`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`761115Orig1s000
`
`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 BLA 761115
`TRODELVY, sacituzumab govitecan-hziy
`
`
`BLA Multi-Disciplinary Review and Evaluation
`Application Type BLA
`Application Number(s) 761115
`Priority or Standard Priority
`Submit Date(s) November 30, 2019
`Received Date(s) December 2, 2019
`PDUFA Goal Date
`June 2, 2020
`Division/Office Division of Oncology 1/Office of Oncologic Diseases
`Review Completion Date Electronic Stamp Date
`Established/Proper Name Sacituzumab govitecan
`(Proposed) Trade Name TRODELVY
`Pharmacologic Class Antibody Drug Conjugate (ADC)
`Code name
`IMMU-132
`Applicant
`Immunomedics, Inc.
`Doseage form
`Intravenous
`Applicant proposed Dosing
`10 mg/kg administered once weekly on days 1 and 8 of a 21-
`Regimen
`day treatment cycle
`Applicant Proposed
`TRODELVY is
`Indication(s)/Population(s)
`
`Applicant Proposed
`SNOMED CT Indication
`Disease Term for each
`Proposed Indication
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Recommended SNOMED
`CT Indication Disease
`Term for each Indication
`(if applicable)
`Recommended Dosing
`Regimen
`
`
`Version date: April 2, 2018
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`Reference ID: 4595750
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`
` for the treatment of patients with
`metastatic triple-negative breast cancer (mTNBC) who
` received at least two prior therapies for metastatic
`
`disease.
`Triple negative malignant neoplasm of breast
`
`Accelerated Approval
`
`TRODELVY is indicated for the treatment of adult patients with
`metastatic triple-negative breast cancer (mTNBC) who have
`received at least two prior therapies for metastatic disease.
`This indication is approved under accelerated approval based
`on tumor response rate and duration of response. Continued
`approval for this indication may be contingent upon verification
`and description of clinical benefit in confirmatory trials.
`Triple negative malignant neoplasm of breast
`
`10 mg/kg administered once weekly on days 1 and 8 of a 21-
`day treatment cycle
`
`1
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`(b) (4)
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`(b) (4)
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
`TRODELVY, sacituzumab govitecan-hziy
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`Table of Contents
`Table of Tables ................................................................................................................................ 4
`Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 5
`Glossary ........................................................................................................................................... 7
`1
`Executive Summary ................................................................................................................. 9
` Product Introduction ........................................................................................................ 9
` Conclusions on the Substantial Evidence of Effectiveness .............................................. 9
` Benefit-Risk Assessment ................................................................................................ 12
` Patient Experience Data ................................................................................................. 16
`Therapeutic Context .............................................................................................................. 17
` Analysis of Condition ...................................................................................................... 17
` Analysis of Current Treatment Options ......................................................................... 17
`Regulatory Background ......................................................................................................... 20
` U.S. Regulatory Actions and Marketing History ............................................................. 20
`Summary of Presubmission/Submission Regulatory Activity ........................................ 20
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................. 27
` Office of Scientific Investigations (OSI) .......................................................................... 27
` Product Quality .............................................................................................................. 29
` Clinical Microbiology ...................................................................................................... 30
`Devices and Companion Diagnostic Issues .................................................................... 30
`5 Nonclinical Pharmacology/Toxicology................................................................................... 31
` Executive Summary ........................................................................................................ 31
`Clinical Pharmacology ............................................................................................................ 31
` Executive Summary ........................................................................................................ 31
` Clinical Pharmacology Questions ............................................................................ 31
`Sources of Clinical Data and Review Strategy ....................................................................... 33
` Table of Clinical Studies .................................................................................................. 33
` Review Strategy .............................................................................................................. 35
`Statistical and Clinical and Evaluation ................................................................................... 37
` Review of Relevant Individual Trials Used to Support Efficacy ...................................... 37
` IMMU-132-01.......................................................................................................... 37
` Trial Results ............................................................................................................. 52
`8.1.3 Integrated Review of Effectiveness ........................................................................ 65
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
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`8.2
`
`8.1.4 Integrated Assessment of Effectiveness ................................................................. 66
`Review of Safety ............................................................................................................. 67
`8.2.1 Safety Review Approach ......................................................................................... 67
`8.2.2 Review of the Safety Database ............................................................................... 68
`8.2.3 Adequacy of Applicant’s Clinical Safety Assessments ............................................ 71
`8.2.4 Safety Results .......................................................................................................... 72
`8.2.5 Analysis of Submission-Specific Safety Issues ......................................................... 93
`8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ........ 95
`8.2.7 Safety Analyses by Demographic Subgroups .......................................................... 95
`8.2.8 Specific Safety Studies/Clinical Trials ...................................................................... 97
`8.2.9 Additional Safety Explorations ................................................................................ 97
`8.2.10
`Safety in the Postmarket Setting ..................................................................... 98
`8.2.11
`Integrated Assessment of Safety ..................................................................... 98
`Statistical Issues ............................................................................................................. 99
`8.3
`Conclusions and Recommendations .............................................................................. 99
`8.4
`9 Advisory Committee Meeting and Other External Consultations ....................................... 101
`10 Pediatrics ............................................................................................................................. 102
`11 Labeling Recommendations ................................................................................................ 103
`11.1
`Prescription Drug Labeling ....................................................................................... 103
`11.2
`Patient Labeling ........................................................................................................ 121
`12 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 123
`13 Postmarketing Requirements and Commitment ................................................................ 124
`14 Division Director (DHOT) ..................................................................................................... 127
`15 Division Director (OCP) ........................................................................................................ 127
`16 Division Director (OB) Comments ....................................................................................... 127
`17 Division Director (Clinical) Comments ................................................................................. 127
`18 Office Director (or designated signatory authority) Comments ......................................... 127
`19 Appendices .......................................................................................................................... 128
`19.1
`References ................................................................................................................ 128
`19.2
`Financial Disclosure .................................................................................................. 130
`19.3
`Additional Clinical Outcome Assessment Analyses .................................................. 131
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
`TRODELVY, sacituzumab govitecan-hziy
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`Table of Tables
`
`Table 1: Summary of Treatments Relevant to Proposed Indication ............................................ 19
`Table 2: Office of Scientific Investigations Site for IMMU-132-01 ............................................... 27
`Table 3. UGT1A1*28 Status by Sacituzumab Govitecan Starting Dose ........................................ 31
`Table 4. Listing of Clinical Trials Relevant to this NDA/BLA .......................................................... 34
`Table 5: Trial Calendar for IMMU-132-01 ..................................................................................... 41
`Table 6: Guidelines for Response Assessment and Censoring for Analysis of PFS ....................... 46
`Table 7: Guidelines for Response Assessment and Censoring for Analysis of DOR ..................... 47
`Table 8: Summary of Amendments to IMMU-132-01 .................................................................. 48
`Table 9: Patient Disposition for the mTNBC Population of IMMU-132-01 .................................. 53
`(cid:100)(cid:258)(cid:271)(cid:367)(cid:286) (cid:1005)(cid:1004)(cid:855) (cid:87)(cid:396)(cid:381)(cid:410)(cid:381)(cid:272)(cid:381)(cid:367) (cid:24)(cid:286)(cid:448)(cid:349)(cid:258)(cid:410)(cid:349)(cid:381)(cid:374)(cid:400) (cid:296)(cid:381)(cid:396) (cid:87)(cid:258)(cid:410)(cid:349)(cid:286)(cid:374)(cid:410)(cid:400) (cid:116)(cid:346)(cid:381) (cid:90)(cid:286)(cid:272)(cid:286)(cid:349)(cid:448)(cid:286)(cid:282) (cid:1096)(cid:1005) (cid:282)(cid:381)(cid:400)(cid:286) (cid:381)(cid:296) (cid:47)(cid:68)(cid:68)(cid:104)-132 ...................... 54
`Table 11: Protocol Deviations for the mTNBC Efficacy Population in IMMU-132-01 .................. 54
`Table 12: Demographic Data for the mTNBC Efficacy Population of IMMU-132-01 ................... 55
`Table 13: Pretreatment Disease Characteristics of the mTNBC Efficacy Population of IMMU-132-
`01 .................................................................................................................................................. 56
`Table 14: Concomitant Medications Used in >30% of Patients in the mTNBC Efficacy Population
`....................................................................................................................................................... 58
`Table 15: Primary Analysis of Confirmed ORR by Investigator ..................................................... 60
`Table 16: Sensitivity Analysis of Confirmed ORR by Double-Read ICR ......................................... 61
`Table 17: Concordance between Investigator and Double-Read ICR Assessment of ORR .......... 62
`Table 18: Exploratory Subgroup Analyses .................................................................................... 63
`Table 19: Tumor Types included in Trial IMMU-132-01 ............................................................... 68
`Table 20: Drug Exposure Summary in Trial ................................................................................... 69
`Table 21: Demographics of Safety Populations in IMMU-132-01 ................................................ 70
`Table 22: Death Narratives from IMMU-132-01 for the mTNBC Population ............................... 73
`Table 23: Death Narratives from IMMU-132-01 for the Safety Population ................................. 75
`Table 24: Serious Adverse Events in >2% of patients in IMMU-132-01 ....................................... 85
`(cid:100)(cid:258)(cid:271)(cid:367)(cid:286) (cid:1006)(cid:1009)(cid:855) (cid:68)(cid:381)(cid:400)(cid:410) (cid:18)(cid:381)(cid:373)(cid:373)(cid:381)(cid:374) (cid:894)(cid:1096)(cid:1005)(cid:1004)(cid:1081)(cid:895) (cid:4)(cid:282)(cid:448)(cid:286)(cid:396)(cid:400)(cid:286) (cid:28)(cid:448)(cid:286)(cid:374)(cid:410)(cid:400) (cid:349)(cid:374) (cid:47)(cid:68)(cid:68)(cid:104)-132-01 ............................................. 88
`Table 26: Grade 3-4 Laboratory Abnormalities in IMMU-132-01 ................................................ 90
`Table 27: Incidence of AEs by UGT1A1 Mutation Status in the Safety Population ...................... 94
`(cid:100)(cid:258)(cid:271)(cid:367)(cid:286) (cid:1006)(cid:1012)(cid:855) (cid:100)(cid:28)(cid:4)(cid:28)(cid:400) (cid:1096)(cid:1005)(cid:1004)(cid:1081) (cid:349)(cid:374) (cid:87)(cid:258)(cid:410)(cid:349)(cid:286)(cid:374)(cid:410)(cid:400) (cid:1096)(cid:1010)(cid:1009) (cid:455)(cid:286)(cid:258)(cid:396)(cid:400) ................................................................................. 96
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
`TRODELVY, sacituzumab govitecan-hziy
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`Reviewers of Multi-Disciplinary Review and Evaluation
`
`Regulatory Project Manager
`Jeannette Dinin
`Nonclinical Reviewer
`Kimberly Ringgold, PhD
`Nonclinical Team Leader
`Tiffany Ricks, PhD
`Office of Clinical Pharmacology Reviewer
`Salaheldin Hamed, PhD
`Office of Clinical Pharmacology Team Leader
`Pengfei Song, PhD
`Genomics Reviewer
`Sarah Dorff, PhD
`Genomics Team Leader
`Rosane Charlab Orbach, PhD
`Clinical Reviewer
`Sakar Wahby, PharmD
`Clinical Team Leader
`Christy Osgood, MD
`Statistical Reviewer
`Joyce Cheng, PhD
`Statistical Team Leader
`Mallorie Fiero, PhD
`Associate Director for Labeling
`William Pierce, PharmD, MPH
`Cross-Disciplinary Team Leader
`Christy Osgood, MD
`Division Director (OCP)
`Nam Atiqur Rahman, PhD
`Division Director (OB)
`Shenghui Tang, PhD
`Associate Division Director (DO1)
`Laleh Amiri-Kordestani, MD
`Office Director (or designated signatory authority) Richard Pazdur, MD
`
`
`Additional Reviewers of Application
`OPQ
`Anh-Thy Ly, PharmD
`Andrea Siegel, PhD
`Brian Janelsins, PhD
`Rohit Tiwari, PhD
`Wayne Seifert
`Hakim Ali Al, PhD
`Scott Dallas, RPh
`Candace Gomez-Broughton, PhD
`Maxwell Van Rassell, PhD
`Thuy Nguyen Thanh, DHSc
`Willie Wilson, PhD
`Qing Zhou, PhD
`Kathleen A Clouse Strebel, PhD
`Zhihao Peter Qiu, PhD
`Kevin Wright, PharmD
`Lauren Iacono-Connor, PhD/Susan Thompson, MD
`(Reviewers of initial BLA submission)
`Carolyn McCloskey
`Tingting N. Gao, PharmD
`Mei-Yean Chen, Elizabeth Everhart, Cynthia LaCivita
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`OSE/DEPI
`OSE/DMEPA
`OSE/DRISK
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`OPDP
`OSI
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`Sharon Mills, Kevin Wright, LaShawn M. Griffiths
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`Other
`Patient Labeling
`OPQ=Office of Pharmaceutical Quality
`OPDP=Office of Prescription Drug Promotion
`OSI=Office of Scientific Investigations
`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
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`Glossary
`
`
`AC
`ADME
`AE
`
`AR
`
`BLA
`
`BRF
`
`CBER
`
`CDER
`
`CDRH
`
`CDTL
`
`CFR
`
`CMC
`
`CR
`
`CRF
`
`CRO
`
`CRT
`
`CSR
`
`DHOT
`DMC
`
`ECG
`
`eCTD
`
`ETASU
`FDA
`
`FDAAA
`FDASIA
`GCP
`
`GRMP
`ICH
`
`IND
`
`ISE
`
`ISS
`
`ITT
`
`MBC
`
`MedDRA
`NCI-CTCAE
`NME
`
`OCS
`
`OPQ
`
`OSE
`
`OSI
`
`
`Version date: April 2, 2018
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`advisory committee
`absorption, distribution, metabolism, excretion
`adverse event
`adverse reaction
`biologics license application
`Benefit Risk Framework
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Cross-Discipline Team Leader
`Code of Federal Regulations
`chemistry, manufacturing, and controls
`Complete Response
`case report form
`contract research organization
`clinical review template
`clinical study report
`Division of Hematology Oncology Toxicology
`data monitoring committee
`electrocardiogram
`electronic common technical document
`elements to assure safe use
`Food and Drug Administration
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`good clinical practice
`good review management practice
`International Conference on Harmonization
`Investigational New Drug
`integrated summary of effectiveness
`integrated summary of safety
`intent to treat
`Metastatic breast cancer
`Medical Dictionary for Regulatory Activities
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`new molecular entity
`Office of Computational Science
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
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`
`PD
`
`PI
`
`PK
`
`PMC
`
`PMR
`
`PP
`
`PPI
`
`PREA
`
`PRO
`REMS
`SAE
`
`SAP
`
`SOC
`
`TEAE
`
`TNBC
`
`mTNBC
`
`
`pharmacodynamics
`prescribing information
`pharmacokinetics
`postmarketing commitment
`postmarketing requirement
`per protocol
`patient package insert (also known as Patient Information)
`Pediatric Research Equity Act
`patient reported outcome
`risk evaluation and mitigation strategy
`serious adverse event
`statistical analysis plan
`standard of care
`treatment emergent adverse event
`triple negative breast cancer
`metastatic triple negative breast cancer
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`
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`Version date: April 2, 2018
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
`TRODELVY, sacituzumab govitecan-hziy
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`1 Executive Summary
`
`1.1.
`
`Product Introduction
`
`Sacituzumab govitecan-hziy (TRODELVY) is an antibody-drug conjugate made up of SN-38, a
`topoisomerase I inhibitor that is the active metabolite of irinotecan, coupled by a CL2A linker to
`the humanized monoclona l antibody hRS7 lgGK which binds to Trop-2 (the trophoblast cell(cid:173)
`surface antigen-2). The chemical structure of sacituzumab govitecan-hziy is shown below.
`
`0
`
`Linker
`
`hRS71gGk
`(antibody)
`
`n
`
`Where n- 7.6
`SN-38/Mab
`
`Pharmacology data suggest that sacituzumab govitecan-hziy binds to Trop-2-expressing cancer
`cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38
`interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single
`strand breaks. The resu lting DNA damage leads to apoptosis and cell death. Sacituzumab
`govitecan-hziy decreased tumor growth in mouse xenograft models of triple negative breast
`cancer.
`
`Sacituzumab govitecan-hziy (TRODELVY) for injection is a sterile, preservative-free, off-white to
`yellowish lyophilized powder for intravenous use in a 50 ml clear glass single dose vial, with a
`rubber stopper and crimp-sealed with an aluminum flip-off cap. The proposed dosage for
`sacituzumab govitecan-hziy is 10 mg/kg administered as an intravenous infusion on days 1 and
`8 of a 21-day treatment cycle.
`
`1.2.
`
`Conclusions on the Substantial Evidence of Effectiveness
`
`The recommendation for the accelerated approval of sacituzumab govitecan-hziy, according to
`21 Code of Federal Regu lations (CFR), Part 601.41, Subpart E of the Biological Licensing
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
`TRODELVY, sacituzumab govitecan-hziy
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`Regulations, is based on efficacy and safety data from Trial IMMU-132-01.
`
`On May 18, 2018, Immunomedics, Inc., (Immunomedics), submitted original Biologics License
`Application (BLA) 761115 requesting marketing authorization for TRODELVY (sacituzumab
`govitecan) injection. In the BLA submission, Immunomedics sought accelerated approval for
`TRODELVY for the following indication:
`
`
` is indicated for the treatment of patients with
`SACITUZUMAB GOVITECAN,
`metastatic triple-negative breast cancer (mTNBC) who
` received at least two
`prior therapies for metastatic disease.
`
`
`The applicant submitted the results of Trial IMMU-132-01, a single-arm, multicenter (US only)
`trial of sacituzumab in patients with advanced solid tumor malignancies to support the BLA.
`Among the 420 patients who received sacituzumab at various doses, a total of 108 patients
`who enrolled and received the proposed dose of 10 mg/Kg had mTNBC and had received at
`least two prior lines of therapy in the metastatic setting; it is this subgroup of patients that
`comprises the efficacy population for this BLA. Based on a June 30, 2017, data cut-off, among
`the 108 patients in the efficacy population, the investigator-assessed ORR by RECIST 1.1 was
`33.3% (95% CI: 24.6, 43.1). The median duration of response (DOR) among responders was 7.7
`months (95% CI: 4.9, 10.8) per local investigator assessment based on a December 1, 2017, data
`cut-off. The ORR based on Independent central review (ICR) was performed on patients with
`tumor scans showing complete response, partial response, or at least 20% shrinkage by local
`site evaluation (n=55). Objective response rate based on this subgroup ICR was 32.4% (95% CI:
`23.7, 42.1) with a median DOR among responders of 9.1 months (95% CI: 4.6, 10.7) based on a
`December 1, 2017, data cut-off. This was supportive of the investigator-assessed response rate;
`however, results per ICR should be interpreted with caution given that this was based on
`assessment in a subgroup of patients.
`
`During review of the initial BLA submission, FDA identified several deficiencies in the chemistry,
`manufacturing, and controls (CMC) data package. FDA issued a complete response (CR) letter
`on January 17, 2019. On December 2, 2019, Immunomedics submitted a complete response to
`the CMC deficiencies. The submission also included an updated safety report of Trial IMMU-
`132-01 with a data cut-off date of March 1, 2019, to support the assessment of any significant
`changes or findings in the safety profile of sacituzumab.
`
`During review of the complete response submission, FDA learned that the confirmatory trial
`IMMU-132-05 was fully accrued and that topline results for the primary endpoint of
`progression free survival (PFS) may be available during the review of the complete response
`submission. An informal teleconference was held on January 9, 2020, during which
`Immunomedics stated that topline data would not be available during the BLA review cycle.
`Consequently, FDA requested Immunomedics to submit ORR and DOR data from both arms in
`order to support the efficacy observed in trial IMMU-132-01. To maintain data integrity for the
`ongoing trial, Immunomedics used an independent third-party statistician and put in access
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`(b) (4)
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`(b) (4)
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`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
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`restrictions so that their trial statisticians remained blinded to the results. IMMU-132-05 is a
`phase 3 trial of sacituzumab vs. treatment of physician’s choice (TPC) in patients with mTNBC
`(cid:258)(cid:296)(cid:410)(cid:286)(cid:396) (cid:1096)(cid:1006) (cid:393)(cid:396)(cid:349)(cid:381)(cid:396) (cid:272)(cid:346)(cid:286)(cid:373)(cid:381)(cid:410)(cid:346)(cid:286)(cid:396)(cid:258)(cid:393)(cid:349)(cid:286)(cid:400) (cid:296)(cid:381)(cid:396) (cid:258)(cid:282)(cid:448)(cid:258)(cid:374)(cid:272)(cid:286)(cid:282) (cid:282)(cid:349)(cid:400)(cid:286)(cid:258)(cid:400)(cid:286) (cid:381)(cid:396) (cid:1093)(cid:1005) (cid:410)(cid:346)(cid:286)(cid:396)(cid:258)(cid:393)(cid:455) (cid:296)(cid:381)(cid:396) (cid:393)(cid:410)(cid:400) (cid:449)(cid:346)(cid:381) (cid:393)(cid:396)(cid:381)(cid:336)(cid:396)(cid:286)(cid:400)(cid:400) (cid:449)(cid:349)(cid:410)(cid:346)(cid:349)(cid:374)
`12 months of adjuvant therapy. Patients were randomized 1:1 to receive either IMMU-132 or
`TPC from one of 4 prespecified single-agent regimens (capecitabine, eribulin, vinorelbine or
`gemcitabine). The primary endpoint is PFS as assessed by BICR. Secondary endpoints include
`overall survival (OS), ORR, DOR, safety and quality of life. As of the data cut off date of January
`31, 2020, the preliminary results showed that ORR and DOR by BICR were supportive of the
`efficacy of sacituzumab. Additionally, on April 2, 2020, the data safety monitoring committee
`(DSMC) recommended that Trial IMM-132-05 be halted due to evidence of “compelling
`efficacy.” FDA requested the topline results from the DSMC without individual-level data. The
`results further supports the efficacy of sacituzumab.
`
`The safety profile of sacituzumab is acceptable for the intended population. The most common
`adverse reactions (cid:894)(cid:1096)(cid:1006)5% in incidence: nausea, neutropenia, diarrhea, fatigue, anemia, vomiting,
`alopecia, constipation, rash, decreased appetite, and respiratory infection, abdominal pain) are
`manageable with monitoring, dose modifications, and supportive measures. Neutropenia was a
`common and serious toxicity observed in Trial IMMU-132-01 with one death due to
`neutropenic typhlitis. Diarrhea was also common and severe. Neutropenia and diarrhea are
`included in the “Warnings and Precautions” section of the prescribing information and as boxed
`warnings to provide adequate caution to prescribers regarding these toxicities, particularly in
`patients known to be homozygous for the UGT1A1*28 allele, who are at increased risk for
`neutropenia.
`
` Available therapies for patients with mTNBC who have received at least two prior therapies for
`metastatic disease are eribulin and ixabepilone. Ixabepilone as a single agent was approved
`with an investigator-assessed ORR of 18.3% (95% CI: 11.9, 26.1) and an ORR by central
`assessment of 12.4% (95% CI: 6.9, 19.9); median duration of response was 6.0 months (95% CI:
`5.0, 7.6) by central assessment. The ORR for patients receiving eribulin was 11% (95% CI: 8.6,
`14.3) and median duration of response of 4.2 months (95% CI: 3.8, 5.0). Therefore, the
`investigator-assessed ORR of 33.3% (95% CI: 24.6, 43.1) supported with a median DOR of 7.7
`months (95% CI: 4.9, 10.8) is a surrogate endpoint that is reasonably likely to predict clinical
`benefit (i.e., improved survival or progression free survival) and to be better than the available
`therapies.
`
`Applicant has adequately addressed all the CMC deficiencies outlined in the CR letter. Given the
`favorable benefit-risk profile, all disciplines were in agreement with accelerated approval of
`sacituzumab for the following indication:
`
`, is indicated for the treatment of patients with
`Sacituzumab govitecan-hziy,
`metastatic triple-negative breast cancer (mTNBC) who
` received at least two prior
`therapies for metastatic disease. Continued approval for this indication may be contingent
`upon verification and description of clinical benefit in confirmatory trials.
`
`
`Version date: April 2, 2018
`
`
`
`11
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`Reference ID: 4595750
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation BLA 761115
`TRODELVY, sacituzumab govitecan-hziy
`
`
`Benefit-Risk Assessment
`
`[Do not insert text here. Use the table]
`Benefit-Risk Summary and Assessment
`
`Approximately 20% of breast cancer diagnoses worldwide are deemed to be triple negative breast cancer (TNBC), which describes a subtype of
`breast cancer that has low expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor
`2 (HER2). This subtype of breast cancers is histologically and molecularly heterogenous. The TNBC subtype is more commonly diagnosed in
`women younger than 40 years compared with hormone-positive breast with a nearly two-fold higher attributable risk of TNBC in women under
`40 years compared with women over 50 years (odds ratio [OR] 2.13, 95% CI 1.34-3.39) [Trivers KF, et al; 2009]. In addition, TNBC appears to be
`more common among black women compared with white women, with a more than two-fold increase in incidence in the former. Other risk
`factors for the disease include the presence of BRCA mutation, premenopausal status, obesity, and maternal related factors such as parity and
`age at first pregnancy.
`
`Metastatic triple negative breast cancer (mTNBC) is incurable. It is a disease with a poor prognosis with a median survival of approximately 13.3
`months (Kassam, F et al; 2009). Chemotherapy is the mainstay of treatment of TNBC and in general, patients first receive standard
`chemotherapy regimens that include taxane or anthracycline- containing combinations in the neoadjuvant and adjuvant settings. Because the
`major cause of disease progression in the metastatic setting is multidrug resistance (either primary or acquired), following progression on these
`regimens, and in the metastatic setting, patients may receive agents thought to not be cross-resistant (e.g., capecitabine, gemcitabine,
`vinorelbine or albumin-bound paclitaxel, and combination regimens). For patients whose tumors are PD-L1 positive atezolizumab in
`combination with nab-paclitaxel is available under accelerated approval. There is no preferred or standard regimen used. In patients who have
`previously received anthracycline- and/or taxane based treatment, sequential, single agent chemotherapy is typically used, with multi-agent
`regimens reserved for patients who present with visceral crisis. For the approximately 20% of patients with TNBC who harbor a germline BRCA
`1 or 2 mutation, the poly ADP-ribose polymerase (PARP) inhibitors olaparib and talazoparib have been approved for patients who have been
`previously treated with chemotherapy.
`
`Treatment options are limited for patients who have received two or more regimens in the metastatic setting. FDA-approved therapies that
`constitute available therapies in this setting are eribulin and ixabepilone. Eribulin was approved in the third-line metastatic setting based on an
`improvement in OS of less than 3 months (13.1 months versus 10.6 months; HR 0.81; 95% CI: 0.66, 0.99) in a randomized controlled trial of 762
`patients who had received at least two prior lines of therapy compared to physician’s choice c