Cholangiocarcinoma (CCA) represents a group of heterogeneous cancers that originate in the bile ducts that connect the liver and gallbladder to the small intestine. Although the exact prevalence of CCA is unknown, CCA is a rare cancer; approximately 8000 new cases of CCA are diagnosed annually in the United States.1
CCA is divided into 2 major types—intrahepatic or extrahepatic (including the perihilar and distal subtypes)—based on the location of the tumor relative to the liver.1,2 Most (90%) cases of CCA are extrahepatic, and the remaining 10% are intrahepatic.2 The majority of patients diagnosed with CCA are aged ≥65 years.1
The 5-year relative survival rate for patients with CCA (all stages) is approximately 9% to 10%; the 5-year survival rate drops to 2% for patients with metastatic disease.3 Metastatic CCA can invade the adjacent liver, adjacent lymph nodes, and the portal vein; in some cases, intra-abdominal metastases, particularly peritoneal metastases, can occur.2
The fibroblast growth factor receptor 2 (FGFR2) gene is involved in the FGFR2 proteins that are implicated in angiogenesis and cell growth and division (ie, proliferation).4 Approximately 13% to 17% of individuals with intrahepatic CCA harbor an FGFR2 fusion or other alteration.5
The treatments for CCA include surgery, radiation therapy, chemotherapy, targeted therapy, and palliative care.5 Because CCA is often not diagnosed until it has advanced or metastasized, the treatment of advanced disease can be challenging.1 Until recently, the therapeutic options for advanced or metastatic CCA were very limited.6,7
Recently, genetic alterations in the FGFR2 pathway have emerged as promising targets in the management of patients with CCA. In 2020, the first targeted therapy, pemigatinib (Pemazyre), was approved by the US Food and Drug Administration (FDA) for advanced or metastatic CCA with FGFR2 fusion or other rearrangement.8 More recently, the second targeted therapy became available for this patient population.9
Truseltiq Approved for Advanced CCA with FGFR2 Alteration
On May 28, 2021, the FDA accelerated the approval of infigratinib capsules (Truseltiq; QED Therapeutics), an ATP-competitive FGFR1-3–selective oral kinase inhibitor of FGFR, for the treatment of adults with previously treated, unresectable, locally advanced or metastatic CCA with an FGFR2 fusion or other rearrangement, as detected by an FDA-approved test.7,9
The FDA granted infigratinib a priority review, based on the overall response rate and duration of response in the CBGJ398X2204 phase 2 clinical trial,7 as well as an orphan drug designation. The continued approval of infigratinib for this indication may be contingent on confirmatory trials to verify its clinical benefits.9
“While targeted treatments have extended survival for many types of cancer, people diagnosed with cholangiocarcinoma have previously been presented with extremely limited treatment options, coupled with low statistical survival data,”10 said Milind Javle, MD, lead investigator of the study and Professor, Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, in his comments on the approval of infigratinib.
“In this study, Truseltiq showed promise as a targeted treatment option for patients with FGFR2 fusion–driven cholangiocarcinoma, with a well-tolerated safety profile in line with previous observations,”10 Dr Javle added.
Stacie Lindsey, Chief Executive Officer of the Cholangiocarcinoma Foundation, noted that, “The approval of Truseltiq provides a new and exciting treatment option for patients with CCA harboring an FGFR2 fusion. We appreciate the fact that there is a robust patient support program, ForgingBridges, to help patients access care and support them throughout their treatment journey.”10
Mechanism of Action
FGFR expression and signaling regulates the survival and proliferation of malignant cells. Infigratinib is a small-molecule kinase inhibitor of FGFR that inhibits FGFR signaling and decreases cell proliferation in cancer-cell lines.11
In preclinical studies, infigratinib showed antitumor activity in xenograft models of human tumors with activating FGFR2 or FGFR3 alterations, including 2 patient-derived xenograft models of CCA tumors.11
Dosing and Administration
Infigratinib is available as 25-mg and 100-mg capsules.11
The presence of an FGFR2 fusion or rearrangement in patients with CCA should be confirmed before initiating treatment with infigratinib. The infigratinib capsules should be swallowed whole with a glass of water; the capsules should not be crushed, chewed, or dissolved.11
The recommended dose of infigratinib is 125 mg orally, once daily, for 21 consecutive days, followed by 7 days off therapy, in 28-day cycles. Infigratinib should be taken on an empty stomach at least 1 hour before or 2 hours after eating, at approximately the same time each day.11
For patients with mild or moderate renal impairment or mild hepatic impairment, the dose should be reduced to 100 mg orally, once daily, for 21 consecutive days, followed by 7 days off therapy, in 28-day cycles. For patients with moderate hepatic impairment, the recommended reduced dose is 75 mg orally, once daily, for 21 consecutive days, followed by 7 days off therapy, in 28-day cycles.11
Pivotal Clinical Trial: CBGJ398X2204
The efficacy of infigratinib was evaluated in the CBGJ398X2204 study, an open-label, single-arm phase 2 clinical trial that included 108 patients (median age, 53 years), including 88 (73%) patients with previously treated, unresectable locally advanced or metastatic CCA and an FGFR2 fusion or rearrangement.7,11
Nearly all (99%) patients had metastatic (stage IV) disease and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Of eligible patients, all received at least 1 previous line of therapy, 32% received 2 previous lines of therapy, and 29% received 3 or more previous lines of therapy.11
The patients enrolled in the study received 125 mg of infigratinib orally once daily for 21 consecutive days, followed by 7 days off therapy, in 28-day cycles until disease progression or unacceptable toxicity. Furthermore, 99% of the patients previously received gemcitabine-based chemotherapy, and in 88% of them, the disease progressed while receiving this therapy.11
The overall response rate with infigratinib was 23%, which included 1 complete response and 24 partial responses (Table).7,11 The median duration of response was 5 months. Of patients who achieved a response, 8 (32%) patients maintained their treatment response for ≥6 months (Table).7,11
The most common (≥20%) adverse reactions associated with infigratinib were nail toxicity (57%), stomatitis (56%), dry eye (44%), fatigue (44%), alopecia (38%), palmar-plantar erythrodysesthesia syndrome (33%), arthralgia (32%), dysgeusia (32%), constipation (30%), abdominal pain (26%), dry mouth (25%), eyelash changes (25%), diarrhea (24%), dry skin (23%), decreased appetite (22%), vision blurred (21%), and vomiting (21%).11
The most common (≥20%) laboratory abnormalities associated with infigratinib were increased creatinine (93%), increased phosphate (90%), decreased phosphate (64%), increased alkaline phosphatase (54%), decreased hemoglobin (53%), increased alanine aminotransferase (51%), increased lipase (44%), increased calcium (43%), decreased lymphocytes (43%), decreased sodium (41%), increased triglycerides (38%), increased aspartate aminotransferase (38%), increased urate (37%), decreased platelets (37%), decreased leukocytes (26%), decreased albumin (24%), increased bilirubin (24%), and decreased potassium (21%).11
Overall, serious adverse reactions were reported in 32% of patients receiving infigratinib, and 15% of patients permanently discontinued infigratinib because of side effects.11
Infigratinib has no contraindications.11
Infigratinib should not be used concomitantly with strong or moderate cytochrome (CY) P3A inhibitors, because of the potential to increase the plasma concentrations of infigratinib.11
Infigratinib should not be used concomitantly with strong or moderate CYP3A inducers, because such use can decrease the plasma concentration of infigratinib.11
Infigratinib should not be used concomitantly with proton pump inhibitors, H2-antagonists, and locally acting antacids; coadministration with a gastric acid–reducing agent can decrease the plasma concentrations of infigratinib.11
Warnings and Precautions
Infigratinib can cause retinal pigment epithelial detachment. A comprehensive ophthalmic examination, including optical coherence tomography, should be conducted before initiating infigratinib treatment, and at 1 month and 3 months, then every 3 months thereafter during treatment.11
Increases in phosphate levels, a potential pharmacodynamic effect of infigratinib, can cause hyperphosphatemia. Patients should be monitored for hyperphosphatemia. Should hyperphosphatemia occur, infigratinib may need to be withheld, dose-reduced, or discontinued.11
Infigratinib can cause fetal harm when administered during pregnancy. Patients of reproductive potential should be advised of the potential risk to the fetus and instructed to use effective contraception during treatment with infigratinib and for 1 month after the final dose. Males with female partners of reproductive potential should be advised to use effective contraception during infigratinib treatment and for 1 month after the final dose.11
Use in Specific Populations
No data are available on the use of infigratinib during pregnancy, but infigratinib may cause fetal harm when administered during pregnancy.11
No data are available on the effects of infigratinib on human milk production or the breastfed child. Given the potential for serious adverse effects on breastfed children, women should be advised not to breastfeed during infigratinib treatment and for 1 month after the final dose.11
In clinical trials, no overall differences in the safety or efficacy of infigratinib were observed between patients aged ≥65 years and younger patients.11
For patients with mild or moderate renal impairment, a reduced dose of infigratinib is recommended. Similarly, a reduced dose of infigratinib is recommended for patients with mild or moderate hepatic impairment. A dose recommendation for patients with severe renal impairment or with severe hepatic impairment has not been established.11
The treatment options for patients with CCA after disease progression during chemotherapy are limited. The approval of infigratinib, a selective oral kinase inhibitor of FGFR, provides a promising new targeted therapy option for patients with previously treated, locally advanced or metastatic CCA that is associated with an FGFR2 fusion or other alteration. In the pivotal study that led to its approval, patients who received treatment with infigratinib achieved a 23% overall response rate and a 5-month median duration of response. Infigratinib has been shown to improve outcomes for patients with metastatic FGFR2-driven CCA, a population whose treatment options are limited.
- National Institutes of Health. Cholangiocarcinoma. Genetics Home Reference. Updated August 18, 2020. https://ghr.nlm.nih.gov/condition/cholangiocarcinoma. Accessed July 15, 2021.
- National Cancer Institute. Bile duct cancer (cholangiocarcinoma) treatment (PDQ)–health professional version. Updated June 2, 2021. www.cancer.gov/types/liver/hp/bile-duct-treatment-pdq#_1. Accessed July 7, 2021.
- American Cancer Society. Survival rates for bile duct cancer. Updated January 27, 2021. www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html. Accessed July 7, 2021.
- National Institutes of Health. FGFR2 gene: fibroblast growth factor receptor 2. Genetics Home Reference. Updated August 18, 2020. https://ghr.nlm.nih.gov/gene/FGFR2. Accessed July 15, 2021.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Hepatobiliary Cancers. Version 3.2021. June 15, 2021. www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed July 8, 2021.
- Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276-282.
- Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol. 2021;39(3_suppl):Abstract 265.
- US Food and Drug Administration. FDA approves first targeted treatment for patients with cholangiocarcinoma, a cancer of bile ducts. April 17, 2021. www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-treatment-patients-cholangiocarcinoma-cancer-bile-ducts. Accessed July 7, 2021.
- US Food and Drug Administration. FDA grants accelerated approval to infigratinib for metastatic cholangiocarcinoma. May 28, 2021. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-infigratinib-metastatic-cholangiocarcinoma. Accessed July 7, 2021.
- BridgeBio Pharma. BridgeBio Pharma’s affiliate QED Therapeutics and partner Helsinn Group announce FDA approval of Truseltiq (infigratinib) for patients with cholangiocarcinoma. May 28, 2021. https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-pharmas-affiliate-qed-therapeutics-and-partner-helsinn. Accessed July 7, 2021.
- Truseltiq (infigratinib) capsules, for oral use [prescribing information]. QED Therapeutics; May 2021. www.truseltiq.com/pdfs/prescribing-information.pdf. Accessed July 7, 2021.