⬇ ⬇Futibatinib is an antineoplastic agent and small molecule kinase inhibitor of fibroblast growth factor receptor (FGFR) 1, 2, 3, and 4.1
⬆ ⬇Intrahepatic Cholangiocarcinoma 
Futibatinib is used for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.1 Futibatinib received accelerated approval based on overall response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.1 Futibatinib has been designated an orphan drug by FDA for use in the treatment of cholangiocarcinoma.2
Select patients for treatment with futibatinib based on the presence of an FGFR2 gene fusion or rearrangement; an FDA-approved test for detection of FGFR2 gene fusions or other rearrangements is not available.1
Efficacy of futibatinib is based on the results of a multicenter, open-label, single-arm, phase 2 trial (FOENIX-CCA2).1,3 Adult patients (N=103) with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusion or other rearrangement were treated with oral futibatinib 20 mg once daily.1,3 Treatment was continued until disease progression or unacceptable toxicity occurred.1,3 The primary outcome was overall response rate; duration of response was examined as a secondary outcome.1,3
Patients were a median of 58 years of a 56% were female, 50% were white, and 29% were Asian.1,3 Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 47% of patients and 1 in 53% of patients.1,3 All patients had received at least 1 previous systemic therapy; 30% had received 2 prior therapies, and 23% had received 3 or more.1,3 An FGFR2 gene fusion was present in 78% of patients; 22% had other FGFR2 rearrangements.1 3 Overall response rate was 42%, with all responses being considered partial responses.1 Median duration of response was 9.7 months; 72% of patients had a duration of response ≥6 months, and 14% had a duration of response ≥12 months.1,3
Cholangiocarcinoma, a biliary tract cancer, accounts for 10-15% of all primary liver cancers.4 Intrahepatic cholangiocarcinoma specifically refers to cancer arising from bile ductules near the second-order bile ducts.4 Five-year survival rates with intrahepatic cholangiocarcinoma are low, ranging from 2-15%; factors contributing to this high mortality rate include the aggressive nature of the cancer and frequent late diagnosis.5,6
Treatment of intrahepatic cholangiocarcinoma is based on stage at diagnosis.4,5 For early stage, resectable disease, surgery with adjuvant chemotherapy (capecitabine) is typically recommended.4,5 For unresectable advanced or metastatic disease, international experts recommend a regimen of gemcitabine, cisplatin, and durvalumab as first-line therapy; FGFR inhibitors (e.g., pemigatinib, infigratinib, futibatinib) are recommended as second-line therapy in patients with FGFR2 fusions who progress on first-line chemotherapy.4,5
⬆ ⬇Administer orally once daily.1
Administer futibatinib tablets with or without food at approximately the same time each day.1 Swallow tablets whole; do not crush, chew, split, or dissolve the tablets.1
If a dose is missed by ≥12 hours, or if vomiting occurs after the dose is taken, resume dosing with the next scheduled dose.1
Store tablets at 20-25°C (excursions permitted between 15-30°C).1
Intrahepatic Cholangiocarcinoma
For the treatment of previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma with FGFR2 gene fusion or other rearrangement, the recommended adult dosage of futibatinib is 20 mg (five 4 mg tablets) orally once daily.1 Continue treatment until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur during futibatinib therapy, temporary interruption, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage modification is required, reduce the dosage of futibatinib as described in Table 1.1
Dosage Reduction | Recommended Dosage |
|---|---|
First dosage reduction | 16 mg (four 4 mg tablets) orally once daily |
Second dosage reductiona | 12 mg (three 4 mg tablets) orally once daily |
aPermanently discontinue futibatinib if unable to tolerate 12 mg once daily.
Recommended dosage modifications for specific adverse reactions of futibatinib are listed in Table 2.1
Adverse Reaction | Severity | Recommendation |
|---|---|---|
Retinal pigment epithelial detachment | Not applicable | Continue futibatinib therapy at the current dosage and continue periodic ophthalmic evaluations. If condition improves within 14 days, continue futibatinib at current dosa if no improvement within 14 days, withhold therapy and resume at previous or lower dosage once the condition improves. |
Hyperphosphatemia | Serum phosphate ≥5.5 to ≤7 mg/dL | Continue futibatinib therapy at the current dosage, initiate phosphate lowering therapy, and monitor serum phosphate weekly. |
Serum phosphate >7 to ≤10 mg/dL | Initiate or adjust phosphate lowering therapy, monitor serum phosphate weekly, and reduce futibatinib to the next lower dosage. If serum phosphate resolves to ≤7 mg/dL within 2 weeks after dosage reduction, continue at this reduced dosage. If serum phosphate is not ≤7 mg/dL within 2 weeks, further reduce futibatinib to the next lower dosage. If serum phosphate is not ≤7 mg/dL within 2 weeks after second dosage reduction, withhold futibatinib until serum phosphate is ≤7 mg/dL and resume at the dosage prior to suspending. | |
Serum phosphate >10 mg/dL | Initiate or adjust phosphate lowering therapy and monitor serum phosphate weekly. Withhold futibatinib until phosphate is ≤7 mg/dL and resume futibatinib at the next lower dosage. Permanently discontinue futibatinib if serum phosphate is not ≤7 mg/dL within 2 weeks following 2 dosage interruptions and reductions. | |
Other toxicities | Grade 3 | Withhold futibatinib until toxicity resolves to grade 1 or baseline, then resume futibatinib at the dosage prior to suspending for hematological toxicities resolving within 1 week, or at the next lower dosage level for other toxicities. |
Grade 4 | Permanently discontinue futibatinib therapy. |
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
⬆ ⬇Retinal Pigment Epithelial Detachment
Futibatinib can cause retinal pigment epithelial detachment (RPED), which may cause symptoms such as blurred vision.1 In clinical trials of futibatinib where ophthalmologic monitoring did not routinely include optical coherence tomography (OCT), RPED occurred in 9% of patients.1 The median time to first onset of RPED was 40 days.1 RPED led to dosage interruption, dosage reduction, and permanent discontinuation of futibatinib in 1.3, 1.6, and 0.3% of patients, respectively.1
Perform a comprehensive ophthalmological examination, including OCT of the macula, prior to initiation of futibatinib, every 2 months for the first 6 months of therapy, and every 3 months thereafter.1 Refer patients for urgent ophthalmologic evaluation if visual symptoms occur, and follow up every 3 weeks until resolution or discontinuation of futibatinib.1
If RPED occurs, withhold or reduce the dosage of futibatinib as recommended.1
In clinical trials of futibatinib, dry eye occurred in 15% of patients.1
Administer ocular demulcents as needed for management.1
Hyperphosphatemia and Soft Tissue Mineralization
Increased serum phosphate concentration is a consequence of inhibition of the fibroblast growth factor receptor (FGFR).1 Futibatinib can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis, and vascular calcification.1 Across clinical trials of futibatinib, hyperphosphatemia was reported in 88% of patients.1 The median time to onset of hyperphosphatemia was 5 days (range 3-117 days) following initiation of futibatinib.1 Phosphate binders were required in 77% of patients.1
Monitor serum phosphate concentrations during therapy.1 For serum phosphate levels ≥5.5 mg/dL, initiate a low phosphate diet and phosphate-lowering therapy.1 For serum phosphate levels >7 mg/dL, initiate or intensify phosphate-lowering therapy and adjust, withhold, or permanently discontinue futibatinib based on the duration and severity of hyperphosphatemia.1
Fetal/Neonatal Morbidity and Mortality
Futibatinib use during pregnancy can cause fetal harm based on findings in an animal study and the mechanism of action of the drug.1 Administration of oral futibatinib to pregnant rats during the period of organogenesis resulted in fetal malformations, fetal growth retardation, and embryofetal death at maternal exposures below the human exposure at the clinical dose of 20 mg based on area under the concentration-time curve (AUC).1
Confirm pregnancy status prior to initiating futibatinib in females of reproductive potential.1 Apprise patients of the potential hazard to the fetus if futibatinib is used during pregnancy.1 Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose of futibatinib.1
Futibatinib use during pregnancy can cause fetal harm based on findings in an animal study and the mechanism of action of the drug.1
Human data on futibatinib use during pregnancy are not available.1 Administration of oral futibatinib to pregnant rats during the period of organogenesis resulted in fetal malformations, fetal growth retardation, and embryofetal death at maternal exposures lower than the human exposure at the clinical dose of 20 mg based on AUC.1
Confirm pregnancy status prior to initiating futibatinib in females of reproductive potential.1 Apprise patients of the potential hazard to the fetus if futibatinib is used during pregnancy.1
It is unknown whether futibatinib or its metabolites are distributed into human milk; effects on milk production or the breast-fed infant are also unknown.1
Because of the potential for serious adverse reactions in breast-fed infants, advise women to not breast-feed during treatment with futibatinib and for 1 week after the last dose.1
Females and Males of Reproductive Potential
Perform pregnancy testing in females of reproductive potential prior to initiating futibatinib.1
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with futibatinib and for 1 week after the last dose.1
Safety and efficacy of futibatinib in pediatric patients have not been established.1
In animal toxicity studies (duration of 4 or 13 weeks in rats and dogs, respectively), futibatinib was associated with increased inorganic phosphorus and calcium in plasma, ectopic mineralization in different organs and tissues, lesions in bone/cartilage, and corneal lesions when given at exposures lower than those achieved in humans at the recommended dosage of 20 mg.1
Clinical studies of futibatinib included patients ≥65 years of age.1 There were no overall differences in the safety or efficacy of futibatinib between geriatric and younger patients.1
No clinically important differences in futibatinib systemic exposures were observed based on age (range, 18-82 years).1
No clinically important differences in futibatinib systemic exposures were observed in patients with mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] and AST greater than the ULN, or total bilirubin greater than 1-1.5 times the ULN and any AST).1
The effect of moderate or severe hepatic impairment (total bilirubin >1.5 times the ULN, irrespective of AST) on futibatinib pharmacokinetics has not been studied.1
No clinically important differences in futibatinib systemic exposures were observed in patients with mild to moderate renal impairment (creatinine clearance [Clcr] 30-89 mL/minute).1
The effect of severe renal impairment (Clcr 15-29 mL/minute) or renal dialysis in end-stage renal disease (Clcr<15 mL/minute) on futibatinib pharmacokinetics has not been studied.1
Adverse effects reported in ≥20% of patients receiving futibatinib were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, and vomiting.1
Laboratory abnormalities reported in ≥20% of patients receiving futibatinib were increased phosphate, increased creatinine, decreased hemoglobin, increased/decreased glucose, increased calcium, decreased sodium, decreased phosphate, increased ALT/AST, increased alkaline phosphatase, decreased lymphocytes, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, increased prothrombin international normalized ratio, and decreased potassium.1
⬆ ⬇Futibatinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 in vitro, and by isoenzymes 2C9 and 2D6 to a lesser extent.1
Futibatinib is a substrate of CYP3A4.1 Futibatinib does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A, and does not induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.1
Futibatinib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not organic anion transporting polypeptide (OATP) 1B1 or OATP1B3.1 Futibatinib inhibits P-gp and BCRP, but does not inhibit organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, OATP1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, or MATE2K at clinically relevant concentrations.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Dual P-gp and Strong CYP3A Inhibitors
Concomitant use of futibatinib with dual P-gp and strong CYP3A inhibitors may increase futibatinib exposure and consequently increase the risk for toxicity.1
When itraconazole (dual P-gp and strong CYP3A inhibitor) was administered concomitantly with futibatinib, peak plasma concentrations and area under the concentration-time curve (AUC) of futibatinib were increased by 51 and 41%, respectively.1
Avoid concomitant use of futibatinib with dual P-gp and strong CYP3A inhibitors.1
The effect of a strong CYP3A modulator (without P-gp modulation) on futibatinib exposures has not been studied.1
Dual P-gp and Strong CYP3A Inducers
Concomitant use of futibatinib with dual P-gp and strong CYP3A inducers may decrease futibatinib exposure and consequently reduce the efficacy of futibatinib.1
When rifampin (dual P-gp and strong CYP3A inducer) was administered concomitantly with futibatinib, peak plasma concentrations and AUC of futibatinib were decreased by 53 and 64%, respectively.1
Avoid concomitant use of futibatinib with dual P-gp and strong CYP3A inducers.1
The effect of a strong CYP3A modulator (without P-gp modulation) on futibatinib exposures has not been studied.1
Drugs Affecting or Affected by Transport Systems
Futibatinib may increase exposure of P-gp or BCRP substrates.1
Consider more frequent monitoring for adverse reactions associated with concomitantly used drugs that are sensitive P-gp or BCRP substrates; reduce the dosage of these drugs as recommended in their prescribing information.1
The effect of a P-gp modulator (without CYP3A modulation) on futibatinib exposures has not been studied.1
Avoid grapefruit products during treatment with futibatinib.1
Coadministration of futibatinib with lansoprazole (a proton pump inhibitor) did not have an effect on the AUC of futibatinib.1
Coadministration of futibatinib with midazolam (a sensitive CYP3A substrate) did not have an effect on the AUC of midazolam.1
⬆ ⬇Futibatinib is a highly selective, irreversible small molecule kinase inhibitor of fibroblast growth factor receptor (FGFR); it covalently binds to and inhibits FGFR1, FGFR2, FGFR3, and FGFR4.1,3 Constitutive FGFR signaling can support the proliferation and survival of malignant cells.1 Inhibition of FGFR phosphorylation and downstream signaling by futibatinib results in decreased cell viability in cancer cell lines expressing FGFR genetic alterations (including FGFR fusions/rearrangements, amplifications, and mutations).1 Futibatinib exhibited anti-tumor activity in rat and mouse xenograft models of human tumors with activating FGFR genetic alterations.1
Futibatinib-induced FGFR inhibition increases serum phosphate concentrations.1 The increase in serum phosphate concentration is concentration-dependent across the futibatinib dosage range of 4-24 mg once daily (0.2-1.2 times the approved recommended dosage); the risk of hyperphosphatemia is increased at higher futibatinib exposure.1
Futibatinib exposure (area under the concentration-time curve [AUC]) increases proportionally across the dosage range of 4-24 mg once daily (0.2-1.2 times the approved recommended dosage).1 The median time to peak plasma concentrations is 2 hours (range, 1.2-22.8 hours).1 After administration with a high-fat, high-calorie meal (900-1000 calories with approximately 50% of calories from fat), the peak plasma concentrations and AUC of futibatinib decreased by 42 and 11%, respectively.1 Futibatinib is 95% bound to plasma proteins (primarily albumin and α1-acid glycoprotein).1 Futibatinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 in vitro, and by CYP2C9 and 2D6 to a lesser extent.1 Following a single radiolabeled oral dose (20 mg) of futibatinib, approximately 91 and 9% of the total recovered radioactivity was observed in feces and urine, respectively, with negligible unchanged futibatinib in feces or urine.1 The mean terminal half-life of futibatinib is 2.9 hours.1 The systemic exposure of futibatinib does not appear to be affected by age (range 18-82 years), sex, race, or body weight (range 36-152 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
⬆ ⬇Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Futibatinib is available through a specialty pharmacy network.7 Clinicians may consult the manufacturer website for more information.7
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 4 mg | Lytgobi® (Available in 20 mg, 16 mg, and 12 mg daily dose packs containing a 7-day supply) | Taiho Pharmaceutical |
⬆ ⬇AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions December 12, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
⬆Only references cited for selected revisions after 1984 are available electronically.
1. Taiho Pharmaceutical. Lytgobi® (futibatinib) oral prescribing information. 2022 Sep.
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2023 October 27. http:/
3. Goyal L, Meric-Bernstam F, Hollebecque A, et al; FOENIX-CCA2 Study Investigators. Futibatinib for FGFR2 -rearranged intrahepatic cholangiocarcinoma. N Engl J Med . 2023;388(3):228-239.
4. Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol . 2023;34(2):127-140.
5. European Association for the Study of the Liver. EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol . 2023;79:181-208.
6. Shroff R, Kennedy E, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO Clinical Practice Guideline. J Clin Oncol . 2019; 37(12):1015-1027.
7. Taiho Pharmaceutical. Lytgobi® Patient Access Guide. Accessed 2023 Sep 25. From Lytgobi® for US Healthcare Professionals website.