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Application Number CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213246Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Division of Risk Management (DRM) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) Application Type NDA Application Number 213246 PDUFA Goal Date May 8, 2020 OSE RCM # 2019-2471 and 2473 Reviewer Name(s) Mei-Yean Chen, Pharm.D. Team Leader (Acting) Elizabeth Everhart, MSN, RN, ACNP and Naomi Boston, Pharm.D. Division Director Cynthia LaCivita, Pharm.D. Review Completion Date April 21, 2020 Subject Evaluation of Need for a REMS Established Name Selpercatinib Trade Name Retevmo Name of Applicant Loxo Oncology, Inc. Therapeutic Class A kinase inhibitor Formulation(s) 40 mg and 80 mg capsules Dosing Regimen 160 mg orally twice daily 1 Reference ID: 4595591 Table of Contents EXECUTIVE SUMMARY ......................................................................................................................................................... 3 1 Introduction ..................................................................................................................................................................... 3 2 Background ...................................................................................................................................................................... 3 2.1 Product Information ........................................................................................................................................... 3 2.2 Regulatory History............................................................................................................................................... 4 3 Therapeutic Context and Treatment Options .................................................................................................... 5 3.1 Description of the Medical Condition .......................................................................................................... 5 3.2 Description of Current Treatment Options ............................................................................................... 5 4 Benefit Assessment ....................................................................................................................................................... 7 5 Risk Assessment & Safe-Use Conditions ............................................................................................................ 11 6 Expected Postmarket Use ......................................................................................................................................... 12 7 Risk Management Activities Proposed by the Applicant ............................................................................. 13 8 Discussion of Need for a REMS ............................................................................................................................... 13 9 Conclusion & Recommendations ........................................................................................................................... 13 10 Appendices ................................................................................................................................................................ 13 10.1 References ............................................................................................................................................................. 13 2 Reference ID: 4595591 EXECUTIVE SUMMARY This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Retevmo (selpercatinib) is necessary to ensure the benefits outweigh its risks. Loxo Oncology Inc. submitted a New Drug Application (NDA) 213246 for selpercatinib with the proposed indications for the treatment of x Adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC). x Adults and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy. x Adults and pediatric patients 12 years of age and older with advanced or metastatic RET fusion- positive thyroid cancer who requires systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) These indications are proposed for approval under accelerated approval based on overall response rate and duration of response. If approved, the continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. The risks associated with selpercatinib include hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity. The applicant did not submit a proposed REMS or risk management plan with this application. The Division of Risk Management (DRM) and the Division of Oncology 2 (DO2) agree that a REMS is not needed to ensure the benefits of selpercatinib outweigh its risks. There are no FDA approved therapies specifically for RET fusion positive or mutation positive cancers. Metastatic NSCLC, advanced/metastatic MTC, and advanced thyroid cancer are life-threatening conditions with poor survival. The significant overall response rate and durability of these responses to selpercatinib establish the clinical benefit in this population with unmet need. The clinical reviewer believes the risks associated with selpercatinib are manageable with dose reduction, interruption, or discontinuance, and these risks can be adequately handled with the labeling alone. This reviewer recommends that, if selpercatinib is approved, a REMS is not needed to ensure its benefits outweigh its risks. Hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity can be communicated in Section 5 Warnings and Precautions, as well as instructions how to withhold, reduce dose, and discontinue therapy in Section 2 Dosage and Administration. At the time of this review, none the previously mentioned risks were included in a boxed warning. 3 Reference ID: 4595591 1 Introduction This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME)a Retevmo (selpercatinib) is necessary to ensure the benefits outweigh its risks. Loxo Oncology Inc. submitted a New Drug Application (NDA) 213246 for selpercatinib with the proposed indication for the treatment of x Adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC). x Adults and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy. x Adults and pediatric patients 12 years of age and older with advanced or metastatic RET fusion positive thyroid cancer who requires systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate) These indications are proposed for approval under accelerated approval based on overall response rate and duration of response. If approved, continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. This application is under review in the Division of Oncology 2 (DO2). The applicant did not submit a proposed REMS or risk management plan with this application. 2Background 2.1 PRODUCT INFORMATION Selpercatinib is a small molecule kinase inhibitor. In enzyme assays, selpercatinib inhibited wild type of RET and multiple mutant RET isoforms, as well as vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR3 at clinically relevant concentrations. RET gene is a known proto-oncogene. Oncogenic activation can occur via mutation or rearrangement.1 RET alternations have been implicated to be human cancer drivers. In NSCLS, RET rearrangements occur in 1% to 2% of unselected cases. In in vitro and in vivo tumor models, selpercatinib exhibited anti-tumor activity in cells harboring activation of RET protein resulting from gene fusions and mutations. Selpercatinib is available as 40 mg and 80 mg capsules. The recommended dose is 160 mg taken orally twice daily until disease progression or unacceptable toxicity occurs.b Selpercatinib is not currently approved in any jurisdiction. 2.2 REGULATORY HISTORY a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity. b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug. 4 Reference ID: 4595591 The following is a summary of the regulatory history for NDA 213246 relevant to this review: x March 2017: IND 133193 submitted. x August 2018: Breakthrough therapy designation granted for RET fusion positive NSCLC and for RET mutant MTC x October 2018: Breakthrough therapy designation granted for RET fusion positive thyroid cancer x December 2019: NDA 213246 submission received. x 02/26/2020: A Post Mid-cycle meeting was held between the Agency and the Applicant via teleconference. The Agency informed the Applicant that based on the currently available data, there were no safety issues that require a REMS for selpercatinib 3 Therapeutic Context and Treatment Options 3.1 DESCRIPTION OF THE MEDICAL CONDITION 3.1.1 RET fusion positive Non-small cell lung cancers (NSCLC) In the United States
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