Review section

Field	Value
Drug	Lyrfigtu (lirafugratinib)
Indication reviewed	Previously treated FGFR2 fusion or rearrangement-positive cholangiocarcinoma
Therapeutic category	Fibroblast growth factor receptor 2 (FGFR2) kinase inhibitors
Manufacturer	Elevar Therapeutics
Regulatory status	Approved September 23, 2026
Data as of	September 27, 2026
Prepared by	To be completed by the reviewing plan
Review status	Draft for pharmacy and therapeutics committee review

Indications

Table 1. FDA-approved indications

Indications	Lyrfigtu (lirafugratinib)
“treatment of adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma harboring a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement”	✓

Patient selection by FGFR2 status

“Select patients for the treatment of locally advanced or metastatic cholangiocarcinoma with LYRFIGTU based on the presence of an FGFR2 gene fusion or rearrangement”

“An FDA-authorized test for detection of FGFR2 gene fusions or other rearrangements in patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma for selecting patients for treatment with LYRFIGTU is not available.” (opens the prescribing information at this quote)

Age limit of the indication

“The safety and efficacy of LYRFIGTU have not been established in pediatric patients.” (opens the prescribing information at this quote)

Pharmacokinetics

Table 2. Pharmacokinetic parameters

Generic Name(s)	Bioavailability	Protein Binding	Metabolism	Excretion	Half-Life
Lirafugratinib	Not reported	“>99%”	“primarily metabolized by CYP3A4 and CYP2J2 and to a lesser extent by non-CYP enzymes in vitro”	“approximately 80% of the dose was recovered in feces (23% unchanged), and 8% was recovered in urine (unchanged lirafugratinib not quantified)”	“23 (34%) hours”

How the label reports pharmacokinetic values

“in patients with cholangiocarcinoma or other solid tumors at the approved recommended dosage and are presented as mean (coefficient of variation [CV]%) unless otherwise specified.” (opens the prescribing information at this quote)

Drug interactions

Table 3. Major drug interactions

Generic Name(s)	Interaction	Mechanism
Lirafugratinib	Strong CYP3A inhibitors	“Lirafugratinib is a substrate of CYP3A. Concomitant use of a strong or moderate CYP3A inhibitor increases lirafugratinib exposure”“which may increase the risk of LYRFIGTU adverse reactions.”“Lirafugratinib Cmax increased 1.3-fold and AUC 2-fold following coadministration with itraconazole 200 mg once daily for 8 days.”“Avoid concomitant use. If concomitant use cannot be avoided, reduce LYRFIGTU dosage to 40 mg once daily.”“After a CYP3A inhibitor has been discontinued for 3 elimination half-lives, resume LYRFIGTU at the dosage that was used before starting the inhibitor”
Lirafugratinib	Moderate CYP3A inhibitors	“Lirafugratinib is a substrate of CYP3A. Concomitant use of a strong or moderate CYP3A inhibitor increases lirafugratinib exposure”“which may increase the risk of LYRFIGTU adverse reactions.”“Lirafugratinib Cmax is predicted to increase 1.1-fold and AUC 1.7-fold following coadministration with erythromycin (moderate CYP3A inhibitor) 500 mg four times a day for 15 days.”“Avoid concomitant use. If concomitant use cannot be avoided, reduce LYRFIGTU dosage to 50 mg once daily.”“After a CYP3A inhibitor has been discontinued for 3 elimination half-lives, resume LYRFIGTU at the dosage that was used before starting the inhibitor”
Lirafugratinib	Strong or moderate CYP3A inducers	“Avoid concomitant use of strong or moderate CYP3A inducers.”“Concomitant use of LYRFIGTU with a strong or moderate CYP3A inducer may decrease lirafugratinib exposure”“which may reduce the effectiveness of LYRFIGTU.”“Lirafugratinib Cmax is predicted to decrease to 65% and AUC to 25% following coadministration of rifampicin (strong CYP3A inducer) 600 mg once daily for 19 days.”“Lirafugratinib Cmax is predicted to decrease to 85% and AUC to 43% following coadministration of efavirenz (moderate CYP3A inducer) 600 mg once daily for 19 days.”
Lirafugratinib	P-gp inhibitors	“No clinically significant differences in lirafugratinib pharmacokinetics are predicted when used concomitantly with quinidine (P-gp inhibitor).”
Lirafugratinib	Proton pump inhibitors	“No clinically significant differences in lirafugratinib pharmacokinetics were observed when administered concomitantly with esomeprazole (proton pump inhibitor).”
Lirafugratinib	P-gp, BCRP, OATP1B1, and OATP1B3 substrates	“Monitor for increased adverse reactions for P-gp, BCRP, OATP1B1, and/or OATP1B3 substrates in which minimal concentration changes may lead to serious adverse reactions. Follow the recommended dosage modifications in the approved prescribing information for these substrates.”“Lirafugratinib inhibits P-gp, BCRP, OATP1B1, and OATP1B3 in-vitro. Lirafugratinib may increase exposure of drugs that are substrates of P-gp, BCRP, OATP1B1, or OATP1B3, which may increase the risk of adverse reactions of these substrates”
Lirafugratinib	CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A substrates	“No clinically significant differences in the pharmacokinetics of the following drugs are predicted when used concomitantly with lirafugratinib: repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), omeprazole (CYP2C19 substrate), desipramine (CYP2D6 substrate), midazolam (CYP3A substrate), and caffeine (CYP1A2 substrate).”

Abbreviations: AUC=area under the plasma concentration-time curve; BCRP=breast cancer resistance protein; Cmax=maximum plasma concentration; CYP=cytochrome P450; OATP=organic anion transporting polypeptide; P-gp=P-glycoprotein

Adverse drug events

Table 4. Adverse drug events reported in 15% or more of patients in REFOCUS

Adverse Event	Lyrfigtu (N = 116), all grades (%)	Lyrfigtu (N = 116), Grade 3 or 4 (%)
Nail toxicity	“89”	“12”
Palmar-plantar erythrodysaesthesia syndrome	“82”	“33”
Alopecia	“66”	“0”
Dry skin	“37”	“0”
Rash	“34”	“5”
Stomatitis	“80”	“12”
Dry mouth	“50”	“0”
Constipation	“37”	“0.9”
Abdominal pain	“28”	“3.4”
Diarrhea	“22”	“0.9”
Nausea	“21”	“1.7”
Vomiting	“16”	“0.9”
Dry eye	“53”	“0”
Retinal pigment epithelial detachment	“38”	“1.7”
Blurred vision	“22”	“0.9”
Corneal toxicity	“16”	“0”
Infection	“34”	“8”
Urinary tract infection	“19”	“0.9”
Fatigue	“43”	“3.4”
Pyrexia	“18”	“0.9”
Edema	“17”	“0”
Dysgeusia	“39”	“0.9”
Neuropathy peripheral	“18”	“0.9”
Hemorrhage	“22”	“2.6”
Musculoskeletal pain	“22”	“0”
Decreased appetite	“20”	“0”
Nasal dryness	“15”	“0”

Serious adverse reactions, discontinuations, interruptions, and dose reductions

“Serious adverse reactions occurred in 32% of patients receiving LYRFIGTU. Serious adverse reactions in ≥2% of patients who received LYRFIGTU were infection (6%), pneumonia (3.4%), fatigue (2.6%), and hemorrhage (2.6%). A fatal adverse reaction of hemorrhage occurred in one patient.”

“Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received LYRFIGTU.”

“Dosage interruptions due to an adverse reaction occurred in 88% of patients who received LYRFIGTU 70 mg once daily.”

“Dose reductions due to an adverse reaction occurred in 81% of patients who received LYRFIGTU.” (opens the prescribing information at this quote)

Laboratory abnormalities occurring in 20% or more of patients

“The most common laboratory abnormalities (≥20%) were increased phosphate, increased alanine aminotransferase, increased creatinine, decreased hemoglobin, decreased sodium, decreased lymphocytes, increased blood bilirubin, increased aspartate aminotransferase, decreased platelets, increased glucose, decreased leukocytes, increased alkaline phosphatase, decreased albumin, decreased phosphate, decreased neutrophils, decreased bicarbonate.” (opens the prescribing information at this quote)

Ocular toxicity in the pooled safety population of 385 patients

“Among 385 patients who received LYRFIGTU”

“and underwent ophthalmologic monitoring, including optical coherence tomography (OCT), RPED occurred in 31% of patients with 12% patients having Grade 2 and 1.8% Grade 3. The median time to onset of RPED was 57 days (range 4 to 221). RPED led to dose interruption of LYRFIGTU in 15% of patients, and dose reduction in 10% of patients.”

“Perform a comprehensive ophthalmological examination, including OCT of the macula, prior to initiation of therapy, every 2 months for the first 13 months, and every 4 months thereafter. For onset of visual symptoms, obtain ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of LYRFIGTU.” (opens the prescribing information at this quote)

Dosing and administration

Table 5. Usual dosing regimens

Generic Name	Usual Adult Dose	Usual Pediatric Dose	Availability
Lirafugratinib	“The recommended dosage of LYRFIGTU is 70 mg orally once daily until disease progression or unacceptable toxicity.”“Take LYRFIGTU with or without food”“Swallow capsules whole. Do not open, break or chew the capsules.”	“The safety and efficacy of LYRFIGTU have not been established in pediatric patients.”	“Capsules: 20 mg and 30 mg.”“LYRFIGTU capsules are packaged in blister cards and supplied in child-resistant DosePaks”

See the current prescribing information for full details.

Dosage in hepatic and renal impairment

“No dosage modifications are recommended for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. LYRFIGTU has not been studied in patients with severe (Child-Pugh Class C) hepatic impairment.”

“The effect of severe renal impairment (CLcr < 30 mL/min) and severe (Child-Pugh Class C) hepatic impairment on lirafugratinib pharmacokinetics is unknown.” (opens the prescribing information at this quote)

Effectiveness

Table 6. Comparative clinical trials

Study and Drug Regimen	Study Design and Demographics	Study Size and Duration	End Points	Results
REFOCUS (RLY-4008-101; NCT04526106): “Patients received LYRFIGTU 70 mg once daily until disease progression or unacceptable toxicity.”	“a multicenter, open-label, single-arm trial”“with unresectable or metastatic cholangiocarcinoma who were naïve to FGFR inhibitor treatment and had received prior chemotherapy or chemoimmunotherapy”“The presence of FGFR2 fusions or other rearrangements was determined in 112 (97%) enrolled patients using next-generation sequencing (NGS) testing.”“The median age was 57 years (range 29- 81), 61% female, 55% White, 22% Asian, 1.7% Black or African American”“50% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 50% had ECOG of 1, and 96% had intrahepatic cholangiocarcinoma. Ninety percent (90%) of patients had in-frame FGFR2 gene fusions”“All patients had received at least one prior line of platinum-based systemic therapy, 28% had 2 prior lines of therapy, and 10% had 3 or more prior lines of therapy”	“116 patients”“Among the 116 patients who received LYRFIGTU, 73% were exposed for 6 months or longer and 37% were exposed for greater than 12 months.”	“The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1.”	ORR (95% CI): “46% (36, 55)”Complete response, n (%): “3 (2.6%)”Partial response, n (%): “50 (43%)”Median DoR, months (95% CI): “11.8 (7.5, 13.0)”DoR ≥6 months, n (%): “33 (62)”DoR ≥12 months, n (%): “11 (21)”“The median time to response was 1.9 months (range 1.1, 10.9 months).”“The 95% confidence interval (CI) was calculated using the Clopper-Pearson method.”

Abbreviations: CI=confidence interval; DoR=duration of response; ECOG=Eastern Cooperative Oncology Group; FGFR=fibroblast growth factor receptor; IRC=independent review committee; NGS=next-generation sequencing; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors

References

Elevar Therapeutics LYRFIGTU prescribing information (2026) (opens in a new tab)