761163Orig1s000

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

761163Orig1s000

OTHER REVIEW(S) Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy

PATIENT LABELING REVIEW

Date: July 10, 2020

To: Jennifer Lee, PharmD Senior Regulatory Health Project Manager Division of Hematologic Malignancies 2 (DHM2)

Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP)

Barbara Fuller, RN, MSN, CWOCN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP)

From: Ruth Mayrosh, PharmD Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Nisha Patel, PharmD Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Patient Package Insert (PPI)

Drug Name (established MONJUVI (tafasitamab-cxix) name): Dosage Form and for injection, for intravenous use Route: Application BLA 761163 Type/Number: Applicant: MorphoSys US Inc.

Reference ID: 4639014 1 INTRODUCTION On December 30, 2019, MorphoSys US Inc. submitted for the Agency’s review an original Biologics License Application (BLA) 761163 for MONJUVI (tafasitamab- cxix) for injection. The proposed indication for MONJUVI (tafasitamab-cxix) for injection is in combination with lenalidomide followed by MONJUVI (tafasitamab- cxix) monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade (b) (4) lymphoma, and who are not eligible for, autologous stem cell transplant (ASCT). This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Hematologic Malignancies 2 (DHM2) on June 1, 2020 and January 22, 2020, respectively, for DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI) for MONJUVI (tafasitamab-cxix) for injection.

2 MATERIAL REVIEWED • Draft MONJUVI (tafasitamab-cxix) for injection PPI received on June 1, 2020, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on July 1, 2020. • Draft MONJUVI (tafasitamab-cxix) for injection Prescribing Information (PI) received on December 30, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on July 1, 2020.

3 REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. We reformatted the PPI document using the Arial font, size 10. In our collaborative review of the PPI we: • simplified wording and clarified concepts where possible • ensured that the PPI is consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the PPI is free of promotional language or suggested revisions to ensure that it is free of promotional language

Reference ID: 4639014 • ensured that the PPI meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

4 CONCLUSIONS The PPI is acceptable with our recommended changes.

5 RECOMMENDATIONS • Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. • Our collaborative review of the PPI is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the PPI. Please let us know if you have any questions.

4 Pages of Draft Labeling have been Withheld in Full as B4(CCI/TS) Immediately Following this Page

Reference ID: 4639014 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

RUTH I MAYROSH 07/10/2020 11:15:45 AM

NISHA PATEL 07/10/2020 11:18:55 AM

BARBARA A FULLER 07/10/2020 11:32:27 AM

LASHAWN M GRIFFITHS 07/10/2020 11:51:23 AM

Reference ID: 4639014 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information****

Memorandum

Date: July 2, 2020

To: Jennifer Lee, Regulatory Project Manager Division of Hematologic Malignancies 2 (DHM2)

Stacy Shord, Associate Director for Labeling, DHM2

From: Nisha Patel, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

CC: Trung-Hieu (Brian) Tran, Team Leader, OPDP

Subject: OPDP Labeling Comments for MONJUVI (tafasitamab-cxix) for injection, for intravenous use

BLA: 761163

In response to DHM2’s consult request dated January 22, 2020, OPDP has reviewed the proposed product labeling (PI) and patient package insert (PPI) for the original BLA submission for MONJUVI (tafasitamab-cxix) for injection, for intravenous use (Monjuvi).

PI and PPI: OPDP’s comments on the proposed labeling are based on the draft PI emailed to OPDP on June 30, 2020, and are provided below.

A combined OPDP and Division of Medical Policy Programs (DMPP) review will be completed, and comments on the proposed PPI will be sent under separate cover.

Thank you for your consult. If you have any questions, please contact Nisha Patel at (301) 796-3715 or [email protected].

15 Pages of Draft Labeling have been Withheld in Full as B4(CCI/TS) Immediately Following this Page

Reference ID: 4635333 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

NISHA PATEL 07/02/2020 02:04:03 PM

Reference ID: 4635333 Clinical Inspection Summary BLA 761163 tafasitamab

CLINICAL INSPECTION SUMMARY

Date June 30, 2020 From Anthony Orencia M.D., F.A.C.P., Medical Officer Min Lu, M.D., M.P.H., Team Leader Kassa Ayalew, M.D., M.P.H., Branch Chief Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations To Alexandria Schwarsin, M.D., Medical Officer Bindu Kanapuru, M.D., Cross Discipline Team Leader Nicole Gormley, M.D., Acting Director Jennifer Lee, Pharm.D., Senior Regulatory Project Manager Division of Hematology Malignancy 2 Office of Oncologic Diseases BLA 761163 Applicant MorphoSys US Inc. Drug Monjuvi (tafasitamab) NME Yes Division Classification Monoclonal Antibody Proposed Indication Treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) Consultation Request Date January 30, 2020 (Priority Review) Summary Goal Date June 30, 2020 (original request: June 1, 2020) Action Goal Date July 30, 2020 PDUFA Date August 30, 2020

I. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS

(b) (4) A single clinical investigator site (Johannes Duell, M.D.), (contract research organization [CRO] for Study MOR208C203), (b) (4) (CRO for Study MOR208C206) (b) (4) , and MorphoSys (sponsor) were part of a remote site data investigation in support of BLA 761163.

At the current time, the COVID-19 global pandemic has significantly limited our ability to conduct on-site GCP investigations. As a result, a remote investigation was conducted using a WebEx platform for meetings, and review of original records that were uploaded to a secure box account licensed to the FDA for the investigation.

Based on the investigations, the study data derived from Dr. Duell’s clinical site are considered reliable. There were no significant investigational findings for the Sponsor (MorphoSys) and CROs (b) (4) .

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II. BACKGROUND

Tafasitamab (MOR00208 [XmAb®5574]) is an Fc-engineered monoclonal antibody (mAb) that binds to the human B-cell surface antigen CD19. MOR00208 has been shown to significantly enhance in vitro antigen-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and direct cytotoxic effects (apoptosis) on CD19+ tumor cell lines spanning a broad range of human lymphomas and leukemias.

The sponsor proposes tafasitamab, in combination with lenalidomide followed by tafasitamab monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade lymphoma, and who are not eligible for, (b) (4) autologous stem cell transplant (ASCT). A single-arm, open-label study (Study MOR208C203), in part, forms the basis for the regulatory decision-making process for this application.

As an auxiliary component, in part, of the applicant’s tafasitamab submission, a retrospective study was conducted to observe the isolated effect of lenalidomide. Thus, the applicant submitted an observational retrospective study (Study MOR208C206) of supportive evidence of the single agent activity of lenalidomide.

These study protocols are:

1) Study MOR208C203 (L-MIND), entitled “A Phase II, Single-Arm, Open-Label, Multicentre Study to Evaluate the Safety and Efficacy of Lenalidomide Combined with MOR00208 in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R-R DLBCL)”, and

2) Study MOR208C206 (REMIND), entitled “An Observational Retrospective Cohort Study of Lenalidomide Monotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) to Generate a Historical Control for Clinical Trial MOR208C203”.

Phase 2 Single-Arm Open-Label Study MOR208C203 (L-MIND)

Study MOR208C203 was a Phase 2, single-arm, open-label study of lenalidomide combined with tafasitamab in adult patients with diffuse large B-cell lymphoma, who had relapsed after or were refractory to at least one, but no more than three previous systemic regimens administered for the treatment of their diffuse large B-cell lymphoma, and who were not candidates for high-dose chemotherapy and subsequent autologous stem cell transplantation. These subjects were considered to have exhausted their therapeutic options. One prior therapy line had to include an anti-CD20 targeted therapy (e.g., rituximab).

Tafasitamab and lenalidomide were administered for up to 12 cycles (28 days each), followed by tafasitamab monotherapy until progression, in patients with at least stable disease or a better response.

Reference ID: 4633606 Page 3 Clinical Audit Summary BLA 761163 (tafasitamab)

The primary study objective for this clinical investigational evaluation was to determine the treatment response of the drug combination of lenalidomide with tafasitamab in adult patients with relapsed/refractory diffuse large B-cell lymphoma.

The primary efficacy endpoint of interest was treatment response in all subjects. Objective response rate (ORR) comprised complete response [CR] + partial response [PR].

Disease response assessments were evaluated according to the revised response criteria for malignant lymphoma, based on the guidelines of the International Working Group (IWG, as reported by Cheson et al.,2007) and based on a central review (radiological + clinical) of the disease assessments.

Study MOR208C203 was conducted at 35 centers screened and enrolled patients in up to 10 countries outside the U.S. The study period extended from March 29, 2016 to November 30, 2018 (analysis cut- off date). A total of 81 subjects were enrolled, of whom 81 patients received both tafasitamab and lenalidomide, and one patient received only tafasitamab.

Observational Retrospective Study MOR208C206

Study MOR208C206 was an observational, retrospective, cohort study that was designed to characterize the effectiveness of lenalidomide monotherapy in the treatment of relapsed or refractory diffuse large B-cell lymphoma patients not eligible for high dose chemotherapy followed by autologous stem cell transplant.

Eligible patients were identified from sites selected according to geographic distribution and data completeness/quality in about 500 available patients. Of 490 enrolled patients, 348 were included in the Full Analysis Set, and 76 in the Matched Analysis Set.

Data were collected retrospectively from health records of patients in either real world, compassionate use or clinical trial setting. Specifically, patient records originated from academic institutes, national/international study groups, single centers, health networks, commercial databases, and research consortiums (henceforth referred to as “sites”). Source documents consisted of electronic or paper health records (including scans) of patients identified.

The observational study consisted of adult patients with relapsed or refractory diffuse large B-cell lymphoma, who were not eligible for high dose chemotherapy followed by autologous stem cell transplant who were treated with lenalidomide monotherapy.

Following data collection, lenalidomide monotherapy was compared with the efficacy outcomes of tafasitamab-lenalidomide combination therapy using a propensity score-based analytical methodology.

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III. RESULTS (by site)

1. Johannes Duell, M.D./ Site 38003 Universitaetsklinikum Wuerzburg Zentrum fuer Innere Medizin Medizinische Klink und Poliklinik II Oberdürrbacher Straße 6 97080 Wurzburg, Germany

Remote study site investigation dates under FDA ORA Operations Code 15: May 20–29, 2020.

For Study MOR208C203 (L-MIND), a total of seven subjects were screened and enrolled at the site. Seven study subjects received study drug, but only two study patients are in follow- up. For those not in follow-up who received study treatment drug: four patients refused further follow-up, and one patient who developed progressive disease subsequently died. All enrolled study subjects’ records were reviewed.

Source documents were reviewed for study eligibility, review/approval, monitoring, test article accountability, concomitant medication, and adverse event/serious adverse event reporting; radiology documents such as PET-CT scans were made available to the field investigation staff as part of the primary efficacy raw data endpoint remoted site assessment. Records were in German and English. Some translation service was provided by a Sponsor/CRO employee who had not been involved in this study.

A sampling of source documents was verified, in part, for this remote study site assessment versus the sponsor data line listings submitted to the Agency. There were no limitations during conduct of the clinical investigation.

The primary efficacy endpoint, as assessed by the principal investigator, was verifiable at the study site. There was no under-reporting of adverse events.

In general, this clinical investigator appeared to be in compliance with Good Clinical Practice.

2. MorphoSys AG Semmelweisstr. 7 82152 Planegg Germany

Remote site investigation dates under FDA ORA Operations Code 15: May 26 – June 03, 2020

This investigation principally evaluated compliance with the sponsor’s responsibilities concerning the conduct of Study MOR208C203.

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The remote investigation included review of organizational charts, transfer of obligations, investigator agreements, and financial disclosures with the sponsor. FDA ORA International Headquarters conducted a remote desktop assessment capacity. Sections of electronic trial master files were further reviewed and made available to ORA field staff to evaluate monitoring plans, monitoring reports, monitor qualifications, safety reports, adverse events, protocol deviations, and standard operating procedures. No underreporting of significant adverse events (SAEs) to the Agency was noted. During this remote site engagement with FDA, the investigational staff did not encounter any barriers to their evaluation.

At the end of the remote audit assessment, some isolated observations and concerns that required clarifications were discussed verbally with the sponsor during the close out meeting. Specifically, the following findings were discussed:

A. Inadequate monitoring: monitors failed to identify site/clinical investigator noncompliance and bring about corrective actions for subject ineligibility and investigational product dosing errors (see examples below).

1) Eligible subjects who failed to meet inclusion and/or exclusion criteria prior to randomization and treatment were not identified during the periodic monitoring.

Subject # Inclusion / Exclusion criteria Comments (b) (6) Exclusion criteria 1b Exclusion criteria 1b The review division Exclusion criteria 1b may choose to Exclusion criteria 1b consider these subjects Exclusion criteria 1b and Inclusion criteria 4a as protocol deviations Inclusion criteria 3 during analysis Exclusion criteria 2d Key to Inclusion / Exclusion criteria: Exclusion criteria 1b: primary refractory DLBCL Inclusion criteria 3: Tumor sample sent to the central pathology lab greater than 3 months Inclusion criteria 4a: Relapsed/refractory disease criteria not met Inclusion criteria 2d: IV antibiotics administered within 14 days of treatment C1D1 Patients in Study MOR208C203 listed above were considered analysis eligible for the primary study endpoint, that included the proportion of complete responders and partial responders

OSI Reviewer’s Comments: The sponsor monitoring obligations had been transferred to the CRO (b) (4) in writing. Therefore, the contract research organization (b) (4) is the one that would be responsible for monitoring. The Sponsor acknowledged the above observations and provided adequate written response.

The monitors should have properly identified listed the subjects who did not meet inclusion and/or exclusion criteria prior to randomization and treatment to the sponsor. The observed violation may not have significant impact on the safety and welfare of the above subjects. They do not also appear to impact on data reliability or safety because they were isolated. However, the review division may choose to consider those subjects as protocol deviations during analysis.

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Examples of isolated dosing errors for study subjects mainly in the first three treatment cycle who were not identified during periodic monitoring:

Subject # Dosing Error Comments (b) (6) C2D1 underdose C23D15 underdose C17D15 and C18D1 underdose Within treatment compliance dosage range* C3D8 overdose, C3D15 overdose, and C16D1 underdose C27D15 overdose Patient received 780mg instead of 770mg *Per Study MOR208C203 Section 6.8: A patient will be considered treatment compliant with the protocol, if the lenalidomide dose was dose was administered is ≥80% to ≤120% of the assigned dosage during a particular cycle.

In addition, the sponsor and CRO (b) (4) co-monitoring visit report for site 10004, conducted in 2017 showed that a site monitor failed to ensure that the clinical investigator obtained pregnancy prevention plans from each study subject prior to enrollment and at each site visit.

OSI Reviewer’s Comments: The Sponsor acknowledged the above observations and provided adequate written response. The sponsor monitoring obligations had (b) (4) been transferred to the CRO .

Although the CRO(b) (4) failed to conduct adequate monitoring of the study and assure timeliness of dosing errors reporting to the sponsor, based on our review of the investigation report and the Applicant’s response, the finding is unlikely to impact data reliability, nor compromise the rights, safety and welfare of subjects in the study.

B. Inadequate Drug Accountability: The Sponsor failed to recognize the accurate status of drugs Allocated, Used/Unused by Patients, or Damaged. Specifically, a review of Investigational Kit History Reports revealed that at least seven subjects from five clinical trial sites (b) (6) , (b) (6) ) were recorded as having “Allocated Not Given” – “Unused by Patient.

OSI Reviewer’s Comments: The sponsor did transfer its responsibility for drug accountability to (b) (4) in writing. Based on OSI’s review of the investigation report and the sponsor’s response, all subjects appeared to have adequate drug accountability information. Therefore, the observation is unlikely to impact study data reliability, nor did it compromise the rights, safety and welfare of subjects.

The sponsor response and preliminary results from the remote investigation were discussed and shared with DMH2. Although some observations were noted, the sponsor appeared to have ensured adequate oversight of the two clinical trials, MOR208C203 and MOR208C206. The data from MOR208C203 and MOR208C206 submitted to the Agency in support of this application, appear reliable.

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(b) (4) 3.

CRO for Phase 2, Single-Arm, Open-Label Study MOR208C203

Remote site investigation dates under FDA ORA Operations Code15: May 19–29, 2020

This investigation principally evaluated compliance with the sponsor’s transferred responsibilities to (b) (4) as CRO concerning the conduct of Study MOR208C203 (L-MIND), a Phase 2 Single-Arm Open-Label Study.

Prior to(b) (4) , the CRO was (b) (4) responsible for site selection and site initiation. (b) (4) took over and initiated the remainder of the sites. (b) (4) conducted every monitoring visit for each site as the first subject of the study was enrolled during the transition period from (b) (4) .

At each initiation visit, the (b) (4) monitor reviewed the study protocol, the eCRF and EDC system, proper source documentation, the Investigator’s Brochure, investigator obligations, regulatory files, informed consent procedures, AE/SAE reporting procedures, and study product accountability/storage procedures with the investigator and other site personnel. Additionally, (b) (4) conducted necessary study-specific training at site visits. While (b) (4) previously initiated a total of 35 sites,(b) (4) assumed 22 site initiations out of the 57 sites. Monitoring plans in effect stated that (b) (4) clinical research associates performed 100% source data verification.

The remote investigation included review of firm organization for research and monitoring activities; transfer of responsibility from sponsor to CRO; vendor contracts for study-related services; SOPs related to selection and monitoring of study sites; monitoring SOPs and monitor qualifications for the study; SOPs related to the collection and handling of study- related data; computer system validation plans and related SOPs, and investigator financial disclosure forms as well as the electronic trial master file (eTMF).

The remote site audit also evaluated routine site visit monitoring reports, medical monitoring procedures (especially with regards to the retrospective eligibility review performed on study subjects, e.g., inclusion and exclusion deviations or violations), data handling and control during transfers (e.g., imaging and safety data), CRO qualifications, safety reports, adverse events, protocol deviations, and standard operating procedures.

During the remote site audit, transfer of CRO responsibilities from (b) (4) overlapped and appeared seamless. FDA focused on the assessment of all the protocol deviations, communications, regulatory documents, adverse event and serious adverse event reporting, and related monitoring reports. The Drug Preparation Manual containing drug reconstitute was also evaluated extensively. (b) (4) appeared to conduct adequate oversight of this study (L-MIND).

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At the end of this remote site investigation, one discussion item was presented to the firm for failure to follow the monitoring plans for Study MOR208C203. (b) (4) provided an overview of medical monitoring and medical review activities where these eligibility items were detected. This investigation detected additional eligibility violations that had not previously been detected by monitoring.

The retrospective eligibility review process was implemented and detected 16 subjects who were enrolled, who had at least one violation with either inclusion or exclusion criteria. The specific clinical study site investigator and the sponsor (via MorphoSys’s Medical Director) performed an assessment on each of these subjects to decide whether study treatment should be continued. All study subjects were allowed to continue with study treatment after these assessments and included in the clinical study report (CSR).

OSI Reviewer’s Comment: It is important to note that inadequate monitoring and drug accountability issues were observed during the sponsor’s investigation. Both monitoring and drug accountability responsibilities were transferred in writing from the sponsor to the CRO (b) (4) , and later to the CRO (b) (4) as discussed under section #2 of this report (see above).

The reported observations related to monitoring and drug accountably have been included in the clinical study report (CSR) submitted to the agency as summary of key protocol deviations.

(b) (4) 4.

CRO for Observational, Retrospective Study MOR208C206

Remote site investigation assessment dates under FDA ORA Operations Code 15: May 26 – June 03, 2020

This remote site investigation principally evaluated compliance with the (b) (4) (b) (4) responsibilities concerning the conduct of observational, retrospective Study MOR208C206.

The remote site investigation assessed: firm organization for research and monitoring activities; transfer of responsibility from sponsor to CRO; vendor contracts for study-related services; SOPs related to selection and monitoring of study sites; monitoring SOPs and monitor qualifications for the study; SOPs related to the collection and handling of study- related data; investigator financial disclosure forms and eTMF.

The investigation showed that Site 01010 was not monitored as per the site management plan, which stated that sites would have at least one on-site monitoring visit. The site had to be monitored remotely because the data was entered by the study site late in the study.

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(b) (4) stated that the remote monitoring was done over the phone between the monitor and the sub-investigator at the site.

OSI Reviewer’s Comments: (b) (4) appeared to have adequate oversight of Study MOR208206. Clinical trial monitoring appeared to be adequate.

{See appended electronic signature page} Anthony Orencia, M.D., Ph.D. Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page} Min Lu, M.D., M.P.H. Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page} Kassa Ayalew, M.D., M.P.H. Branch Chief Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

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ANTHONY J ORENCIA 06/30/2020 02:28:29 PM

MIN LU 06/30/2020 02:31:02 PM

KASSA AYALEW 06/30/2020 03:23:28 PM

Reference ID: 4633606 MEMORANDUM REVIEW OF REVISED LABEL AND LABELING Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: June 10, 2020 Requesting Office or Division: Division of Hematologic Malignancies 2 (DHM 2) Application Type and Number: BLA 761163 Product Name and Strength: Monjuvi (tafasitamab-cxix) for Injection, 200 mg/vial Applicant/Sponsor Name: MorphoSys US Inc. OSE RCM #: 2019-2677-1 DMEPA Safety Evaluator: Nicole Iverson, PharmD, BCPS DMEPA Team Leader: Hina Mehta, PharmD

1 PURPOSE OF MEMORANDUM The Applicant submitted revised container label and carton labeling received on May 29, 2020 for Monjuvi. We reviewed the revised container label and carton labeling for Monjuvi (Appendix A) to determine if they are acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 CONCLUSION The Applicant implemented all of our recommendations and we have no additional recommendations at this time.

2 Pages of Draft Labeling have been WIthheld in Full as B4(CCI/TS) Immediately Following This Page

a Iverson N. Label and Labeling Review for Monjuvi (BLA 761163). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 MAY 14. RCM No.: 2019-2677. 1

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NICOLE F IVERSON 06/10/2020 10:35:14 AM

HINA S MEHTA 06/11/2020 01:31:38 PM

Reference ID: 4622375 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology (OSE) Office of Pharmacovigilance and Epidemiology (OPE) Division of Epidemiology I

Epidemiology: Review of Tafasitamab RWE study report

Date: May 5, 2020

Reviewer(s): Richard Scott Swain, PhD, MPH Division of Epidemiology I

Division Director Simone Pinheiro, ScD, MSc Division of Epidemiology I

Office Deputy Director Michael D. Blum, MD, MPH Office of Pharmacovigilance and Epidemiology

Subject Epidemiology Review of RWE Study Titled “An Observational Retrospective Cohort Study of Lenalidomide Monotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) to Generate a Historical Control for Clinical Trial MOR208C203”

Drug Name(s): MONJUVI (tafasitamab)

Application Type/Number: BLA 761163

Applicant/sponsor: MorphoSys US Inc.

OSE RCM #: 2020-102

Reference ID: 4619965

APPEARS THIS WAY ON ORIGINAL

** This document contains proprietary drug use data obtained by FDA under contract. The drug use data/information cannot be released to the public/non-FDA personnel without contractor approval obtained through the FDA/CDER Office of Surveillance and Epidemiology. **

Reference ID: 4619965

TABLE OF CONTENTS

EXECUTIVE SUMMARY ...... 3 1 INTRODUCTION ...... 4 1.1 Background ...... 4 1.2 Regulatory History ...... 5 1.3 Product Labeling (DRAFT; as of 23MAR2020) ...... 6 2 REVIEW METHODS AND MATERIALS ...... 6 2.1 Documents to be reviewed ...... 6 2.2 Additional Materials ...... 7 3 RE-MIND (MOR208C206) study report ...... 7 3.1 Study background ...... 7 3.2 Study Objectives/Specific Aims/Scope ...... 9 3.3 RE-MIND (MOR208C206) Study Methods ...... 9 3.3.1 Study Design ...... 9 3.3.2 Data Sources ...... 9 3.3.3 Study Population ...... 10 3.3.4 Time Period ...... 10 3.3.5 Inclusion and Exclusion Criteria ...... 10 3.3.6 Index Date and Follow-up ...... 11 3.3.7 Exposures ...... 12 3.3.8 Outcomes ...... 12 3.3.9 Covariates ...... 13 3.3.10 Sample Size and Power ...... 13 3.3.11 Statistical Analyses ...... 14 3.3.12 Unmeasured Confounding Analyses ...... 14 3.3.13 Validation of Response Assessments ...... 15 3.4 Study Results ...... 15 3.4.1 Patient Selection ...... 15 3.4.2 Baseline Patient Demographics and Disease Characteristics ...... 16 3.4.3 Dose Interruptions and Drug Safety Outcomes ...... 19 3.4.4 Efficacy Endpoints...... 19 3.4.5 Subgroup Analyses ...... 22 3.4.6 Sensitivity Analyses ...... 22 3.4.7 Validation of Response Assessments ...... 22 3.4.8 Unmeasured Confounding Analysis ...... 23

Reference ID: 4619965

3.4.9 Literature Review ...... 23 3.5 Sponsor’s Study Conclusions ...... 23 4 DISCUSSION ...... 24 4.1 Overall Summary ...... 24 4.2 Protocol Amendments in Response to FDA Comments ...... 24 4.3 Study Design ...... 25 4.4 Sample size and power ...... 26 4.5 Statistical Analysis ...... 26 4.6 6-Month Follow-up Rule ...... 26 4.7 Study Population ...... 26 4.8 Covariates ...... 27 4.9 Exposure ...... 28 4.10 Outcomes ...... 29 4.11 Unmeasured Confounding Analysis ...... 29 4.12 Validation of Response Assessments vs. Outcome Validation ...... 30 4.13 Literature Review ...... 30 5 CONCLUSION ...... 31 6 RECOMMENDATIONS To DHM-II ...... 31 7 REFERENCES ...... 33 8 APPENDICES ...... 36 8.1 Appendix Figure A1. L-MIND (MOR208C203) Treatment Emergent Adverse Events 36 8.2 Appendix Figure A2. Findings form NHL Study (MOR208C201) of Tafasitamab Monotherapy ...... 36 8.3 FDA Feedback for November 9, 2018 Type C Meeting ...... 37 8.4 Inclusion Criteria for the L-MIND (MOR208C203) ...... 38 8.5 Exclusion Criteria for the L-MIND (MOR208C203) ...... 39 8.6 Appendix Table A1. Follow-up Rules Examples for RE-MIND (MOR208C206) ..... 40 8.7 Analysis Cohorts for RE-MIND (MOR208C206) ...... 41 8.8 Appendix Figure A3. Forrest Plot of Best Objective Response Rate by Subgroups (MAS25) ...... 42

Reference ID: 4619965

EXECUTIVE SUMMARY

The Division of Hematologic Malignancies 2 (DHP-II) in the Office of New Drugs (OND) consulted the Office of Surveillance and Epidemiology (OSE) Division of Epidemiology I (DEPI-I) to review the final report of a real-world evidence for efficacy study (MOR208C206) titled “An Observational Retrospective Cohort Study of Lenalidomide Monotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) to Generate a Historical Control for Clinical Trial MOR208C203.”

Tafasitamab, as monotherapy or in combination with lenalidomide, is intended for the treatment of adult patients with R/R DLBCL. Because tafasitamab and lenalidomide have complementary mechanisms of action, combination therapy with these drugs may result in improved clinical outcomes in patients with R/R DLBCL.

The applicant submitted the RE-MIND (MOR208C206) real-world evidence (RWE) analysis to provide context for interpretation of the efficacy findings observed in the single-arm L-MIND pivotal trial. The primary objective was to isolate the contribution of tafasitamab to efficacy of a tafasitamab+LEN regimen in a cohort for real-world data (RWD) patients matched to trial patients from L-MIND. Data for the L-MIND patients were collected from the clinical trials, and data for the RE-MIND (RWD) patients were collected from the medical records of patients in real-world and compassionate use settings. The study periods for patients enrolled in the L-MIND trial (MOR208C203) and the RE-MIND patients were March 2016 to November 2018 and January 2007 to August 2019, respectively. The primary endpoint was best overall objective response rate (ORR).

The primary analysis consisted of 76 L-MIND patients taking tafasitamab+LEN matched 1:1 to 76 RE-MIND patients taking LEN monotherapy. Baseline covariates used for ePS matching were generally well-balanced between the tafasitamab+LEN and lenalidomide monotherapy cohorts. However, data for many important prognostic indicators was missing for much of the RE-MIND arm, and imbalances tended to indicate the L-MIND cohort was healthier at baseline. Best ORR was 67.1% (95% CI: 55.4, 77.5) in the tafasitamab+LEN cohort and 34.2% (95% CI: 23.7, 46.0) in the LEN-mono cohort (OR=3.1 [95% CI: 1.61, 5.91]). All study endpoints estimated superior treatment efficacy in the tafasitamab+LEN cohort.

The validity of the study is compromised by several limitations in the study design. Bias resulting from key differences in patient selection and unequal distribution of important measured and unmeasured prognostic indicators between treatment arms are likely to favor survival for the L-MIND patients. Most importantly, given important differences in the patient populations included in the L-MIND trial and RE-MIND study, primarily as a result of selection bias, this study does not provide sufficient evidence to isolate the contribution of tafasitamab to efficacy of tafasitamab+LEN combination therapy for DLBCL. DEPI defers to DHP as to the interpretation of the single arm, phase II trial.

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1 INTRODUCTION The Division of Hematologic Malignancies II (DHM-II) in the Office of New Drugs (OND) consulted the Office of Surveillance and Epidemiology (OSE) Division of Epidemiology I (DEPI-I) to review the final report of a real-world evidence for efficacy study (MOR208C206) titled “An Observational Retrospective Cohort Study of Lenalidomide Monotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) to Generate a Historical Control for Clinical Trial MOR208C203.” The report was submitted by the applicant through Biological License Application (BLA) to provide a historical control arm for the Phase II pivotal trial (MOR208C203) to compare clinical outcomes in patients with relapsed or refractory diffuse large B-cell lymphoma.

1.1 BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma (NHL). However, DLBCL comprises a heterogeneous group of lymphomas with diverse, yet overlapping, clinical and molecular features and different prognoses.1 In the US, annual incidence of DLBCL is approximately 7 cases per 100,000 in the general population.2 The mean age at disease presentation is 70 years, though DLBCL can present at any age, and it is more common in men than women.3,4 Additional risk factors are primarily associated with immunosuppression and include: autoimmune disease, Human Immunodeficiency Virus, Hepatitis C Virus, high BMI during childhood, and organ transplantation, as a result of the immunosuppressive regimen.5

Symptoms of DLBCL frequently include painless, rapidly growing lumps in lymph nodes located in the neck, armpit, or groin. However, symptoms can vary by DLBCL location and sub-type. For example, DLBCL in the gastrointestinal system can cause stomach pain, nausea, diarrhea or bleeding, while DLBCL in the chest can cause chest pain and cough. Other common symptoms include fever, night sweats, fatigue, loss of appetite, unexplained weight loss, and itching.6,7 DLBCL is typically diagnosed by biopsy of a peripheral lymph node where, under microscopic examination, large malignant B-cells are spread diffusely.8 Though most people with DLBCL are not classified as having a specific type (NOS), rare sub-types include: primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive DLBCL not otherwise specified, ALK-positive large B-cell lymphoma, and intravascular large B-cell lymphoma.9 DLBCL can also be classified based on cell of organ as germinal center B cell (GCB) or activated B cell (ABC) DLBCL.10,11

Treatment of DLBCL depends on stage at diagnosis, though age and disease signs and symptoms may also be taken into consideration. Early-stage (stage 1-2) DLBCL patients are typically treated with 3-4 cycles of chemotherapy or chemo-immunotherapy followed by radiotherapy. The most common chemotherapy regimen in early-stage DLBCL, CHOP, consists of cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin®) and prednisolone and is typically administered in combination with rituximab (R-CHOP). In advanced-stage DLBCL (stage 3-4), treatment consists of 6-8 cycles of R-CHOP; however, patients with late-stage disease may receive reductions or substitutions to R- CHOP if they are not healthy enough to tolerate the full regimen. Patients with R/R DLBCL typically receive ‘salvage’ treatment consisting of rituximab with a combination

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of chemo-immunotherapy agents, and some late-state and R/R patients receive autologous or allogenic stem cell transplantation or chimeric antigen receptor T-cell (CAR T) therapy.12,13 Lenalidomide is not currently approved to treat DLBCL; however, studies have demonstrated improved clinical outcomes among DLBCL patients taking lenalidomide as monotherapy or in combat ion with R-CHOP.14,15

Prognosis is generally favorable for the majority of DLBCL patients, though approximately 20-40% of patients will eventually relapse or progress.16,17 Approximately half of patients achieve a complete response with R-CHOP with a 5-year progression free survival (PFS) of nearly 80% and median overall survival (OS) is longer than a decade.18 Prognosis among R/R DLBCL patients is considerably worse, with OS ranging from a few months to a few years depending on stage and treatment, with patients receiving stem-cell therapy generally achieving the highest rates of long-term survival.19 Recent studies have shown promising results for check-point inhibitors and chimeric antigen receptor (CAR) T cell therapy in R/R patients with DLBCL.20,21 Though genetic markers have been shown to predict prognosis,22,23,24 evidence showing differing treatment success based on genotype has been inconsistent.25 However, recently, lenalidomide monotherapy has been shown to be substantially more effective in R/R DLBCL patients with non-GCB, compared to GCB, cell of origin.26,27

1.2 REGULATORY HISTORY December 01, 2014 FDA granted Orphan Drug Designation to tafasitamab.

October 29, 2014 FDA granted Fast Track Designation (FTD) to tafasitamab, in combination with lenalidomide followed by tafasitamab monotherapy, for the treatment of adult patients with relapsed or refractory DLBCL.

October 23, 2017 FDA granted Breakthrough Therapy Designation (BTD) to tafasitamab.

October 22, 2018 Tafasitamab RWE proposal discussed at Real-World Evidence Subcommittee Meeting.

November 9, 2018 Type C Meeting with Morphosys to discuss RWE proposal.

July 1, 2019 FDA agreed with applicant’s proposal for a 3-part rolling submission during pre-BLA meeting.

October 28, 2019 Applicant submitted original BLA application Sequence 0001 for tafasitamab to FDA.

November 15, 2019 Applicant submitted original BLA application Sequence 0002 for tafasitamab to FDA.

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December 30, 2019 Applicant submitted original BLA application Sequence 0003 for tafasitamab to FDA and request priority review.

February 21, 2020 Applicant presentation of clinical studies and RWE to support safety and efficacy during Application Orientation Meeting.

June 30, 2020 Current PDUFA date.

1.3 PRODUCT LABELING (DRAFT; AS OF 23MAR2020) • Information regarding the indication of tafasitamab in provided in Section 1 of the product label:

INDICATIONS AND USAGE

(b) (4)

• The draft WARNINGS AND PRECAUTIONS (Section 5) includes information pertaining to Infusion Related Reactions (5.1), myelosuppression (5.2), and infection (5.3).

2 REVIEW METHODS AND MATERIALS

2.1 DOCUMENTS TO BE REVIEWED • Final Protocol for RE-MIND RWE Study (MOR208C206) submitted to FDA on January 15, 2019

• Statistical Analysis Plan for RE-MIND RWE Study (MOR208C206) submitted to FDA on September 9, 2019

• Observational Retrospective RE-MIND Study (MOR208C206) titled, “An Observational Retrospective Cohort Study of Lenalidomide Monotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) to Generate a Historical Control for Clinical Trial MOR208C203,” submitted to FDA on December 18, 2019

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2.2 ADDITIONAL MATERIALS DEPI considered the following submission materials for reference in the review of the final study report (MOR208C206):

• Type C Meeting Briefing Book from MorphoSys IND 114856 / MOR00208 submitted to FDA on September 21, 2018

• Applicant slides from MorphoSys IND 114856 / MOR00208 in R/R DLBCL Type C Meeting held November 8, 2018

• FDA slides from MorphoSys IND 114856 / MOR00208 in R/R DLBCL Type C Meeting held November 8, 2018

• Cover letter for original BLA application for tafasitamab (MOR00208) submitted to FDA December 30, 2019

• Clinical Overview Section 2.5 of MorphoSys Tafasitamab BLA 761163

• Summary of Clinical Efficacy Section 2.7.3 of MorphoSys Tafasitamab BLA 761163

• Clinical Study Report: A Phase II, Single-Arm, Open-Label, Multicentre Study to Evaluate the Safety and Efficacy of Lenalidomide Combined with MOR00208 in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R-R DLBCL)

• Applicant slides from MorphoSys BLA 761163 Applicant Orientation Meeting held February 21, 2020

3 RE-MIND (MOR208C206) STUDY REPORT

3.1 STUDY BACKGROUND Tafasitamab, as monotherapy or in combination with lenalidomide, is intended for the treatment of adult patients with R/R DLBCL. Tafasitamab is an Fc-enhanced humanized monoclonal antibody which binds to the CD19 antigen on the surface of B lymphocytes and causes B-cell depletion. The proposed dose regimen for tafasitamab is 12 mg/Kg via IV infusion. The tafasitamab+LEN regimen runs on a 28-day cycle as follows:

• Tafasitamab Cycle 1: 12 mg/kg administered on days 1, 4, 8, 15, 22

• Tafasitamab Cycles 2 and 3: 12 mg/kg administered on days 1, 8, 15, 22

• Tafasitamab Cycle 4 to progression: 12 mg/kg administered on days /kg Day 1, 15

• Lenalidomide Cycles 1-12: 25 mg taken on days 1-21

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Lenalidomide is an immunomodulatory drug, administered via oral capsule, that acts to stimulate the activity of immune effector cells which may provide tafasitamab with an increased and more potent effector cell pool for tumor cell killing. Thus, because these agents have complementary mechanisms of action, combination therapy with tafasitamab and lenalidomide may result in improved clinical outcomes in patients with R-R DLBCL.

The applicant has submitted findings from 2 phase II trials to support the safety and efficacy of tafasitamab. The phase II trials conducted to support clinical efficacy include:

• L-MIND (MOR208C203): Pivotal single arm combination (tafasitamab+LEN) trial for primary evidence of efficacy

• NHL Study (MOR208C201): Tafasitamab single agent activity

The pivotal trial (MOR208C203) observed an overall response rate (ORR) of 59%, including 41% with a complete response (CR) and 18% with a partial response (PR). Median duration of response (DoR) was 35 months, median PFS was 16 months, and median overall survival was 32 months. All patients (N=81) experiences at least one treatment emergent adverse event (TEAE), with 63 (78%) experiencing a Grade 3-5 TEAE. Patients were more likely to report TEAEs while on combination therapy with lenalidomide compared to the tafasitamab monotherapy phase of the study (TEAEs are displayed in Appendix 8.1: Figure A1).

The NHL Study (MOR208C201) of tafasitamab monotherapy (N=35) observed an ORR of 26%, including 6% with a CR and 20% with a PR. Median DoR was 20 months, and median PFS was 3 months (Appendix 8.2 Figure A2).

The applicant also submitted a real-world analysis to provide context for interpretation of the efficacy findings observed in the single-arm L-MIND trial:

• RE-MIND (MOR208C206): An Observational Retrospective Cohort Study of Lenalidomide Monotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) to Generate a Historical Control for Clinical Trial MOR208C203 (RE-MIND)

MorphoSys met with the FDA during a Type C Meeting on November 9, 2018 to discuss the proposed RWE study, MOR208C206. As part of the meeting package, the sponsor submitted a draft protocol for the proposed RWE study. Upon review, FDA identified multiple methodological issues of significant concern. Feedback provided to the sponsor is displayed in (Appendix 8.3).

The RWE study compared response rates and overall survival in patients treated with combination (tafasitamab+LEN) therapy from the pivotal trial (MOR208C203) vs. a retrospective, observational cohort of patients treated with lenalidomide monotherapy (the RE-MIND cohort). The study used 9 baseline covariates to match patients (N=76)

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from the pivotal trial (MOR208C203) to the RE-MIND cohort (N=76). The study met its primary endpoint with an ORR of 67% in the tafasitamab+LEN arm and 34% in the lenalidomide monotherapy cohort (Odds Ratio 3.9 [95% C.I. 1.9 – 8.1]). The proportion of patients with a CR was larger in the tafasitamab+LEN arm compared to the lenalidomide cohort (40% vs. 13%) and median DoR (21 vs. 7 months), median PFS (12 vs. 4 months), and median OS (not reached vs. 9 months) was longer.

The RE-MIND study methods, results, and strengths and limitations are discussed in detail below.

3.2 STUDY OBJECTIVES/SPECIFIC AIMS/SCOPE • To isolate the contribution of tafasitamab to efficacy of tafasitamab-lenalidomide combination in a matched cohort comparison

• To characterize the effectiveness of lenalidomide monotherapy in the treatment of R/R DLBCL patients

3.3 RE-MIND (MOR208C206) STUDY METHODS

3.3.1 Study Design RE-MIND was an observational, retrospective, cohort study designed to characterize the effectiveness of tafasitamab+LEN vs. lenalidomide monotherapy in the treatment of R/R DLBCL patients not eligible for high dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT). Data were collected from the medical records of patients in real world and compassionate use for the RE-MIND cohort, and from clinical trial settings for the L-MIND cohort.

3.3.2 Data Sources Patients in the tafasitamab+LEN arm were selected from the L-MIND trial (MOR208C203). All covariates measured at baseline and during follow-up and all treatment safety and efficacy endpoints were extracted from the L-MIND trial.

Patients for the lenalidomide monotherapy (RE-MIND) cohort were selected from sites based on regions in the US and Europe (Italy, France and Spain) of study sites that participated in the L-MIND study. In total, 42 sites from three healthcare companies (b) (4)

were identified for selection of the lenalidomide monotherapy arm including 33 in Italy, 4 in the US, 3 in Spain, and 2 in France. Information on baseline covariates, exposures, and outcomes were extracted from electronic medical records and medical charts review (including: positron emission tomography-computed tomography (PET-CT) scans, CT and magnetic resonance imaging (MRI) scans, nodal/bone marrow biopsies, and histopathology reports) via an electronic case report form. Missing exposure and outcome dates were imputed as follows: when the day was missing and the month and year was complete, the day was imputed to the first of the month. If day and month or year was missing, the date was not imputed and was reported as missing.

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3.3.3 Study Population The study population consisted of R/R DLBCL patients not eligible for HDC followed by ASCT treated with tafasitamab+LEN (L-MIND cohort) or lenalidomide monotherapy (RE-MIND cohort).

3.3.4 Time Period The study period for patients enrolled in the L-MIND trial (MOR208C203) treated with tafasitamab+LEN was March 29, 2016 to November 30, 2018. The study period for the real-world patients treated with lenalidomide monotherapy was January 14, 2007 to August 25, 2019.

3.3.5 Inclusion and Exclusion Criteria Inclusion criteria for the L-MIND trial are displayed in Appendix 8.4.

Inclusion criteria for the RE-MIND study were:

1. Age > 18 at index date.

2. One of the following: histologically confirmed diagnosis of DLBCL not otherwise specified, T cell/histiocyte rich large B-cell lymphoma, Epstein-Barr virus positive DLBCL of the elderly, Grade 3b Follicular Lymphoma, Composite lymphoma with a DLBCL component with a subsequent DLBCL relapse according to REAL/WHO classification, evidence of histological transformation to DLBCL from an earlier diagnosis of low grade lymphoma into DLBCL with a subsequent DLBCL relapse

3. Relapsed after or refractory to at least 1 previous systemic therapy for DLBCL

4. Received at least 1, but no more than 3 previous systemic regimens for the treatment of DLBCL, including at least 1 anti CD20 containing therapy in past treatment lines.

5. Received LEN monotherapy for R/R DLBCL while being considered not eligible for an autologous stem cell transplant.

Exclusion criteria for the L-MIND trial are displayed in Appendix 8.5.

Exclusion criteria for the RE-MIND study were:

1. Patients with central nervous system (CNS) involvement by lymphoma, prior to start of LEN monotherapy.

2. Patients who received LEN (as the treatment of interest for this study) in combination with another anti-lymphoma therapy (including radiation).

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3. Patients who were previously (prior to the index date in this retrospective study) treated with CD19-targeted therapy or immunomodulatory drugs (IMiDs) (e.g., thalidomide, LEN).

4. Patients who previously underwent an allogeneic stem cell transplant.

5. Patients with a known double-or triple hit genetics DLBCL characterized by simultaneous detection of MYC with B-cell lymphoma (BCL)2 and/or BCL6 translocation(s) defined by fluorescence in situ hybridization (FISH).

6. Patients who had a prior history of malignancies other than DLBCL, unless the patient has been free of the disease for ≥5 years prior to index date. Exceptions to the ≥5 years year time limit include a history of the following: a. basal cell carcinoma of the skin b. squamous cell carcinoma of the skin c. carcinoma in situ of the cervix d. carcinoma in situ of the breast e. carcinoma in situ of the bladder f. incidental histological finding of prostate cancer (Tumor/Node/Metastasis [TNM] stage of T1a or T1b)

3.3.6 Index Date and Follow-up Patients were assigned an index date based on the first documented treatment record for tafasitamab+LEN or lenalidomide monotherapy. The pre-index period for patients treated with lenalidomide monotherapy was defined as the time between first documented DLBCL diagnosis, or history of cancer other than DLBCL, and the index date. The observation period was defined as the time between the index date and end of follow-up. End of follow-up was defined as either death or last available medical record.

A minimum of 6-months follow-up was required for all patients in the study. A minimum of 6 months’ follow-up time as met if:

• a patient responded (CR or PR) or progressed or died within 6 months from index date (from study day 1 to 183), OR

• a responding patient (CR or PR as best response) has a baseline tumor assessment and at least 1 post-baseline response assessment available at 6 months or later (on or after study day 184), OR

• any patient who has at least one disease response assessment with stable disease (SD), “indeterminate”, “not evaluable” or ‘other’ within 6 months from index date (from study day 1 to 183) with at least one assessment or death at 6 months or later (or on after study day 184).

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Patients did not fulfill the minimum of 6 months’ follow-up if they did non-respond (stable disease [SD] or progressive disease [PD] as best response) with a first tumor response assessment beyond 6 months.

Figure 1. Examples of 6-month follow-up rule.

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

See Appendix 8.6: Table A1 for additional exemplified cases of follow-up rules.

The maximum follow-up for patients in the L-MIND trial was 32 months (March 2016, to November 2018). To ensure a comparable distribution of follow-up, patients in the observational study arm were censored at 32 months (974 days).

3.3.7 Exposures The treatment exposure in the L-MIND clinical trial was a tafasitamab+LEN combination regimen. The comparison group, from the RE-MIND cohort, was treated with lenalidomide monotherapy. Only patients, from each cohort, with a starting dose of lenalidomide 25mg were included the primary analysis.

3.3.8 Outcomes • Best Overall/objective Response Rate (ORR) - Primary Efficacy Endpoint: the proportion of patients with complete response (CR) or partial response (PR) as best response achieved at any time within the analysis window or between index date and date of initiation of a new anti-DLBCL treatment or death.

• Complete Response (CR) Rate: the proportion of patients with CR as best response achieved at any time within the analysis window or between index date and date of initiation of a new anti-DLBCL treatment or death.

• Overall Survival (OS): time from the index date until death from any cause.

• Disease Control Rate (DCR): the proportion of patients having CR, PR or stable disease (SD) based on the best objective response achieved at any time within the analysis window or between index date and date of initiation of a new anti- DLBCL treatment or death

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• Duration of Response (DoR): time between the date of first documented response (CR or PR) and the date of event defined as the first documented progression or death.

• Progression-free Survival (PFS): time (in months) from the index date to the date of tumor progression or death from any cause. The date of progression was the first date for which progressive disease was assessed as the objective response.

• Time to Next Treatment (TTN'D): time from index date to the start of next anti- DLBCL therapy (therapies included medication, surgery, or radiotherapy for any reason including disease progression, treatment toxicity, and patient preference) or death due to any cause, whatever came first. Corticosteroids were not considered as anti-DLBCL treatment. Patients without documented start of a new anti-DLBCL treatment or who did not die within the analysis window were censored at the date of last contact.

• Event-Free Survival (EFS): time from the index date to the date of disease progression, initiation of a new non-study anti-DLBCL treatment, or death from any cause, whatever came first. Patients who did not have a record of disease progression, initiation of a new non-study anti-DLBCL treatment, or death from any cause were censored on the date of last available response assessment, or at index date if no post-baseline assessment was available.

3.3.9 Covariates The following covariates were used for ePS weighting and matching: • Age (categorical) • Ann Arbor Stage (stage I/II vs. III/IV) • Refractoriness to last line of therapy (yes/no) • Number of prior lines of therapy (1 vs 2/3) • History of primary refractoriness (yes/no) • Prior ASCT (yes/no) • Elevated lactate dehydrogenase (LDH): LDH > upper limit of normal (yes/no) • Neutropenia: absolute neutrophil count < 1.5 x 109/L (yes/no) • Anemia: hemoglobin < 10g/dL (yes/no)

3.3.10 Sample Size and Power The L-MIND trial enrolled n=81 patients. Based on 1:1 matching (N=162), the sponsor estimated the RWE analysis would have 80% power (α=0.05) to detect a 23% difference in the primary outcome (ORR) between tafasitamab+LEN and lenalidomide monotherapy treatment arms.

The sponsor expected that approximately 500 patients would be necessary in the observational arm of the RE-MIND study to provide a sufficient number of patients

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(approximately 80) to achieve a successfully balanced cohort (with L-MIND) before conducting the comparative efficacy outcome analyses.

3.3.11 Statistical Analyses Descriptive statistics were presented for baseline patient characteristics and covariates used for matching. The number and percentage of patients classified as having best overall response of CR or PR or SD with 95% confidence limits (calculated using Clopper-Pearson exact method) were presented. Estimated propensity scores (ePS) were calculated using logistic regression to estimate the probability of treatment (in the L- MIND cohort), conditional on the 9 observed baseline covariates (described above) to perform a Nearest Neighbor 1:1 match between the L-MIND and RE-MIND patients. Only patients with complete covariate data were used for ePS matching for the primary analyses.

The primary analysis calculated an odds ratio (OR) for treatment response, with 95% confidence intervals, using logistic regression based on Fisher’s exact test. Time to event data were analyzed using Kaplan-Meier estimates, with log-ranked tests where applicable, and Cox proportional hazards.

The sponsor used multiple analysis sets for a variety of sub-group and sensitivity analyses. The primary analysis set was the matched analysis set (MAS25), consisting of the 1:1 matched cohort with a lenalidomide starting dose of 25 mg/day. The sponsor also created 17 additional analytical RWD cohorts based on varying requirements (patient follow-up, inclusion/exclusion criteria, missing data, LEN starting dose, matching strategy, unmeasured confounding, etc) for the purpose of conducting exploratory data analyses and sensitivity analyses. Further details about the sensitivity analyses are available in the Appendix 8.7. The discussion of this review will focus on the primary analysis.

Best objective response rate, CR rate, PFS, and OS were summarized by cohort for the subgroups listed below; however, no statistical tests were performed to compare estimates between subgroups:

• Age <70 versus (vs.) ≥ 70 • Ann Arbor stage I/II vs. III/IV • Refractoriness to last therapy line (Yes vs. No) • Number of prior lines of therapy (1 vs. 2/3) • History of primary refractoriness (Yes vs. No) • Prior ASCT (Yes vs. No)

3.3.12 Unmeasured Confounding Analyses The sponsor performed an assessment to estimate the potential impact of unmeasured confounding on the significance of the observed treatment effect using methods developed by Rosenbaum and Rubin.28 In short, г is a measure of unmeasured confounding. A study with no unmeasured confounding would be represented by г=1,

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and a study with unmeasured confounding by г>1, where a higher value of г indicates a higher degree of unmeasured confounding. The purpose of this analysis is to determine to what extent an unmeasured binary confounder could increased the odds of exposure, assuming the confounder is a near perfect predictor of the outcome, thus potentially nullifying the statistical significance of the primary outcome (ORR).

3.3.13 Validation of Response Assessments An independent validation of response assessments as was performed on a subset of patients from the RE-MIND observational cohort. Patients were eligible for the validation assessment if they had a LEN starting dose of 20 or 25 mg/day, imaging scans within 56 days before baseline and at least one post-baseline scan, 6 months of follow-up, physician recorded tumor response assessment, and relevant available clinical data. Response assessments from the physician-reported (INV) and the independent review committee (IRC) were subjected to a concordance analysis. A Cohen’s kappa for pairwise agreement was not calculated.

3.4 RE-MIND (MOR208C206) STUDY RESULTS

3.4.1 Patient Selection The sponsor identified an observational cohort of 490 patients with a diagnosis for DLBCL taking lenalidomide monotherapy, of which 140 met inclusion and exclusion criteria, the 6-month follow-up criteria, had a lenalidomide starting dose of 25 mg per day, and available data on all 9 baseline covariates. Of the 81 patients enrolled in L- MIND, 5 patients were excluded from RE-MIND study for no lenalidomide treatment (n=1), not meeting inclusion/exclusion criteria (n=1), and not having the 6-month follow- up (n=3). The primary analysis (MAS25 analysis set) consisted of the remaining 76 L- MIND patients matched to 76 (of 140 eligible) patients in the real-world arm (see Figure 2).

Figure 2. RWE study (MOR208C206) patient selection for L-MIND and RE-MIND cohorts.

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

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3.4.2 Baseline Patient Demographics and Disease Characteristics Patients included in the RE-MIND arm of the study were selected from a broader time range compared to the L-MIND patients (Figure 3). The demographic characteristics at the index date and covariates used for ePS matching were generally well-balanced between the tafasitamab+LEN and lenalidomide monotherapy cohorts (Tables 1 and 2), with an absolute standardized difference of <0.2 for 7 of the 9 covariates used for matching (ePS overlap displayed in Figure 4).

Figure 3. Distribution of Index Date for L-MIND and RE-MIND cohorts.

*Figure displayed in RE-MIND (MOR208C206) study report.

Figure 4. Distribution of Index Date for L-MIND and RE-MIND cohorts.

*Figure displayed in RE-MIND (MOR208C206) study report.

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Values for covariates used to calculate ePS are displayed din Table 1, and patient characteristics and prognostic indicators not included in ePS, as well as previous DLBCL treatments, are summarized in Table 2.

There were slightly more male patients in each cohort (52.6% tafasitamab+LEN vs 56.6% LEN-mono), and the median age was 71 years for both arms. The majority of patients with data were White (98.6% tafasitamab+LEN vs 65.8% LEN-mono), though more patients were classified as non-white or missing in the RE-MIND cohort. The L- MIND trial included few (7%) from US while a majority (62%) of patients in the RE- MIND cohort were from the US (see Table 6).

Table 1. Covariates used to calculate ePS for matched analysis for L-MIND and RE- MIND patients. Tafasitamab+LEN LEN monotherapy Variable Value (N=76) (N=76) Mean (SD) 69.1 (9.71) 70.0 (8.65) Age (years) Median (range) 71.5 (41-86) 71.0 (41-86) I 4 (5.3) 0 Ann Arbor Stage; II 15 (19.7) 12 (15.8) n (%) III 14 (18.4) 12 (15.8) IV 43 (56.6) 52 (68.4) Refractory to last prior therapy; Yes 34 (44.7) 34 (44.7) n (%) No 42 (55.3) 42 (55.3) Number of prior lines of therapy; 1 39 (51.3) 28 (36.8) n (%) 2 or 3 37 (48.7) 48 (63.2) History of primary refractoriness; Yes 14 (18.4) 16 (21.1) n (%) No 62 (81.6) 60 (78.9) Prior ASCT; Yes 9 (11.8) 6 (7.9) n (%) No 67 (88.2) 70 (92.1) Elevated LDH; Yes 41 (53.9) 45 (59.2) n (%) No 35 (46.1) 31 (40.8) Neutropenia; Yes 2 (2.6) 2 (2.6) n (%) No 74 (97.4) 74 (97.4) Anemia; Yes 6 (7.9) 5 (6.6) n (%) No 70 (92.1) 71 (93.4)

DLBCL cell of origin was missing for the majority of patients (58.8% tafasitamab+LEN vs 100% LEN-mono). However, among L-MIND patients with genetic profiling data for cell of origin, 17 of 28 (60.7%) were non-GCB. Though many of the RE-MIND patients had missing data for Ann Arbor Stage, International Prognostic Index (IPI), and Eastern Cooperative Oncology Group (ECOG) scale, on average, the RE-MIND patients were distributed towards more advanced DLBCL. For example, 36.8% of the tafasitamab+LEN patients and 5.9% of the LEN-mono patients had an ECOG of 0, while 8.8% of the tafasitamab+LEN patients and 29.4% of the LEN-mono patients had an ECOG of 2-3.

RE-MIND patients also had more previous lines of therapy (48.7% tafasitamab+LEN vs 63.2% LEN-mono had 2-3 prior treatment lines), and months since last treatment was shorter (17.4 tafasitamab+LEN vs 13.6 LEN-mono). Refractoriness to prior line of

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therapy (44.7% for both) and to rituximab (42.1% tafasitamab+LEN vs 43.4% LEN- mono) was similar between treatment arms.

Table 2. Patient characteristics, prognostic indicators, and previous treatments not included in ePS for L-MIND and RE-MIND patients. Tafasitamab+LEN LEN monotherapy Variable Value (N=76) (N=76) Total follow-up Mean (SD) 15.5 (8.8) 11.7 (9.3) (months) Median (range) 15 (0.6-32) 9.2 (1-32) Sex; Female 36 (47.4) 33 (43.4) n (%) Male 40 (52.6) 43 (56.6) Mean (SD) 77.9 (17.5) 77.0 (17.6) Weight (kg) Median (range) 77.9 (43-145) 78.5 (37-117) Missing; n (%) 1 (1.3) 12 (15.8) White 70 (92.1) 50 (65.8) Race; Other 1 (1.3) 26 (34.2) n (%) Missing 5 (6.6) 0 0-2 40 (52.6) 16 (21.1) IPI Score; 3-5 36 (47.4) 32 (42.1) n (%) Missing 0 28 (36.8) 0 29 (38.2) 5 (6.6) 1 41 (53.9) 36 (47.4) ECOG; 2 6 (7.9) 16 (25.0) n (%) 3 0 6 (7.9) Missing 0 10 (13.2) ≤12 months 32 (42.1) 32 (42.1) Relapse after 1L; > 12 months 41 (53.9) 39 (51.3) n (%) Missing 3 (3.9) 5 (6.6) GCB 7 (9.2) 0 Cell of origin; ABC 19 (25.0) 0 n (%) Unclassified 4 (5.3) 0 Missing 46 (60.5) 76 (100) Primary refractoriness; Yes 14 (18.4) 16 (21.1) n (%) No 62 (81.6) 60 (78.9) Rituximab refractoriness; Yes 32 (42.1) 33 (43.4) n (%) No 44 (57.9) 43 (56.6) Creatinine clearance; ≥60 ml/min 69 (90.8) 42 (55.3) n (%) Missing 7 (9.2) 34 (44.7) Mean (SD) 40.0 (36.0) 38.0 (35.5) Time since first DLBCL diagnosis Median (range) 25.9 (7.8-189.7) 24.9 (3.0-193.1) (months) Missing; n (%) 0 1 (1.3) Time since discontinuation of prior Mean (SD) 17.4 (22.3) 13.6 (19.6) therapy or ASCT (months) Median (range) 9.2 (0.6-121.9) 6.5 (0.1-103.2) 1 Line 39 (51.3) 28 (36.8) Previous lines of therapy 2 Lines 32 (42.1) 42 (55.3) n (%) 3 Lines 5 (6.6) 6 (7.9) Time between prior anti-DLBCL Mean (SD) 17.4 (22.3) 13.7 (19.6) medication and index date (months) Median (range) 9.2 (0.6-121.9) 6.7 (0.1-103.2) n (%) 9 (11.8) 6 (7.9) Time since ASCT until the index Mean (SD) 32.5 (34.4) 12.8 (12.6) date (months) Median (range) 18.1 (3.5-93.0) 7.3 (5.1-37.7)

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3.4.3 Dose Interruptions and Drug Safety Outcomes All patients included in the primary analysis initiated lenalidomide at a dose of 25 mg on the index day. More patients in the LEN-mono (78.9%) cohort had a dose reduction compared to the tafasitamab+LEN (51.3%) cohort. Lenalidomide dose was temporarily interrupted for 18.4% of patients in LEN-mono cohort and 5.3% of patients in the tafasitamab+LEN cohort. Reasons for dose reduction were not well captured.

Safety was not an objective in the retrospective observational study. Thus, safety endpoints were not evaluated.

3.4.4 Efficacy Endpoints The study endpoints are summarized below and displayed in Table 3:

• Best ORR was 67.1% (95% CI: 55.4, 77.5) in the tafasitamab+LEN cohort and 34.2% (95% CI: 23.7, 46.0) in the LEN-mono cohort (OR=3.1 [95% CI: 1.61, 5.91]). Best ORR, CR, and PR are displayed in Figure 1.

• The proportion of patients with CR was higher for the tafasitamab+LEN cohort (39.5%) compared with the LEN-mono cohort (13.2%).

• The proportion of patients with PR was higher for the tafasitamab+LEN cohort (27.6%) compared with the LEN-mono cohort (21.1%).

Figure 1. Best ORR, CR, and PR in tafasitamab+LEN and LEN-mono cohorts.

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

• The median OS (Figure 2) was non-estimable for the tafasitamab+LEN cohort and 9.4 (95% CI: 5.1, 20.0) months in the LEN-mono cohort (HR=0.50 [95% CI: 0.32, 0.79]); however, the median follow-up time was 21.5 and 20.9 months in the tafasitamab+LEN and LEN-mono cohorts, respectively. The probabilities of OS at 6, 12 and 24 months were 86. 7%, 74.3% and 52.7% in the tafasitamab+LEN cohort and 57.9%, 45.6% and 30.8% in the LEN-mono cohort.

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Figure 2. Kaplan Meier OS estimates in tafasitamab+LEN and LEN-mono cohorts.

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

• DCR was 77.6% (95% CI: 66.6, 86.4) in the tafasitamab+LEN cohort and 48.7% (95% CI: 37.0, 60.4) in the LEN-mono cohort (OR=3.0 [95% CI: 1.5, 5.9]).

• The median DoR excluding non-responders was 20.5 (95% CI: 12.3, NR) months in the tafasitamab+LEN cohort and 6.6 (95% CI: 4.1, 17.2) months in the LEN- mono cohort.

Figure 3. Kaplan Meier DoR estimates in tafasitamab+LEN and LEN-mono cohorts.

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

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• The proportion of patients with a PFS event was lower in the tafasitamab+LEN (55.3%) cohort compared to the LEN-mono (76.3%) cohort. The median PFS was 12.1 (95% CI: 5.9, NE) months in the tafasitamab+LEN cohort and 4.0 (95% CI: 3.1, 7.4) months in the LEN-mono cohort (HR=0.46 [95% CI: 0.31, 0.70]).

Figure 4. Kaplan Meier PFS estimates in tafasitamab+LEN and LEN-mono cohorts.

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

• The median TTNT was 16.7 (95% CI: 7.6. NR) months in the tafasitamab+LEN cohort and 5.1 (95% CI: 4.7, 7.3) months in the LEN-mono cohort.

• The median EFS was 12.1 (95% CI: 5.5, 21.0) months in the tafasitamab+LEN cohort and 4.0 (95% CI: 3.1, 6.2) months in the LEN-mono cohort (HR=0.44 [95% CI: 0.30, 0.65]).

Table 3. Findings from study efficacy endpoints. Tafasitamab+LEN LEN monotherapy Study Endpoint P-value (n=76) (n=76) Best Overall/objective Response Rate (ORR) 67.1 (55.4, 77.5) 34.2 (23.7, 46.0) <0.0001 Complete Response (CR) Rate 39.5 (28.4, 51.4) 13.2 (6.5, 22.9) * Median Overall Survival (OS) N.E. (15.5, N.E.) 9.4 (5.1, 20.0) 0.0026 Disease Control Rate (DCR) 77.6 (66.6, 86.4) 48.7 (37.0, 60.4) 0.0004 Median Duration of Response (DoR) 20.5 (12.3, N.E.) 6.6 (4.1, 17.2) * Progression-free Survival (PFS) 12.1 (5.9, N.E.) 4.0 (3.1, 7.4) 0.0002 Time to Next Treatment (TTND) 16.7 (7.6, N.E.) 5.1 (4.7, 7.3) * Event-free Survival (EFS) 12.1 (5.5, 21.0) 4.0 (3.1, 6.2) <0.0001 *Not Given

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3.4.5 Subgroup Analyses All subgroup analyses were consistent with analyses for all study endpoints, showing higher response rates and improved survival in the tafasitamab+LEN arm. No statistical testing was performed to estimate modification of treatment effect within subgroups. Subgroup analyses for ORR are displayed in Appendix 8.8 Figure A3.

3.4.6 Sensitivity Analyses The sponsor created 18 analytical cohorts, including a primary analysis set (MAS25) and 17 sets for data exploration and sensitivity analyses (further details available in the Appendix 8.7). Overall, the results obtained in the primary analysis were consistent across sensitivity analyses.

3.4.7 Validation of Response Assessments In total, 79 patients, including 22 from the LEN monotherapy (RE-MIND) primary analysis set (MAS25), were eligible for the validation of response assessment. Findings from the validation of response assessment are displayed in Table 4.

Table 4. Findings from validation of physician-reported vs. independent review committee response assessments. Validation Set N=79 Summary of concordance for best response – Validation Set % n N Concordance Concordance for the responder category (Concordance %) CR+PR as best response per IRC and INV/ CR+PR as best response per INV 13 22 59.1 Concordance for the non-responder category (Concordance %) SD+PD as best response per IRC and INV/ SD+PD as best response per INV 50 56 89.3 Combined concordance for responder + non-responder categories (Concordance %) Responder (CR+PR) + Non-Responder (SD+PD) per IRC & INV / Total Patients 63 79 79.8 Concordance for individual response categories (Concordance %) CR as best response per IRC and INV/CR Best response per INV 3 13 23.1 PR as best response per IRC and INV/ PR best response per INV 3 9 30.3 SD as best response per IRC and INV/ SD as best response per INV 6 12 50.0 PD as best response per IRC and INV/ PD as best response per INV 40 44 90.9 Overall Concordance for individual response categories 52 79 65.8 Difference of agreement between IRC and INV assessment CR or PR as best response per IRC/Total number of patients (A) 13 79 16.5 CR or PR as best response per INV/Total number of patients (B) 22 79 27.9 A-B -11.4% SD or PD as best response per IRC/Total number of patients (C) 57 79 72.2 SD or PD as best response per INV/Total number of patients (D) 56 79 70.9 C-D 1.3%

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The combined concordance between physician-reported and the independent review committee reported outcomes for all treatment responses, including responders (CR+PR) and non-responders (SD+PD), was 79.8%. The overall concordance across individual response assessments (CR, PR, SD, PD and Not Evaluable [NE]) was 65.8%. The concordance for responders (CR+PR) and non-responders (SD+PD) was 59.1% and 89.3%, respectively. See Table 5 for full results of the validation assessment.

3.4.8 Unmeasured Confounding Analysis The unmeasured confounding analysis found that if an unmeasured binary variable increased the odds of exposure by a factor of 1.6, assuming the factor was a near perfect predictor of ORR, then the unmeasured confounder would nullify the statistical significance of the observed treatment effect in the primary analysis. The sponsor concluded that unmeasured confounding had a low likelihood of producing sufficient hidden bias to change statistical inferences for the primary analysis.

3.4.9 Literature Review The sponsor conducted a targeted literature review to identify clinical trials evaluating the efficacy of lenalidomide monotherapy to provide a historical context to the L-MIND and RE-MIND study findings. They identified 4 previous clinical trials estimating the efficacy of lenalidomide monotherapy with similar ORR, CR, median PFS, and median OS compared to the RE-MIND cohort (Table 5).

Table 5. RE-MIND and L-MIND in Context of Historical Trials. Outcome Study Treatment Median Median OS, ORR, % CR, % PFS, months months L-MIND (N=76) Taf+LEN 67.1 39.5 12.1 Not reached RE-MIND (N=76) LEN 34.5 13.2 4.0 9.4 RWD Broccoli 2019 (N=153) LEN 29 24 6.0 12.0 Witzig 2011 (N=108) LEN 28 7 2.7 — Czuczman 2017 (N=51) LEN 27 10 3.1 7.1 Wiernik 2008 (N=29)* LEN 21 10 4* — * Including 3 transformed low-grade lymphoma cases.

3.5 SPONSOR’S STUDY CONCLUSIONS The study conclusions made by the sponsor were as follows:

• Compared with LEN monotherapy, the tafasitamab+LEN combination increased best ORR by 33%, median OS was not reached (vs 9.3 months for lenalidomide monotherapy), and median PFS was extended by 8 months, suggesting substantial additional activity for the novel combination of tafasitamab+LEN versus lenalidomide monotherapy in transplant-ineligible R/R DLBCL patients.

• All time to event endpoints supported the primary analysis results and were in line with the overall result, with clinically meaningful and statistically significant differences between tafasitamab+LEN combination and lenalidomide monotherapy.

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• Cohort balancing of baseline characteristics via ePS-based 1: 1 matching allowed for a robust estimation of the additional treatment effect attributable to tafasitamab when added to lenalidomide as in the L-MIND trial.

• All sensitivity analyses demonstrated that the results obtained in the primary analysis were robust.

• The validation assessment demonstrated that response assessment by an independent and blinded panel of experts was concordant with the response assessment by the physicians.

• Outcomes observed for LEN monotherapy in RE-MIND vs. published clinical trials are comparable.

4 DISCUSSION

4.1 OVERALL SUMMARY DEPI disagrees with the sponsor’s conclusion that compared with LEN monotherapy, the tafasitamab+LEN combination increased best ORR by 33%, median OS (not reached vs 9.3 months), and median PFS by 8 months, due to the likelihood that this study lacks internal and externally validity. Primary limitations to the study include: selection bias, covariate imbalances and missing data for important prognostic indicator variables, exposure and outcome misclassification, and an incomplete literature review of previous clinical trials of LEN monotherapy. Importantly, due to these limitations, this study is not appropriately designed to address the primary objective. For a study to isolate the specific contribution of a single substance to the efficacy of a combination regimen, treatment arms should demonstrate balance on important baseline covariates, and determinants of the primary exposure must not be predictive of treatment effect. Otherwise, the observed difference in treatment effect will be the summation of the true effect and an un- measurable amount of bias caused by imbalances in patient characteristics between the treatment arms (e.g.: prognosis, refractoriness, adherence, cell of origin, geographic differences in treatment, etc.). Consequently, the distinct contribution of a single substance to a combination regimen will be difficult to ascertain in a non-randomized setting, particularly if the treatment arms are not sampled from the same data source. The sponsor did not provide adequate evidence to demonstrate the study was able to overcome this significant issue.

The strengths and limitations of the RE-MIND study elements are discussed in further detail below.

4.2 PROTOCOL AMENDMENTS IN RESPONSE TO FDA COMMENTS The sponsor submitted a protocol for the RE-MIND study with the meeting package for a Type C meeting which was held on November 9, 2018. The submission of a pre-specified protocol should be considered a strength for this study. In response to FDA suggestions

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during the Type C meeting, the sponsor made several protocol amendments which are reflected in the study design elements described above: • Summarizing missing data and patient follow-up • Requiring 6 months of follow-up • Adding ePS 1:1 matching • Multiple imputation was not used to account for missing data in covariates included in the ePS and the study endpoints for the primary analysis (this was done separately as a sensitivity analysis) • Performing a Validation of Response Assessment for the primary outcome • Requiring a minimum lenalidomide dosage of 25 mg/day • Applying a de-duplication algorithm to remove duplicate patients

In general, these amendments to the original protocol resulted in improved study methods. However, we note several suggested design elements that were not implemented. FDA suggested including additional covariates for matching, such as common laboratory values and other variables likely to be associated with prognosis. Though a few lab values were added (LDH, neutrophil count, and hemoglobin), other important prognostic indicators, such as demographic and lifestyle risk factors, DLBCL cell of origin, ECOG score, or liver and kidney function tests, were not used for matching. Further, we note that IPI, which was originally included as a matching covariate, was not used for matching and the exclusion of this covariate was not listed as a protocol amendment. FDA requested the sponsor perform an outcome validation study to ascertain the accuracy of the study endpoints. Though a response assessment was performed to assess agreement between chart abstractors, no outcome validation was performed. Covariate misclassification was a not assessed via validation as requested.

4.3 STUDY DESIGN In general, a retrospective analysis evaluating treatment efficacy of a combination regimen observed in clinical trial patients compared to single agent activity in an observational cohort is not ideal. As a result of substantial differences in patient selection criteria, ascertainment of exposures and outcomes, and in data quality between clinical trials and RWD observational cohorts, differences in observed treatment efficacy are difficult to interpret without substantial evidence that inherent biases associated with these issues has been overcome. Comparison of prospectively collected data with active screening for study outcomes, as in a clinical trial setting, to observational data collected from a real-world setting, as with the RE-MIND cohort, is likely to result in substantial imbalances in both known and unknown confounders. For this reason, and due to the limitations discussed below, DEPI does not consider the study design adequate to satisfy the first objective, “to isolate the contribution of tafasitamab to efficacy of tafasitamab+LEN combination in a matched cohort comparison.”

The impact of imputed and missing dates was not discussed in the study report. By imputing the first day of the month when day was missing, the study may have slightly underestimated DoR.

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4.4 SAMPLE SIZE AND POWER The sponsor estimated 80% power to detect a 23% difference in the primary outcome (ORR) between tafasitamab+LEN and lenalidomide monotherapy treatment arms for a 1:1 matched cohort with 81 patients in each arm (N=162). The final study size (N=152) was slightly smaller, but the estimated difference in ORR (33%) was higher than the estimated necessary threshold. Thus, the study was adequately powered to detect differences in treatment effect for the primary, and all secondary outcomes. However, the sponsor’s decision not to perform statistical testing for subgroup analyses was likely driven by a lack of statistical power.

4.5 STATISTICAL ANALYSIS The statistical analyses performed to calculate study endpoints, including p-values and confidence intervals, and measures of statistical comparison were appropriate. Though, additional or alternative covariates more closely corelated with disease prognosis or treatment effect in the ePS may have increase internal validity. Also, a sub-group analyses by cell of origin (non-GBC vs. GBC) would have substantially contributed important information to the secondary objective, “to characterize the effectiveness of lenalidomide monotherapy in the treatment of R/R DLBCL patients.”

4.6 6-MONTH FOLLOW-UP RULE In response to FDA comments, the sponsor added a 6-month follow-up rule. The 6-month follow-up rule will have excluded patients under the following circumstances: • Patients with no medical records with DLBCL assessments after index • Patients with a medical record indicating stable disease before 6-months follow- up with no assessments after 6 months • Patients with no assessments during first 6 months after index, but with a record of stable disease or progression after 6 months • Patients with no assessments during first 6 months after index, but with CR, PR, or death after 6 months

While the sponsor implemented the 6-month follow-up rule at the FDA’s request, the specific approach taken was inappropriate. The purpose of a 6-month follow-up requirement is to improve the likelihood of a medical assessment indicating tumor response. Typically, this is done by excluding only patients lost to follow-up during the specified time period after the index day. The effect of the follow-up rule used in this study is difficult to predict. A sensitivity analysis was performed without a 6-month follow-up rule with findings consistent with the primary analysis, indicating the effect of the follow-up rule was minimal.

4.7 STUDY POPULATION This study was performed in R/R DLBCL patients not eligible for HDC followed by ASCT treated with tafasitamab+LEN or lenalidomide monotherapy. This is an appropriate target population. However, R/R DLBCL patients are likely more accurately classified in a trial setting, compared to RWD, due to more rigorous screening procedures.

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For example, even with rigorous screening, for 11 (14%) of 81 patients diagnosed with a R/R DLBCL at time of L-MIND study entry by local pathology assessment, DLBCL diagnosis could not be confirmed by the central pathology lab. Of these 11 patients, 4 could be re-assessed based on availability of additional tumor tissue and 2 of the 4 were reclassified as R/R DLBCL. Thus, 9 (11%) patients in L-MIND were not confirmed as having R/R DLBCL. The study report does not specify the number of L-MIND patients without confirmed R/R DLBCL that were included in the RWE study.

Misdiagnosis of R/R DLBCL is likely more common among the RE-MIND cohort compared to the L-MIND patients, which would result in non-differential misclassification of disease. Consequently, the L-MIND patients may be more likely to respond to treatment.

Furthermore, though the sponsor attempted to select study sites for the RE-MIND cohort that were geographically similar to sites that recruited patients for the L-MIND trial, the final cohorts were not well balanced with respect to location of residence (Table 6). This largely due to patients not being matched based on location. Regional differences in treatment of R/R DLBCL may make the cohorts less comparable, threatening the validity of both study objectives.

Table 6: Country of Residence for L-MIND (N=81) and RE-MIND (N=76) patients. L-MIND RE-MIND Country of Residence (N=81) (N=76) n % n % US 6 7.4 47 61.8 Europe 75 92.6 29 38.2 Belgium 5 6.2 ‧ ‧ Czech Republic 3 3.7 ‧ ‧ France 9 11.1 ‧ ‧ Germany 11 13.6 ‧ ‧ Great Britain 5 6.2 ‧ ‧ Hungary 7 8.6 ‧ ‧ Italy 13 16.0 29 38.2 Poland 7 8.6 ‧ ‧ Spain 15 18.5 ‧ ‧

4.8 COVARIATES Measured and unmeasured confounding was not adequately controlled in the RE-MIND study. Based on the 9 covariates used for matching, the study claimed an absolute standardized difference of <0.2 for 7 of the 9 covariates. However, an absolute standardized difference of <0.1, achieved for 5 of 9 covariates, is considered standard for minimization of covariate imbalance.29,30 Notably, the largest imbalances were for Ann Arbor Stage and number of prior lines of therapy, both indicating more advanced disease progression in the RE-MIND patients. Among measured covariates not used for

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matching, including ECOG score and IPI, imbalances also tended to indicate more advanced disease progression in the RE-MIND patients.

Data on cell of origin, an important predictor or treatment response to lenalidomide, was missing for most L-MIND patients and RE-MIND patients. Further, among available data on DLBCL cell of origin in the L-MIND patients, the distribution of patients is different based on method of ascertainment, with cell of origin determined through immune- histochemistry indicating a higher proportion of GBC patients while cell of origin determined through genetic expression showed a higher proportion of non-GBC patients (Table 7). These data may be a result of poor agreement between tests or misclassification. Alternatively, this apparent discrepancy may be a result of L-MIND patients may have one test or the other, but not both. However, the large amount of missingness renders this data difficult to interpret without patient-level test values.

Table 7: DLBCL Cell of Origin ascertained through immune-histochemistry vs. genetic profiling. Tafasitamab+LEN LEN monotherapy Variable Value N=76 N=76 Cell of origin GBC 34 (44.7) 14 (18.4) (immune-histochemistry); Non-GBC 20 (26.3) 16 (21.1) n (%) Missing 22 (28.9) 46 (60.5) GBC 7 (9.2) 0 Cell of origin ABC 19 (25.0) 0 (genetic expression); Unclassified 4 (5.3) 0 n (%) Missing 46 (60.5) 76 (100)

Additional confounders which were not evaluated in the analysis but may have an important influence on patient treatment and disease prognosis include: lifestyle risk factors (smoking, alcohol use, nutrition, etc.), BMI, previous treatments, and other patient comorbidities (diabetes, heart disease, hypertension, etc.). The difficulties in ascertaining this information in a real-world setting underlines the importance of treatment randomization in a clinical trial setting. Furthermore, patients were not matched by age, gender, or geographic location.

4.9 EXPOSURE The sponsor aims to market tafasitamab as a combination treatment to be administered with lenalidomide. Because the pivotal trial did not include a randomized control arm, the RE-MIND cohort was established with the primary purpose of isolating the specific contribution of tafasitamab to the efficacy of tafasitamab+LEN combination. Thus, the lenalidomide monotherapy arm is likely the most appropriate comparison treatment.

However, though a growing body of evidence show that lenalidomide as monotherapy or incubation with other drugs has demonstrated efficacy in treating R/R DLBCL,31 according to the FDA label for lenalidomide, R/R DLBCL is not an approved indication for this drug in the US or in Europe. According to the FDA label, approved indications for lenalidomide include:

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• Multiple myeloma (MM), in combination with dexamethasone, in patients who have received at least one prior therapy.

• Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

• Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide is also approved to treat MM, MDS, and MCL in Europe. Because lenalidomide is not currently indicated to treat R/R DLBCL, patient undergoing off-label treatment with lenalidomide monotherapy may not be representative of the R/R DLBCL target population.

4.10 OUTCOMES This study analyzed 8 study endpoints, including: • Best Overall/objective Response Rate (ORR) • Complete Response (CR) Rate • Median Overall Survival (OS) • Disease Control Rate (DCR) • Median Duration of Response (DoR) • Progression-free Survival (PFS) • Time to Next Treatment (TTND) • Event-free Survival (EFS)

Though overall survival is known to be well measured within FlatIron, with high accuracy and validity, none of the other study outcomes have been validated. Ascertainment of tumor response and time to event outcomes is likely to occur under very different circumstances in a regular treatment setting compared to a clinical trial where patients are actively and rigorously screened at regular, pre-set time intervals. By contrast, real-world patient visits may occur at varying frequency with inconsistent time intervals between appointments, depending on the patients’ health, availability and capability for healthcare visits, and provider preferences. Further, validity of real-world outcomes is dependent on accurate provider records. Given differences in outcome ascertainment methods between study arms, non-differential misclassification of outcomes is likely. The effects of non-differential misclassification on the study findings are difficult to predict.

4.11 UNMEASURED CONFOUNDING ANALYSIS The unmeasured confounding analysis was limited. The analysis found an unmeasured binary variable that was a near perfect predictor of the outcome and increased the odds of exposure by a factor of 1.6 would nullify the statistical significance of the primary outcome. While this is an unlikely scenario for a single binary variable, it is not

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impossible that multiple unmeasured confounders could increase the probability of tafasitamab+LEN exposure by 60%. For example, physicians may have been more likely to enroll their patients in L-MIND if they new the patient was a non-GBC, and other factors, such as overall health, smoking status, and patient compliance and motivation can increase their odds of enrollment in a trial. While these unmeasured confounders may not eradicate the differences in treatment effect between the L-MIND and RE-MIND cohorts, there is likely a substantial influence, primarily a consequence of selection bias, which renders the study’s primary objective unobtainable.

4.12 VALIDATION OF RESPONSE ASSESSMENTS VS. OUTCOME VALIDATION Findings from the Validation of Response Assessments are concerning, showing uneven agreement between chart reviewers dependent on treatment response. The sponsor did not calculate a Cohen's kappa coefficient (κ), which would have aided in interpretation of the assessment.

DEPI notes that medical chart review is generally considered of high quality for epidemiological study when all study data is observational. However, the motivation for the outcome validation study suggested in response to the November 2018 Type C meeting questions was to estimate differences in outcome ascertainment between the clinical trial data and real-world data. As mentioned above, non-differential misclassification of study outcomes is likely, and the effects on the study findings can not be estimated without validation.

4.13 LITERATURE REVIEW The sponsor’s literature comparing findings from L-MIND and RE-MIND to previous clinical trials of LEN monotherapy excluded two important studies.26,27 Hernandez- Ilizaliturri (2011) and Mondello (2016) each found large differences in treatment response among DLBCL patients with non-GBC (or ABC) cell of origin compared to GBC cell of origin. Among L-MIND patients with known cell of origin ascertained via genetic expression (n=30), a high proportion (76.6%) were non-GBC, which is a higher proportion observed by either Hernandez-Ilizaliturri (42.5%) and Mondello (53.7%). Therefore, if this was representative of the patient population as a whole, a high rate of treatment response in the L-MIND arm would be expected. Table 8 shows an expanded comparison of L-MIND and RE-MIND to previous clinical trials of LEN monotherapy including Hernandez-Ilizaliturri (2011) and Mondello (2016).

Table 8. RE-MIND and L-MIND in Context of Historical Trials – Expanded to include Hernandez-Ilizaliturri (2011) and Mondello (2016). Outcome Study Treatment Median Median OS, ORR, % CR, % PFS, months months L-MIND (N=76) Taf+LEN 67.1 39.5 12.1 Not reached RE-MIND (N=76) LEN 34.5 13.2 4.0 9.4 RWD Broccoli 2019 (N=153) LEN 29 24 6.0 12.0 Witzig 2011 (N=108) LEN 28 7 2.7 — Czuczman 2017 (N=51) LEN 27 10 3.1 7.1 Wiernik 2008 (N=29)* LEN 21 10 4** —

Reference ID: 4619965

Ilizaliturri 2011 (N=40)*** LEN 53 / 9 24 / 4 6 / 2 14 / 13.5 Mondello 2016 (N=123)*** LEN 65 / 3 32 / 0 67 / 30 38 / 42 * Including 3 transformed low-grade lymphoma cases. ** Numbers are based on the overall population, including R/R DLBCL. ***Results split into non-germinal center B‐cell–like (non-GBC) / germinal center B‐cell–like (GBC)

Notably, a subgroup analysis among L-MIND patients with non-missing cell of origin data found an ORR of 71% among non-GBC patients and 49% among GBC patients, which is noticeably higher than previous trials of lenalidomide monotherapy (Table 9). A similar subgroup analysis was not conducted among the RE-MIND cohort.

Table 9. Treatment Responses Among L-MIND Patients with Non-Missing Cell of Origin Data (n=58). Non-GBC GBC Response Categories (n=37) (n=21) n % n % Best Objective Response Rate 15 71.4 18 48.6 Complete Response 11 52.4 11 29.7 Partial Response 4 19.0 7 18.9 * Cell of origin determined via immune-histochemistry.

5 CONCLUSION The validity of the study is compromised by several limitations in the study design. Bias resulting from key differences in patient selection and unequal distribution of important prognostic indicators between treatment arms are likely to favor the L-MIND patients. Consequently, because the treatment arms are not directly comparable, this study does not provide sufficient evidence to isolate the contribution of tafasitamab to the efficacy of tafasitamab+LEN combination therapy for DLBCL.

DEPI defers to DHP as to the interpretation of the single arm, phase II trial. We note the ORR observed in L-MIND was higher than has been observed in previous trials, especially among patients with GBC cell of origin.

6 RECOMMENDATIONS TO DHM-II • RWD patients in the RE-MIND study are not comparable to patients enrolled in L-MIND, with imbalances tending to favor estimated treatment efficacy in the L- MIND arm.

• The study did not meet its primary objective, to isolate the contribution of tafasitamab to efficacy of tafasitamab+LEN combination in a matched cohort, primarily due to limitations associated with comparing patients across datasources that differ in terms of purpose of collection, study period, patient eligibility, geographic location, and methods for recording and ascertaining covariates, exposures, and outcomes.

Reference ID: 4619965

• The study partially met its secondary objective, to characterize the effectiveness of lenalidomide monotherapy in the treatment of R/R DLBCL patients. However, a sub-group analyses by cell of origin (non-GBC vs. GBC), addition of additional descriptive variables, such as lifestyle factors and comorbidities, and exploration of differences in treatment patterns and prognosis across geographic region would have substantially contributed important information to this analysis.

• DEPI defers to the clinical review team as the interpretation of the single arm data for a combination treatment as observed in the L-MIND phase II pivotal trial.

Reference ID: 4619965

7 REFERENCES

1 Gurbaxani S. et al. Diffuse large B-cell lymphoma—more than a diffuse collection of large B cells: an entity in search of a meaningful classification. Arch Pathol Lab Med.2009 Jul; 133(7):1121–1134. doi: 10.1043/1543-2165-133.7.1121. 2 Li Y, Wang Y, Wang Z, Yi D, Ma S. Racial differences in three major NHL subtypes: Descriptive epidemiology. Cancer Epidemiol. 2015;39:8–13. doi: 10.1016/j.canep.2014.12.001. 3 Smith A. et al. Incidence of haematological malignancy by sub-type: a report from the Hematological Malignancy Research Network. Br J Cancer.2011 Nov; 105(11):1684–92. Epub 2011 Nov 1. 4 Cairo MS, Perkins SL. Hematological Malignancies in Children, Adolescents and Young Adults. First edition. World Scientific Publishing Co.; Singapore: 2012. 5 James R. Cerhan, Anne Kricker, Ora Paltiel, et al. Medical History, Lifestyle, Family History, and Occupational Risk Factors for Diffuse Large B-Cell Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project, JNCI Monographs, Volume 2014, Issue 48, August 2014, Pages 15–25. 6 López-Guillermo A. et al. Diffuse large B-cell lymphoma: clinical and biological characterization and outcome according to the nodal or extranodal primary origin. J Clin Oncol. 2005 April; 23(12): 2797–04. Epub 2005 Feb 22. 7 Fameli-Pavlaki M. Diffuse large B-cell lymphoma–part I: towards homogeneity. Haema. 2005; 8:201–14. 8 Kristin E. Hunt and Kaaren K. Reichard (2008) Diffuse Large B-Cell Lymphoma. Archives of Pathology & Laboratory Medicine: January 2008, Vol. 132, No. 1, pp. 118-124. 9 Swerdlow S.H. et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May; 127:2375–2390. doi: 10.1182/blood- 2016-01-643569. Epub 2016 Mar 15. 10 Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–511. 11 Lenz G, Wright GW, Emre NCT, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA. 2008;105:13520–13525. 12 Kwak JY. Treatment of diffuse large B cell lymphoma. Korean J Intern Med. 2012;27(4):369–377. doi:10.3904/kjim.2012.27.4.369 13 FDA News Release. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. October 18, 2017. https://www.fda.gov/news- events/press-announcements/fda-approves-car-t-cell-therapy-treat-adults-certain- types-large-b-cell-lymphoma (Accessed: 35MAR2020)

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14 Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2008; 26:4952-7. 15 Nowakowski GS, Chiappella A, Witzig TE, et al. ROBUST: lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Future Oncology. 2016;12(13):1553-63. 16 Vitolo U, Trneˇ ny´ M, Belada D, et al: Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol 35:3529-3537, 2017. 17 Armitage JO, Mauch PM, Harris NL, Dalla-Favera R, Bierman PJ. Diffuse large B-cell lymphoma. In: Mauch PM, Armitage JO, Coiffier B, Dalla-Favera R, Harris NL, eds. Non-Hodgkin Lymphomas. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:304-326. 18 Rovira J et al. Prognosis of patients with diffuse large B cell lymphoma not reaching complete response or relapsing after frontline chemotherapy or immunochemotherapy. Ann Hematol. 2015; 94: 803–812. 19 Galaznik A, Huelin R, Stokes M, et al. Systematic review of therapy used in relapsed or refractory diffuse large B‐cell lymphoma and follicular lymphoma. Future Sci OA. 2018; 4( 7):FSO322. 20 Zhang, X.; Schwartz, J.C.; Guo, X.; Bhatia, S.; Cao, E.; Lorenz, M.; Cammer, M.; Chen, L.; Zhang, Z.Y.; Edidin, M.A.; et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 2004, 20, 337–347. 21 Chavez JC, Bachmeier C, Kharfan-Dabaja MA. CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Ther Adv Hematol. 2019; 10: 1-10. 22 Gutierrez-Garcia G, Cardesa-Salzmann T, Climent F, et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117:4836–4843. 23 Lossos, I. S. , D. K. Czerwinski , and A. A. Alizadeh . et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004. 350:1828–1837. 24 Linderoth, J. , M. Jerkeman , E. Cavallin-Stahl , S. Kvaloy , and E. Torlakovic . Immunohistochemical expression of CD23 and CD40 may identify prognostically favorable subgroups of diffuse large B-cell lymphoma: a Nordic Lymphoma Group Study. Clin Cancer Res 2003. 9:722–728. 25 Liu Y, Barta SK. Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2019;94:604–16. 26 Mondello P, Steiner N, Willenbacher W, et al. Lenalidomide in relapsed or refractory diffuse large B-cell lymphoma: Is it a valid treatment option? Oncologist. 2016;21 (9):1107-1112.

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27 Hernandez-Ilizaliturri, F. J. et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell- like than in germinal center B-cell-like phenotype. Cancer 117, 5058–5066 (2011). 28 Rosenbaum PR and Rubin DB. The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika 1983; 70:41-55. 29 Normand SLT, Landrum MB, Guadagnoli E, Ayanian JZ, Ryan TJ, Cleary PD, McNeil BJ. Validating recommendations for coronary angiography following an acute myocardial infarction in the elderly: a matched analysis using propensity scores. Journal of Clinical Epidemiology. 2001;54:387–398. 30 Peter C. Austin (2009) Using the Standardized Difference to Compare the Prevalence of a Binary Variable Between Two Groups in Observational Research, Communications in Statistics - Simulation and Computation, 38:6, 1228-1234, DOI: 10.1080/03610910902859574 31 Li-Yangxue Ma, Li Su. Application of Lenalidomide on Diffused Large B-cell Lymphoma: Salvage, Maintenance, and Induction Treatment. Chin Med J (Engl). 2018 Oct 20; 131(20): 2510–2513.

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8 APPENDICES

8.1 APPENDIX FIGURE A1. L-MIND (MOR208C203) TREATMENT EMERGENT ADVERSE EVENTS

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

8.2 APPENDIX FIGURE A2. FINDINGS FORM NHL STUDY (MOR208C201) OF TAFASITAMAB MONOTHERAPY

*Figure presented during MorphoSys Applicant Orientation Meeting for BLA 761163; February 21, 2020

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8.3 FDA FEEDBACK FOR NOVEMBER 9, 2018 TYPE C MEETING Question form MorphoSys: Does the Division agree with the principles of the provided feasibility report, as well as the research protocol and statistical analysis plan for the collection and analysis of person-level data obtained from Real World Data Sources for R/R-DLBCL patients treated with LEN monotherapy?

FDA Response: We have significant concerns with your proposal, which are further outlined below:

a. The data quality from the LMIND study may differ from that of the lenalidomide monotherapy cohort. For example, they may have different type and/or amount of missing data and/or different duration of follow-up. Provide summary data such as the amount of missing data (e.g. lab assessments) and duration of follow-up to demonstrate comparability. Additionally, for each data element collected, evidence should be provided demonstrating that these data elements can be captured adequately, accurately, and non-differentially for the LMIND study and lenalidomide monotherapy arms.

b. The lenalidomide monotherapy cohort should resemble patients in the LMIND study. We note several differences in study inclusion and exclusion criteria exist between the LMIND study and the lenalidomide monotherapy cohort. These differences can lead to selection bias and should be addressed and mitigated in the protocol.

Additionally, we recommend you use a matching approach rather than the overlap weights approach. The lenalidomide monotherapy cohort should be induced by matching patients from the database to patients in the LMIND study. You mentioned that matching has the potential to lead to sample size attrition. We acknowledge that this can happen. However, a substantial attrition is indicative of two very different populations such that it may not be reasonable to compare them.

The issue of including only covariates that affect the outcome and predict treatment assignment is not adequately addressed as it is not established a priori what covariates affect the outcome. It is not clear that the covariates you proposed are comprehensive as there may be other covariates, measured or unmeasured, that also affect the outcome. In randomized studies, we do not worry about which covariates affect the outcome as randomization ensures balance. When conducting observational studies, you should consider matching on as many reasonable covariates. You have listed Age; Ann-Arbor stage; IPI score; refractoriness to previous line of therapy; number of prior lines of therapy; history of primary refractoriness; prior ASCT. Other covariates such as laboratory values prior to index date should be included.

c. At this time, the Agency does not accept imputation of missing covariates for the purpose of estimating propensity scores. The Agency also has concerns regarding imputation of last assessments for missing response assessments in the lenalidomide monotherapy cohort as this can bias the response assessment against the lenalidomide monotherapy cohort.

d. We have concerns with the collection of response data for assessment of the ORR endpoint (primary endpoint in the LMIND STUDY):

Data collected from clinical notes alone may not allow assessment of different aspects of response criteria (CR, PR). You should consider a validation study in patients who have clinical notes and imaging studies to ensure robustness of collected data.

• Additionally, it is not clear that such information is captured with the same kind of rigor as that captured in the LMIND study: – Is a reported response an actual response? – Is a reported lack of response an actual lack of response?

We refer to this as outcome misclassification. To the extent that there is outcome misclassification in the lenalidomide monotherapy cohort, the response rate in this cohort is not identifiable as it is contaminated by the misclassification process. To the extent that outcome misclassification is differential between the MOR208+Len LMIND cohort and the lenalidomide monotherapy cohort, the estimated difference (or ratio, odds ratio) of the response rates is also biased. Please note that for accurate assessment of the endpoints a minimum duration of follow up of 6 months for each patient included in the monotherapy cohort is recommended.

e. In addition to outcome misclassification, you also have not addressed covariate misclassification. While covariates such age, race, and gender may be less susceptible to misclassification, it is not clear that characteristics such as medical history, disease staging, prior therapies at the time of the lenalidomide monotherapy index date, are adequately captured. As the propensity scores are derived from covariates, it is critical that their values at the time of the index date are captured accurately.

f. Lenalidomide has been used in different dose levels in the treatment of DLBCL. You should only include patients if they were initiated on a 25 mg dose of lenalidomide at the index date (dose of lenalidomide in LMIND study).

g. Potential overlap between these data sources may exist, such that an individual patient maybe in more than one database. Please clarify whether the data sources contain unique patients and if there is any way to verify this.

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8.4 INCLUSION CRITERIA FOR THE L-MIND (MOR208C203) 1. Age > 18 years 2. Histologically confirmed diagnosis of DLBCL not otherwise specified; T-cell/histiocyte rich large B-cell lymphoma; Epstein-Barr virus (EBV) positive DLBCL of the elderly (EBV-positive DLBCL), Grade 3b Follicular Lymphoma, Composite lymphoma with a DLBCL component with a subsequent DLBCL relapse, according to the Revised European American Lymphoma/World Health Organization (WHO) classification. Additionally, patients with the evidence of histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma (e.g., an indolent pathology such as follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia) into DLBCL with a subsequent DLBCL relapse were also eligible. 3. Fresh tumor tissue for central pathology review and correlative studies had to be provided as an adjunct to participation in this study. If it was not possible to obtain a fresh tumor tissue sample from the patient, archival paraffin embedded tumor tissue acquired: 3 years prior to screening for this protocol had to be available for this purpose. 4. Patients had to demonstrate: a) a relapsed and/or refractory disease as defined in the protocol b) at least one bidimensionally measurable disease site. The lesion had to have a greatest transverse diameter of ≥ 1.5 cm and greatest perpendicular diameter of ≥ 1.0 cm at baseline. The lesion had to be positive on positron emission tomography scan c) received at least one, but no more than three previous systemic regimens for the treatment of DLBCL and one therapy line had to include a CD20 targeted therapy (e.g., RTX) d) an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 5. Patients not considered eligible in the opinion of the investigator, or patients unwilling to undergo intensive salvage therapy including ASCT because of, but not limited to, advanced age, comorbidities, impossibility or, refusal to perform ASCT. Documentation of the reason for a patient's ineligibility had to be provided in the patient's source data. 6. Patients had to meet the following laboratory criteria at screening: a) absolute neutrophil count ≥ 1.5 x 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy) b) platelet count ≥ 90 x 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy) c) total serum bilirubin ≤ 2.5 x upper limit of normal (ULN) unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma. Patients with Gilbert's syndrome or with documented liver involvement by lymphoma may have been included if their total bilirubin was ≤ 5 x ULN (see exclusion criterion 5g) d) alanine transaminase (ALT); aspartate aminotransferase (AST), and alkaline phosphatase (AP) ≤ 3 x ULN or < 5 x ULN in cases of documented liver involvement e) serum creatinine clearance had to be ≥ 60 mL/minute either measured or calculated using a standard Cockcroft and Gault formula. 7. Females of childbearing potential (FCBP) had to: a) be non-pregnant as confirmed by a negative serum pregnancy test at screening and a medically supervised urine pregnancy test prior to starting study therapy b) have refrained from breastfeeding and donating blood or oocytes during the course of the study and for 3 months after the last dose of study medication. Restrictions concerning blood donation also applied to females who were not of childbearing potential c) have agreed to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applied even if the patients practiced complete and continued sexual abstinence d) have committed to continued abstinence from heterosexual intercourse if it was in accordance with her lifestyle (which must be reviewed on a monthly basis) or agreed to use and were able to comply with the use of effective contraception without interruption during the study and for 3 months after the last dose of study medication. 8. Males had to use an effective barrier method of contraception without interruption, refrained from donating blood or sperm during the study participation and for 3 months after the last dose of study medication if the patient was sexually active with a FCBP 9. In the opinion of the investigator the patients had to: a) be able and willing to receive adequate prophylaxis and/or therapy for thromboembolic events b) be able to understand, give written informed consent and comply with all study-related procedures, medication use, and evaluations c) have no history of noncompliance in relation to medical regimens or not be considered potentially unreliable and/or uncooperative d) be able to understand the reason for complying with the special conditions of the pregnancy prevention risk management plan and give written acknowledgement of this.

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8.5 EXCLUSION CRITERIA FOR THE L-MIND (MOR208C203) 1. Patients who had: a) any other histological type of lymphoma including primary mediastinal (thymic) large B-cell or Burkitt lymphoma b) primary refractory DLBCL c) a history of "double/triple-hit" genetics DLBCL characterized by simultaneous detection of MYC with BCL-2 and/or BCL-6 translocation(s) defined by fluorescence in-situ hybridization. MYC, BCL-2, BCL-6 testing prior to study enrolment was not required 2. Patients who had, within the 14 days prior to Day 1 dosing: a) not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anti-cancer therapy or other lymphoma-specific therapy b) undergone major surgery or suffered from significant traumatic injury c) received live vaccines d) required parenteral antimicrobial therapy for active, intercurrent infections 3. Patients who: a) had, in the opinion of the investigator, not recovered sufficiently from the adverse toxic effects of prior therapies b) were previously treated with CD19-targeted therapy or immunomodulatory drugs (IMiDs)® (e.g., thalidomide, LEN) c) had a history of hypersensitivity to compounds of similar biological or chemical composition to MOR00208, IMiDs® and/or the excipients contained in the study drug formulations d) had undergone ASCT within the period ≤ 3 months prior to the signing of the Informed Consent Form. Patients who had a more distant history of ASCT had to exhibit full hematological recovery before enrolment into the study e) had undergone previous allogenic stem cell transplantation f) had a history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia or were at a high risk for a thromboembolic event in the opinion of the investigator and who were not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period g) concurrently used other anti-cancer or experimental treatments 4. Prior history of malignancies other than DLBCL, unless the patient had been free of the disease for ≥ 5 years prior to screening. Exceptions to the ≥ 5-year time limit included history of the following: a) basal cell carcinoma of the skin b) squamous cell carcinoma of the skin c) carcinoma in situ of the cervix d) carcinoma in situ of the breast e) carcinoma in situ of the bladder f) incidental histological finding of prostate cancer (Tumour/Node/Metastasis stage of T1a or T1b) 5. Patients exhibiting: a) positive hepatitis B and/or C serology b) known seropositivity for or history of active viral infection with human immunodeficiency virus c) central nervous system (CNS) lymphoma involvement - present or past medical history d) history or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that in the investigator's opinion precluded participation in the study or compromised the patient's ability to give informed consent e) history or evidence of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption f) gastrointestinal abnormalities including the inability to take oral medication, requiring intravenous alimentation, or prior surgical procedure affecting absorption g) history or evidence of severe hepatic impairment (total serum bilirubin > 3 mg/dL), jaundice unless secondary to Gilbert's syndrome or documented liver involvement by lymphoma (see inclusion criterion 6c)

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8.6 APPENDIX TABLE A1. FOLLOW-UP RULES EXAMPLES FOR RE-MIND (MOR208C206) Baseline 6 months Best response from index Best response from day 184 Situation Response FU rule date to day 183 onwards assessment fulfilled Disease progression or death No assessment/Assessment 1 Available (as a best response or Yes done/Death otherwise)

2 Available SD, indeterminate, NE, “other” At least one assessment/Death Yes

SD, indeterminate, NE, “other” 3 Available No assessment No and no PD/Death

4 Available CR or PR At least one assessment/Death Yes

5 Available CR or PR No assessment Yes

6 Available No assessment CR or PR Yes

7 Available No assessment Disease progression/Death No

8 Available No assessment SD, indeterminate, NE, other No

9 Available No assessment No assessment No

Not 10 N/A N/A Excluded Available

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8.7 ANALYSIS COHORTS FOR RE-MIND (MOR208C206) 1. Enrolled Patients (ENR): all patients enrolled in the RWD and L-MIND studies and received at least one dose of LEN and Tafasitamab+LEN, respectively 2. Observational Enrolled Analyses Set (Ob-ENR): all patients enrolled in the observational study for whom any data was collected 3. Observational Full Analysis Set (OB-FAS): all patients in Ob-ENR with a minimum of 6 months follow-up and meeting inclusion/exclusion criteria 4. Observational Full Analysis Set with LEN starting dose of 25 mg/day (Ob-FAS25): subset of Ob-FAS that includes all patients with LEN starting dose of 25 mg/day 5. Modified Observational Full Analysis Set (mOb-FAS): subset of Ob-ENR who meet inclusion/exclusion criteria but without consideration of 6-month follow-up 6. Modified Observational Full Analysis Set with LEN starting dose of 25 mg/day (mOb- FAS25): subset of mOb-FAS that includes all patients with LEN starting dose of 25 mg/day 7. Full Analysis Set (FAS): includes patients from Ob-FAS and patients from L-MIND who received at least one dose of tafasitamab and one dose of lenalidomide with at least 6 months follow-up and meeting inclusion/exclusion criteria 8. Full Analysis Set with LEN starting dose of 25 mg/day (FAS25): subset of FAS that includes all patients with LEN starting dose of 25 mg/day 9. Modified Full Analysis Set (mFAS): includes patients from Ob-ENR meeting inclusion/exclusion criteria and patients from L-MIND who received at least one dose of tafasitamab and one dose of lenalidomide also meeting inclusion/exclusion criteria 10. Modified Full Analysis Set with LEN starting dose of 25 mg/day (mFAS25): subset of m- FAS that includes all patients with LEN starting dose of 25 mg/day 11. Matched Analysis Set (MAS): subset of FAS that includes 1:1 matched patients from L- MIND and RWD cohort using 9 baseline covariates 12. Primary analysis set - Matched Analysis Set with LEN starting dose of 25 mg/day (MAS25): subset of FAS25 that includes 1:1 matched patients from L-MIND and RWD cohort using 9 baseline covariates 13. Modified Matched Analysis Set (mMAS): subset of mFAS that includes 1:1 matched patients from L-MIND and RWD cohort using 9 baseline covariates 14. Modified Matched Analysis Set with LEN starting dose of 25 mg/day (mMAS25): subset of mFAS25 that includes 1:1 matched patients from L-MIND and RWD cohort using 9 baseline covariates 15. Matched Analysis Set with the use of calipers (MAS_Cal): subset of FAS and includes 1:1 caliper-matched patient from L-MIND and RWD cohort using 9 baseline covariates 16. Matched Analysis Set with the use of calipers with LEN starting dose of 25 mg/day (MAS25_Cal): subset of FAS25 and includes 1:1 caliper-matched patient from L-MIND and RWD cohort using 9 baseline covariates 17. Modified Matched Analysis Set with the use of calipers (mMAS_Cal): subset of mFAS and includes 1:1 caliper-matched patient from L-MIND and RWD cohort using 9 baseline covariates 18. Modified Matched Analysis Set with the use of calipers with LEN starting dose of 25 mg/day (mMAS25_Cal): subset of mFAS25 and includes 1:1 caliper-matched patient from L-MIND and RWD cohort using 9 baseline covariates

Reference ID: 4619965

8.8 APPENDIX FIGURE A3. FORREST PLOT OF BEST OBJECTIVE RESPONSE RATE BY SUBGROUPS (MAS25)

*Figure displayed in RE-MIND (MOR208C206) study report.

Reference ID: 4619965 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

RICHARD S SWAIN 06/10/2020 11:33:28 AM

SIMONE P PINHEIRO 06/10/2020 01:46:05 PM

MICHAEL D BLUM 06/11/2020 06:56:05 AM

Reference ID: 4619965 LABEL AND LABELING REVIEW Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: May 14, 2020 Requesting Office or Division: Division of Hematologic Malignancies 2 (DHM 2) Application Type and Number: BLA 761163 Product Name, Dosage Form, Monjuvi (tafasitamab-cxix) for Injection, 200 mg/vial and Strength: Product Type: Single Ingredient Product Rx or OTC: Prescription (Rx) Applicant/Sponsor Name: MorphoSys US Inc. FDA Received Date: December 30, 2019, March 17, 2020, and April 21, 2020 OSE RCM #: 2019-2677 DMEPA Safety Evaluator: Nicole Iverson, PharmD, BCPS DMEPA Team Leader: Hina Mehta, PharmD

Reference ID: 4608619 1 REASON FOR REVIEW As part of the approval process for BLA 761163 Monjuvi (tafasitamab-cxix) for Injection, 200 mg/vial, this review evaluates the proposed container label, carton labeling, and Prescribing Information (PI) for areas that may lead to medication errors.

2 MATERIALS REVIEWED We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed. Table 1. Materials Considered for this Review Material Reviewed Appendix Section (for Methods and Results) Product Information/Prescribing Information A Previous DMEPA Reviews B Human Factors Study C- N/A ISMP Newsletters* D – N/A FDA Adverse Event Reporting System (FAERS)* E – N/A Other F- N/A Labels and Labeling G N/A=not applicable for this review *We do not typically search FAERS or ISMP Newsletters for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED MorphoSys US Inc. submitted a 351 (a) application to obtain marketing approval of Monjuvi for Injection. Monjuvi is proposed in combination with lenalidomide followed by Monjuvi monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade lymphoma and who are not eligible for, (b) (4) autologous stem cell transplant (ASCT). We performed a risk assessment of the proposed container label, carton labeling, and PI for Monjuvi (tafasitamab-cxix) for Injection to determine whether there are significant concerns in terms of safety related to preventable medication errors. We identified areas of the proposed label and labeling that could be revised to improve clarity and readability of important information. For the Division, we note that the PI lacks clarity in the recommended dosage schedule, reconstitution instructions, dilution instructions, and storage information. In 2

Reference ID: 4608619 addition, the PI uses as placeholder for the conditionally accepted nonproprietary name, tafasitamab-cxix and the National Drug Code (NDC) numbers. For the Applicant, we note the label and labeling have a placeholder for the conditionally accepted nonproprietary name, tafasitamab-cxix proprietary name and NDC numbers. We also note the administration and storage information lack prominence on the labels and labeling. These factors may confuse the user and inadvertently lead to medication errors. We provide recommendations for the Division in Section 4.1 and the Applicant in Section 4.2 to address these deficiencies.

4 CONCLUSION & RECOMMENDATIONS We identified areas in the proposed PI that can be improved to increase readability and prominence of important information and promote the safe use of the product. We provide recommendations in Section 4.1 for the Division and Section 4.2 for MorphoSys US Inc to address our concerns.

4.1 RECOMMENDATIONS FOR DIVISION OF HEMATOLOGIC MALIGNANCIES 2 (DHM 2) A. Highlights of Prescribing Information 1. General Comments a. Replace all presentations of the nonproprietary name, “tafasitamab” to the conditionally acceptable nonproprietary name, “tafasitamib-cxix”. 2. Dosage and Administration Section a. The dosage information as presented in the Dosage and Administration section lacks clarity due to the layout in which the information is presented. Lack of clarity may lead to underdose or overdose medication errors. Revise the statements for clarity, (b) (4) (b) (4) (b) (4) to “The recommended dosage of MONJUVI is 12 mg/kg as an intravenous infusion according to the following dosing schedule:”. B. Full Prescribing Information 1. Dosage and Administration Section a. Section 2 Dosage and Administration i. Revise the statement under Section 2 Dosage and Administration, (b) (4)

Reference ID: 4608619 (b) (4)

(b) (4) to ““MONJUVI should be administered by a healthcare professional, with immediate access to emergency equipment and appropriate medical support to manage infusion related reactions (IRRs) [see Warnings and Precautions (5.1)].”

b. Section 2.1 Recommended Dosage i. The dosage information as presented in the Dosage and Administration section lacks clarity, which may lead to underdose or overdose medication errors. We recommend clarifying if the dosing per weight should be based on actual body weight or ideal body weight. ii. The dosage information as presented in the Dosage and Administration section lacks clarity due to the layout in which the information is presented. As currently presented, it is not clear when Monjuvi should be administered in combination with lenalidomide or as monotherapy. Therefore, we recommend putting this information in a tabular format for clarity to appear in Section 2.1 Recommended Dosage as follows: Table: Monjuvi Dosing Schedule in Combination with Lenalidomide (up to 12 cycles)

Cycle* Dosing schedule

Cycle 1 Days 1, 4, 8, 15, and 22

Cycles 2-3 Days 1, 8, 15, and 22 of each cycle

Cycle 4 until disease progression Days 1 and 15

Reference ID: 4608619 iii. Revise the statement, (b) (4) To “Each treatment cycle consists of a 28-day period.” for clarity and place below the table with an asterisk. iv. Delete the statements, (b) (4) (b) (4)

c. Section 2.2 (b) (4) and Section 2.3 (b) (4)

i. The dosage modification table contains the symbols, “µL”, “≥”, or “<”. We recommend avoiding the use of symbols in text that will be used to make dosing decisions as they can be misinterpreted. Replace abbreviations and symbols in relevant sections with the intending meaning. d. Section 2.4 Preparation and Administration i. The Prescribing Information advises (b) (4) (b) (4)

(b) (4), we recommend deleting the statement, (b) (4) (b) (4)

ii. The reconstitution instructions lack clarity, which may lead to product preparation errors. Therefore we recommend: a. Delete the statement, (b) (4) (b) (4) (b) (4) as the second step already contains this information. b. Revise Step 1 to appear as, “Calculate the dose (mg) and determine the number of vials needed. c. Revise Step 2 to appear as, “Reconstitute each 200 mg MONJUVI vial with 5 mL Sterile Water for Injection, USP, 5

Reference ID: 4608619 with the stream directed toward the inside wall of each vial to obtain a final concentration of 40 mg/mL of tafasitamb-cxix. d. Revise Step 3 to read “Gently swirl the vial until completely dissolved. Do not shake or swirl vigorously. Complete dissolution may take up to 5 minutes.” for increased clarity. e. Revise Step 5 to appear as, “Use reconstituted solution immediately. If needed, store the reconstituted solution in the vial for a maximum of 12 hours refrigerated at 36°F to 46°F (2°C to 8°C) or room temperature at 68°F to 77°F (20°C to 25°C) prior to dilution.” iii. The dilution instructions lack clarity, which may lead to product preparation errors. Therefore we recommend: a. Revise Step 1 to appear as, “Determine the volume of 40 mg/mL reconstituted solution needed based on the required dose.” b. Add a step (b) (4) (b) (4) . Revise the statement to read “Remove a volume equal to the required volume of MONJUVI solution from a 250 mL infusion bag of 0.9% Sodium Chloride, USP and discard it. c. Revise Step (b) (4) to appear as, “Withdraw the necessary amount of MONJUVI solution and slowly dilute in the infusion bag containing 0.9% Sodium Chloride, USP to a final concentration of 2 mg/mL to 8 mg/mL. Discard any unused reconstituted solution left in the vial.”.

(b) d. Revise Step(4) to read “Gently mix the bag by slowly inverting the bag. Do not shake.” for increased clarity. e. Add a step to inform users of inspecting the bag. Add “Inspect the intravenous bag visually for particulate matter and discoloration prior to administration.”. f. Revise Step 5 to appear as, “If not used immediately, store the diluted MONJUVI infusion solution refrigerated for up 6

Reference ID: 4608619 to 18 hours at 36°F to 46°F (2°C to 8°C), and/or at room temperature up to 12 hours at up to 77°F (up to 25°C ). The room temperature storage includes time for infusion. iv. The route of administration is abbreviated as “IV”. Presenting the route of administration as an abbreviation may lead to misinterpretation of the correct route of administration. Therefore, revise the route of administration from “IV” to intravenous. C. How Supplied/Storage and Handling Section 1. As currently presented, the NDC number is denoted by a placeholder (xxxxx-xxxxx). We request the actual NDC numbers for the container label and carton labeling to determine if they are appropriate. 2. Delete the statements, (b) (4) (b) (4)

(b) (4) As this information is duplicated in Section 2 Dosage and Administration. 4.2 RECOMMENDATIONS FOR MORPHOSYS US INC. We recommend the following be implemented prior to approval of this BLA: A. General Comments (Container labels & Carton Labeling) 1. Replace all presentations of the nonproprietary name, “tafasitamab” to the conditionally acceptable nonproprietary name, “tafasitamib-cxix”. 2. The Rx Only statement appears prominently in bold font. Decrease the prominence by debolding the Rx Only statement. 3. The format for the expiration date is not defined. Clearly defining the expiration date will minimize confusion and risk for deteriorated drug medication errors. Identify the expiration date format you intend to use. FDA recommends that the human-readable expiration date on the drug package label include a year, month, and non-zero day. FDA recommends that the expiration date appear in YYYY-MM-DD format if only numerical characters are used or in YYYY-MMM-DD if alphabetical characters are used to represent the month. If there are space limitations on the drug package, the human-readable text may include only a year and month, to be expressed as: YYYY-MM if only numerical characters are used or YYYY-MMM if alphabetical characters are used to represent the month.

Reference ID: 4608619 FDA recommends that a hyphen or forward be used to separate the portions of the expiration date. 4. Consider revising the statement, (b) (4) (b) (4) to “Dosage: See Prescribing Information.”. B. Container Label 1. Revise and bold the statement from, (b) (4) to “Store refrigerated at 36°F to 46°F (2°C to 8°C) in the carton to protect from light.” We recommend this to increase prominence of this important information and minimize the risk of the storage information being overlooked. If space permits, please consider include the statement “Do not shake or freeze”. Please note the Prescribing Information will be revised to present the Fahrenheit temperatures before the Celsius temperatures. C. Carton Labeling 1. Consider revising your reconstituted statement to include the final concentration of the reconstituted solution. Consider revising the statement to read, “Reconstitute with 5 mL Sterile Water for Injection, USP, resulting in a concentration of 40 mg/mL Do not shake.” . 2. Revise the statement, (b) (4) (b) (4) to “Must be further diluted with 0.9% Sodium Chloride Injection, USP before use.”. 3. The side panel is cluttered and information to see prescribing information is already present, therefore we recommend deleting the statement,(b) (4) (b) (4)

4. As currently presented, there is no instructions on the principal display panel of the carton labeling to indicate that the product must be reconstituted and further diluted for intravenous infusion. This lack of information may lead to wrong preparation errors. Therefore, we recommend revising the route of administration from, (b) (4) to “For Intravenous Infusion Only. Reconstitute and Dilute prior to administration.”. 5. Revise and bold the statement from, (b) (4) to “Store refrigerated at 36°F to 46°F (2°C to 8°C) in the carton to protect from light. Do not shake. Do not freeze." We recommend this to increase prominence of this important information and minimize the risk of the storage information being overlooked. Please note the Prescribing Information will be revised to present the Fahrenheit temperatures before the Celsius temperatures.

Reference ID: 4608619 APPEARS THIS WAY ON ORIGINAL

Reference ID: 4608619 APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION Table 2 presents relevant product information for Monjuvi received on and April 21, 2020 from MorphoSys US Inc.. Table 2. Relevant Product Information for Monjuvi Initial Approval Date N/A Nonproprietary Name tafasitamab-cxix Indication In combination with lenalidomide followed by MONJUVI monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from low grade lymphoma and who are not eligible for,(b) (4) autologous stem cell transplant (ASCT). Route of Administration Intravenous infusion Dosage Form for Injection Strength 200 mg/vial Dose and Frequency The recommended dose is 12 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule:  Cycle length: 28 days.  Cycle 1: Administer MONJUVI infusion on Day 1, 4, 8, 15 and 22.  Cycles 2 - 3: Administer MONJUVI infusion on Day 1, 8, 15 and 22 of each cycle.  Cycle 4 until disease progression: Administer MONJUVI infusion on Days 1 and 15. How Supplied MONJUVI (tafasitamab-XXXX) for injection is a sterile, preservative-free, white to slightly yellowish lyophilized powder (b) (4) , supplied in 200 mg single-dose vial. Each 200 mg vial is individually packaged in a carton (NDC xxxxx- xxx-xx). (b) (4) Storage Store at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Reference ID: 4608619 (b) (4)

APPENDIX B. PREVIOUS DMEPA REVIEWS On April 21, 2020, we searched for previous DMEPA reviews relevant to this current review using the terms, Monjuvi. Our search did not identify any previous label and labeling reviews.

Reference ID: 4608619 APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed Using the principles of human factors and Failure Mode and Effects Analysis,a along with postmarket medication error data, we reviewed the following Monjuvi labels and labeling submitted by MorphoSys US Inc..

 Container label received on December 30, 2019  Carton labeling received on December 30, 2019  Prescribing Information (Image not shown) received on April 21, 2020, available from \\cdsesub1\evsprod\bla761163\0018\m1\us\annotated-draft-labeling-text-tc.doc

G.2 Label and Labeling Images

Container label

(b) (4)

a Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.

Reference ID: 4608619 Carton labeling

(b) (4)

Reference ID: 4608619 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

NICOLE F IVERSON 05/14/2020 12:20:20 PM

HINA S MEHTA 05/15/2020 02:18:15 PM

Reference ID: 4608619 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS

Date: March 23, 2020

From: Interdisciplinary Review Team for Cardiac Safety Studies

Through: Christine Garnett, PharmD Clinical Analyst Division of Cardiology and Nephrology

To: Jennifer Lee, RPM DHM2

Subject: QT Consult to BLA 761163 (SDN 003)

Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document.

This memo responds to your consult to us dated 1/22/2020 regarding the sponsor’s QT related language in section 12.2 of the proposed label. The QT-IRT reviewed the following materials:  Sponsor’s proposed label (Submission 0003);  Summary of clinical pharmacology and clinical safety (Submission 0003);  Sponsor’s integrated summary of safety;  Submissions and meeting records under IND 101971 (FDA pre-IND preliminary draft comments to sponsor questions dated 23 May 2008, IND cover letter dated 29 January 2010 and General Investigational Plan).

1 Responses DHM2 is requesting IRT/QT consult review of Section 12.2 Pharmacodynamics (subsection Cardiac Electrophysiology) of the proposed labeling. Response: As per ICH E14 Q&A (R3) 6.3, thorough QT studies are not recommended for monoclonal antibodies. Therefore, we propose not to include QT-related language in section 12.2. Our proposal is consistent with the labeling practice for the other monoclonal antibodies for which a dedicated QT study has not been conducted.

Reference ID: 4579505 2 Internal Comments to the Division The available ECG and cardiac safety data do not suggest an unexpected effect on the QTc interval. The findings are consistent with our prior experience for monoclonal antibodies which have low likelihood of direct interaction with cardiac ion channels.

3 BACKGROUND

3.1 Product Information Tafasitamab (also known as MOR00208) is a CD19 directed Fc-enhanced antibody (MW: >140 kDa) indicated in combination with lenalidomide followed by tafasitamab monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (b) (DLBCL), including DLBCL arising from low grade lymphoma, and who are not eligible for, (4) (b) (4) autologous stem cell transplant (ASCT). The recommended dose of tafasitamab is 12 mg/kg body weight administered as an intravenous infusion (2.5-hr infusion on Cycle 1 Day 1, 2-hr infusion otherwise) according to the following dosing schedule:  Cycle length: 28 days  Cycle 1: Tafasitamab infusion on Day 1, Day 4. Day 8, Day 15 and Day 22.  Cycles 2 - 3: Tafasitamab infusion on Day 1, Day 8, Day 15 and Day 22 of each cycle  Cycle 4 until disease progression: Tafasitamab infusion on Days 1 and 15. For the first 12 cycles, tafasitamab is given in combination with lenalidomide. Patients should self-administer lenalidomide capsules at the recommended starting dose of 25 mg daily on Days 1-21 of each cycle. Reviewer’s comment: Lenalidomide label suggests a lack of clinically relevant effect on the QTc interval at a dose two times the maximum recommended dose.

3.2 Sponsor’s position related to the question No “Thorough QT/QTc Study” was performed for tafasitamab. The molecular target of tafasitamab is restricted to cells of the B lymphocyte lineage and is not identified in cardiac tissue. There is no evidence that tafasitamab has the potential to induce a change in QT/QTc interval. For confirmation and in agreement with pre-IND feedback by FDA (FDA pre-IND preliminary draft comments to sponsor questions dated 23 May 2008, IND cover letter dated 29 January 2010 and General Investigational Plan), an electrocardiogram (ECG) collection schedule was introduced in all clinical trials conducted thereafter.

3.3 Nonclinical Cardiac Safety Electrocardiograms (ECGs) were obtained in the 8-week repeat-dose toxicology study in cynomolgus monkeys during the pre-study period, on study day 1 (between 1 and 2 hours post- dose), and on study day 43 (between 1 and 2 hours post-dose). QTc was derived at each time point using Bazett’s formula (QT/[square root of RR]; units msec). All ECGs evaluated in this study were qualitatively and quantitatively considered normal for cynomolgus monkeys.

3.4 Clinical Cardiac Safety Refer to section 2.7.4.2.1.4.3 Torsade de pointes and QT Prolongation in the summary of clinical safety

Reference ID: 4579505 The SMQ Torsade de pointes/QT Prolongation (20000001) was used to identify events of possible interest. Ten cases were identified and reviewed in detail. “Electrocardiogram QTc prolonged” was reported for 1 subject in L-MIND and 2 subjects in MOR208C201. Four subjects with syncope (3 in L-MIND and 1 in MOR208C202) and 1 with loss of consciousness in L-MIND were identified and upon review of these cases none were associated with QTc prolongation or Torsade de pointes. One subject in L-MIND with a history of cardiac failure had sudden death attributed to cardiac arrhythmia and/or ischemic heart disease, per Investigator. Another subject in LMIND experienced cardio-respiratory arrest of Grade 4. Case narratives for the 3 subjects with ECG findings of prolonged QTc are provided in Appendix 3 and summarized in Table 2.7.4-12. Review of these cases showed that the subjects had factors contributing to QTc prolongation including history of cardiotoxic chemotherapy, history of cardiac issues, concomitant medications known to cause QT prolongation, or diarrhea with electrolyte abnormalities.

(b) (6)

3.5 Summary results of QTc assessments The sponsor has not conducted any formal QTc assessments. …, in an expert review 176 ECGs from 23 subjects in MOR208C203 (L-MIND) were analyzed when the QTc interval exceeded 480 ms or when the QTc interval increased >60 ms from baseline. No case of true QTc prolongation (i.e., abnormal QTc interval duration [QTc > 480 ms]) in an ECG with sufficient technical quality and with normal sinus rhythm, heart rate, and QRS duration was identified. Thus, this analysis did not reveal any abnormal QTc prolongation or any ECG abnormality potentially associated with the study medications (Section 5.3.5.3/ Integrated Summary of Safety - ECG Assessment Report). Similarly, an assessment of QTc changes in MOR208C202 did not reveal any trend towards QTc prolongation (Section 5.3.5.3, Integrated Summary of Safety - ECG Assessment Report.). Reviewer’s comment: MOR208C201 is a Phase 2a, open label, single arm study of tafasitamab in lymphoma patients. Resting ECGs were collected 1 hour ± 10 minutes post dose on C1D1, C2 (and C3 in the recent protocol updates) Days 8 and 22, and EOT. Additionally, ECG were

Reference ID: 4579505 collected on C1D1 predose. MOR208C203 is a Phase 2a, open label, single arm study of tafasitamab in combination with lenalidomide in lymphoma patients. Resting ECG were collected within 3-hours post tafasitamab dose on C1 D1, C1D15, C2D1 and C3D1. Both studies used the 12 mg/kg dose weekly dose (with one additional dose on C1D4 in study MOR208C203). For the first infusion, IV infusion was started with an infusion rate of 70 mL/h for the first 30 minutes and then subsequently increased to a rate of 125 mL/h; the total infusion duration should ideally not exceed 2.5 hours. Subsequent infusions were administered at a constant rate over a 2-hour period. It is not known if ECG data collected from these two studies would capture drug effect around maximum exposure, however, the ECG collection schedule appear reasonable to detect potential QT prolonging risks due to tafasitamab treatment.

Thank you for requesting our input into the development of this product. We welcome more discussion with you now and in the future. Please feel free to contact us via email at [email protected]

Reference ID: 4579505 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

NAN ZHENG 03/23/2020 01:23:17 PM

CHRISTINE E GARNETT 03/23/2020 01:25:23 PM

Reference ID: 4579505