What is futibatinib?
Futibatinib is a small molecule kinase inhibitor that specifically and irreversibly inhibits fibroblast growth factor receptor (FGFR) 1, 2, 3, and 4. It is a kinase inhibitor that covalently and selectively binds to FGFR 1, 2, 3, and 4. Futibatinib inhibits FGFR phosphorylation resulting in decreased FGFR-related signaling and decreased cell viability in cell lines expressing FGFR genetic alternations, including FGFR fusions/rearrangements, amplifications, and mutations. FGFR kinase inhibition leads to decreased proliferation and survival of malignant cells.
Futibatinib is approved for adults with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements. Futibatinib received FDA approval through the accelerated approval pathway and granted priority review and breakthrough designation.
Futibatinib was approved for previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement based on results from the FOENIX-CCA2 trial (N Engl J Med 2023; doi: 10.1056/NEJMoa2206834). The trial was a multicenter, single-arm, open-label, Phase II trial of futibatinib 20 mg by mouth daily until disease progression in patients with locally advanced or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma who had progressed after one or more previous lines of systemic therapy.
A total of 103 patients were enrolled on the trial. The primary endpoint was objective response (complete or partial response). The observed objective response was 42 percent (95% CI: 32-52), with all 43 responders achieving a partial response. Key secondary endpoints observed were a median duration of response of 9.7 months, median progression-free survival of 9 months, and median overall survival of 21.7 months.
Futibatinib has a starting dose of 20 mg and is administered as 5 x 4 mg tablets taken by mouth daily with or without food. Tablets should be swallowed whole and not crushed, chewed, split, or dissolved.
Are there any premedications needed for futibatinib?
No premedications are required for futibatinib. It is listed as minimal to low (< 30%) emetic potential. Oral antiemetics are recommended on an as-needed basis.
What are the common side effects associated with futibatinib (> or =10%)?
The following side effects are reported for futibatinib:
* Gastrointestinal: diarrhea (39%), constipation (39%), abdominal pain (30%), nausea (24%), dysgeusia (25%), decreased appetite (23%), vomiting (20%)
* Dermatologic: nail disease (47%), alopecia (34%), xeroderma (29%), palmar-plantar erythrodysesthesia (21%)
* Decreased lab values: sodium (51%), phosphate (50%), albumin (31%), magnesium (26%), potassium (22%), glucose (25%)
* Increased lab values: phosphate (97%), calcium (51%), glucose (52%), creatinine (58%), aspartate aminotransferase (AST) (46%), alanine aminotransferase (ALT) (50%), alkaline phosphatase (47%), creatinine kinase (31%), prolonged partial thromboplastin time (36%), bilirubin (28%), INR (25%), potassium (16%)
* Neuromuscular & Skeletal: musculoskeletal pain (43%), arthralgia (25%)
* Genitourinary: urinary tract infection (23%)
* Hematologic: anemia (52%), thrombocytopenia (42%), lymphocytopenia (46%), neutropenia (31%), leukopenia (33%)
* Ophthalmic: dry eye syndrome (25%)
* Other: fatigue (37%), weight loss (18%)
What are the uncommon side effects associated with futibatinib (less than 10%)?
Biliary obstruction, gastrointestinal hemorrhage, ascites, and fever were observed in less than 10 percent.
Are there any important drug interactions I should be aware of?
Futibatinib is a minor substrate of BCRP/ABCG2, CYP2C9, CYP2D6, CYP3A4 and P-glycoprotein/ABCB1. Coadministration of dual P-gp and strong CYP3A4 inhibitors or inducers should be avoided.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Dose adjustments are not required for renal or hepatic insufficiency. However, the effects of severe renal or hepatic impairment and end-stage kidney or liver disease on the pharmacokinetics of futibatinib have not been evaluated.
What should my patients know about futibatinib?
* Monitor phosphate levels throughout treatment. Alert your provider for symptoms of hyperphosphatemia (e.g., muscle cramps, numbness, periorbital tingling).
* A comprehensive ophthalmological exam prior to therapy initiation, every 2 months for the first 6 months, and every 3 months therapy is recommended while on futibatinib. Notify your provider for prompt evaluation with new onset visual symptoms (e.g., visual changes or dry eyes).
What else should I know about futibatinib?
Futibatinib may cause hyperphosphatemia, leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis, and vascular calcification. Hyperphosphatemia occurred in the majority of patients. The median onset was 5 days (range: 3-117 days). Phosphate binders were administered in over 75 percent of patients.
* Initiate a low phosphate diet when serum phosphate >=5.5 mg/dL.
* Continue treatment with futibatinib at the current dose and initiate phosphate lowering therapy with weekly phosphate monitoring for serum phosphate levels >=5.5 to <7 mg/dL.
* If the serum phosphate >7 mg/dL to >=10 mg/dL, initiate or adjust phosphate-lowering therapy and weekly monitoring for serum phosphate. Reduce futibatinib dose to the next lower dose level. After 2 weeks at a reduced dose, if the phosphate continues to remain elevated, consider additional dose reductions and potential therapy interruption.
* If the serum phosphate >10 mg/dL, withhold futibatinib and follow recommendations for initiation or adjustment in phosphate-lowering therapy. If phosphate lowers to >=7 mg/dL, consider resuming therapy at a reduced dose.
Futibatinib may cause retinal pigment epithelial detachment (RPED); symptoms may include blurred vision. The median time to first onset of RPED was 40 days. Dry eye has been reported.
What useful links are available regarding futibatinib?
* FDA Accelerate Approval: https://tinyurl.com/h6ucs6j8
* Prescribing Information: https://tinyurl.com/26ecj67p
Any ongoing clinical trials related to futibatinib?
Trials are ongoing for use of futibatinib in combination with other agents for FGFR2 fusion-positive and/or rearranged advanced solid tumors following initial first-line treatment, as well as monotherapy use for specific FGFR aberrations in solid tumors. More information is available about these clinical trials at https://clinicaltrials.gov.
JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/Manager, Clinical Pharmacy Services at Washington University School of Medicine. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.