Pharmacist's Application to Practice: Fruquintinib

Fruquintinib approved for adult patients with metastatic colorectal cancer

What is the potential role for fruquintinib in the treatment of metastatic colorectal cancer?

• Fruquintinib is a small molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 that is FDA-approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy, and, if RAS wild-type and medically appropriate, an anti-epidermal growth factor receptor (EGFR) therapy. [1]
• National Comprehensive Cancer Network (NCCN) Guidelines for Colon Cancer (V 4.2023) recommend fruquintinib (category 2A) for patients with mCRC who have progressed on all available regimens [2]
• Trifluridine-tipiracil +/- bevacizumab (category 2A) and regorafenib (category 2A) are also recommended in the same setting. Fruquintinib is the only selective inhibitor of all three VEGFR kinases.
• The efficacy and safety of fruquintinib has been evaluated in two randomized, phase III trials:
• The FRESCO trial was conducted in China and included 416 patients with mCRC who progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Prior treatment with anti-VEGF therapy (i.e. bevacizumab) and anti-EGFR therapy was allowed, but prior treatment with anti-VEGFR therapy (i.e. regorafenib) was prohibited. Patients were randomized 2:1 to receive fruquintinib or placebo. [3]
• Primary outcome of median overall survival (mOS) was 9.3 months with fruquintinib versus 6.6 months with placebo (HR 0.65; 95% CI 0.51-0.83; P< 0.001)
• Based on this trial, fruquintinib was approved in China, but the FDA did not approve fruquintinib for use in the United States due to significant differences in standard of care practices between China and the rest of the world
• The FRESCO-2 trial was conducted in 14 countries in North America, Europe, Asia, and Australia. It included 691 patients with mCRC who had received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, anti-EGFR therapy (if RAS wild type), and had progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Patients with deficient mismatch repair or microsatellite instability-high tumors must have received immunotherapy and patients with BRAF V600E-mutated tumors must have received a BRAF inhibitor, if available in their country. Patients were randomized 2:1 to receive fruquintinib or placebo. [4]
• Primary outcome of mOS was 7.4 months with fruquintinib versus 4.8 months with placebo (HR 0.66; 95% CI 0.55-0.88; P< 0.0001)
• The survival benefit demonstrated in the FRESCO-2 trial led to the FDA-approval of fruquintinib in the United States
• Comparative outcomes to agents that the NCCN recommends in the same setting:
• Trifluridine-tipiracil + bevacizumab had a mOS of 10.8 months (vs. 7.5 months for trifluridine-tipiracil alone) in the SUNLIGHT trial [5]
• Regorafenib had a mOS of 6.4 months (vs. 5.0 months for best supportive care) in the CORRECT trial [6]

What role can the pharmacists play in the management of patients on fruquintinib?

• Recommended dose of fruquintinib is 5 mg by mouth daily on days 1-21 of each 28-day cycle [1]
• No empiric renal or hepatic dose adjustments are recommended
• May be administered with or without food
• Fruquintinib is major CYP3A4 substrate [1]
• Avoid concomitant use of fruquintinib with strong CYP3A inducers
• If possible, concomitant use of fruquintinib with moderate CYP3A inducers should be avoided
• No clinically significant differences in pharmacokinetics have been observed when fruquintinib is concomitantly used with strong CYP3A inhibitors
• Adverse effects (AEs): [1,3,4]
• The most common AEs (> 20%) are hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia
• Hypertension (49%)
• Do not initiate fruquintinib unless blood pressure is adequately controlled
• Monitor blood pressure weekly for first month and at least monthly thereafter
• Manage hypertension according to respective guidelines
• Palmar-plantar erythrodysesthesia (PPE) (35%)
• Median onset of palmar-plantar erythrodysesthesia was 19 days from initiation of fruquintinib
• Consider holding fruquintinib based on severity, then resume at the same or reduced dose
• Hepatotoxicity (48% experienced an increased in AST/ALT)
• Monitor liver function tests before initiation and periodically throughout treatment
• Proteinuria (36%)
• For proteinuria >2 g/24 hours, hold fruquintinib until resolution and resume at reduced dose
• Discontinue fruquintinib in patients who develop nephrotic syndrome
• Impaired wound healing
• Do not administer fruquintinib for at least 2 weeks before or after major surgery
• Other rare but serious adverse events include hemorrhage, arterial thromboembolic events, gastrointestinal perforation, and infection
• Patient assistance program for fruquintinib is available through TakedaOncology Here2Assist®

Clinical Pearls

• Dosage forms and strengths: 1 mg and 5 mg capsules [1]
• Storage: 20°C to 25°C (68°F to 77°F) [1]
• NCCN guidelines recommend fruquintinib, trifluridine-tipiracil +/- bevacizumab, or regorafenib in the same line of therapy for patients with mCRC who have progressed on all available regimens [2]
• Sequencing of therapies remain a challenge due to lack of evidence
• There is no data evaluating the use of fruquintinib following trifluridine-tipiracil + bevacizumab
• There is no data evaluating the use of trifluridine-tipiracil +/- bevacizumab following fruquintinib
• There is no data evaluating the use of regorafenib following trifluridine-tipiracil +/- bevacizumab or fruquintinib
• Significant differences in tolerability and toxicities exist between treatment options
• Fruquintinib [1,3,4]
• Most common AEs: Hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, and abdominal pain
• 24% of patients in the FRESCO-2 trial required dose modification
• Trifluridine-tipiracil [7,8]
• Most common AEs: Neutropenia, anemia, thrombocytopenia, fatigue, and nausea
• 14% of patients in the RECOURSE trial required dose modification
• Regorafenib [6,9]
• Most common AEs: Fatigue, anorexia, palmar-plantar erythrodysesthesia, diarrhea, and mucositis
• 67% of patients in the CORRECT trial required dose modification
• The FRESCO-2 trial best represents the place in therapy for fruquintinib, therefore fruquintinib should likely be reserved for patients with disease progression on trifluridine-tipiracil or regorafenib

References:

1.FRUZAQLA™ (fruquintinib). Package insert. Takeda Pharmaceuticals America, Inc.; Revised November 2023. Accessed November 18, 2023.

2.National Comprehensive Cancer Network. NCCN Guidelines Version 4.2023 Colon Cancer.  Accessed November 18, 2023.

3.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

4.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

5.Prager GW, Taieb J, Fakih M, et al. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023;388(18):1657-1667. doi:10.1056/NEJMoa2214963

6.Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X

7.LONSURF™ (trifluridine and tipiracil). Package insert. Taiho Oncology, Inc.; Revised December 2021. Accessed December 6, 2023.

8.Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi:10.1056/NEJMoa1414325

9.STIVARGA™ (regorafenib). Package insert. Bayer Healthcare Pharmaceuticals, Inc.; Revised December 2020. Accessed December 6, 2023.