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Identifying FGR2 Fusions in Cholangiocarcinoma: Assay Selection

Narrator: This promotional presentation is being sponsored by Incyte Corporation. The speaker is presenting on behalf of, and is being compensated by, Incyte Corporation.

INDICATIONS AND USAGE

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).

Important Safety Information is discussed later in this video.

Dr Javle: Hello, I’m Milind Javle, a GI oncologist practicing in Houston, TX. In this video, I’m going to address molecular profiling assay selection for the purpose of identifying FGFR2 fusions in cholangiocarcinoma.

It’s important to select the right type of assay when identifying FGFR2 fusions and rearrangements in patients with intrahepatic cholangiocarcinoma.

A variety of molecular profiling techniques are now available, with next-generation sequencing (or NGS) and fluorescence in situ hybridization (or FISH) being the most common assays.

It is important to recognize the difference between these two types of assays

  • FISH tests are conducted to identify 1 specific, predetermined alteration at a time, so there is a risk of missing other possible alterations
  • NGS allows the opportunity to analyze a tissue sample for multiple alterations at the same time

An NGS assay called FoundationOne® CDx was used in the FIGHT-202 trial for PEMAZYRE to identify the presence of FGFR2 fusions and rearrangements

  • FoundationOne® CDx is the FDA-approved companion diagnostic for PEMAZYRE

PEMAZYRE is the first FDA-approved treatment for adult patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangements.

FoundationOne® CDx is a high-sensitivity, NGS-based assay that can detect FGFR2 fusions, including those with known or unknown fusion partners.

Two important considerations for molecular testing are timing and biopsy technique.

  • Regarding timing, FGFR2 fusions are detectable early in disease progression and are key drivers of tumor progression
    • Because FGFR2 fusions are detectable early, this elevates the importance of identifying these alterations at diagnosis
    • The information provided by molecular profiling can help inform disease management decisions throughout the course of this disease
  • Compared with the amount of tissue required for histological diagnosis, additional tissue may be required to satisfy molecular profiling needs
  • Selecting a biopsy technique that accounts for the additional tissue requirements needed for molecular profiling may help avoid re-biopsy at a later time

However, even if a patient has already undergone a biopsy, they may be willing to undergo re-biopsy, if necessary, to collect additional tissue for molecular profiling if the results may inform subsequent treatment decisions.

Thank you for joining me here today to explore the importance of assay selection in identifying FGFR2 fusions and other rearrangements in patients with cholangiocarcinoma. Please keep watching to view the Important Safety Information for PEMAZYRE.

Narrator: INDICATIONS AND USAGE

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 466 patients who received PEMAZYRE across clinical trials, RPED occurred in 6% of patients, including Grade 3-4 RPED in 0.6%. The median time to first onset of RPED was 62 days. RPED led to dose interruption of PEMAZYRE in 1.7% of patients, and dose reduction and permanent discontinuation in 0.4% and in 0.4% of patients, respectively. RPED resolved or improved to Grade 1 levels in 87.5% 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 466 patients who received PEMAZYRE across clinical trials, dry eye occurred in 27% of patients, including Grade 3-4 in 0.6% 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 466 patients who received PEMAZYRE across clinical trials, hyperphosphatemia was reported in 92% 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 29% 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 final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the final dose.

Adverse Reactions

Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE. 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, 1.3% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N=466]).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.

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 final 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 available on this website.

Identifying FGFR2 Fusions in CCA: Assay Selection

Hear from gastrointestinal oncologist Milind Javle, MD, as he discusses molecular profiling assay selection and timing for the purpose of identifying FGFR2 fusions and rearrangements in patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma.

Milind Javle, MD

Gastrointestinal Oncologist

INDICATIONS AND USAGE

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 466 patients who received PEMAZYRE across clinical trials, RPED occurred in 6% of patients, including Grade 3-4 RPED in 0.6%. The median time to first onset of RPED was 62 days. RPED led to dose interruption of PEMAZYRE in 1.7% of patients, and dose reduction and permanent discontinuation in 0.4% and in 0.4% of patients, respectively. RPED resolved or improved to Grade 1 levels in 87.5% 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 466 patients who received PEMAZYRE across clinical trials, dry eye occurred in 27% of patients, including Grade 3-4 in 0.6% 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 466 patients who received PEMAZYRE across clinical trials, hyperphosphatemia was reported in 92% 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 29% 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 final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the final dose.

Adverse Reactions
Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE. 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, 1.3% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N=466]). 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.

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 final 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.

INDICATIONS AND USAGE

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).