LYTGOBI- futibatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D.[2]
Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Black Box Warning
|
Warning: Ocular Toxicity, Hyperphosphatemia, and Soft Tissue Mineralization
See full prescribing information for complete Boxed Warning.
LYTGOBI may cause detachment of the retinal pigment epithelium (RPED). Conduct a thorough eye examination, including optical coherence tomography (OCT), before starting treatment, every 2 months during the initial 6 months, and every 3 months afterward. Additionally, promptly assess for any visual symptoms at any time.
|
Overview
LYTGOBI- futibatinib is a kinase inhibitor that is FDA approved 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. This indication is approved under accelerated approval based on overall response rate and duration of response. Further approval for this indication may depend on confirming and describing the clinical benefits in one or more additional trials. There is a Black Box Warning for this drug as shown here. Common adverse reactions include soft tissue mineralization,calcinosis, 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. Most common laboratory abnormalities (≥20%) were increased phosphate, increased creatinine, decreased hemoglobin, increased glucose, increased calcium, decreased sodium, decreased phosphate, increased alanine aminotransferase, increased alkaline phosphatase, decreased lymphocytes, increased aspartate aminotransferase, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, decreased glucose, increased prothrombin international normalized ratio, and decreased potassium.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- Confirm the presence of an FGFR2 gene fusion or other rearrangement prior to initiation of treatment with LYTGOBI.
- Recommended dose is 20 mg orally (five 4 mg tablets) once daily until disease progression or unacceptable toxicity occurs.
- Swallow tablet whole, with or without food.
- LYTGOBI is indicated for treating adult patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma, possessing fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. This approval is granted under accelerated approval criteria, relying on overall response rate and response duration. Continued approval for this indication may require confirmation and description of clinical benefits in a confirmatory trial.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding LYTGOBI- futibatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
None.
Warnings
|
Warning: Ocular Toxicity, Hyperphosphatemia, and Soft Tissue Mineralization
See full prescribing information for complete Boxed Warning.
LYTGOBI may cause detachment of the retinal pigment epithelium (RPED). Conduct a thorough eye examination, including optical coherence tomography (OCT), before starting treatment, every 2 months during the initial 6 months, and every 3 months afterward. Additionally, promptly assess for any visual symptoms at any time.
|
- Dry Eye/Corneal Keratitis:
In the same clinical trials, dry eye occurred in 15% of patients. Manage dry eye symptoms with ocular demulcents as necessary.
- Hyperphosphatemia and Soft Tissue Mineralization:
LYTGOBI may induce hyperphosphatemia leading to soft tissue mineralization and related complications. Among the studied patients, hyperphosphatemia was reported in 88%, with onset typically occurring within 5 days. Monitor serum phosphate levels regularly, initiate a low phosphate diet, and consider phosphate-lowering therapy if serum phosphate levels exceed 5.5 mg/dL. Adjust LYTGOBI dosing accordingly, based on the severity and duration of hyperphosphatemia.
- Embryo-Fetal Toxicity:
LYTGOBI poses a risk of fetal harm based on animal studies. Administering futibatinib to pregnant rats during organogenesis led to fetal malformations, growth retardation, and embryo-fetal death at exposures lower than those at the human clinical dose of 20 mg. Advise pregnant women and females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose. Similarly, advise males with female partners of reproductive potential to employ effective contraception during treatment and for 1 week post-treatment.
Adverse Reactions
Clinical Trials Experience
Due to the variability in conditions across clinical trials, comparing adverse reaction rates between different drugs or trials may not accurately reflect real-world rates. The safety profile of LYTGOBI was assessed in a pooled analysis of 318 patients, including those with cholangiocarcinoma and other advanced solid tumors. Among them, 37% were treated for at least 6 months, and 13% for over 12 months. In a study involving patients with previously treated, unresectable locally advanced or metastatic intrahepatic cholangiocarcinoma, serious adverse reactions occurred in 39% of patients receiving LYTGOBI. Common serious adverse reactions included pyrexia, gastrointestinal hemorrhage, ascites, musculoskeletal pain, and bile duct obstruction. Permanent discontinuation due to adverse reactions affected 4.9% of patients. Adverse reactions leading to discontinuation included esophagitis, oral dysesthesia, bile duct obstruction, dizziness, and anemia.
- Dosage interruptions due to adverse reactions were necessary for 66% of patients, with common reactions being hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and liver enzyme abnormalities.
- Dose reductions due to adverse reactions were required for 58% of patients. Common adverse reactions leading to dosage reduction included hyperphosphatemia, skin reactions, fatigue, and liver enzyme abnormalities.
- The most frequently observed adverse reactions (≥20%) were nail toxicity, musculoskeletal pain, gastrointestinal issues, fatigue, dry mouth, alopecia, and stomatitis.
- Common laboratory abnormalities (≥20%) included changes in phosphate, creatinine, hemoglobin, glucose, calcium, sodium, liver enzymes, platelets, and clotting factors.
- Clinically relevant adverse reactions occurring in ≤15% of patients included retinal pigment epithelial detachment (RPED, 7.8%).
Postmarketing Experience
There is limited information regarding LYTGOBI- futibatinib Postmarketing Experience in the drug label.
Drug Interactions
- Effect of Other Drugs on LYTGOBI:
Futibatinib is a substrate of CYP3A and P-gp.
- Dual P-gp and Strong CYP3A Inhibitors:
Avoid concomitant use of drugs that are dual P-gp and strong CYP3A inhibitors with LYTGOBI. Concomitant use of drugs that are dual P-gp and strong CYP3A inhibitors with LYTGOBI may increase futibatinib exposure [see CLINICAL PHARMACOLOGY (12.3)], which may increase the incidence and severity of adverse reactions.
- Dual P-gp and Strong CYP3A Inducers:
Avoid concomitant use of dual P-gp and strong CYP3A inducers with LYTGOBI. Concomitant use of drugs that are dual P-gp and strong CYP3A inducers may reduce the efficacy of LYTGOBI.
- Effect of LYTGOBI on Other Drugs
Futibatinib is an inhibitor of P-gp and BCRP.
- P-gp or BCRP Substrates:
Consider more frequent monitoring for adverse reactions associated with concomitantly administered drugs that are sensitive substrates of P-gp or BCRP and reduce the dose of these drugs per their Prescribing Information.
- Futibatinib may increase exposure of drugs that are substrates of P-gp or BCRP.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
LYTGOBI can cause fetal harm when administered to a pregnant woman.
Verify pregnancy status of females of reproductive potential prior to initiating LYTGOBI.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of LYTGOBI- futibatinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of LYTGOBI- futibatinib during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of LYTGOBI- futibatinib in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of LYTGOBI- futibatinib in pediatric settings.
Geriatic Use
Of the 103 patients treated with LYTGOBI in Study TAS-120-101, 22% were 65 years or older. Based on available data, no overall differences in safety or effectiveness of LYTGOBI have been observed between patients 65 years of age and older and younger adult patients.
Gender
There is no FDA guidance on the use of LYTGOBI- futibatinib with respect to specific gender populations.
Race
There is no FDA guidance on the use of LYTGOBI- futibatinib with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of LYTGOBI- futibatinib in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of LYTGOBI- futibatinib in patients with hepatic impairment.
Females of Reproductive Potential and Males
- Advise females of reproductive potential to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose.
- Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose.
Immunocompromised Patients
There is no FDA guidance one the use of LYTGOBI- futibatinib in patients who are immunocompromised.
Administration and Monitoring
Administration
- Confirm the presence of an FGFR2 gene fusion or other rearrangement prior to initiation of treatment with LYTGOBI.
- Recommended dose is 20 mg orally (five 4 mg tablets) once daily until disease progression or unacceptable toxicity occurs.
- Swallow tablet whole, with or without food.
- LYTGOBI is indicated for treating adult patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma, possessing fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. This approval is granted under accelerated approval criteria, relying on overall response rate and response duration. Continued approval for this indication may require confirmation and description of clinical benefits in a confirmatory trial.
- Dosage Modification for Adverse Reactions:
1-Recommended dose reductions for adverse reactions associated with LYTGOBI.
- If unable to tolerate 12 mg orally once daily, discontinue LYTGOBI permanently.
- First dose reduction: Take 16 mg (four 4 mg tablets) orally once daily.
- Second dose reduction: Take 12 mg (three 4 mg tablets) orally once daily.
2-Recommended dosage modifications for adverse reactions are:
Severity: Not applicable Action: Continue LYTGOBI at the current dose and maintain periodic ophthalmic evaluations. If RPED resolves within 14 days, continue LYTGOBI at the current dose. If RPED does not resolve within 14 days, suspend LYTGOBI until resolution; then resume at previous or lower dose.
- Hyperphosphatemia:
- Serum phosphate ≥5.5 - ≤7 mg/dL:
Continue LYTGOBI at the current dose and start phosphate-lowering therapy. Monitor serum phosphate weekly.
- Serum phosphate >7 - ≤10 mg/dL:
Initiate or adjust phosphate-lowering therapy. Monitor serum phosphate weekly and reduce LYTGOBI dosage to the next lower level.
- If serum phosphate returns to ≤7 mg/dL within 2 weeks, maintain this reduced dose.
- If serum phosphate remains >7 mg/dL after 2 weeks, further reduce LYTGOBI dosage.
- If serum phosphate is still >7 mg/dL after the second dose reduction, suspend LYTGOBI until levels normalize, then resume at the previous dose.
- Serum phosphate >10 mg/dL:
Initiate or adjust phosphate-lowering therapy and closely monitor serum phosphate levels.
- Other Adverse Reactions Grade 3a:
Action: Suspend LYTGOBI until toxicity resolves to Grade 1 or baseline. Then, resume LYTGOBI as follows: For hematological toxicities resolving within 1 week, resume at the dose prior to suspension. For other adverse reactions, resume at the next lower dose.
- Grade 4a:
Action: Permanently discontinue LYTGOBI.
Monitoring
- Conduct a thorough eye examination, including optical coherence tomography (OCT), before starting treatment, every 2 months during the initial 6 months, and every 3 months afterward. Additionally, promptly assess for any visual symptoms at any time.
- Monitor serum phosphate levels regularly, initiate a low phosphate diet, and consider phosphate-lowering therapy if serum phosphate levels exceed 5.5 mg/dL
IV Compatibility
There is limited information regarding the compatibility of LYTGOBI- futibatinib and IV administrations.
Overdosage
There is limited information regarding LYTGOBI- futibatinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding LYTGOBI- futibatinib Pharmacology in the drug label.
Mechanism of Action
Futibatinib is a small molecule kinase inhibitor of FGFR 1, 2, 3, and 4 with IC50 values of less than 4 nM. Futibatinib covalently binds FGFR. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Futibatinib inhibited FGFR phosphorylation and downstream signaling and decreased cell viability in cancer cell lines with FGFR alterations including FGFR fusions/rearrangements, amplifications, and mutations. Futibatinib demonstrated anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR genetic alterations.
Structure
Futibatinib is a kinase inhibitor, has a molecular formula of C22H22N6O3 and molecular mass of 418.45 g/mole. Futibatinib has the following chemical structure:
Futibatinib is a white crystalline powder. The solubility of futibatinib is pH dependent with decreasing solubility with increasing pH, being practically insoluble at pH 3 or higher. Futibatinib is insoluble in water and poorly soluble in common solvents. LYTGOBI is supplied as 4 mg film-coated tablets for oral administration. Each tablet contains inactive ingredients of corn starch, crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, and sodium lauryl sulfate. The film coating material contains hypromellose, magnesium stearate, polyethylene glycol, and titanium dioxide.
Pharmacodynamics
- Futibatinib, by inhibiting FGFR, elevates serum phosphate levels. This increase correlates with higher futibatinib exposure, ranging from 4 to 24 mg orally once daily Higher exposure to futibatinib is associated with an elevated risk of hyperphosphatemia.
- LYTGOBI, even at four times the approved recommended dose, does not induce clinically significant prolongation of the QTc interval.
Pharmacokinetics
The pharmacokinetics of futibatinib were examined in patients with advanced solid tumors, with particular focus on the 20 mg once-daily dosage unless specified otherwise. Futibatinib exposure increased proportionally within the dose range of 4 to 24 mg orally once daily, corresponding to 0.2 to 1.2 times the maximum recommended dose. At the recommended dose, the geometric mean maximal concentration at steady state was 144 ng/mL with a coefficient of variation of 50%, and the area under the concentration-time curve at steady state was 790 ng∙hr/mL. There was no accumulation observed after multiple doses.
- absorption
the median time to reach maximum plasma concentration was 2 hours, with a range from 1.2 to 22.8 hours.
- food effect
Administration of LYTGOBI with a high-fat and high-calorie meal led to an 11% decrease in futibatinib AUC and a 42% decrease in Cmax in healthy subjects.
- distribution
futibatinib exhibited a geometric mean apparent volume of distribution of 66 L and showed high plasma protein binding (95%), primarily to albumin and α1-acid glycoprotein.
- Elimination was characterized by a mean elimination half-life of 2.9 hours and a geometric mean apparent clearance.
- metabolism
primarily involves CYP3A, with minor contributions from CYP2C9 and CYP2D6. In vitro studies demonstrated that unchanged futibatinib is the primary drug-related component in plasma.
- Excretion
Following a single oral dose of 20 mg radiolabeled futibatinib revealed approximately 91% of radioactivity recovered in feces and 9% in urine, with minimal unchanged futibatinib detected in either urine or feces. No significant differences in systemic exposure to futibatinib were observed across various demographic and clinical subgroups, including age, sex, race, body weight, and mild to moderate renal or hepatic impairment. However, pharmacokinetics in severe renal impairment, renal dialysis, or moderate to severe hepatic impairment have not been studied. Regarding drug interactions, co-administration of dual P-gp and strong CYP3A inhibitors or inducers significantly impacted futibatinib exposure. However, the effect of P-gp or CYP3A modulation alone on futibatinib exposure remains unexplored.
- In vitro studies indicated that futibatinib is a substrate for P-gp and BCRP but does not significantly interact with other transporters or CYP enzymes at clinically relevant concentrations.
Nonclinical Toxicology
Carcinogenicity studies have not been conducted with futibatinib. Futibatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Futibatinib was clastogenic in an in vitro chromosomal aberration assay. Futibatinib was not clastogenic in a rat bone marrow micronucleus assay or a rat DNA damaging (Comet) assay. Dedicated fertility studies with futibatinib have not been conducted
Clinical Studies
In the TAS-120-101 trial (NCT02052778), which was a multicenter, open-label, single-arm study, the efficacy of LYTGOBI was assessed in 103 patients diagnosed with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma. Next-generation sequencing (NGS) testing was utilized to identify FGFR2 fusions or other rearrangements in 102 out of 103 enrolled patients (99%). These genetic alterations, including qualifying in-frame fusions, were anticipated to affect intron 17/exon 18 of the FGFR2 gene, preserving the integrity of the FGFR2 kinase domain. Patients were administered LYTGOBI orally at a dose of 20 mg once daily until they experienced disease progression or unacceptable levels of toxicity. The primary efficacy endpoints were determined by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, focusing on overall response rate (ORR) and duration of response (DoR). The characteristics of the trial population were as follows: The median age was 58 years (ranging from 22 to 79 years), with 22% of patients aged 65 or older. Among the patients, 56% were female. Regarding racial distribution, 50% were White, 29% Asian, 8% Black or African American, 1% Native Hawaiian or Other Pacific Islander, and 13% were of unknown racial background. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was categorized as 0 for 47% of patients and 1 for 53%. Notably, 78% of patients had in-frame FGFR2 gene fusions, with the most frequently identified fusion partner being BICC1 (n=24, 23%). Additionally, 22% of patients exhibited other FGFR2 rearrangements that may not have been in-frame with the partner gene or for which the partner gene was not identifiable. All patients had previously undergone at least one systemic therapy, with 30% having received two prior lines of therapy and 23% having received three or more prior lines. Notably, all patients had received prior platinum-based therapy, including 91% who had received gemcitabine/cisplatin therapy
How Supplied
LYTGOBI are round, white, film-coated 4 mg tablets debossed with “4MG” on one side, and “FBN” on the other side, packaged in blister cards and supplied in child-resistant as follows:
- 20 mg daily dose: Each carton contains 1 blister card containing a 7-day supply (35 tablets; 4 mg futibatinib per tablet). [NDC-64842-0120-6]
- 16 mg daily dose: Each carton contains 1 blister card containing a 7-day supply (28 tablets; 4 mg futibatinib per tablet). [NDC-64842-0120-5]
- 12 mg daily dose: Each carton contains 1 blister card containing a 7-day supply (21 tablets; 4 mg futibatinib per tablet). [NDC-64842-0120-4]
Storage
Store LYTGOBI tablets at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F)
Images
Drug Images
{{#ask: Page Name::LYTGOBI- futibatinib |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
{{#ask: Label Page::LYTGOBI- futibatinib
|?Label Name
|format=template
|template=DrugLabelImages
|mainlabel=-
|sort=Label Page
}}
Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Advise patients that LYTGOBI may cause ocular toxicity including RPED and to immediately inform their healthcare provider if they experience any visual changes. Advise patients to use artificial tears, or hydrating or lubricating eye gels to prevent or treat dry eyes.
- Inform patients that LYTGOBI may cause hyperphosphatemia and soft tissue mineralization and to immediately inform their healthcare provider of any symptoms related to acute change in phosphate levels such as muscle cramps, numbness, or tingling around the mouth.
- Advise patients that LYTGOBI may cause nail disorders.
- Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of pregnancy
Advise females of reproductive potential to use effective contraception while on LYTGOBI and for 1 week after the last dose. Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 1 week after receiving the last dose of LYTGOBI.
- Advise patients not to breastfeed during treatment with LYTGOBI and for 1 week after the last dose.
- Instruct patients to not crush, chew, split or dissolve tablets.
Instruct patients if they miss a dose by 12 or more hours or if they vomit after taking a dose, resume dosing with the next scheduled dose. Extra tablets should not be taken to make up for the missed dose.
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products. Advise patients to avoid grapefruit products during treatment with LYTGOBI.
Precautions with Alcohol
Alcohol-LYTGOBI- futibatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding LYTGOBI- futibatinib Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding LYTGOBI- futibatinib Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.