Understanding Cholangiocarcinoma: How Biomarker Testing Can Lead to a Targeted Treatment for Patients

PEMAZYRE® (pemigatinib) is indicated 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)¹. 

PEMAZYRE can cause serious adverse reactions including Ocular Toxicity (Retinal Pigment Epithelial Detachment [RPED] and Dry Eye), Hyperphosphatemia and Soft Tissue Mineralization, and Embryo-Fetal Toxicity. See Additional Important Safety Information Below¹.

Cholangiocarcinoma, or CCA, is a rare cancer formed in the bile duct. It is difficult to diagnose due to generalized symptoms patients often experience². As with any serious disease, the initial diagnosis can be an incredibly overwhelming experience for patients and their families. For people living with CCA specifically, the diagnosis process can be very long and arduous, which often means a patient’s condition can reach an advanced stage where the prognosis is poor by the time he or she is diagnosed³.

Scientific advancements, such as biomarker testing, or genomic analysis of a patient’s tissue, have made it possible to better understand a person’s specific cancer. Understanding patients’ tumors at the molecular level may help health care professionals individualize a treatment plan that is specific to each patient. 

As the genomic profile of CCA has become clearer, actionable alterations in the DNA that are amenable to treatment with either existing agents or those in development have come into focus. Certain actionable genomic alterations have been identified in up to 2/3 of patients with the intrahepatic subtype of CCA, although this percentage may vary in actual practice⁴. Specifically, research has found that fibroblast growth factor receptor 2 (FGFR2) alterations, which play an important role in the development of cancers like CCA, especially the intrahepatic subtype, is on the rise³. This has prompted recognition of comprehensive genomic testing. Due to the rapid advances in precision medicine for CCA, the NCCN guidelines recommend the use of biomarker testing for advanced CCA⁵. 

The First Targeted Treatment Option for CCA

Though an incredibly useful tool, there is a need for further education about the importance of early biomarker testing amongst the medical community. In one large community-based hospital in California, the implementation of a precision medicine program allowed oncologists and pathologists to standardize all tumor biomarker testing, resulting in an increase in testing⁵. However, there is still much improvement needed. What’s more, scientific advancements in recent years have opened the door to targeted treatment options including Pemazyre® (pemigatinib). Pemazyre was approved by the U.S. Food and Drug Administration (FDA) under accelerated approval in 2020 as the first targeted treatment for adults with previously treated, unresectable locally advanced or metastatic CCA with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test.

“The FDA approval of Pemazyre was and continues to be an encouraging milestone for the CCA community, as patients historically had limited options after first-line chemotherapy or surgery, after which relapse rates were high,” said Dr. Sahai.

Pemazyre works by helping to stop the activity of the abnormal FGFR2 protein, which may help reduce the size of CCA tumors or cause them to disappear. Pemazyre’s approval was based on the results of the multicenter, open-label, single arm FIGHT-202 study in 146 previously treated patients with locally advanced or metastatic CCA1. 

• The efficacy population consisted of 107 patients with disease that had progressed on or after at least 1 prior therapy and who had an FGFR2 fusion or non-fusion rearrangement, as determined by a clinical trial assay (FoundationOne® CDx) performed at a central laboratory.
• The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR). The study found an ORR of 36%, and median DoR of 9.1 months. 
• The most common adverse reactions (incidence ≥20%) in all patients were 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.

Meet Fred, Battling CCA

Meet Fred – a man living with CCA. After noticing an unusual amount of blood following what he thought was a normal kidney stone, Fred contacted his doctor right away. Unfortunately, it was not clear from his initial symptoms what the problem was. A computed tomography (CT or CAT) scan revealed Fred did indeed have a kidney stone, but it also showed a large mass had formed on his liver, leading to more testing. After several tests, Fred was diagnosed with CCA. Because of the nonspecific symptoms he had been experiencing, his cancer unfortunately had time to grow. Upon advice from his doctor, Fred met with a CCA specialist who quickly ordered biomarker testing, revealing that he had FGFR2-driven CCA. With a molecular understanding of Fred’s specific CCA, his health care team was able to prescribe him Pemazyre. 

“I’m grateful I was able to start receiving treatment for my condition following chemotherapy and continue to see improvements in my condition,” noted Fred. “Though I fight side effects such as great fatigue, dry eye, dry skin, and fingernail discoloration, these innovations in science that lead to treatments like Pemazyre are what continue to give my family and I hope.”

Through his own experience, Fred has become an advocate for encouraging others living with CCA to educate themselves about the disease and the importance of early biomarker testing. “My advice is to be your own health advocate. Take charge of how your diagnosis and treatment plan is formed with your doctor, and don’t be afraid to speak openly with your doctor about the tools, like biomarker testing, that are available,” said Fred. “I feel fortunate that my health care team initiated biomarker testing quickly after my diagnosis, which enabled me to find an appropriate treatment option for my specific condition. I know that’s not always the case for my fellow CCA warriors, so I urge those in the community to take charge of their health conversations.” 

Leverage The Leading Tools at Hand 

Fred’s story, like that of so many other CCA patients, was a long and winding road to an accurate diagnosis; however, once he was diagnosed, biomarker testing allowed for Fred’s health care team to fully understand his condition, which led to a tailored treatment plan with Pemazyre. While the regular use of biomarker testing is on the rise, it’s critical that health care providers continue to institute early biomarker testing as standard practice, as it may provide the opportunity to quickly and accurately determine the best path forward for their patients. 

For more information about treatment with Pemazyre, visit Pemzayre.com and Full Prescribing Information.  

###

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

PEMAZYRE^® is indicated 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).

IMPORTANT SAFETY INFORMATION

Ocular Toxicity
Retinal Pigment Epithelial Detachment (RPED): PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended in the prescribing information for PEMAZYRE. 

Dry Eye:  Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia and Soft Tissue Mineralization
PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is >5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia as recommended in the prescribing information.

Embryo-Fetal Toxicity
Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Adverse Reactions:  Cholangiocarcinoma
Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE (n=146). Serious adverse reactions in ≥2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE.  Adverse reactions requiring dosage interruption in ≥1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE.  Adverse reactions requiring dosage reductions in ≥1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N = 635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

In cholangiocarcinoma (n=146) the most common adverse reactions (incidence ≥20%) were 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%).

Drug Interactions
Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.  
Special Populations
Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information. 

Please see Full Prescribing Information for PEMAZYRE.

Incyte and the Incyte logo are registered trademarks of Incyte.
PEMAZYRE  and the PEMAZYRE logo are registered trademarks of Incyte.
All other trademarks are the property of their respective owners.
© 2022, Incyte. MAT-PEM-00414  10/22

^{References:
1.    Pemazyre. Prescribing Information. Incyte Corporation. Accessed August 22, 2022.https://www.pemazyre.com/pdf/prescribing-information.pdf.
2.    Signs and Symptoms of Bile Duct Cancer. American Cancer Society. Updated January 27, 2021. Accessed June 16, 2022. https://www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html.
3.    Banales JM, Cardinale V, Carpino G, et al. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the study of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2016;13(5):261-280.
4.    Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncol. 2014;19(3):235-242. 
5.    Cho M, Gholami S, Gui D, et al. Optimizing the diagnosis and biomarker testing for patients with intrahepatic cholangiocarcinoma: a multidisciplinary approach. National Library of Medicine. 2022;13(1).}