FDA Approves Infigratinib for Cholangiocarcinoma (Bile Duct Cancer): FGFR2-Targeted Drug No. 2.
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For previously treated adults with unresectable, locally advanced or metastatic cholangiocarcinoma (bile duct cancer) and a fibroblast growth factor receptor 2 (FGFR2) genetic alteration, one kinase inhibitor is infigratinib (Truseltiq, QED Therapeutics, Inc.). On 28 May 2021, FDA (the US Food and Drug Administration) granted accelerated approval to this drug.
Infigratinib brought the number of FDA-approved drugs for FGFR2 mutation-positive cholangiocarcinoma to 2. Previously, pemigatinib had received FDA approval on 17 April 2020.
The FDA also approved FoundationOne® CDx (Foundation Medicine, Inc.) for selecting patients with an FGFR2 gene fusion or another rearrangement, as a companion genetic test for infigratinib treatment.
Update: FDA Withdraws Approval (21.05.2024)
The FDA announced that it had withdrawn the accelerated approval it granted in 2021 for infigratinib (Truseltiq) for patients with certain types of previously treated cholangiocarcinoma.
Infigratinib initially received accelerated approval in May 2021 for treating adults with unresectable locally advanced or metastatic cholangiocarcinoma and a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement. This approval was conditional on the manufacturer, QED Therapeutics, Inc., demonstrating the drug’s clinical benefit in confirmatory trials.
The approval was voluntarily withdrawn at the sponsor’s request. According to the FDA update, "difficulties in recruiting and enrolling study subjects for the required confirmatory clinical trial" led to the withdrawal. The confirmatory clinical trial was investigating the drug’s efficacy in first-line treatment under a new indication. QED determined that, because of recruitment and enrollment difficulties, distribution of the drug in second-line treatment for cholangiocarcinoma (the accelerated approval indication) was “not commercially reasonable.” According to QED, however, the agent continues to be investigated for other FGFR-focused conditions.
The classification of bile duct cancers according to their anatomical shadows is shown below.
Driver mutations in cholangiocarcinoma
Cholangiocarcinoma management is changing rapidly with emerging precision drug strategies. Most research in this cancer type focuses on patients harboring specific genetic alterations, which can be found in approximately 40%of patients with intrahepatic cholangiocarcinoma (bile duct cancer inside the liver). These alterations include fibroblast growth factor receptor-2 (FGFR2) fusions and isocitrate dehydrogenase-1 (IDH1) mutations.
The clinical and genetic characteristics of cholangiocarcinomas are summarized below.
FDA approval based on the CBGJ398X2204 study
Infigratinib showed efficacy in CBGJ398X2204 (NCT02150967), a multicenter, open-label, single-arm trial involving 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement.
Patients received 125 mg of infigratinib once daily for 21 consecutive days, followed by a 7-day treatment break. Each 28-day cycle was considered 1 course, and treatment continued until disease progression or unacceptable toxicity.
Results
The main efficacy outcome measures were overall response rate and duration of response, determined by blinded independent central review according to RECIST 1.1.
- The overall response rate for infigratinib was 23%, with 1 complete response and 24 partial responses (95% CI: 16, 32).
- Median duration of response was 5 months (95% CI: 3.7, 9.3).
- Of 23 responders, 8 patients maintained a response for 6 months or longer.
The most common (frequency ≥ %20) side effects were reported as hyperphosphatemia, increased creatinine, 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, blurred vision and vomiting. Serious risks include hyperphosphatemia and retinal pigment epithelial detachment, and monitoring these adverse reactions during treatment is recommended.
The recommended infigratinib dose is 125 mg once daily on an empty stomach for 21 consecutive days.
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