FDA Approves PEMAZYRE (Pemigatinib) for the Treatment of Adults with Previously Treated, Locally Advanced or Metastatic Cholangiocarcinoma with a Fibroblast Growth Factor Receptor 2 Fusion or Rearrangement

FDA Approves PEMAZYRE (Pemigatinib) for the Treatment of Adults with Previously Treated, Locally Advanced or Metastatic Cholangiocarcinoma with a Fibroblast Growth Factor Receptor 2 Fusion or Rearrangement

On April 17,2020, the U.S. Food and Drug Administration (FDA) approved PEMAZYRE (pemigatinib) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. 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). Information on FDA-approved test(s) for the detection of an FGFR2 fusion or rearrangement in cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics.

The approved recommended dosage of PEMAZYRE is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy, in 21-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs. Administer PEMAZYRE with or without food at approximately the same time every day. If the patient misses a dose of PEMAZYRE by 4 or more hours or if vomiting occurs, resume dosing with the next scheduled dose.

Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as important warnings and precautions about retinal pigment epithelial detachment, hyperphosphatemia, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: Pemigatinib is a small molecule kinase inhibitor that targets FGFR1, 2 and 3.
• General PK: The geometric mean steady-state pemigatinib AUC_0-24h was 2620 nM·h (54% CV) and C_max was 236 nM (56% CV) for 13.5 mg orally once daily. Steady state pemigatinib concentrations increased proportionally over the dose range of 1 mg to 20 mg (0.07 to 1.5 times the recommended dose). Steady-state was achieved within 4 days following repeated once daily dosing. With repeated once daily dosing, pemigatinib accumulated with a median accumulation ratio of 1.63 (range 0.63 to 3.28).
• Absorption: The median time to achieve peak pemigatinib plasma concentration was 1.13 (0.50 - 6.00) hours. Administration of PEMAZYRE with a high-fat and high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500-600 calories from fat) had no clinically meaningful effect on pemigatinib pharmacokinetics.
• Distribution: The estimated apparent volume of distribution of pemigatinib was 235 L (60.8%) following a 13.5 mg oral dose. Pemigatinib was 90.6% bound to human plasma proteins at concentrations ranging from 1 to 10 µM, in vitro.
• Elimination: The geometric mean elimination half-life of pemigatinib was 15.4 (51.6% CV) hours and the geometric mean apparent clearance was 10.6 L/h (54% CV).
• Metabolism: Pemigatinib is predominantly metabolized by CYP3A4, in vitro.  
• Excretion: Following a single oral dose of radiolabeled pemigatinib 11 mg, 82.4% of the dose was recovered in feces (1.4% as unchanged) and 12.6% in urine (1% as unchanged).
• PD: Pemigatinib increased serum phosphate levels due to FGFR inhibition. In patients, the increase in serum phosphate observed after treatment with pemigatinib was exposure-dependent across the dose range of 1 mg to 20 mg once daily (0.07 to 1.5 times the recommended dose), with increased risk of hyperphosphatemia with higher pemigatinib exposure.

Drug Interactions

• Strong or Moderate CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE. Concomitant use of PEMAZYRE with a strong or moderate CYP3A inducer decreases pemigatinib plasma concentrations, which may reduce the efficacy of PEMAZYRE.
• Strong or Moderate CYP3A Inhibitors: Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. If concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided, reduce PEMAZYRE dose from 13.5 mg to 9 mg or reduce PEMAZYRE dose from 9 mg to 4.5 mg. If concomitant use of a strong or moderate CYP3A inhibitor is discontinued, increase the PEMAZYRE dose (after 3 plasma half-lives of the CYP3A inhibitor) to the dose that was used before starting the strong inhibitor. Concomitant use of a strong or moderate CYP3A inhibitor with PEMAZYRE increases pemigatinib plasma concentrations, which may increase the incidence and severity of adverse reactions.

Use in Specific Populations

No clinically meaningful differences in the systemic exposure of pemigatinib were observed based on age (21 ‑ 79 years), sex, race/ethnicity, or body weight (39.8 - 156 kg).

• Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (glomerular filtration rate (GFR) ≥30 to <90 been="" by="" dialysis="" diet="" disease="" dose="" effect="" end-stage="" equation="" established="" estimated="" exposure="" for="" has="" impairment="" in="" is="" li="" min="" ml="" modification="" not="" of="" on="" patients="" pemazyre="" pemigatinib="" recommended="" renal="" severe="" the="" unknown.="" with="">
• Hepatic Impairment: No dose adjustment is recommended for patients with mild (total bilirubin > upper limit of normal (ULN) to 1.5 × ULN or AST > ULN) or moderate hepatic impairment (total bilirubin >1.5–3 × ULN with any AST). The recommended dose of PEMAZYRE has not been established for patients with severe hepatic impairment (total bilirubin >3 × ULN with any AST).
• Lactation: Advise women not to breastfeed during treatment with PEMAZYRE and for 1 week after the final dose because of the potential for serious adverse reactions in breastfed children from PEMAZYRE. There are no data on the presence of pemigatinib or its metabolites in human milk or their effects on either the breastfed child or on milk production.

Efficacy and Safety

Efficacy of PEMAZYRE was demonstrated in a multicenter open-label single-arm trial, in patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least 1 prior therapy and who had an FGFR2 gene fusion or non-fusion rearrangement, as determined by a clinical trial assay performed at a central laboratory. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 20%) are hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin.

Full prescribing information is available at https://go.usa.gov/xv5MM.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.