Table 5.

Practical recommendations for the management of FGFR inhibitor side effects.

Clinical presentation or CTCAE grade	Recommendationsa
Hyperphosphatemia
Serum phosphate ≥5.5 to ≤7 mg/dL	Continue FGFR inhibitor at standard dose Initiate phosphate binder Reinforce low-phosphate diet and monitor serum phosphate weekly
Serum phosphate >7 to ≤10 mg/dL	Initiate or increase dose of phosphate binder and/or add phosphaturic acid Reinforce low-phosphate diet and monitor serum phosphate weekly Dose reduction of FGFR inhibitor should be considered once the phosphate levels reach >7 mg/dL on two separate occasions despite optimization of diet and phosphate binding agents ○ If the serum phosphate resolves to ≤7 mg/dL within 2 weeks after dose reduction, continue at reduced dose ○ If serum phosphate is not ≤7 mg/dL within 2 weeks, further reduce to next lower dose ○ If serum phosphate is not ≤7 mg/dL within 2 weeks after the second dose reduction, withhold FGFR inhibitor until serum phosphate is ≤7 mg/dL and resume at the dose prior to interruption
Serum phosphate >10 mg/dL	Initiate or adjust phosphate lowering therapy Reinforce low-phosphate diet and monitor serum phosphate weekly Hold FGFR inhibitor until serum phosphate is ≤7 mg/dL ○ When serum phosphate reaches <7 mg/dL, restart FGFR inhibitor at one dose reduction ○ Consider permanently discontinuing FGFR inhibitor if serum phosphate is not ≤7 mg/dL within 2 weeks following two dose interruptions and reductions
Nail disorders
Onycholysis
Grade 1	If infected, begin oral antibiotics with anti-S. aureus and Gram-positive coverage
Grade 2	If infected, begin oral antibiotics with anti-S. aureus and Gram-positive coverage If painful hematoma or subungual abscess is suspected, partial or total nail avulsion is required Refer to a dermatologist for intolerable grade 2 events, or grade 2 events that have not responded to 4 weeks of therapy
Grade ≥3	Withhold FGFR inhibitor until onycholysis has resolved to grade ≤1 If infected, begin oral antibiotics with anti-S. aureus and Gram-positive coverage If painful hematoma or subungual abscess is suspected, partial or total nail avulsion is required Reassess after 2 weeks; if necessary, interrupt treatment until severity decreases to grade ≤1; if reactions worsen or do not improve, consider withdrawing treatment Refer to a dermatologist
Paronychia
Grade 1	Clindamycin 1% solution (or other topical antibiotic) around and under nails TID, or antibiotic ointment Topical povidone iodine 2% (antiseptic) Soak for 15 min daily in a 1:1 mix of white vinegar and water
Grade 2	Clindamycin 1% solution (or other topical antibiotic) around and under nails TID, or antibiotic ointment Topical povidone iodine 2% (antiseptic) and soak in mix of white vinegar and water Cefadroxil 500 mg BID or TMP/SMX DS BID (oral antibiotics) for 14 days Refer to a dermatologist for intolerable grade 2 events, or grade 2 events that have not responded to 4 weeks of therapy
Grade ≥3	Withhold FGFR inhibitor until paronychia has resolved to grade ≤1 Obtain bacterial cultures to confirm sensitivity to antimicrobial agents Clindamycin 1% solution (or other topical antibiotic) around and under nails TID, or antibiotic ointment Cefadroxil 500 mg BID or TMP/SMX DS BID (oral antibiotics) for 14 days Consider partial nail avulsion Refer to a dermatologist
Stomatitis
Grade 1	Dexamethasone elixir (corticosteroid) 0.5 mg/mL swish and spit 1 teaspoon (5 mL) TID Alcohol-free mouthwash for oral hygiene
Grade 2	Dexamethasone elixir 0.5 mg/mL swish and spit 5 mL TID AND doxepin 10 mg/mL solution (analgesic) or “magic mouthwash” (i.e., diphenhydramine plus lidocaine plus antacid) swish and spit 5 mL PRN for pain Consider intralesional triamcinolone acetonide (corticosteroid) 10 mg/mL to area if localized
Grade ≥3	Withhold FGFR inhibitor until stomatitis has resolved to grade ≤1, and restart at one dose reduction Dexamethasone elixir 0.5 mg/mL swish and spit 5 mL TID AND doxepin 10 mg/mL solution or “magic mouthwash” swish and spit 5 mL PRN for pain Clotrimazole (antifungal) 10 mg lozenges QID
PPES
Grade 1	Apply topical urea 20% or ammonium lactate 12% lotion BID to hands and feet
Grade 2	Apply topical urea 20% or ammonium lactate 12% lotion BID to hands and feet Fluocinomide 0.05% or other high-potency corticosteroid cream BID to hands and feet Refer to a dermatologist for intolerable grade 2 events, or grade 2 events that have not responded to 4 weeks of therapy
Grade ≥3	Withhold FGFR inhibitor until PPES has resolved to grade ≤1, and restart at one dose reduction Apply topical urea 20% or ammonium lactate 12% lotion BID to hands and feet Fluocinomide 0.05% or other high-potency corticosteroid cream BID to hands and feet Refer to dermatologist
Rash
Grade 1	Initiate topical agents such as emollients, lidocaine cream, super-potent topical steroids (clobetasol), and nonsteroid anti-inflammatory agents Reassess after 2 weeks (either by clinician or patient self-report)
Grade 2	Initiate or escalate topical agents such as emollients, lidocaine cream, super-potent topical steroids (clobetasol), and nonsteroid anti-inflammatory agents Reassess after 2 weeks (either by clinician or patient self-report) Refer to a dermatologist for intolerable grade 2 events, or grade 2 events that have not responded to 4 weeks of therapy
Grade ≥3	Withhold FGFR inhibitor until rash has resolved to grade ≤1, and restart at one dose reduction Continue topical agents Initiate oral antibiotics and consider a short course of systemic corticosteroids Reassess after 2 weeks; if reactions worsen or do not improve, dose interruption or discontinuation per protocol may be necessary Refer to a dermatologist
Retinal pigment epithelial dystrophy/retinopathy
	Recommend comprehensive ophthalmologic examination prior to initiation of treatment Recommend detailed ophthalmologic evaluation every 2 months for the first 6 months, and every 3 months thereafter that includes optical coherence tomography, and fundus examination along with routine slip lamp and visual acuity testing If RPED asymptomatic and stable on serial examination, continue FGFR inhibitor and continue periodic ophthalmic evaluation If RPED symptomatic AND visual acuity is 20/40 or better, or ≤3 lines of decreased vision from baseline ○ Withhold FGFR inhibitor until resolution of symptoms and significant examination findings ○ If condition resolves within 4 weeks, resume FGFR inhibitor at one dose reduction ○ If condition recurs with rechallenge, withhold FGFR inhibitor again; if condition resolves within 4 weeks, resume FGFR inhibitor at two reductions ○ Continue close monitoring with an ophthalmologist If RPED symptomatic and visual acuity is worse than 20/40 or >3 lines decreased vision from baseline ○ Withhold FGFR inhibitor until resolution of symptoms and significant examination findings ○ If condition resolves within 4 weeks, resume FGFR inhibitor at two dose reductions ○ If condition recurs, consider permanently discontinuing FGFR inhibitor ○ Continue close monitoring with an ophthalmologist If visual acuity severely compromised (e.g., worse than 20/200 in affected eye; limiting activities of daily living), consider permanently discontinuing the FGFR inhibitor, and continue close monitoring with an ophthalmologist

Note: Table adapted from Lacouture and colleages (22), Kommalapati and colleagues (23), and Mahipal and colleagues (24) based on clinical expertise of futibatinib investigators.

Abbreviations: AE, adverse event; AECI, adverse event of clinical interest; BID, twice daily; CTCAE, Common Terminology Criteria for Adverse Events; FGFR, fibroblast growth factor receptor; PPES, palmar-plantar erythrodysesthesia syndrome; PRN, as required; QID, four times a day; RPED, retinal pigment epithelial dystrophy; TID, three times a day; TMP/SMX DS, trimethoprim/sulfamethoxazole double strength.

^aFor all AECIs, continue FGFR inhibitor without dose reduction unless otherwise specified. Management may differ based on regulatory approval. For more information on the use of individual FGFR inhibitors, please refer to the corresponding US Prescribing Information or European Summary of Product Characteristics.