Cholangiocarcinoma (CCA), a group of heterogeneous cancers that originate in the bile ducts that connect the liver and gallbladder to the small intestine, affects 2000 to 3000 individuals annually in the United States.1 The disease most often affects older people aged ≥65 years and occurs slightly more frequently in men than in women.1
CCA is classified into 2 major types—intrahepatic or extrahepatic (including the perihilar and distal subtypes)—based on the location of the tumor relative to the liver. Approximately 10% of CCA cases are intrahepatic, and the remaining cases are extrahepatic.1 From 2003 to 2012, the incidence of intrahepatic CCA increased at an annual rate of 4.36%.2
The fibroblast growth factor receptor 2 (FGFR2) gene signals the production of FGFR2 proteins that are implicated in cell growth and division.3 Alterations in FGFR2, including fusions or other rearrangements, can lead to aberrant signaling, which triggers the proliferation and survival of cancer cells.4,5 FGFR2 alterations, which occur almost entirely in intrahepatic subtype, are found in 10% to 16% of patients with CCA.4 FGFR2 has been identified as a key biomarker in CCA, particularly in the intrahepatic subtype.4,5
CCA is often asymptomatic at early stages and is therefore usually diagnosed at advanced stages, when the prognosis is poor and surgery is no longer an effective treatment option.6,7 The treatment options for unresectable or metastatic intrahepatic or extrahepatic CCA are limited.
Until recently, these treatments included enrollment in a clinical trial, systemic chemotherapy, best supportive care, or locoregional therapy, including chemoradiation and radiation therapy.8 Recently, the first treatment that targets the FGFR2 biomarker became available for patients with advanced CCA that harbors this biomarker.
Pemigatinib First Agent Approved for CCA with FGFR2 Alterations
On April 17, 2020, the US Food and Drug Administration (FDA) accelerated the approval of pemigatinib (Pemazyre; Incyte), a kinase inhibitor, for 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 Pemazyre is the first targeted therapy FDA-approved for this indication.5,7 Pemigatinib received breakthrough therapy and orphan drug designations for this indication.
Pemigatinib was granted an accelerated approval, based on overall response rate and duration of response; its final approval is contingent on confirmatory trials to validate its clinical benefit.
Commenting on the approval of pemigatinib, Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence, said, “With Pemazyre, we considered the observed efficacy results to be clinically meaningful and the overall risk to benefit assessment for patients with tumors harboring FGFR2 gene fusions and other rearrangements to be favorable, particularly when we considered that these patients have no other good options following first line treatment with chemotherapy.”7
On the same day that pemigatinib was approved, the FDA also approved a companion diagnostic (FoundationOne CDx; Foundation Medicine) to identify patients with CCA and FGFR2 fusions and rearrangements who may benefit from treatment with pemigatinib.9 The FoundationOne CDx genomic profiling assay was previously approved as a companion diagnostic test for many other types of cancer.9
It is important for clinicians to confirm the presence of FGFR2 to identify which patients may benefit from targeted treatment with pemigatinib. Tailoring a biomarker-driven treatment to the appropriate patient can optimize outcomes for these patients while minimizing its use in patients who may not benefit from this treatment.
Mechanism of Action
Pemigatinib is a potent, selective, small-molecule kinase inhibitor that targets FGFR1, FGFR2, and FGFR3. Constitutive FGFR signaling can lead to the proliferation of cancer cells.4,5 Pemigatinib inhibits phosphorylation and signaling along the FGFR1, 2, and 3 pathways, thereby decreasing the proliferation of cancer cells with FGFR alterations. In xenograft models of human tumors with FGFR1, FGFR2, and FGFR3 alterations, pemigatinib demonstrated antitumor activity.5
Dosing and Administration
Pemigatinib is available as a tablet for oral use in 3 dosage strengths, including 4.5 mg, 9 mg, and 13.5 mg. The tablet should be swallowed whole and should not be crushed, chewed, split, or dissolved. Pemigatinib can be taken with or without food at approximately the same time every day.5
Before the initiation of treatment with pemigatinib, the presence of an FGFR2 fusion or rearrangement should be confirmed. The recommended dose of pemigatinib is 13.5 mg orally once daily for 14 consecutive days, followed by 7 days off therapy, in 21-day cycles. Treatment should be continued until disease progression or unacceptable toxicity occurs.5
Pivotal Clinical Trial: FIGHT-202
The FDA approval of pemigatinib was based on findings from the FIGHT-202 study, an open-label, single-arm, phase 2 clinical trial of 107 patients (median age, 56 years) with locally advanced unresectable or metastatic CCA associated with FGFR2 gene fusion or nonfusion rearrangement whose disease progressed with or after ≥1 previous therapies.4,5
All patients received pemigatinib 13.5 mg orally once daily in 21-day cycles for 14 consecutive days, followed by 7 days of therapy until disease progression or unacceptable toxicity. The primary efficacy end point was overall response rate (ORR); the secondary end point was duration of response, as determined by an independent review committee.5
Patients who received pemigatinib monotherapy achieved an ORR of 36% and a median duration of response of 9.1 months (Table). Moreover, 63% of patients receiving pemigatinib had response to treatment lasting ≥6 months, and 18% had a response lasting ≥12 months. The median time to pemigatinib response was 2.7 months (range, 0.7-6.9 months).5
The most common adverse reactions (incidence ≥20%) associated with pemigatinib are hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), decreased appetite (33%), vomiting (27%), arthralgia (25%), abdominal pain (23%), hypophosphatemia (23%), back pain (20%), and dry skin (20%).5
Serious adverse reactions occurred in 45% of patients who received treatment with pemigatinib. In all, 9% of patients permanently discontinued treatment because of adverse reactions. Fatal adverse events, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion, occurred in 4.1% of patients.5
Pemigatinib has no contraindications.5
The concomitant use of pemigatinib with a strong or moderate cytochrome (CY) P3A inducer decreases the plasma levels of pemigatinib, which may reduce the drug’s efficacy. The concomitant use of a strong or moderate CYP3A inhibitor with pemigatinib increases the drug’s plasma levels, which may increase the incidence and severity of adverse reactions.5
Use in Specific Populations
Pemigatinib can cause fetal harm or loss of pregnancy when administered to a pregnant woman. Pregnant women should be advised of these potential risks.5
Data are not available on the presence of pemigatinib in human milk or its effect on the breastfed child or on milk production. Women should not breastfeed during treatment and for 1 week after the final dose of pemigatinib.5
No overall differences in safety or effectiveness were reported between patients aged ≥65 years and patients aged <65 years.5
No dose adjustment is necessary for patients with mild or moderate renal impairment. For patients with severe renal impairment, the recommended dose of pemigatinib has not been established.5
No dose adjustment of pemigatinib is recommended for patients with mild or moderate hepatic impairment. For patients with severe hepatic impairment, the recommended dose of pemigatinib has not been established.5
Warnings and Precautions
Pemigatinib can cause retinal pigment epithelial detachment. Patients should be given an ophthalmologic examination, including optical coherence tomography, before initiating treatment with pemigatinib, every 2 months for the first 6 months of treatment, every 3 months thereafter, and immediately if visual symptoms occur.5
Hyperphosphatemia is a pharmacodynamic effect of pemigatinib. Patients should be monitored for hyperphosphatemia. Depending on the duration and severity of hyperphosphatemia, it may be necessary to withhold, reduce the dose of, or discontinue pemigatinib.5
Pemigatinib can cause embryo-fetal toxicity when administered to pregnant women. Patients at risk should use effective contraception during treatment and for 1 week after the final dose of pemigatinib.5
Patients with advanced CCA have few treatment options and poor prognosis. The new kinase inhibitor pemigatinib became the first FDA-approved targeted therapy for the treatment of adults with advanced CCA and the FGFR2 biomarker, offering patients a new treatment option. The presence of FGFR2 fusions or rearrangements must be confirmed with the FDA-approved test, the FoundationOne CDx.
In the FIGHT-202 study, pemigatinib demonstrated a 36% ORR and a 9.5-month median duration of response in patients with CCA harboring FGFR2 fusions or rearrangements. For patients with advanced CCA and the FGFR2 biomarker, the approval of pemigatinib provides a new therapeutic option that may improve outcomes.
- National Institutes of Health. Cholangiocarcinoma. Genetics Home Reference. April 28, 2020. https://ghr.nlm.nih.gov/condition/cholangiocarcinoma. Accessed April 28, 2020.
- Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21:594-599.
- National Institutes of Health. FGFR2 gene: fibroblast growth factor receptor 2. Genetics Home Reference. April 28, 2020. https://ghr.nlm.nih.gov/gene/FGFR2. Accessed May 5, 2020.
- Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671-684.
- Pemazyre (pemigatinib) tablets, for oral use [prescribing information]. Wilmington, DE: Incyte Corporation; April 2020.
- Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13:261-280.
- US Food and Drug Administration. FDA approves first targeted treatment for patients with cholangiocarcinoma, a cancer of bile ducts. April 17, 2020. www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-treatment-patients-cholangiocarcinoma-cancer-bile-ducts. Accessed April 27, 2020.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Hepatobiliary Cancers. Version 1.2020. March 23, 2020. www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed May 5, 2020.
- Foundation Medicine. Foundation Medicine receives FDA approval for FoundationOne CDx as the companion diagnostic for Pemazyre (pemigatinib), the first FDA-approved targeted therapy for adults with previously treated locally advanced or metastatic cholangiocarcinoma. April 17, 2020. www.foundationmedicine.com/press-releases/6beca68c-63aa-4c41-969a-12ee7449dd8b. Accessed May 5, 2020.