Pemazyre Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS section reflects exposure to PEMAZYRE at a starting dose of 13.5 mg orally once daily (intermittent or continuous administration) in 635 patients with advanced malignancies. Among the 635 patients, 31% were exposed for 6 months or longer and 11% were exposed greater than one year, including patients with previously treated, advanced, or metastatic cholangiocarcinoma in FIGHT-202 and patients with MLNs with FGFR1 rearrangement in FIGHT-203. Cholangiocarcinoma FIGHT-202 The safety of PEMAZYRE was evaluated in FIGHT-202, which included 146 patients with previously treated, locally advanced or metastatic cholangiocarcinoma.

Patients were treated orally with PEMAZYRE 13.5 mg once daily for 14 days on followed by 7 days off therapy until disease progression or unacceptable toxicity. The median duration of treatment was 181 days (range: 7 to 730 days). The median age of PEMAZYRE-treated patients was 59 years (range 26-78), 58% were females, and 71% were White. 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. Table 3 summarizes the adverse reactions in FIGHT-202. Table 4 summarizes laboratory abnormalities in FIGHT-202. Table 3: Adverse Reactions (≥ 15%) in Patients Receiving PEMAZYRE in FIGHT-202 Adverse Reaction PEMAZYRE N=146 All Grades Graded per NCI CTCAE 4.03. (%) Grades 3 or 4 (%) Metabolism and nutrition disorders Hyperphosphatemia Includes hyperphosphatemia and blood phosphorous increased; graded based on clinical severity and medical interventions taken according to the "investigations-other, specify" category in NCI CTCAE v4.03. 60 0 Decreased appetite 33

Hypophosphatemia Includes hypophosphatemia and blood phosphorous decreased. 23 12 Dehydration 15 3.4

Skin and subcutaneous tissue disorders Alopecia 49 0 Nail toxicity Includes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail ridging, nail infection, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. 43

Dry skin 20 0.7 Palmar-plantar erythrodysesthesia syndrome 15 4.1 Gastrointestinal disorders Diarrhea

47

Nausea 40 2.1 Constipation 35 0.7 Stomatitis 35 5 Dry mouth 34

0 Vomiting 27

Nervous system disorders Dysgeusia 40 0 Headache 16 0 Eye disorders Dry

eye Includes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis. 35

Musculoskeletal and connective tissue disorders Arthralgia 25 6 Back pain 20 2.7

Pain in extremity 19

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 ). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment. Table 4: Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients Receiving PEMAZYRE in FIGHT-202 PEMAZYRE The denominator used to calculate the rate varied from 142-146 based on the number of patients with a baseline value and at least one post-treatment value. N=146 Laboratory Abnormality All Grades Graded per NCI CTCAE 4.03. (%) Grades 3 or 4 (%) Hematology Decreased hemoglobin 43 6 Decreased lymphocytes 36 8 Decreased platelets 28

Increased leukocytes 27 0.7 Decreased leukocytes 18 1.4 Chemistry Increased phosphate

Based on CTCAE 5.0 grading. 94 0 Decreased phosphate 68 38 Increased alanine aminotransferase 43

Increased aspartate aminotransferase 43 6 Increased calcium 43 4.1 Increased alkaline phosphatase

41 11 Increased creatinine Graded based on comparison to upper limit of normal. 41

Decreased sodium 39 12 Increased glucose 36 0.7 Decreased albumin 34 0

Increased urate 30 10 Increased bilirubin 26 6 Decreased potassium 26 5 Decreased calcium 17

Increased potassium 12 2.1 Decreased glucose 11 1.4 Increased Creatinine 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. Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement FIGHT-203 The safety of PEMAZYRE was evaluated in FIGHT-203, which included 34 patients who were treated for MLN with FGFR1 rearrangement . Patients were treated with PEMAZYRE 13.5 mg once daily on a continuous schedule (the approved recommended starting dosage) or for 14 days on followed by 7 days off therapy (an unapproved dosage regimen in MLN with FGFR1 rearrangement) until disease progression, unacceptable toxicity, or they were able to receive allogeneic stem cell transplant.

The median duration of treatment was 205 days (range: 30-1347 days). Serious adverse reactions occurred in 53% of patients receiving PEMAZYRE at all dosages. Serious adverse reactions in > 5% of patients included acute kidney injury. Fatal adverse reactions occurred in 9% of patients who received PEMAZYRE, including acute kidney injury, multiple organ dysfunction syndrome, and malignant neoplasm progression, occurring in one patient each.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received PEMAZYRE at all dosages. Adverse reactions requiring permanent discontinuation included cardiac failure, multiple organ dysfunction syndrome, blood alkaline phosphatase increase, and calciphylaxis. In patients who started treatment on the recommended dosage (n = 20), adverse reactions requiring dosage interruption of PEMAZYRE occurred in 80% of patients.

Adverse reactions which required dosage interruption in > 2 patients treated at the recommended dosage included nail toxicities (20%) and hyperphosphatemia (15%). Dose reductions of PEMAZYRE due to an adverse reaction occurred in 80% of patients who started treatment on the recommended dosage. Adverse reactions requiring dose reductions occurring in > 2 patients were nail toxicities (20%), hyperphosphatemia (20%), and alopecia (15%). The most common (≥ 20%) adverse reactions were hyperphosphatemia, nail toxicity, alopecia, stomatitis, diarrhea, dry eye, fatigue, rash, abdominal pain, anemia, constipation, dry mouth, epistaxis, serous retinal detachment, extremity pain, decreased appetite, dry skin, dyspepsia, back pain, nausea, blurred vision, peripheral edema, and dizziness. The most common (≥ 20%) laboratory abnormalities were increased phosphate, decreased lymphocytes, decreased leukocytes, increased alkaline phosphatase, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased neutrophils, increased creatinine, decreased phosphate, decreased sodium, increased glucose, decreased platelets, decreased calcium, increased calcium, decreased potassium, and increased bilirubin.

Table 5 summarizes the adverse reactions in FIGHT-203. Table 5: Adverse Reactions (≥ 15%) in Patients Receiving PEMAZYRE in FIGHT-203 Adverse Reaction PEMAZYRE N=34 All Grades Graded per NCI CTCAE 4.03. (%) Grade 3 or 4 (%) Metabolism and nutrition disorders Hyperphosphatemia Includes hyperphosphatemia and blood phosphorous increased; graded based on clinical severity and medical interventions taken according to the "investigations-other, specify" category in NCI CTCAE v4.03. 74

Decreased appetite 24 6 Skin and subcutaneous tissue disorders Nail toxicity Includes

ingrowing nail, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail growth abnormal, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. 62 21 Alopecia 59 0 Rash Includes dermatitis, dermatitis acneiform, lichen planus, rash, rash macular, and skin exfoliation. 35 6 Dry skin Includes dry skin and xerosis. 24 0 Palmar-plantar erythrodysaesthesia Includes palmar erythema, palmar-plantar erythrodysaesthesia, and plantar erythema. 18 9 Gastrointestinal disorders Stomatitis Includes aphthous ulcer, cheilitis, lip ulceration, mouth ulceration, pharyngeal inflammation, stomatitis, and tongue ulceration. 53 15 Diarrhea 50

Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, and

abdominal rigidity. 35

Constipation 32 2.9 Dry mouth 32 0 Dyspepsia 24 0 Nausea 21

0 Eye disorders Dry eye Includes dry eye, keratitis, lacrimation increased, meibomian gland dysfunction, and punctate keratitis 50 6 Retinal pigment epithelial detachment Includes detachment of retinal pigment epithelium, maculopathy, retinal detachment, retinal disorder, retinal thickening, serous retinal detachment, and subretinal fluid. 26 0 Vision blurred 21

Trichiasis 18 2.9 General disorders Fatigue Includes asthenia and fatigue. 44 9

Edema peripheral 21 0 Pyrexia 18

Blood and lymphatic system disorders Anemia 35 18 Respiratory, thoracic, and mediastinal

disorders Epistaxis 29 0 Musculoskeletal and connective tissue disorders Pain in extremity 26 12 Back pain Includes back pain and spinal pain. 24 9 Nervous system disorders Dizziness 21 0 Table 6 summarizes laboratory abnormalities in FIGHT-203. Table 6: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients Receiving PEMAZYRE in FIGHT-203 Laboratory Abnormality PEMAZYRE N=34 The denominator used to calculate the rate varied from 31 to 34 based on the number of patients with a baseline value and at least one post-treatment value. All Grades Graded per NCI CTCAE 4.03. (%) Grade 3 or 4 (%) Hematology Decreased lymphocytes 65 16 Decreased leukocytes 65 15 Decreased hemoglobin 53 9 Decreased neutrophils 45 12 Decreased platelets 29 15 Chemistry Increased phosphate Graded per NCI CTCAE 5.0. 97

Increased alkaline phosphatase 62 9 Increased alanine aminotransferase 50 12 Increased aspartate

aminotransferase 47 9 Increased creatinine Based on comparison to upper limit of normal. 44 0 Decreased phosphate 41 26 Decreased sodium 41 9 Increased glucose 33 3 Decreased calcium 26

Increased calcium 26 2.9 Decreased potassium 24 2.9 Increased bilirubin 21 0

Other clinically significant laboratory abnormalities: Prothrombin time/international normalized ratio was elevated in 16% (Grade 1 or 2 elevation) of patients. Uric acid was elevated in 18% of patients, including 2.9% with a Grade 3 or 4 elevation.

Effect of Other Drugs on

PEMAZYRE Strong and Moderate CYP3A Inducers Concomitant use of PEMAZYRE with a strong or moderate CYP3A inducer decreases pemigatinib plasma concentrations, which may reduce the efficacy of PEMAZYRE. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE. Strong and Moderate CYP3A Inhibitors Concomitant use of a strong or moderate CYP3A inhibitor with PEMAZYRE increases pemigatinib plasma concentrations, which may increase the incidence and severity of adverse reactions. Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce PEMAZYRE dosage if concomitant use of strong and moderate CYP3A inhibitors cannot be avoided .

Pregnancy Risk Summary Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm or loss of pregnancy when administered to a pregnant woman . There are no available data on the use of PEMAZYRE in pregnant women. Oral administration of pemigatinib to pregnant rats during the period of organogenesis at maternal plasma exposures below the human exposure at the clinical dose of 13.5 mg resulted in fetal malformations, fetal growth retardation, and embryo-fetal death (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal Data Once daily oral administration of pemigatinib to pregnant rats during the period of organogenesis resulted in 100% embryofetal mortality due to post-implantation loss at doses ≥ 0.3 mg/kg (approximately 0.6 times the human exposure based on AUC at the clinical dose of 13.5 mg). Fetal survival was unaffected at 0.1 mg/kg per day; however, once daily oral administration of pemigatinib at the 0.1 mg/kg dose level (approximately 0.2 times the human exposure based on AUC at the clinical dose of 13.5 mg) resulted in reduced mean fetal body weight and an increase in fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification.

Pediatric Use The safety and effectiveness of PEMAZYRE have not been established in pediatric patients. Animal Toxicity Data In 4- or 13-week repeat-dose toxicology studies in rats and non-human primates, animals displayed toxicities in bone and teeth at pemigatinib exposures lower than the human exposure at the clinical dose of 13.5 mg. Physeal and cartilage dysplasia were present in multiple bones in both species, and tooth (incisor) abnormalities (complete loss of ameloblasts with associated secondary changes) occurred in rats.

Six weeks after cessation of dosing, these findings did not show complete evidence of recovery, and additional tooth-related findings (mal-aligned, whitened, broken, and trimmed/thinned incisors) developed in the 13-week study.