FDA Approves LYTGOBI (Futibatinib) for Adult Patients with Intrahepatic Cholangiocarcinoma Harboring FGFR2 Gene Fusions or Other Rearrangements

label On September 30, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to LYTGOBI (futibatinib) 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). The approved recommended dosage of LYTGOBI is 20 mg orally (five 4 mg tablets) once daily until disease progression or unacceptable toxicity occurs. Presence of an FGFR2 gene fusion or other rearrangement should be confirmed prior to initiation of treatment with LYTGOBI. The tablets can be taken with or without food and swallowed whole, at approximately the same time each day. Additional information regarding dosage and administration as well as warnings and precautions about ocular toxicity, hyperphosphatemia and soft tissue mineralization, and embryo-fetal toxicity can be found in the full prescribing information linked below. Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) MOA: Futibatinib is a small molecule kinase inhibitor of FGFR 1, 2, 3, and 4. General PK: The futibatinib PK parameters were evaluated in patients with advanced solid tumors and presented as geometric mean (coefficient of variation [CV] %) unless otherwise specified. Futibatinib exposure (AUC) increased proportionally over the dose range from 4 to 24 mg orally once daily (0.2 to 1.2 times the maximum approved recommended dosage). Absorption: Median time to reach maximum futibatinib plasma concentration was 2 (range: 1.2 to 22.8) hours. Effect of Food: Administration of futibatinib with a high-fat and high-calorie meal (900 to 1000 calories, 50% fat) decreased futibatinib AUC by 11% and Cmax by 42% in healthy subjects. Distribution: The apparent volume of distribution of futibatinib is 66 L (18%). Futibatinib is 95% bound to human plasma protein in vitro, primarily to albumin and α1-acid glycoprotein. Elimination: The elimination half-life of futibatinib is 2.9 hours (27%) and the apparent clearance is 20 L/h (23%). Metabolism: Futibatinib is primarily metabolized by CYP3A and to a lesser extent by CYP2C9 and CYP2D6 in vitro. Unchanged futibatinib is the major drug-related moiety in plasma in healthy subjects. Excretion: Following a single oral dose of 20 mg radiolabeled futibatinib, approximately 91% of the total recovered radioactivity was observed in feces and 9% in urine, with negligible unchanged futibatinib in urine or feces. PD: Futibatinib increased serum phosphate levels due to FGFR inhibition. Serum phosphate increased with increasing futibatinib exposure across the dose range of 4 to 24 mg orally once daily, with increased risk of hyperphosphatemia at higher futibatinib exposure. Drug Interactions 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, 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 decrease futibatinib exposure, which may reduce the efficacy of LYTGOBI. The effect of a P-gp modulator (without CYP3A modulation), or a strong CYP3A modulator (without P-gp modulation) on the exposure of futibatinib has not been investigated. 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 No clinically meaningful differences in the systemic exposure of futibatinib were observed based on age (18 - 82 years), sex, race (White, Asian, and African American), body weight (36 - 152 kg), mild to moderate renal impairment (creatinine clearance [CLcr] 30 - 89 mL/min estimated by Cockcroft-Gault), or mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) > ULN, or total bilirubin > 1 to 1.5x ULN and any AST). The PK of futibatinib has not been studied in patients with severe renal impairment (CLcr 15 - 29 mL/min), renal dialysis in end-stage renal disease (CLcr < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5x ULN and any AST). Efficacy and Safety Efficacy of LYTGOBI was demonstrated in a multicenter, open-label, single-arm trial that enrolled patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma. FGFR2 fusions or other rearrangements were confirmed in 99% of the enrolled patients using next generation sequencing (NGS) testing. The major efficacy outcome measures were overall response rate and duration of response as determined by an independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional information regarding the efficacy trial can be found in the full prescribing information linked below. Most common (≥ 20%) adverse reactions observed with LYTGOBI treatment 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. Most common laboratory abnormalities (≥ 20%) observed with LYTGOBI treatment 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.