Futibatinib – Uses, Dosage, Side Effects, Interaction

Futibatinib is an inhibitor of the Fibroblast Growth Factor receptor (FGFR), which comprises a group of receptor tyrosine kinases that play a key role in cell proliferation, differentiation, migration, and survival. FGFR was investigated in oncology as a therapeutic? target, as FGFR genomic aberrations and dysregulated FGFR signaling pathways are observed in some cancers such as cholangiocarcinoma and urothelial malignancies.^[rx,rx]

As a novel inhibitor of FGFR, futibatinib was first approved by the FDA in September 2022 to treat different types of intrahepatic cholangiocarcinoma.^[rx]

Mechanism of action

The fibroblast Growth Factor receptor (FGFR) pathway play a key role in cell proliferation, differentiation, migration, and survival. Notably, FGFR genomic aberrations and aberrant FGFR signaling pathways are observed in some cancers,^[rx,rx] as constitutive FGFR signaling can support the proliferation and survival of malignant? cells.^[rx]

Futibatinib is a selective, irreversible inhibitor of FGFR 1, 2, 3, and 4 with IC₅₀ values of less than 4 nM. It binds to the FGFR kinase domain by forming a covalent bond with cysteine in the ATP-binding pocket.^[rx] Upon binding to FGFR, futibatinib blocks FGFR phosphorylation and downstream signaling pathways,^[rx] such as the RAS-dependent mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3KCA)/Akt/mTOR, phospholipase Cγ (PLCγ), and JAK/STAT.^[rx] Futibatinib ultimately decreases cell viability in cancer cell lines with FGFR alterations, including FGFR fusions or rearrangements, amplifications, and mutations.^[rx]

Futibatinib is an anticancer agent with demonstrated anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR genetic? alterations.^[rx] Futibatinib is not expected to affect cell lines with no FGFR genomic aberrations.^[rx] It suppresses the growth of tumors in a dose-dependent manner.^[rx]

Use in Cancer

Fulvestrant is approved to be used alone or with other drugs to treat:

• Breast cancer. It is used:
  • Alone in postmenopausal women with hormone receptor-positive (HR+) and HER2-negative advanced cancer that has not been treated with hormone therapy.
  • Alone in postmenopausal women with HR+ advanced cancer that got worse after treatment with hormone therapy.
  • Palbociclib succinate in postmenopausal women with HR+ and HER2-negative advanced or metastatic cancer. It is used as first-line hormone therapy or after cancer got worse during treatment with hormone therapy.
  • Palbociclib or abemaciclib in women with HR+ and HER2-negative advanced or metastatic cancer that got worse after treatment with hormone therapy.

Fulvestrant is also being studied in the treatment of other types of cancer.

Contraindications

• Futibatinib can cause hypersensitivity reactions.[rx] Therefore, it is contraindicated? in patients who have experienced hypersensitivity
• sickle cell anemia?
• pain? crisis in sickle cell disease?
• decreased blood platelets
• capillary? leak syndrome? is a condition where fluid leaks out of small blood vessels
• acute respiratory distress syndrome?, a type of lung disorder
• glomerulonephritis?, a condition that affects the kidneys?
• myelodysplastic syndrome, a bone marrow? disorder
• rupture of the spleen?
• Pregnancy
• Lactating mother

Dosage?

Cholangiocarcinoma of the biliary tract

• Usual dose: 20 mg (five 4 mg tablets) taken orally once daily
• Confirm the presence of an FGFR2 gene fusion or another rearrangement prior to initiation of treatment.
• Treatment is to be continued until disease progression? or unacceptable toxicity occurs.

Dose Adjustments

DOSE MODIFICATION FOR ADVERSE REACTIONS:

• First dose reduction: 16 mg (four 4 mg tablets) orally once daily
• Second dose reduction: 12 mg (three 4 mg tablets) orally once daily
• Permanently discontinue this drug if unable to tolerate 12 mg orally once daily.

DOSE MODIFICATION FOR RETINAL PIGMENT EPITHELIAL DETACHMENT (RPED):

• Continue this drug at the current dose and continue periodic ophthalmic evaluation:
• If resolved within 14 days, continue this drug at the current dose.
• If not resolved within 14 days, withhold this drug until resolved; then resume at the previous or a lower dose.

DOSE MODIFICATION FOR HYPERPHOSPHATEMIA:
Serum phosphate 5.5 to 7 mg/dL:

• Continue this drug at the current dose and start with phosphate-lowering therapy.
• Monitor serum phosphate weekly.

Serum phosphate of more than 7 to 10 mg/dL:

• Initiate or adjust phosphate lowering therapy and monitor serum phosphate weekly.
• If the serum phosphate resolves to 7 mg/dL or less within 2 weeks after dose reduction, continue at this reduced dose.
• If serum phosphate is not 7 mg/dL or below within 2 weeks, further reduce to the next lower dose.
• If serum phosphate is not 7 mg/dL or below within 2 weeks after the second dose reduction, withhold this drug until serum phosphate is 7 mg/dL or below and resume at the dose prior to suspending.

Serum phosphate of more than 10 mg/dL:

• Initiate or adjust phosphate lowering therapy and monitor serum phosphate weekly.
• Withhold this drug until phosphate is 7 mg/dL or below and resume at the next lower dose.
• Permanently discontinue this drug if serum phosphate is not equal to or less than 7 mg/dL within 2 weeks following 2 dose interruptions and reductions.

DOSE MODIFICATION FOR OTHER ADVERSE REACTIONS:
Grade 3:

• Withhold this drug until toxicity resolves to Grade 1 or baseline?, then resume.
• For hematological toxicities that get resolved within 1 week, continue at the dose prior to suspending.
• For other adverse reactions, continue at the next lower dose.

Grade 4:

• Permanently discontinue this drug.

Administration advice:

• Administer this drug with or without food at approximately the same time each day.
• Swallow the tablets whole. Do not crush, chew, split or dissolve tablets.
• If a dose is missed for more than 12 hours or if vomiting? occurs, resume dosing the next day as scheduled.

Side Effects

The Most Common

• change in appearance or color of nails
• muscle pain?
• constipation?
• diarrhea? or loose stools
• feeling tired or weak
• dry mouth
• hair loss
• mouth sore
• stomach area pain
• dry skin
• joint pain
• changes in taste
• dry eye
• nausea? or vomiting
• decrease in appetite
• difficulty or painful urination, lower back? pain, or fever?
• redness, swelling, pain or tenderness on the hands or feet
• dry or inflamed eyes, increased tears, blurred vision, flashes of light, or seeing black spots
• muscle cramps or numbness or tingling around your mouth

More common

• Bladder pain
• bloody or cloudy urine
• bone or joint pain
• confusion
• constipation
• cracked lips
• diarrhea
• difficult, burning, or painful urination
• difficulty in breathing
• difficulty in swallowing
• dry eyes
• dry mouth
• fever
• frequent urge to urinate
• irregular heartbeats
• loss of appetite
• lower back or side pain
• mood or mental changes
• muscle cramps in the hands, arms, feet, legs, or face
• nausea
• numbness and tingling around the mouth, fingertips, or feet
• painful irritation of the clear front part of the eye
• redness, swelling, or pain of the skin
• scaling of the skin on the hands and feet
• sores, ulcers, or white spots on the lips, tongue, or inside the mouth
• stomach cramps, tenderness, or pain
• swelling, irritation, soreness, or inflammation of the mouth
• tingling of the hands and feet
• ulceration of the skin
• vomiting
• vomiting of blood or material that looks like coffee grounds
• watering of the eyes
• watery or bloody diarrhea
• weakness

Rare

• Black, tarry stools
• bloody stools
• pale skin
• unusual bleeding or bruising
• unusual tiredness or weakness
• Bluish-brownish hands
• change in taste
• difficulty in moving
• lack or loss of strength
• loss of taste
• muscle aches, cramps, pains, or stiffness
• redness or soreness around the fingernails or loosening of the fingernails

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

Based on findings from animal studies and its mechanism of action, this drug has the potential to cause fetal harm when administered to a pregnant woman. Women of childbearing potential should use effective contraception during treatment and for 1 week after the last dose. Male patients with female partners of childbearing potential should be advised to use effective contraception during therapy and for 1 week after the last dose. Pregnancy status should be verified in females of childbearing potential prior to initiating therapy. Females of childbearing potential should be apprised of the embryofetal risk associated with this drug.

Lactation

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

References