibitor.

Fruquintinib was given at 5 mg orally once a day on days 1 to 21 in a 28-day cycle, and placebo was matched. Best supportive care was determined by local clinical practices and guidelines.

The previously reported primary analysis showed that the median overall survival (OS) with fruquintinib was 7.4 months vs 4.8 months with placebo (HR, 0.66; 95% CI, 0.55-0.80; P <.0001); the median progression-free survival was 3.7 months vs 1.8 months (HR, 0.32; 95% CI, 0.27-0.39; P <.0001).²

Thus far, fruquintinib has been approved as a treatment for pretreated metastatic CRC by the US FDA, the EU’s European Commission, and Japan’s Ministry of Health, Labour, and Welfare.^3,4,5

References

1. Eng C, Dasari A, Lonardi S, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer: safety analysis of FRESCO-2. Oncologist. 2025;30(3):oyae360. doi:10.1093/oncolo/oyae360
2. 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
3. Takeda receives U.S FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. News release. Takeda. November 8, 2023. Accessed April 16, 2025. https://bit.ly/3SwkD8U
4. Takeda receives approval from European Commission for FRUZAQLA in previously treated metastatic colorectal cancer. News release. Takeda. June 21, 2024. Accessed April 16, 2025. https://tinyurl.com/ry49wm9r
5. Takeda receives approval for FRUZAQLA (fruquintinib) in Japan for the treatment of unresectable advanced or recurrent colorectal cancer. News release. Takeda. September 24, 2024. Accessed April 16, 2025. https://tinyurl.com/yckbwjrk