APPLICATION NUMBER · 2020. 5. 18. · Office of Clinical Pharmacology Reviewer(s) Robert Schuck,...

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

213736Orig1s000

MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review

NDA/BLA Multi-disciplinary Review and Evaluation NDA 213736 PEMAZYRE (pemigatinib)

NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NME

Application Number(s) NDA 213736 Priority or Standard Priority

Submit Date(s) September 30, 2019 Received Date(s) September 30, 2019

PDUFA Goal Date May 30, 2020 Division/Office Division of Oncology 3

Review Completion Date April 17, 2020 Established/Proper Name pemigatinib

(Proposed) Trade Name Pemazyre Pharmacologic Class Kinase Inhibitor

Code name INCB054828 Applicant Incyte Corporation

Dosage form tablet Applicant proposed Dosing

Regimen 13.5 mg orally once daily for 14 days followed by 7 days off therapy. Continue treatment until disease progression or unacceptable toxicity occurs.

Applicant Proposed Indication(s)/Population(s)

Treatment of adults with previously treated, locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or 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).

Applicant Proposed SNOMED CT Indication Disease Term

Cholangiocarcinoma of biliary tract (disorder)

Recommendation on Regulatory Action

Accelerated Approval

Recommended Indication(s)/Population(s)

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.


1 Version date: April 2, 2018

Reference ID: 4594191


Recommended SNOMED CT Indication Disease Term

312104005/Cholangiocarcinoma of biliary tract (disorder)

Recommended Dosing Regimen

13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy, in 21-day cycles




Table of Contents Table of Tables ................................................................................................................................ 6

Table of Figures............................................................................................................................... 8

Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9

Glossary......................................................................................................................................... 11

1 Executive Summary ............................................................................................................... 13 Product Introduction .................................................................................................. 13 Conclusions on the Substantial Evidence of Effectiveness ........................................ 14 Benefit-Risk Assessment............................................................................................. 16 Patient Experience Data ............................................................................................. 24

2 Therapeutic Context .............................................................................................................. 25 Analysis of Condition .................................................................................................. 25 Analysis of Current Treatment Options...................................................................... 25

3 Regulatory Background ......................................................................................................... 27 U.S. Regulatory Actions and Marketing History ......................................................... 27 Summary of Presubmission/Submission Regulatory Activity .................................... 27

4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on

Efficacy and Safety................................................................................................................. 30

Office of Scientific Investigations (OSI) ...................................................................... 30 Product Quality........................................................................................................... 30 Clinical Microbiology .................................................................................................. 31 Devices and Companion Diagnostic Issues................................................................. 31

5 Nonclinical Pharmacology/Toxicology................................................................................... 32 Executive Summary .................................................................................................... 32 Referenced NDAs, BLAs, DMFs................................................................................... 35 Pharmacology ............................................................................................................. 36 ADME/PK .................................................................................................................... 42 Toxicology ................................................................................................................... 45

General Toxicology.................................................................................................. 45 Genetic Toxicology.................................................................................................. 58 Carcinogenicity........................................................................................................ 59 Reproductive and Developmental Toxicology........................................................ 59 Other Toxicology Studies ........................................................................................ 62

6 Clinical Pharmacology............................................................................................................ 64




Executive Summary .................................................................................................... 64 Summary of Clinical Pharmacology Assessment ........................................................ 65

Pharmacology and Clinical Pharmacokinetics ........................................................ 65 General Dosing and Therapeutic Individualization................................................. 66

Comprehensive Clinical Pharmacology Review.......................................................... 66 General Pharmacology and Pharmacokinetic Characteristics................................ 66 Insert Clinical Pharmacology Questions ................................................................. 68

7 Sources of Clinical Data and Review Strategy ....................................................................... 77 Table of Clinical Studies.............................................................................................. 77 Review Strategy .......................................................................................................... 80

8 Statistical and Clinical and Evaluation ................................................................................... 81 Review of Relevant Individual Trials Used to Support Efficacy .................................. 81

INCB 54828-202 (FIGHT-202).................................................................................. 81 Study Results........................................................................................................... 85

8.1.3 Integrated Review of Effectiveness ........................................................................ 95 8.1.4 Integrated Assessment of Effectiveness................................................................. 95

8.2 Review of Safety ......................................................................................................... 96 8.2.1 Safety Review Approach ......................................................................................... 96 8.2.2 Review of the Safety Database ............................................................................... 97 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 100 8.2.4 Safety Results........................................................................................................ 104 8.2.5 Analysis of Submission-Specific Safety Issues....................................................... 147 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability...... 147 8.2.7 Safety Analyses by Demographic Subgroups........................................................ 147 8.2.8 Specific Safety Studies/Clinical Trials.................................................................... 148 8.2.9 Additional Safety Explorations.............................................................................. 148 8.2.10 Safety in the Postmarket Setting................................................................... 149 8.2.11 Integrated Assessment of Safety................................................................... 149

8.3 Statistical Issues........................................................................................................ 149 8.4 Conclusions and Recommendations ........................................................................ 149

9 Advisory Committee Meeting and Other External Consultations....................................... 152

10 Pediatrics ............................................................................................................................. 153

11 Labeling Recommendations ................................................................................................ 154 11.1 Prescription Drug Labeling ....................................................................................... 154

12 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 160




13 Postmarketing Requirements and Commitment ................................................................ 161

14 Division Director (DHOT) ..................................................................................................... 162

15 Division Director (OCP) ........................................................................................................ 162

16 Division Director (OB) Comments ....................................................................................... 162

17 Division Director (Clinical) Comments................................................................................. 162

18 Office Director (or designated signatory authority) Comments ......................................... 164

19 Appendices .......................................................................................................................... 165 19.1 References ................................................................................................................ 165 19.2 Financial Disclosure .................................................................................................. 167 19.3 Nonclinical Pharmacology/Toxicology...................................................................... 168 19.4 OCP Appendices (Technical documents supporting OCP recommendations) ......... 168

19.4.1 Appendix 1. Summary of Bioanalytical Method Validation and Performance.... 168 19.4.2 Appendix 2. Physiologically based pharmacokinetic (PBPK) analyses review..... 175 19.4.3 Appendix 3. Population PK Analysis..................................................................... 184 19.4.4 Appendix 4. Exposure-Response Analysis ........................................................... 191

19.5 Additional Clinical Outcome Assessment Analyses.................................................. 196




Table of Tables

Table 1. Regulatory Activity for IND 138179 ................................................................................ 27 Table 2. NDA Submission Regulatory History ............................................................................... 29 Table 3. Clinical Sites for Inspection ............................................................................................. 30 Table 4: In Vitro Inhibition of Human and Rat FGFR Kinases and VEGFR2................................... 36 Table 5: Effect of Pemigatinib on the In Vitro Viability of Cells with or without FGFR Alterations ....................................................................................................................................................... 37 Table 6: Summary of In Vivo Anti-Tumor Activity in Mice Bearing FGFR2 Amplified KATOIII Xenografts ..................................................................................................................................... 38 Table 7: Selected Histopathology Findings (3-month Study; Rats) .............................................. 52 Table 8: Summary of General Pharmacology and Pharmacokinetic Characteristics of Pemigatinib ....................................................................................................................................................... 66 Table 9. Effect of mild or moderate renal impairment on pemigatinib apparent clearance. ..... 71 Table 10. Effect of mild or moderate hepatic impairment on apparent pemigatinib clearance. 72 Table 11. Listing of Clinical Trials with Pemigatinib...................................................................... 78 Table 12. Dose Reductions for Toxicity in Study INCB 54828-202 ............................................... 82 Table 13. Schedule of Laboratory Assessments in Study INCB 54828-202 .................................. 83 Table 14: Patient Disposition in Cohort A of Study INCB 54828-202 ........................................... 86 Table 15. Summary of Protocol Deviations in Cohort A of Study INCB 54828-202...................... 87 Table 16: Demographic Characteristics of Patients in Cohort A of Study INCB 54828-202 ......... 88 Table 17: Baseline Disease Characteristics of Patients in Cohort A ............................................. 88 Table 18: ORR per RECIST 1.1 as assessed by IRC......................................................................... 91 Table 19: Subgroup Analysis of Cohort A Responses by Type of FGFR2 Abnormality and Fusion Partner1 ......................................................................................................................................... 91 Table 20: ORR for Demographic Subgroups of Cohort A by IRC per RECIST 1.1 .......................... 92 Table 21: Data cut off dates for Pivotal Studies submitted for the Pemigatinib NDA ................. 97 Table 22: Summary for Exposure of Pemigatinib ......................................................................... 98 Table 23: Narrative Description of Selected Deaths................................................................... 105 Table 24: Serious Adverse Events by Preferred Term ≥ 1% incidence in any safety population 109 Table 25: Summary of Patient Narratives for Serious Adverse Events....................................... 111 Table 26: Adverse Events Leading to Drug Discontinuation in ≥1% Incidence in any Safety Population................................................................................................................................... 114 Table 27: Treatment-Emergent Adverse Events leading to Treatment Interruption

≥ 1% Incidence in Any Safety Population.................................................................................... 118 Table 28: Treatment-Emergent Adverse Events leading to dose reduction ≥ 1% Incidence in any Safety Population........................................................................................................................ 120 Table 29: Incyte Review of Reversibility of Ocular Toxicity for Pemigatinib .............................. 125 Table 30: Nail Toxicity Adverse Events (occurring at any rate) .................................................. 128 Table 31: Bone-related Adverse Events in Patients with Cholangiocarcinoma.......................... 131 Table 32: Narrative Summary of Pathologic Fractures.............................................................. 133 Table 33: Overview of Safety Profile in Integrated Safety Populations ..................................... 135




Table 34: Adverse Reactions (≥ 15% Incidence) in Patients Receiving Pemigatinib in Study-202

Table 40. Summary of predicted vs. observed pemigatinib PK parameters following single dose

Table 41 Summary of predicted and observed effects of itraconazole (a strong CYP3A inhibitor)

Table 42. Summary of predicted effects of moderate CYP3A inhibitors on the PK of pemigatinib

Table 43. Summary of simulated pemigatinib PK parameters at steady state when it is co

..................................................................................................................................................... 136 Table 35: Overview of Safety Profile by Age (Geriatrics)............................................................ 147 Table 36. Summary of Method Performance (Incyte assay). ..................................................... 169 Table 37. Summary of Method Performance ( (b) (4) assay). ................................................. 175 Table 38. Summary of input parameters for pemigatinib PBPK model...................................... 178 Table 39. Updated input parameters for pemigatinib model .................................................... 179

or multiple dose oral administration .......................................................................................... 181

and rifampin (a strong CYP3A inducer) on the PK of pemigatinib.............................................. 181

following single dose or multiple dose administration .............................................................. 182

administered with CYP3A inhibitors ........................................................................................... 183 Table 44. Overview of studies included in the population PK analysis. ..................................... 185 Table 45. Summary of PK sampling times................................................................................... 185 Table 46. Demographics and baseline characteristics of pooled study data ............................. 186 Table 47. Parameter estimates of final population PK model.................................................... 187 Table 48. Summary of ORR by Cycle 1 or During treatment hyperphosphatemia status.......... 193




Table of Figures

Figure 1: Effect of Pemigatinib on In Vivo Anti-Tumor Activity in Mice Bearing KATOIII FGFR2 Amplified Xenografts .................................................................................................................... 38

Figure 8. Simulated and observed pemigatinib PK profiles following single dose or multiple dose

Figure 11. Covariate Evaluation of Pemigatinib Oral Clearance Using Final Population PK Model

Figure 12. Comparison of Patient Predicted Parameters and Exposures between Applicant’s and

Figure 13. Model-predicted vs. observed relationship of serum phosphate concentration change

Figure 14. Model-predicted vs. observed relationship of ORR and serum phosphate

Figure 15. Model-predicted vs. observed relationship of ORR and pemigatinib exposure (Cmax, ss)

Figure 16. PFS Vs. change in serum phosphate concentration from baseline or AUCss following

Figure 2: Effect of Single Oral Administration of Pemigatinib on FGFR2 Phosphorylation in KATO III Xenografts ................................................................................................................................. 39 Figure 3: Effect of Pemigatinib on CTG-0997 Xenograft Growth in Nude Mice........................... 40 Figure 4: Effect of Single Oral Administration of Pemigatinib on Serum Phosphate in Mice ...... 41 Figure 5. Relationship between pemigatinib exposure and probability of hyperphosphatemia. 69 Figure 6: Swimmer’s plot for responders per RECIST 1.1 assessed by IRC................................... 94 Figure 7: Mean (± SE) Change from Baseline in Serum Creatinine Levels Over Time in Study INCB54828-202 ........................................................................................................................... 140

oral administration ..................................................................................................................... 180 Figure 9. Diagnostic plots for the final population PK model..................................................... 188 Figure 10. Visual predictive check stratified by visit and dose for final population PK model .. 189

..................................................................................................................................................... 190

Reviewer’s models. ..................................................................................................................... 190

from baseline and pemigatinib AUCss. ........................................................................................ 191

concentration change from baseline or pemigatinib exposure (Cmax, ss) .................................... 192

..................................................................................................................................................... 192

once daily dosing of 13.5 mg pemigatinib .................................................................................. 193 Figure 17. Probability of Hyperphosphatemia Vs. Pemigatinib Cmax, ss....................................... 195




Reviewers of Multi-Disciplinary Review and Evaluation

Regulatory Project Manager Stacie Woods Nonclinical Reviewer Emily Wearne Nonclinical Team Leader Whitney Helms Office of Clinical Pharmacology Reviewer(s) Robert Schuck, Yangbing Li, Xinyuan

Zhang Office of Clinical Pharmacology Team Leader(s) Jeanne Fourie-Zirkelbach, Rosane

Charlab Orbach, Jiang Liu, Yuching Yang

Clinical Reviewer Naomi Horiba (efficacy), Leigh Marcus (safety)

Clinical Team Leader Martha Donoghue Statistical Reviewer Somak Chatterjee Statistical Team Leader Pallavi Mishra-Kalyani Associate Director of Labeling (acting) Ann Marie Trentacosti Cross-Disciplinary Team Leader Martha Donoghue Division Director (DHOT) John Leighton Division Director (OCP) Atik Rahman Division Director (OB) Shenghui Tang Deputy Division Director (OOD/DO3) Lola Fashoyin-Aje Office Director (or designated signatory authority) Marc Theoret

Additional Reviewers of Application OPQ ATL: Xing Wang, Drug Substance: Raymond

Frankewich/Su Tran TL; Drug Product: Olen Stephens/Anamitro Banerjee; Facilities/Process: Sridhar Thumma/Bogdan Kurtyka; Biopharmaceutics: Mei Ou/Banu Zolnik; Environmental assessment: James Laurenson

Microbiology Sridhar Thumma/ Bogdan Kurtyka TL OPDP Emily Dvorsky/Susannah O’Donnell TL OSI Yang-Min (Max) Ning/Aisha Johnson TL/Kassa Ayalew OSE/DEPI Richard Swain OSE/DMEPA Janine Stewart/Alice Tu TL OSE/DRISK Mei-Yean Chen/Naomi Boston TL Other (CDRH) Bowen Cui, Dun Liang/Donna Roscoe TL Other (ophthalmology consult) Wiley Chambers

CDRH= Center for Devices and Radiological Health DEPI= Division of Epidemiology DMEPA=Division of Medication Error Prevention and Analysis DO3= Division of Oncology 3 DRISK=Division of Risk Management




OOD=Office of Oncologic Diseases OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion OSI=Office of Scientific Investigations OSE= Office of Surveillance and Epidemiology




Glossary

AC advisory committee ADME absorption, distribution, metabolism, excretion AE adverse event AR adverse reaction BLA biologics license application BPCA Best Pharmaceuticals for Children Act BRF Benefit Risk Framework CBER Center for Biologics Evaluation and Research CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CDTL Cross-Discipline Team Leader CFR Code of Federal Regulations CMC chemistry, manufacturing, and controls COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms CRF case report form CRO contract research organization CRT clinical review template CSR clinical study report CSS Controlled Substance Staff DHOT Division of Hematology Oncology Toxicology DMC data monitoring committee ECG electrocardiogram eCTD electronic common technical document ETASU elements to assure safe use FDA Food and Drug Administration FDAAA Food and Drug Administration Amendments Act of 2007 FDASIA Food and Drug Administration Safety and Innovation Act FGFR Fibroblast growth factor receptor GCP good clinical practice GRMP good review management practice ICH International Conference on Harmonisation IND Investigational New Drug ISE integrated summary of effectiveness ISS integrated summary of safety ITT intent to treat MedDRA Medical Dictionary for Regulatory Activities mITT modified intent to treat NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event NDA new drug application NME new molecular entity




OCS Office of Computational Science OPQ Office of Pharmaceutical Quality OSE Office of Surveillance and Epidemiology OSI Office of Scientific Investigation PBRER Periodic Benefit-Risk Evaluation Report PD pharmacodynamics PI prescribing information PK pharmacokinetics PMC postmarketing commitment PMR postmarketing requirement PP per protocol PPI patient package insert (also known as Patient Information) PREA Pediatric Research Equity Act PRO patient reported outcome PSUR Periodic Safety Update report PT Preferred Term REMS risk evaluation and mitigation strategy SAE serious adverse event SAP statistical analysis plan SGE special government employee SOC standard of care TEAE treatment emergent adverse event




1 Executive Summary

Product Introduction

On September 30, 2019, Incyte Corporation (Incyte) submitted a New Drug Application (NDA) 213736 for pemigatinib tablets under Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) seeking accelerated approval of Pemazyre (pemigatinib) for the treatment of adults with previously treated, locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement as detected by an FDA-approved test.

Pemigatinib (previously called INCB054828) is a small molecule kinase inhibitor that inhibits the kinase activities of the fibroblast growth factor receptor (FGFR)1 (FGFR1), FGFR2, and FGFR3. Pemigatinib is the active pharmaceutical ingredient in Pemazyre tablets.

The molecular formula for pemigatinib is C24H27F2N5O4 and the molecular mass is 487.5 g/mole. The chemical name is name 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one. Pemigatinib has the following chemical structure:

O F

O O

O N N F N

NN H

Pemazyre (pemigatinib) is supplied as uncoated tablets for oral administration that contain 4.5 mg, 9 mg, or 13.5 mg of the pemigatinib active ingredient. The inactive ingredients include magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

The proposed recommended dosage regimen for pemigatinib is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles.

Pemazyre (pemigatinib) is a new molecular entity and has not been previously marketed.




Conclusions on the Substantial Evidence of Effectiveness

The clinical, clinical pharmacology, nonclinical, and statistical review teams unanimously agree that the NDA for Pemazyre (pemigatinib) tablets meets the statutory standards for approval under 21 CFR 314, Subpart H (accelerated approval) for the following indication:

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 approval recommendation is primarily based on safety and efficacy results of a single trial, Study INCB 54828-202 (also referred to as Study -202, or FIGHT-202; NCT02924376). Study INCB 54828-202 is an open label, non-randomized, multi-cohort trial that evaluated the efficacy of pemigatinib in 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement, whose disease had progressed on or after at least 1 prior therapy (Cohort A). The safety of pemigatinib was evaluated in 146 patients with previously treated, locally advanced or metastatic cholangiocarcinoma who received at least one dose of pemigatinib in Study INCB 54828-202 (107 patients with tumors harboring a FGFR2 gene fusion or rearrangement enrolled in Cohort A and 39 additional patients whose tumors did not harbor an FGFR2 gene fusion or rearrangement). The safety of pemigatinib is also supported by data from an additional 320 patients treated with pemigatinib as a single agent in other clinical trials.

Study INCB 54828-202 demonstrated a clinically meaningful and durable overall response rate (ORR) in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with a FGFR2 gene fusion or rearrangement, a serious and life-threatening disease. In the first 107 patients with FGFR2 gene fusion/rearrangement--positive solid tumors who received at least one dose of pemigatinib, the estimated ORR was 36% (95% confidence interval [CI]: 27%, 45%). The median duration of response (DOR) was 9.1 months; 24 of the 38 (63%) responders had a DOR lasting at least 6 months and 7 (18%) responders had a DOR lasting at least 12 months at the time of the analysis. There are no available FDA-approved drugs for the second-line treatment of patients with unresectable or metastatic cholangiocarcinoma, and no approved-treatments specifically for the subset of patients with cholangiocarcinoma whose tumors harbor an FGFR2 gene fusion or rearrangement. Taken together, the ORR and DOR results in in Study INCB 54828-202 are reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, and represent a meaningful advantage over existing treatments for the proposed indication, and satisfy the requirements for accelerated approval. Concurrently with the approval of Pemazyre, FDA will approve the Foundation Medicine companion diagnostic assay (Foundation Medicine CDx) supplemental Premarket




Approval (sPMA) application to select patients with cholangiocarcinoma harboring an FGFR2 gene fusion or other select rearrangement, for treatment with Pemazyre. Incyte has agreed to a postmarketing requirement to conduct a randomized clinical trial demonstrating improvement of progression-free survival or overall survival in patients with unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 gene fusion or rearrangement, to confirm the clinical benefit of pemigatinib.




Benefit-Risk Assessment

Benefit-Risk Summary and Assessment

Cholangiocarcinoma (CCA) is a rare cancer arising from epithelial cells of bile ducts that is grouped into anatomic subtypes based on location of origin in the biliary tract: intrahepatic (iCCA), perihilar, or extrahepatic. CCA accounts for approximately 3% of all gastrointestinal cancers and 10-25% of primary hepatic malignancies worldwide and the incidence appears to be rising (Rizvi et al. 2013). In the U.S. in 2014, the annual incidence of iCCA was 1.49 per 100,000, representing a two-fold increase over the past four decades (Saha et al. 2016). The median age at presentation is 65 years in Western industrialized nations, and most patients develop CCA in the absence of identifiable risk factors (Blechacz 2017). Although surgery is the preferred treatment option, most patients have advanced-stage disease at the time of diagnosis, and only 35% are eligible for surgical resection with curative intent. For patients with advanced-stage or unresectable CCA, the median overall survival with standard of care chemotherapy is less than one year (Valle et al. 2010).

Fibroblast growth factor/fibroblast growth factor receptor (FGFR) fusions are a reported genetic modification in iCCA and have been identified as an early driver of oncogenic events in iCCA (Nakamura et al. 2015). FGFR2 fusions are present in an estimated 10-20% of patients with iCCA (Krook et al. 2020). Patients with FGFR rearrangements appear to have a longer median overall survival compared to those with iCCA lacking a FGFR rearrangement. A retrospective review of 377 patients with CCA reported a median OS of 37 months in patients with FGFR gene fusion-positive CCA compared to 20 months in the unselected CCA population (Jain et al. 2018). The baseline demographic and disease characteristics of patients with FGFR rearrangements also appear to be prognostically favorable, including diagnosis at a younger age and an earlier stage of disease. Patients with FGFR fusion-positive CCA are also predominantly female (63%) and usually have iCCA (87%).

There are no FDA-approved drugs for the second-line treatment of patients with unresectable or metastatic cholangiocarcinoma, and no treatments approved specifically for the subset of patients with cholangiocarcinoma with an FGFR2 gene fusion or rearrangement, irrespective of line of treatment.

Study INCB 54828-202 (also referred to as Study -202, or FIGHT-202; NCT02924376) provided the evidence to support the effectiveness of pemigatinib for the proposed indication. Study INCB 54828-202 is an open label, non-randomized, multicohort trial that evaluated pemigatinib in 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma harboring an FGFR2 gene fusion or non-fusion rearrangement, whose disease had progressed on or after at least 1 prior therapy (Cohort A). Qualifying in-frame fusions and other rearrangements were predicted to have a breakpoint within intron17/exon 18 of the FGFR2 gene and leave the FGFR2 kinase domain intact.




Patients received pemigatinib in 21-day cycles at a dosage of 13.5 mg orally once daily for 14 consecutive days, followed by 7 days off therapy. pemigatinib was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. The median age was 56 years (range: 26 to 77 years), 61% were female, 74% were White, and 95% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of less than 2 (ECOG 0: 42%; ECOG 1: 53%). Ninety-eight percent of patients had iCCA. Eighty-six percent of patients had in-frame FGFR2 gene fusions. Among the patients with in-frame FGFR2 gene fusions, the most common FGFR2 fusion identified was FGFR2-BICC1 (34%%). Fourteen percent of patients had other FGFR2 rearrangements that could not be confidently predicted to be in-frame fusions, including rearrangements without an identifiable partner gene. All patients had received at least 1 prior line of systemic therapy, 27% had 2 prior lines of therapy, and 12% had 3 or more prior lines of therapy. Ninety-six percent of patients had received prior platinum-based therapy including 76% with prior gemcitabine/cisplatin.

Study INCB 54828-202 demonstrated a clinically meaningful and durable overall response rate (ORR) in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with a FGFR2 gene fusion or other rearrangement, a serious and life-threatening disease. In the first 107 patients with FGFR2 gene fusion/rearrangement-positive cholangiocarcinoma who received at least one dose of pemigatinib, the estimated overall response rate (ORR) was 36% (95% confidence interval [CI]: 27%, 45%). At the time of the analysis, the median duration of response (DOR) was 9.1 months; 24 of the 38 (63%) responders had a DOR lasting at least 6 months and 7 (18%) responders had DOR lasting at least 12 months .

The primary data supporting the safety of pemigatinib for the proposed indication was derived from a pooled population of 146 patients with previously treated, locally advanced or metastatic cholangiocarcinoma who received at least one dose of pemigatinib in Study INCB 54828-202 (107 patients with tumors harboring a FGFR2 gene fusion or rearrangement enrolled in Cohort A, and 39 additional patients whose tumors did not harbor an FGFR2 gene fusion or rearrangement). The safety evaluation of pemigatinib was also supported by data from an additional 320 patients with a variety of cancers treated with pemigatinib as a single agent in 4 other multicenter single arm trials (Study INCB 54828-101, Study INCB 54828-102, Study INCB 54828-201, and Study INCB 54828-203).

Although assessment of a causal relationship between pemigatinib and treatment-emergent reactions was limited in the context of the single arm design of the trials providing safety data, the adverse reactions observed in patients treated with pemigatinib were largely expected given the mechanism of action and the toxicity profile observed in preclinical studies. Among the 146 patients with cholangiocarcinoma enrolled in Study INCB 54828-202, the most common adverse reactions to pemigatinib (incidence ≥ 20%) are 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. 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).

The most important serious risks of pemigatinib are ocular toxicity and hyperphosphatemia; these adverse reactions appear manageable and largely reversible with dosage modification and supportive care. Among the 466 patients who received pemigatinib across clinical trials, retinal pigment epithelial detachment (RPED), which can cause symptoms such as blurred vision, visual floaters, or photopsia, occurred in 6% of patients, including Grade 3-4 events in 0.6% of patients. The median time to first onset of RPED was 62 days. RPED led to dose interruption of pemigatinib 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 in 87.5% of patients who required dosage modification of pemigatinib for RPED. In order to mitigate the risk of severe RPED, comprehensive ophthalmologic monitoring including ocular coherence tomography is recommended prior to initiation of pemigatinib, every 2 months for the first 6 months of treatment, and every 3 months thereafter during treatment. Increases in phosphate levels are a pharmacodynamic effect of pemigatinib. Among 466 patients who received pemigatinib 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 pemigatinib.

Overall, the toxicity profile of pemigatinib is considered acceptable when considering the anti-tumor effects (i.e., durable responses) in patients with cholangiocarcinoma harboring a FGFR2 fusion or other rearrangement, who have a poor life expectancy and limited treatment options. The major safety risks of pemigatinib are toxicities that oncologists are well-trained to manage and are acceptable for a population with a serious and life-threatening condition.

Taken together, the ORR and DOR results in Study INCB 54828-202 are reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, and represent a meaningful advantage over existing treatments for the proposed indication, meeting the requirements for accelerated approval. Concurrently with the approval of pemigatinib, FDA will approve the supplemental Premarket Approval (sPMA) application for the Foundation Medicine companion diagnostic assay (Foundation Medicine CDx), for the selection of patients with FGFR2 fusions or other select rearrangements for treatment with Pemazyre. Incyte has agreed to a postmarketing requirement to conduct a randomized clinical trial demonstrating improvement of progression-free survival or overall survival in patients with unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 gene fusion or rearrangement, to confirm the clinical benefit of pemigatinib.




Dimension Evidence and Uncertainties Conclusions and Reasons

Analysis of Condition

• Cholangiocarcinoma (CCA) is a rare cancer arising from epithelial cells of bile ducts that is grouped into anatomic subtypes based on location of origin in the biliary tract: intrahepatic (iCCA), perihilar, or extrahepatic. CCA accounts for approximately 3% of all gastrointestinal cancers and 10-25% of primary hepatic malignancies worldwide and the incidence appears to be rising (Rizvi et al. 2013). In the U.S. in 2014, the annual incidence of iCCA was 1.49 per 100,000, representing a two-fold increase over the past four decades (Saha et al. 2016).

• The median age at presentation is 65 years in Western industrialized nations, and most patients develop CCA in the absence of identifiable risk factors (Blechacz 2017).

• Although surgery is the preferred treatment option, most patients have advanced-stage disease at the time of diagnosis, and only 35% are eligible for surgical resection with curative intent. For patients with advanced-stage or unresectable CCA, the median overall survival with standard of care chemotherapy is less than one year (Valle et al 2010).

• Fibroblast growth factor/fibroblast growth factor receptor (FGFR) fusions are a reported genetic modification in iCCA and have been identified as an early driver of oncogenic events in iCCA (Nakamura et al. 2015). FGFR2 fusions are present in an estimated 10-20% of patients with iCCA (Krook et al. 2020). Patients with FGFR rearrangements appear to have a longer median overall survival compared to those with iCCA lacking a FGFR rearrangement. A

Cholangiocarcinoma is a serious and life-threatening illness and there is no satisfactory available therapy for the treatment of cholangiocarcinoma with a FGFR2 gene fusion or other rearrangement that has received at least one prior line of treatment.





retrospective review of 377 patients with CCA reported a median OS of 37 months in patients with FGFR gene fusion-positive CCA compared to 20 months in the unselected CCA population (Jain et al. 2018).

• The baseline demographic and disease characteristics of patients with FGFR rearrangements also appear to be prognostically favorable, including diagnosis at a younger age and an earlier stage of disease. Patients with FGFR fusion-positive CCA are also predominantly female (63%) and usually have iCCA (87%).

Current Treatment

Options

• Current treatment options for patients with CCA are limited, and there are no approved treatments for the treatment of patients with CCA in the second-line setting, irrespective of whether the tumor harbors an FGFR2 gene fusion or rearrangement.

• Entrectinib and larotrectinib are approved for the treatment of patients with solid tumors that harbor NTRK gene fusions and who have no satisfactory alternative treatment options; however, NTRK gene fusions occur rarely in CCA. NTRK fusions are estimated to occur 1.3% of patients with CCA (Kheder et al 2018).

• Pembrolizumab is approved for the treatment of patients with microsatellite-high/mismatch repair deficient (MSI-high/dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory treatment options; however, only approximately 4% of CCA are MSI-H/dMMR (Goeppert et al. 2019).

There is an unmet medical need for new effective treatments for patients with cholangiocarcinoma with a FGFR2 gene fusion or other rearrangement who have received at least one prior line of treatment. Current treatment options for patients with CCA are limited, and there are no approved treatments for the treatment of patients with CCA in the second-line setting, irrespective of whether the tumor harbors an FGFR2 gene fusion or rearrangement.





• The only standard of care second-line chemotherapy option for patients with CCA supported by randomized data is 5fluorouracil/leucovorin in combination with oxaliplatin (FOLFOX). In Study ABC-06, FOLFOX conferred a median OS benefit of 6.2 months as compared to 5.3 months with best supportive care (hazard ratio [HR] 0.69; 95% CI: 0.50-0.97; p = 0.031; Lamarca et al. 2019). Other regimens that are considered acceptable include irinotecan in combination with a fluoropyrimidine, a platinum plus fluoropyrimidine, gemcitabine in combination with a platinum or fluoropyrimidine, or regorafenib(NCCN 2020).

Benefit

• Study INCB 54828-202 (also referred to as Study -202, or FIGHT-202; NCT02924376) provides the evidence of effectiveness for pemigatinib for the proposed indication. Study INCB 54828-202 is an open label, non-randomized, multicohort trial that evaluated pemigatinib in 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma harboring an FGFR2 gene fusion or non-fusion rearrangement, whose disease had progressed on or after at least 1 prior therapy (Cohort A).

• Patients received pemigatinib in 21-day cycles at a dosage of 13.5 mg orally once daily for 14 consecutive days, followed by 7 days off therapy. pemigatinib was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as determined by an independent review committee (IRC) according to RECIST v1.1.

The magnitude and duration of responses observed in patients with cholangiocarcinoma with a FGFR2 gene fusion who received prior treatment was large and clinically meaningful. The submitted evidence meets the statutory evidentiary standard for accelerated approval.

Incyte has agreed to a postmarketing requirement to submit data from a randomized trial to verify and confirm the clinical benefit of pemigatinib in patients with FGFR2 fusion/rearrangement- positive cholangiocarcinoma.





• Study INCB 54828-202 demonstrated a clinically meaningful and durable ORR in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with a FGFR2 gene fusion or other rearrangement. These responses were also durable. In the first 107 patients with FGFR2 gene fusion/rearrangement--positive cholangiocarcinoma who received at least one dose of pemigatinib, the estimated ORR was 36% (95% confidence interval [CI]: 27%, 45%). At the time of the analysis, the median DOR was 9.1 months; 24 of the 38 (63%) responders had a DOR lasting at least 6 months and 7 (18%) responders had a DOR of at least 12 months.

Risk and Risk Management

• The primary data supporting the safety of pemigatinib for the proposed indication was provided from data derived from 146 patients with previously treated, locally advanced or metastatic cholangiocarcinoma who received at least one dose of pemigatinib in Study INCB 54828-202 (107 patients with tumors harboring a FGFR2 gene fusion or rearrangement enrolled in Cohort A and 39 additional patients whose tumors did not harbor an FGFR2 gene fusion or rearrangement).

• The safety evaluation of pemigatinib was also supported by data from an additional 320 patients with a variety of cancers treated with pemigatinib as a single agent in 4 other multicenter single arm trials (Study INCB 54828-101, Study INCB 54828-102, Study INCB 54828-201, and Study INCB 54828-203).

• Although assessment of a causal relationship between pemigatinib and treatment-emergent adverse reactions was limited in the context of the single arm design of the trials providing safety data,

The observed safety profile is acceptable when assessed in the context of the treatment of a life-threatening disease. Most of the adverse reactions to pemigatinib were manageable with supportive care and dose modification as needed. The significant and potentially serious adverse reactions of hyperphosphatemia and ocular toxicity are adequately addressed in the Warnings and Precautions section and the dose modification recommendations included in product labeling.

There were no significant safety concerns identified during the review of the application requiring risk management beyond labeling or





the adverse reactions observed in patients treated with pemigatinib were largely expected given with the mechanism of action and the toxicity profile observed in preclinical studies.

• Among the 146 patients with cholangiocarcinoma enrolled in Study INCB 54828-202, the most common adverse reactions to pemigatinib (incidence ≥ 20%) are 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. 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).

warranting consideration for a Risk Evaluation and Mitigation Strategy(REMS).




Patient Experience Data

Patient Experience Data Relevant to this Application (check all that apply) X The patient experience data that were submitted as part of the

application include: Section of review where discussed, if applicable [e.g., Section 6.1 Study endpoints]

X Clinical outcome assessment (COA) data, such as

X Patient reported outcome (PRO) 8.1.2 Study Results □ Observer reported outcome (ObsRO) □ Clinician reported outcome (ClinRO) □ Performance outcome (PerfO)

□ Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel, etc.)

□ Patient-focused drug development or other stakeholder meeting summary reports

□ Observational survey studies designed to capture patient experience data

□ Natural history studies □ Patient preference studies (e.g., submitted studies or

scientific publications) □ Other: (Please specify):

□ Patient experience data that were not submitted in the application, but were considered in this review: □ Input informed from participation in meetings with patient

stakeholders □ Patient-focused drug development or other stakeholder

meeting summary reports □ Observational survey studies designed to capture patient

experience data □ Other: (Please specify):

□ Patient experience data was not submitted as part of this application.

X Martha Donoghue, MD Cross Discipline Team Leader




2 Therapeutic Context

Analysis of Condition

Cholangiocarcinoma (CCA) is a rare malignancy arising from epithelial cells of bile ducts that is grouped into anatomic subtypes based on location of origin in the biliary tract: intrahepatic (iCCA), perihilar, or extrahepatic. CCA accounts for approximately 3% of all gastrointestinal cancers and 10-25% of primary hepatic malignancies worldwide and the incidence appears to be rising (Rizvi et al. 2013). In the U.S. in 2014, the annual incidence of iCCA was 1.49 per 100,000, representing a two-fold increase over the past four decades (Saha et al. 2016). The median age at presentation is 65 years in Western industrialized nations, and most patients develop CCA in the absence of identifiable risk factors (Blechacz 2017).

Although surgery is the preferred treatment option, most patients have advanced-stage disease at the time of diagnosis, and only 35% are eligible for surgical resection with curative intent. For patients with advanced-stage or unresectable CCA, the median overall survival with standard of care chemotherapy is less than one year (Valle et al 2010).

Fibroblast growth factor/fibroblast growth factor receptor (FGFR) fusions are a reported genetic modification in iCCA and have been identified as an early driver of oncogenic events in iCCA (Nakamura et al. 2015). FGFR2 fusions are present in an estimated 10-20% of patients with iCCA (Krook et al. 2020). Patients with FGFR rearrangements appear to have a longer median overall survival compared to those with iCCA lacking a FGFR rearrangement. A retrospective review of 377 patients with CCA reported a median OS of 37 months in patients with FGFR gene fusion-positive CCA compared to 20 months in the unselected CCA population (Jain et al. 2018). The baseline demographic and disease characteristics of patients with FGFR rearrangements also appear to be prognostically favorable, including diagnosis at a younger age and an earlier stage of disease. Patients with FGFR fusion-positive CCA are also predominantly female (63%) and the location is intrahepatic for the majority of patients (87%).

Analysis of Current Treatment Options

After administration of first-line standard of care chemotherapy with gemcitabine and cisplatin in advanced or metastatic CCA, which confers a 3.6 month median OS benefit compared to gemcitabine alone (Valle et al. 2010), current treatment options for patients with CCA are limited, and there are no approved treatments for the treatment of patients with CCA in the second-line setting. Entrectinib and larotrectinib, and pembrolizumab, respectively, are approved for the treatment of patients with solid tumors with no satisfactory alternative treatment options that harbor NTRK gene fusions or are microsatellite-high/mismatch repair deficient (MSI-high/dMMR), respectively; however, these molecular aberrations occur rarely in




CCA. NTRK fusions are estimated to occur 1.3% of patients with CCA and approximately 4% of CCA are MSI-H/dMMR (Goeppert et al. 2019 and Kheder et al 2018).

Currently, the only standard of care second-line chemotherapy option for patients with CCA supported by randomized data is 5-fluorouracil/leucovorin in combination with oxaliplatin (FOLFOX). In Study ABC-06, FOLFOX conferred a median OS benefit of 6.2 months as compared to 5.3 months with best supportive care (hazard ratio [HR] 0.69; 95% CI: 0.50-0.97; p = 0.031; Lamarca et al. 2019) in patients with locally advanced or metastatic biliary tract cancers previously treated with gemcitabine and cisplatin. Fatigue and neutropenia were more common in the treatment arm, and the rate of Grade 3-4 toxicity was higher than in the control arm (59% vs. 39%). Other regimens that are considered acceptable include irinotecan in combination with a fluoropyrimidine, a platinum plus fluoropyrimidine, gemcitabine in combination with a platinum or fluoropyrimidine, or regorafenib (NCCN 2020).

Limited data exist regarding outcomes for the population of patients with FGFR genetic fusions specifically. One retrospective study of 45 patients with FGFR2 fusions treated with gemcitabine in combination with a platinum showed no significant differences in progression-free survival (PFS; 0.5 vs 0.5 years, HR 1.19, p = 0.36) (Almquist 2019).



http:0.50-0.97


3 Regulatory Background

U.S. Regulatory Actions and Marketing History

Pemigatinib is not approved for marketing in the United States.

Summary of Presubmission/Submission Regulatory Activity

Table 1. Regulatory Activity for IND 138179

Date Event

October 27, 2014

The initial IND for INCB054828 (IND 124358) was submitted, containing the clinical protocol for Study INCB 54828-101, entitled “A Phase 1, Open-Label, Dose-Escalation, Safety and Tolerability Study of INCB054828 in Subjects with Advanced Malignancies”. On November 26, 2014, the study was allowed to proceed.

January 30, 2018

Incyte submitted original IND 138179 for pemigatinib containing Study INCB 54828-202, entitled “A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Safety of INCB054828 in Subjects with Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Including FGFR2 Translocations Who Failed Previous Therapy.”

March 12, 2018 FDA granted orphan drug designation to INCB054828 for the treatment of cholangiocarcinoma.

March 8, 2018

FDA issued preliminary comments in preparation for a Type B End of Phase 2 meeting addressing the design of the proposed trial intended to provide the primary evidence to support regular approval, Study INCB 54828-302. Incyte cancelled the meeting on May 10, 2018, following review of the preliminary responses.

April 5, 2018 FDA held a Type B End of Phase 2 CMC only meeting to discuss the CMC development plan for INCB054828.

May 21, 2018

FDA issued written responses to Incyte regarding the adequacy of a proposed clinical data package to support an NDA comprising results from the unplanned post-hoc interim analysis of Study INCB-202, reflecting data from 45 patients enrolled in Cohort A, stating that it would not be sufficient to adequately characterize the safety and




Date Event

effectiveness of INCB054828 for a marketing application.

FDA recommended a minimum sample size of 100 patients with sufficient follow-up to adequately characterize the safety and effectiveness of pemigatinib in patients with previously treated, unresectable cholangiocarcinoma with an FGFR2 fusion. FDA stated that in general, an ORR with a lower bound of the 95% confidence interval (CI) that is greater than 15%, accompanied by durations of response of sufficient magnitude to be considered clinically meaningful (e.g., at least 6 months in the majority of responders), and a favorable risk/benefit profile may provide sufficient evidence to support a marketing application seeking accelerated approval in the proposed patient population. FDA clarified that ORR should be calculated using a denominator comprising all patients who received at least one dose of pemigatinib. FDA recommended that data be sufficiently mature to assess duration of response for a minimum of 12 months form the time of onset of response for each responder.

August 14, 2018

Incyte submitted Protocol INCB 24828-302, entitled “A Phase 3, Open-Label, Randomized, Active-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of INCB054828 Versus Gemcitabine Plus Cisplatin Chemotherapy in First-Line Treatment of Participants With Unresectable or Metastatic Cholangiocarcinoma With FGFR2 Rearrangement”, to IND 138179.

February 13, 2019

FDA granted breakthrough designation to pemigatinib for the treatment of patients with previously treated advanced/metastatic or unresectable cholangiocarcinoma with an FGFR2 fusion based on results of an interim analysis of Study INCB 54828-202.

June 12, 2019 A meeting between Incyte and FDA was held to discuss the content and format of an anticipated NDA for pemigatinib based on data derived from Study INCB 54828-202.

August 8, 2019

A pre-NDA meeting was held to discuss a planned NDA submission for accelerated approval of pemigatinib, primarily based upon top-line results from Study INCB 54828-202, for the proposed indication ”for the treatment of adult patients with previously treated, advanced/metastatic or surgically unresectable cholangiocarcinoma with an FGFR2 rearrangement or fusion”. Top-line results included data from 107 patients enrolled in Cohort A of Study INCB 54828-202 based on a data cutoff date of March 22, 2019. Incyte proposed to provide a minimum of 6 months follow-up from the time of initial




Date Event

response for 35/38 (92%) of the currently known confirmed responders, and additional follow-up data for duration of response at the 4-month safety update to provide a minimum of 12 months of follow-up for all patients in the efficacy analysis set including a minimum of 6 months’ follow-up from the time of initial response for all confirmed responders.

FDA agreed that the proposed data package could support filing of an NDA under the provisions of accelerated approval for the proposed indication.

Source: reviewer table

Table 2. NDA Submission Regulatory History

Date Event

September 30, 2019

Incyte submitted original NDA 213736. This NDA included a request for categorical exclusion from environmental assessment, and a request for waiver of in vivo bioavailability studies for pemigatinib 9 mg and 13.5 mg tablets.

October 1, 2019 Incyte submitted a request for Proprietary Name Review for the proposed name Pemazyre.

October 1, 2019 Incyte submitted a Request for Priority Review.

November 26, 2019 FDA granted priority review.

December 17, 2019 Division of Medication Error Prevention and Analysis (DMEPA) issued a Proprietary Name Request, Conditionally Acceptable letter.

January 8, 2020 A mid-cycle communication meeting was held with Incyte.

January 17, 2020 A mid-cycle communication Advice-Information Request letter was issued to Incyte.



(b) (4)

(b) (4)


4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety

Office of Scientific Investigations (OSI)

Site inspections were conducted for Incyte Corporation and 3 clinical sites (Table 3. Diagnostic testing performed centrally to determine cohort assignment and reported tumor response data were verifiable with information and documents available at the sponsor’s site. No major deficiencies were identified and the Office of Scientific Investigations concluded that the clinical data generated from the three investigator sites and submitted to the NDA by Incyte appear to be reliable and supportive of this NDA and the proposed indication for pemigatinib.

Table 3. Clinical Sites for Inspection

Site/Investigator Safety Population Reason for Site Selection

Site 012 Vaibhav Sahai University of Michigan Rogel Cancer Center Ann Arbor, MI

8 Site 012 was selected due to enrollment of large numbers of patients.

Site 018 Raed Al-Rajabi University of Kansas Medical Center Westwood, KS

7 Site 018 was selected due to enrollment of large numbers of patients and financial disclosure

.

Site 020 David Gallinson Summit Medical Group Florham, NJ

4 Site 020 was selected due to high treatment effect and financial disclosure .

Product Quality

The Office of Pharmaceutical Quality (OPQ) did not identify any product quality issues that would preclude approval of pemigatinib capsules under this NDA. Please refer to the OPQ review of this application for additional information. No safety or efficacy concerns were identified during this review that related to Chemistry, Manufacturing, and Controls (CMC).

Pursuant to 21 CFR 25.31(b), Incyte submitted a Request for Categorical Exclusion from the preparation of an environmental assessment for pemigatinib and submitted environmental assessment data to support this request. OPQ determined that this request could be granted, as the estimated concentration of the drug substance at the point of entry into the aquatic




environment (EIC) is projected to be (b) (4) less than the 1 ppb limit that allows an exclusion to be granted.

Clinical Microbiology

This NDA was reviewed by OPQ’s Division of Microbiology Assessment. The microbiology reviewers did not identify any issues that would preclude approval of pemigatinib tablets. Pemigatinib should be stored at room temperature 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F).

Devices and Companion Diagnostic Issues

Foundation Medicine submitted a supplemental Premarket Approval (sPMA) application to Center of Devices and Radiological health for a companion diagnostic test, Foundation Medicine CDx, for the selection of patients with FGFR2 fusions or select rearrangements for treatment with pemigatinib. The device will receive marketing approval concurrent with approval of this NDA.




5 Nonclinical Pharmacology/Toxicology

Executive Summary

Pemigatinib (INCB054828) is a kinase inhibitor that has activity against fibroblast growth factor receptor 1 (FGFR1), FGFR2, and FGFR3 at concentrations (0.39-1.2 nM) that have been achieved at the 13.5 mg dose level used in clinical trials conducted to support the approval of the drug (free Cmax of approximately 22 nM based on ~91% protein binding). Pemigatinib also inhibited the kinase activity of FGFR4 at an IC50 of 30 nM. FGFR is a receptor tyrosine kinase involved in angiogenesis, cell proliferation, survival, and migration. Aberrant FGFR signaling resulting from gene amplification or mutation, chromosomal rearrangements, or ligand-dependent receptor activation has been demonstrated in numerous human cancers. While pemigatinib showed biochemical inhibition of vascular endothelial growth factor receptor 2 (VEGFR2; IC50 = 71 nM) at relatively low concentrations, follow-up studies in cell lines did not confirm this activity and pemigatinib did not exhibit substantial off-target activity against other targets in a kinase screen or in in vitro secondary pharmacology screens.

Treatment with pemigatinib inhibited in vitro and in vivo FGFR phosphorylation in FGFR2amplified human gastric cancer cells and inhibited in vitro FGFR phosphorylation in Ba/F3 cells stably expressing TEL-FGFR1 or TEL-FGFR3 fusion proteins and in FGFR2-amplified cells spiked with human whole blood. Pemigatinib also reduced the phosphorylation of FGFR1 and the downstream signaling proteins ERK1/2 and STAT5 in cells expressing the constitutively active FGFR1OP2-FGFR1 fusion protein. Consistent with these findings, incubation with pemigatinib inhibited the in vitro viability of cancer cell lines with FGFR1 or FGFR2 amplification; FGFR1, FGFR2, or FGFR3 fusions; and FGFR3 translocations at clinically relevant concentrations but did not substantially inhibit the viability of cells without FGFR alterations, including human T cells, suggesting that the effects of pemigatinib on cell growth are selective for cells dependent on FGFR pathway signaling. Notably, pemigatinib inhibited the in vitro viability of two Ba/F3 cell lines expressing fusions (FGFR2-CCDC6 and FGFR2-AHCYL) identified in responsive patients with cholangiocarcinoma enrolled in pemigatinib clinical trials. Pemigatinib exhibited in vivo anti-tumor activity in mice bearing subcutaneous (SC) human xenografts with FGFR1, FGFR2, or FGFR3 activation, including patient-derived cholangiocarcinoma xenografts expressing a FGFR2TRA2B fusion and FGFR2-amplified human gastric cancer xenografts. Pemigatinib doses ≥3 mg/kg were generally not tolerated in mice due to ≥20% body weight loss. Consistent with its mechanism of action, single oral administration of pemigatinib resulted in a dose-dependent increase in serum phosphate levels in mice.

Pemigatinib inhibited the hERG potassium current with an IC50 >8 µM, which is not clinically achievable at the recommended dose of 13.5 mg. Consistent with this in vitro finding, pemigatinib did not induce QTc prolongation in a single-dose safety pharmacology study in cynomolgus monkeys or in the 13-week repeat-dose study in monkeys. Single oral




administration of 10 mg/kg pemigatinib resulted in piloerection, increased touch response, and transient effects on respiratory frequency in Sprague-Dawley rats, but did not adversely affect central nervous system (CNS) or respiratory parameters.

There were no unique human metabolites detected in vitro in hepatic microsomes in the presence or absence of metabolic activation and no major metabolites detected in humans at levels ≥10% of the parent that might require further toxicological assessment. Following single oral administration, 14C-pemigatinib-derived radioactivity distributed widely to rat tissues especially excretory, endocrine, alimentary canal, and pigmented tissues, but only minimally in CNS tissues.

The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration. Pemigatinib induced multi-organ histologic mononuclear cell infiltration in both species. Many of the pemigatinib-induced findings (e.g. hyperphosphatemia, mineralization, physeal dysplasia, and bone/teeth findings) were attributable to the primary pharmacology of FGFR inhibition. For example, consistent with the role of FGF/FGFR signaling in bone development/diseases and the maintenance of adult bone homeostasis, pemigatinib induced bone toxicity in rats and monkeys at exposures approximately 0.4 and 0.04 times, respectively, those achieved clinically at the recommended human dose of 13.5 mg. Pemigatinib induced physeal and cartilage dysplasia in the sternum, femur, and/or vertebral bone in both species. Additional bone findings in rats included increased remodeling, hyperostosis, and necrosis in the femur; cartilage degeneration, hyperostosis, inflammation, and necrosis in the vertebral bone; and teeth findings including dysplasia (complete loss of ameloblasts), increased bone remodeling, and missing upper incisors. Physeal/cartilage dysplasia in the femur and/or sternum and histologic findings in the teeth did not show evidence of complete recovery. Additional tooth-related findings developed in rats during the recovery period including malaligned, whitened, broken, and trimmed/thinned incisors. The Applicant has not reported drug-related fractures or tooth abnormalities in clinical trials and pemigatinib-induced physeal dysplasia and teeth findings are unlikely to be relevant to human adults with closed growth plates; however, these findings may be relevant in pediatric patients and are included in Section 8.4 of the label.

In the 3-month toxicology study in rats, administration of pemigatinib at the high dose of 1.05 mg/kg (which resulted in exposures approximately 1.5 times the human exposure based on steady-state AUC0-24h of 2620 nM*hour at the clinical dose of 13.5 mg once daily) resulted in mortality due to systemic drug-related toxicity and poor clinical condition (reduced body weight/food consumption and clinical signs including dermal atonia, thinness, unkempt appearance, soft feces/diarrhea, dried and/or wet red/yellow/clear material on various body surfaces, pale extremities, and/or impaired use of hindlimb). The cause of death in one preterm decedent was marked chronic active inflammation in the kidneys likely secondary to uroliths in the urinary bladder; tubule dilation was also present in animals at lower dose levels. Histologic findings in high dose preterm decedents were generally similar to those seen in high dose rats that survived to scheduled necropsy. Another high dose rat exhibited intussusception in the




colon and jejunum and a distended/gas-filled cecum. Two early mortalities occurred at the low (0.27 mg/kg) dose level; the cause of death was undetermined, but one of the early decedents exhibited impaired use of hindlimb(s) and yellow material on various body surfaces. Treatment with ≥0.27 mg/kg pemigatinib (approximately 0.4 times the exposure based on AUC at the human dose of 13.5 mg) induced hyperphosphatemia in rats, which correlated with firm/white areas in the aorta and vena cava and multi-organ histologic soft tissue and vascular mineralization. Mineralization was still present following 42 days of recovery and is consistent with the role of FGFR in phosphorous metabolism. Increased calcium was also present at the 1.05 mg/kg dose level. Pemigatinib induced hyperphosphatemia/hypophosphatemia and dysregulated calcium in the clinic. Other target organs of pemigatinib toxicity in rats included the eye (bilateral corneal crystals), heart (cardiomyopathy and cartilaginous metaplasia), liver (increased alkaline phosphatase, congestion, and hepatocellular necrosis/vacuolation), lungs (alveolar macrophages), bone marrow in the femur (fibrosis and decreased cellularity), and spinal cord (increased severity of axonal degeneration).

Ocular toxicity, primarily dry eye and serous retinal detachment, has occurred in patients who received pemigatinib. While the Applicant did not record serous retinal detachment in animal studies, there are literature reports supporting a role for basic fibroblast growth factor and FGFR/MAPK signaling in protecting/maintaining retinal pigment epithelial cells (Faktorovich, Steinberg, et al. 1990 and 1992; Guillonneau, Bryckaert, et al. 1998; Rosenthal, Malek, et al. 2005; and Van der Noll, Leijen, et al. 2013). FGF and/or FGFR play a key role in lens, corneal, and retina development and adult function (Rosenthal, Malek, et al. 2005; Zhang, Upadhya, et al. 2015; and Robinson 2006). All four FGFR genes are expressed in the lens; FGFR1 and FGFR2 are also expressed in the retina and cornea. Ophthalmologic findings in the 28-day monkey study included moderate lens opacities and slight attenuation of retinal vessels at pemigatinib dose levels ≥0.33 mg/kg and 1 mg/kg, respectively. Intussusception was not seen in clinical trials.

In the 13-week toxicology study in cynomolgus monkeys, there was no mortality at doses up to the high dose level, 1 mg/kg. Treatment with ≥0.1 mg/kg pemigatinib resulted in dry skin, which was also observed in clinical studies. Treatment with 1 mg/kg pemigatinib (approximately 0.5 times the exposure based on AUC at the human dose of 13.5 mg) resulted in increased phosphorous and calcium, which correlated histologically with mineralization in the kidney and showed evidence of recovery. Increased ALT/AST occurred at the high dose level, but did not correlate with any histologic findings in the liver. Pemigatinib also induced mild histologic edema in the epididymis. In a non-GLP 10-day repeat-dose toxicology study in cynomolgus monkeys, at a dose level of 3 mg/kg (approximately 3.8 times the exposure based on AUC at the human dose of 13.5 mg) animals died beginning on Day 7. The preterm decedents exhibited body weight loss, hyperthermia, facial swelling, and decreased activity. The cause of death was not identified; however, pemigatinib induced multi-organ mineralization in these animals and histologic target organs included the kidney, pancreas, stomach, bone marrow, thymus, lymph node, and lung.




The Applicant did not conduct carcinogenicity or fertility studies, and these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer. Dose-related findings in reproductive organs in the general toxicology studies included inflammation in the prostate (rats) and edema in the epididymis (monkeys). Mineralization was also observed in the ovaries of rats and monkeys but was not clearly dose-related except for in the 10-day toxicity study in monkeys. Overall, data from the general toxicology studies do not suggest that pemigatinib will substantially impair male or female fertility. Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either the in vitro chromosomal aberration assay in human peripheral blood lymphocytes or the in vivo bone marrow micronucleus assay in rats. In addition, pemigatinib did not demonstrate phototoxic potential in an in vitro neutral red uptake phototoxicity assay.

The Applicant conducted a non-GLP dose range-finding embryo-fetal development study in Sprague-Dawley rats. Because this study demonstrated clear findings at exposure levels below the clinical exposure at the 13.5 mg human dose, this study was sufficient to characterize the potential developmental risk. Once daily oral administration of pemigatinib to pregnant rats during the period of organogenesis (gestation Days 6 to 17) resulted in reduced maternal body weight and food consumption at dose levels ≥0.3 mg/kg (approximately 0.6 times the exposure based on AUC at the human dose of 13.5 mg) accompanied by 100% post-implantation loss (early resorptions). The reduced maternal body weight appeared to be a result of fetal loss rather than maternal toxicity. At doses ≥0.1 mg/kg (approximately 0.2 times the exposure based on AUC at the human dose of 13.5 mg) there was reduced gravid uterine weight as well as a decrease in mean fetal body weight and an increase in fetal visceral (retroesophageal aortic arch) and skeletal (vertebral anomaly, only 12 pairs of ribs present) malformations, major blood vessel variations, and skeletal variations (reduced ossifications, 27 presacral vertebrae, 7th cervical rib, bent ribs). Thus, pemigatinib was teratogenic at exposures lower than those achieved in humans at the recommended dose. As a result, the pharmacology/toxicology review team recommends a warning for embryo-fetal toxicity in the US Prescribing Information (USPI) for PEMAZYRE. Consistent with the recommendations for teratogenic or embryo-lethal but non-genotoxic drugs described in the FDA Guidance for Industry Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations, and considering the pemigatinib half-life of 15.4 hours, FDA recommends advising males and females of reproductive potential to use effective contraception during treatment with PEMAZYRE and for at least one week after the final dose. The Applicant did not evaluate the presence of pemigatinib in milk; however, because of potential adverse effects of PEMAZYRE on a breastfeeding child, the review team recommends advising patients not to breastfeed during treatment with PEMAZYRE and for 1 week after the final dose. There are no outstanding issues from a pharmacology/toxicology perspective that would prevent the approval of PEMAZYRE for the treatment of patients with previously treated, locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or rearrangement as detected by an FDA-approved test.

Referenced NDAs, BLAs, DMFs

None




Pharmacology

Primary pharmacology

A. In Vitro Studies

The Applicant investigated whether 100 nM pemigatinib (INCB054828) inhibits 192 kinases in an in vitro (b) (4) Discovery Services Kinase Assay screen (Study #T13-05-06). Incubation with 100 nM pemigatinib inhibited FGFR1, FGFR2, FGFR2 N549H, FGFR3, FGFR3 K650E, and FGFR4 by 99%, 98%, 90%, 98%, 84% and 77%, respectively, but did not inhibit any of the other kinases tested by ≥50%. Of the non-FGFR kinases examined, pemigatinib showed the greatest inhibition of KDR (VEGFR2) and FLT4 (VEGFR3), with but with only 45% and 38% inhibition, respectively. In a second set of in vitro kinase profiling assays (Study #ATG-14.03.1) investigating 56 non-FGFR kinases, pemigatinib did not inhibit the majority of the kinases tested (IC50s ≥ 11201 nM). Pemigatinib inhibited VEGFR2, KIT, and PDGFRβ with IC50 values of 182, 266, and 1787 nM, respectively, suggesting some specificity for FGFR (see Table 4 for FGFR IC50 values).

The Applicant characterized the in vitro activity and selectivity of pemigatinib in biochemical and cellular assays (Study #IN VITRO-14.04.2). In an enzyme activity assay, pemigatinib inhibited the kinase activity of recombinant human FGFR1, FGFR2, and FGFR3 at IC50 concentrations (Table 4) lower than those achieved clinically at the 13.5 mg dose level of pemigatinib (free Cmax at the 13.5 mg clinical dose is approximately 22 nM based on ~90.6% protein binding), but inhibited recombinant human FGFR4 and VEGFR2 with IC50 values ≥30 nM. Pemigatinib inhibited recombinant human and rat FGFR1 and FGFR2 with similar affinity. Additional kinetic studies suggested that pemigatinib is an ATP competitive and reversible inhibitor of FGFR1 (data not shown).

Table 4: In Vitro Inhibition of Human and Rat FGFR Kinases and VEGFR2

(Applicant Table reproduced from Study #IN VITRO-14.04.2)

The Applicant evaluated the effects of pemigatinib on FGFR signaling in cellular assays. As assessed by enzyme-linked immunoassay (ELISA), incubation with pemigatinib for 4 hours inhibited FGFR2 phosphorylation in FGFR2-amplified KATOIII human gastric cancer cells with an




IC50 of 3.1 nM. As assessed by a bead based immunoassay, incubation with pemigatinib for 1 hour inhibited FGFR phosphorylation in Ba/F3 cells stably expressing TEL-FGFR1 or TEL-FGFR3 fusion proteins with IC50 values of 3.2 nM and 3.7 nM, respectively. Further, as assessed by immunoblotting, incubation with pemigatinib for 2 hours reduced the phosphorylation of FGFR1 (Y653/Y654) and the downstream signaling proteins ERK1/2 and STAT5 with an IC50 of ~2 nM in KG-1A cells expressing the constitutively active FGFR1OP2-FGFR1 fusion protein, indicating that pemigatinib inhibits FGFR1 signaling in vitro (data not shown). To evaluate the effect of pemigatinib on in vitro cell proliferation, investigators incubated cancer cells

cells with

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APPLICATION NUMBER · 2020. 5. 18. · Office of Clinical Pharmacology Reviewer(s) Robert Schuck,...

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