FDA Approves TRUSELTIQ (Infigratinib) for Adults with Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with a Fibroblast Growth Factor Receptor 2 (FGFR2) Fusion or Other Rearrangement

On May 28, 2021, the U.S. Food and Drug Administration (FDA) approved TRUSELTIQ (infigratinib) 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 confirmatory trial(s).

Confirm the presence of an FGFR2 fusion or rearrangement prior to initiation of treatment with TRUSELTIQ. Information on FDA-approved test(s) for the detection of FGFR2 fusions or rearrangements in cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics.

The recommended dosage of TRUSELTIQ is 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles. Continue treatment until disease progression or unacceptable toxicity. Take on an empty stomach at least 1 hour before or 2 hours after food, at approximately the same time each day, and swallow capsules whole with a glass of water.

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: Infigratinib is a kinase inhibitor. 

General PK: Infigratinib C_max and AUC increased more than proportionally across the dose range of 5 to 150 mg (0.04 to 1.2 times the approved recommended dose). Steady state was achieved within 15 days and the mean accumulation ratio was 8-fold and 5-fold for C_max and AUC, respectively.

Absorption: Median (range) time to achieve peak infigratinib plasma concentration (T_max) was 6 hours (2 to 7 hours) at steady state. Following administration of TRUSELTIQ with a high-fat and high-calorie meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects, the mean AUC_inf of infigratinib increased by 80%-120% and C_max increased by 60-80%, the median T_max shifted from 4 hours to 6 hours. Following administration of TRUSELTIQ with a low-fat low-calorie meal (approximately 330 calories with 20% of total caloric content of the meal from fat), the mean AUC_inf of infigratinib increased by 70%, C_max increased by 90%, and the median T_max did not change.

Distribution: The geometric mean (CV%) apparent volume of distribution of infigratinib was 1600 L (33%) at steady state. The mean infigratinib protein binding was 96.8%, primarily to lipoprotein, and was dependent of drug concentration.

Elimination: The geometric mean (CV%) total apparent clearance (CL/F) of infigratinib was 33.1 L/h (59%) and terminal half-life was 33.5 h (39%) at steady state.

Metabolism: Infigratinib is predominantly metabolized by CYP3A4 (~94%) and to a lesser extent by FMO3 (6%) in vitro. The major drug-related moiety in plasma was unchanged infigratinib (38% of dose), followed by two active metabolites, BHS697 and CQM157 (each at >10% of dose). BHS697 is mainly metabolized by CYP3A4 and CQM157 is metabolized through both Phase I and Phase II biotransformation pathways. BHS697 and CQM157 contribute about 16% to 33% and 9% to 12% of overall pharmacologic activity, respectively.

Excretion: After a single oral 125 mg dose of radiolabeled infigratinib in healthy subjects, approximately 77% of the dose was recovered in feces (3.4% as unchanged) and 7.2% in urine (1.9% as unchanged).

PD: TRUSELTIQ increased serum phosphate levels due to FGFR inhibition. Serum phosphate increased with increasing exposures across the dose range of 20 to 150 mg once daily (0.16 to 1.2 times the approved recommended dosage), with increased risk of hyperphosphatemia with higher exposure to TRUSELTIQ.

Drug Interactions

Strong or Moderate CYP3A Inhibitors: Avoid coadministration. Concomitant use may increase infigratinib plasma concentrations, which may increase the risk of TRUSELTIQ adverse reactions.

Strong or Moderate CYP3A Inducers: Avoid coadministration. Concomitant use may decrease infigratinib plasma concentrations, which may reduce TRUSELTIQ anti-tumor activity.

Gastric Acid Reducing Agents: Avoid coadministration. If coadministration cannot be avoided:

• H2-antagonist: Separate administration of TRUSELTIQ by 2 hours before or 10 hours after.
• Locally-acting antacid: Separate administration of TRUSELTIQ by 2 hours before or after.

Concomitant use may decrease infigratinib plasma concentrations, which may reduce TRUSELTIQ anti-tumor activity.

Use in Specific Populations

No clinically significant differences in the systemic exposure of infigratinib were observed based on age (19-86 years), sex, race/ethnicity (White, Black, Asian), or body weight (36.4-169 kg).

Efficacy and Safety

Efficacy of TRUSELTIQ was demonstrated in a multicenter open-label single-arm trial in patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR), as determined by blinded independent central review (BICR) 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 were nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, vision blurred and vomiting.

Most common laboratory abnormalities (≥ 20%) were increased creatinine, increased phosphate, decreased phosphate, increased alkaline phosphatase, decreased hemoglobin, increased alanine aminotransferase, increased lipase, increased calcium, decreased lymphocytes, decreased sodium, increased triglycerides, increased aspartate aminotransferase, increased urate, decreased platelets, decreased leukocytes, decreased albumin, increased bilirubin and decreased potassium.

Full prescribing information is available at https://go.usa.gov/x6Csf.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

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