NEW FDA DRUG APPROVALS

NEW FDA DRUG APPROVALS Jennifer Peterson MSN, RN, OCN, BMTCN Jennifer Shamai MS, RN, AOCNS, BMTCN How the Experts Treat Hematologic Malignancies Las Vegas, NV March 15, 2018

Disclosures We have nothing to disclose.

Objectives Review the Food and Drug Administration's (FDA) responsibilities and approval process Recognize common components of generic drug names Review disease processes and new agents approved to treat hematologic malignancies

U.S. Food and Drug Administration (FDA)

FDA Mission Responsible for ensuring the safety, efficacy and security of Drugs and biological products Medical devices Food supply, cosmetics, radiation products Responsible for regulating tobacco products Help the public get accurate, science-based information FDA does not take into account cost or payment FDA does not regulate the practice of medicine Food and Drug Administration (FDA) About FDA, 2017

FDA Accounts for 20 cents of every dollar spent by Americans Over 17,000 prescription drug products Approximately 320 FDA-licensed biologics products FDA at a Glance, 2017

Oncology Therapeutics Center for Drug Evaluation and Research Office of Hematology and Oncology Products (OHOP) Center for Biologics Evaluation and Research Cellular and gene therapies, vaccines Oncology Center of Excellence Severe and lifethreatening diseases Oncology therapeutics are unique! Large public interest, active advocacy groups 40% of drugs being developed, 50% of breakthrough therapies Different risk tolerance for side effects

FDA Drug Review Process Traditional approval (goal of 10 months) Requires substantial evidence of safety and efficacy Well-controlled clinical trials Based on prolongation of life or a better life, or surrogate As safe and effective as existing therapies (allows noninferiority design) FDA s Drug Review Process, 2017

FDA Expedited Programs Fast Track Breakthrough Therapy Accelerated Approval Priority Review Quicker access to lifesaving therapies Early evidence suggests substantial improvement over current therapies Strong early surrogate or intermediate endpoints Late evidence suggests substantial improvement over current therapies Actions to expedite development and review Intensive guidance on drug development, involving senior FDA officials *Fast Track features Approval based on surrogate endpoint that is likely to predict meaningful benefit over existing therapies Action and review time shortened to 6 months For serious conditions and fill an unmet medical need. Must show potential advantage over available therapy For serious conditions and preliminary evidence indicates substantial improvement over available therapies ~ 50% requests have been in oncology ~1/3 have been granted For serious conditions and demonstrates an effect on surrogate endpoint that is likely to predict benefit or clinical endpoint that can be measured earlier For serious conditions and demonstrates significant improvements (clinical endpoint or surrogate) compared to standard

Orphan Drug Designation Special status granted to a drug or biological product that treats a rare disease or condition Both the drug and disease must meet certain criteria Provides development incentives Over 3,500 orphan drug designations issued since 1983 Over 600+ orphan drug indications approved 60% of Breakthrough Therapies approved are indicated for rare diseases FDA Designating an Orphan Product, 2017

Common Components of Generic Drug Names

Monoclonal Antibodies = mab Origin of monoclonal antibodies: Mo = mouse (blinatumomab) Xi = chimeric: cross of mouse and human (rituximab) Zu = humanized (alemtuzumab) U = fully human (daratumumab) Target helps guide knowledge of common side effects: Tu = target is on the tumor cell: blinatumomab Ci = target is circulatory or blood vessels: bevacizumab Li or I = immunomodulator: pomalidomide

Small Molecules - Nibs Many are oral agents Adherence Drug/drug interactions and drug/food interactions Patient education Activity is intracellular Nibs and tinibs Tyrosine kinase inhibitors: block enzymes (i.e. BCR-ABL in CML) found on cancer cells Examples: imatinib, dasatinib, ibrutinib, bosutinib

New FDA Approved Agents

Acute Lymphoblastic Leukemia (ALL) Rapidly progressing, arising from lymphoid line of blood cells Most common pediatric malignancy 85% of children with ALL survive 5 years or longer 15-20% of children with ALL relapse 50% chance of cure if obtain second remission 20-30% chance of cure if relapse during therapy Overall survival for adults with ALL is poor (30-40%) Most common presenting symptoms are palpable liver, palpable spleen, bruising, pallor, and fever Martin, Morgan, &Hijiya, 2012; ACS, 2018

Tisagenlecleucel product information. 2017. https://www.fda.gov/downloads/biologicsbloodvaccines/cellul argenetherapyproducts/approvedproducts/ucm573941.pdf Tisagenlecleucel (Kymriah ) Approved August 2017 (priority review, breakthrough therapy) Mechanism: CD19 directed genetically modified autologous T-cell immunotherapy Indication: patients up to age 25 years with B-cell precursor ALL that is refractory or in a second or late relapse Genetically modified autologous T-cells to target CD19+ B cells (normal and malignant) Tocilizumab approved to treat patient 2 years or older with CRS occurring with CAR T therapy

Novartis, 2017

Tisagenlecleucel (Kymriah ) Key point: only available through the Kymriah REMS program Dosing: Lymphodepleting fludarabine and cyclophosphamide 2-14 days prior to CAR T cells Patients 50 kg or less = 0.2-0.5 x 10 6 CAR T-cells/kg Patients above 50 kg = 0.1 2.5 x 10 8 total CAR T-cells Premedicate with acetaminophen and an H1-antihistamine Tisagenlecleucel product information. 2017. https://www.fda.gov/downloads/biologicsbloodvaccines/cellula rgenetherapyproducts/approvedproducts/ucm573941.pdf

Tisagenlecleucel (Kymriah ) Common AE: cytokine release syndrome (CRS), hypogammoglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding, tachycardia, n/v/d, hypoxia, fatigue, acute kidney injury Warnings and precautions CRS Neurologic toxicities Administration: autologous and intravenous use only Confirm patient identity Confirm availability of tocilizumab prior to infusion Infuse 10-20 ml per minute, rinse with 10-30 mls NS Tisagenlecleucel product information. 2017. https://www.fda.gov/downloads/biologicsbloodvaccines/cellula

Inotuzumab Ozogamicin (Besponsa ) Approved August 2017 (orphan drug, breakthrough therapy, priority review) Mechanism: anti-cd22 monoclonal antibody-drug conjugate with calicheamicin Indication: adults with relapsed or refractory B-cell precursor ALL Dosing: Administered on Day 1, 8, and 15 of each 3-4 week cycle Premedicate with corticosteroid, antipyretic and antihistamine Inotuzumab Ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/7610 40s000lbl.pdf

Inotuzumab Ozogamicin (Besponsa ) Common AE: myelosuppression, thrombocytopenia, neutropenia, infection, anemia, abdominal pain, hyperbilirubinemia Warnings and precautions Hepatotoxicity including VOD Myelosuppression Infusion reactions QT interval prolongation Administration: intravenous Monitor for at least 1 hour after end of infusion Inotuzumab Ozogamicin product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/7610 40s000lbl.pdf

Blinatumomab (Blincyto ) Approved July 2017 expanded indication to Ph+ ALL Mechanism: CD19 directed CD3 T-cell engager that results in lysis of CD19+ cells Indication: relapsed or refractory B-cell precursor ALL in adults and children Blinatumomab product information. 2017.

Blinatumomab (Blincyto ) Dosing: Premedicate with dexamethasone Common AE: infections, fever, headache, infusion reactions, febrile neutropenia, myelosuppression Blinatumomab product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125557s008lbl.pdf

Blinatumomab (Blincyto ) Warnings and Precautions Cytokine release syndrome (CRS) Neurologic toxicities Key points Hospitalization recommended for the first 9 days of the first cycle and first 2 days of second cycle Administration Continuous IV infusion at a constant rate using an infusion pump over 24 hours, 48 hours, or 7 days Do not flush infusion line, flushing can result in excess dosage Blinatumomab product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125557s008lbl.pdf

Chronic GVHD Serious complication of allogeneic hematopoietic stem cell transplantation Affects 30-70% of patients Donor immune cells (the graft) recognize the recipient (host) as foreign and mount an immunologic attack Few effective options after treatment with corticosteroids, no standard of care or second-line treatment

Ibrutinib (Imbruvica ) Approved August 2017 (breakthrough therapy) expanded indication Mechanism: small molecule inhibitor of Bruton s tyrosine kinase (BTK) in B cells Indication: adult patients with chronic GVHD after failure of one or more lines of systemic therapy Dosing: 420 mg taken orally once daily Common AE: fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, pneumonia Ibrutinib product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205552s017l

Ibrutinib (Imbruvica ) Administration Three 140 mg capsules once daily Capsules should be taken with water Do not break, open, or chew the capsules Avoid grapefruit and Seville oranges Ibrutinib product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205552s017l

Follicular Lymphoma Most common indolent non-hodgkin lymphoma Arises from germinal center B-cells Median age of diagnosis 65 years Mostly asymptomatic other than lymph node enlargement Most patients will experience serial relapse, prognosis poor for early relapse after treatment https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/typesof-non-hodgkin-lymphoma.html

Copanlisib (Aliqopa ) Approved September 2017 (orphan drug, fast track, priority review, accelerated approval) Mechanism: PI3K-α and δ inhibitor Indication: adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies Dosing: 1 hour IV infusion on Days 1, 8, and 15 of a 28-day treatment cycle (3 weeks on, 1 week off) Common AE: hyperglycemia, diarrhea, fatigue, hypertension, leukopenia, neutropenia Copanlisib product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000l

Rituximab SQ with Hyaluronidase (Rituxan Hycela ) Approved June 2017 (regular approval) Mechanism: anti-cd20 monoclonal antibody, hyaluronidase cleaves hyaluronan Indications: newly diagnosed DLBCL with CHOP, CLL with FC, FL as a single agent or with chemotherapy Key Point: patients must have had at least one prior rituximab IV infusion Dosing: FL/DLBCL: 11.7 ml over 5 minutes CLL: 13.4 ml over 7 min Premedicate with acetaminophen and antihistamine and potentially glucocorticoid Rituximab product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000l

Rituximab SQ with Hyaluronidase (Rituxan Hycela ) Common AE: infections, neutropenia, nausea, cough, and fatigue, thrombocytopenia, pyrexia, vomiting, injection site erythema Warnings and precautions Hypersensitivity and local administration reactions Hepatitis B reactivation Tumor lysis syndrome Infections Administration: subcutaneous injection in the abdomen Never inject into areas of compromised skin or moles and scars Observe 15 minutes following administration Rituximab product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000l

Hyaluronidase Hyaluronan (hyaluronic acid) is a major component of the extracellular matrix of subcutaneous tissue and creates a barrier to interstitial fluid flow. Hyaluronidase human cleaves hyaluronan through depolyymerization Depolymerization of hyaluronan increases the permeability of tissue, increases the absorption rate into the systemic circulation. Reduces administration time from 3-4 hours to 5-7 minutes! Rituximab product information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf; Genentech, 2018

Lymphoma Cancer that begins in the cells of the lymph system Can occur in both children and adults Two main types: Hodgkin lymphoma: classic (most common) Non-Hodgkin lymphoma: many different types Diffuse large B-cell Follicular Mantle cell Mycosis fungoides www.cancer.gov/types/lymphoma

Acalabrutinib (Calquence ) Approved in October 2017 (accelerated approval) Mechanism: small molecule inhibitor of Bruton's tyrosine kinase (BTK) Indication: mantle cell lymphoma who received at least one prior therapy Dosing: 100 mg orally twice daily, approximately every 12 hours Common AE: anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia and bruising Acalabrutinib product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s0

Axicabtagene ciloleucel (Yescarta ) Approved October 2017 (regular approval) Mechanism: CD19 directed genetically modified autologous chimeric antigen receptor (CAR) T-cell immunotherapy Genetically modified autologous T-cells to target CD19+ B-cells (normal and malignant) Indication: treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy Dosing: 2 x 10 6 CAR-positive viable T-cells per kg Axicabtagene ciloleucel product information 2017 https://www.fda.gov/biologicsbloodvaccines/cellulargene Therapy Products/ApprovedProducts/ucm581222.htm

Axicabtagene ciloleucel (Yescarta ) Key point: available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) program Common AE: fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, nausea/vomiting, hypoxia, tremor, dizziness, and cardiac arrhythmias Warnings and precautions: Cytokine release syndrome (CRS) Neurologic toxicities Axicabtagene ciloleucel product information 2017 https://www.fda.gov/biologicsbloodvaccines/cellulargene Therapy Products/ApprovedProducts/ucm581222.htm

Brentuximab Vedotin (Adcetris ) Approved November 2017 (regular approval) Mechanism: CD30 directed antibody-drug conjugate Indication: treatment of adult patients with primary cutaneous anaplastic large cell lymphoma or CD30 expressing mycosis fungoides who have received prior systemic therapy Dosing: 1.8 mg/kg up to a maximum of 180 mg as an intravenous infusion over 30 minutes every 3 weeks Common AE: anemia, nausea/vomiting, neuropathy, fatigue, neutropenia Brentuximab vedotin product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125388s094lbl.pdf

Pembrolizumab (Keytruda ) Approved March 2017 (accelerated approval) Mechanism: programmed death receptor-1 (PD-1) blocking antibody Indication: treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more prior lines of therapy Dosing: 200 mg every 3 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics Pembrolizumab product information 2017 http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf

Pembrolizumab (Keytruda ) Common AE: fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea Warnings: Immune mediated inflammation Infusion reactions Pembrolizumab product information 2017 http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf

Chronic Myelogenous Leukemia (CML) Occurs most often during or after middle age, rarely in children The bone marrow produces too many white blood cells Common symptoms: fever, night sweats and fatigue Most patients have a gene mutation called Philadelphia chromosome https://www.cancer.gov/types/leukemia/patient/cmltreatment-pdq

Used with permission Terese Winslow 2018 US Gov t has certain rights

Dasatinib (Sprycel ) Approved in November 2017 (regular approval) Mechanism: tyrosine kinase inhibitor for BCR-ABL, SRC family, c-kit, EPHA2, and PDGFRβ Indication: pediatric patients with Philadelphia chromosome positive CML in chronic phase Dosing: by body weight, re-evaluate every 3 months Common AE: myelosuppression, fluid retention, diarrhea, headache, musculoskeletal pain, rash and fatigue Dasatinib product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/02198

https://www.themmrf.org/multiple-myeloma/what-is-multiplemyeloma/ Multiple Myeloma A hematologic malignancy that originates in the plasma cells Myeloma cells produce abnormal antibodies, M proteins Ultimately overproduction of M proteins lead to bone and kidney damage Genetic factors may influence one s likelihood of developing multiple myeloma Prognosis varies and many new treatments have recently been approved

Multiple Myeloma https://www.themmrf.org

Lenalidomide (Revlimid ) Approved in February 2017 (expanded indication) Mechanism: immunomodulatory, antiangiogenic, and antineoplastic properties. Inhibits production and induces apoptosis of certain hematopoietic tumor cells Indication: maintenance therapy for multiple myeloma post autologous stem cell transplant Dosing: 10mg PO daily administered day 1-28 of a 28 day cycle for maintenance post HCT Lenalidamide product information 2017 http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s049lbl.pdf

Lenalidomide (Revlimid ) Common AE: diarrhea, fatigue, anemia, constipation, neutropenia, peripheral edema, insomnia Warnings: Fetal toxicity Thrombosis risk Hematologic toxicity Lenalidamide product information 2017 http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s049lbl.pdf

Acute Myelogenous Leukemia (AML) Most common acute leukemia in adults The bone marrow produces abnormal myeloblasts Risk factors: smoking, radiation exposure and previous chemotherapy exposure There are multiple subtypes of AML Common presenting symptoms are easy bruising, bleeding, fever and fatigue https://www.cancer.gov/types/leukemia/patient/adult-amltreatment-pdq

Midostaurin (Rydapt ) Approved in April 2017 (breakthrough designation) Mechanism: small molecule that inhibits multiple receptor tyrosine kinases Indication: newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation positive in combination with standard cytarabine and daunorubicin induction and standard consolidation with cytarabine Dosing: 50mg BID with food on days 8-21 of induction and consolidation Common AE: febrile neutropenia, nausea/vomiting, mucositis, headache, petechiae, musculoskeletal pain, epistaxis, infection, and hyperglycemia Midostaurin product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf

Enasidenib (Idhifa ) Approved in August 2017 (regular approval) Mechanism: small molecule isocitrate dehydrogenase-2 inhibitor (IDH2) Indication: treatment of adult patients with relapsed or refractory AML with an IDH2 mutation Dosing: 100 mg PO daily Common AE: nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite Enasidenib product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/2 09606s000lbl.pdf

Liposomal cytarabine and daunorubicin product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl. pdf Liposomal Cytarabine and Daunorubicin (Vyxeos ) Approved August 2017 (regular approval) Mechanism: daunorubicin has antimitotic and cytotoxic activity, cytarabine is a cell cycle phase-specific antineoplastic agent Indication: treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia related changes Dosing: daunorubicin 44mg/m2 and cytarabine 100 mg/m2 on days 1, 3 and 5 Common AE: hemorrhagic events, febrile neutropenia, rash, edema, nausea/vomiting/diarrhea, mucositis, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, and bacteremia

Gemtuzumab Ozogamicin (Mylotarg ) Approved in September 2017 (regular approval) Mechanism: CD33 directed monoclonal antibody-drug conjugate Indication: the treatment of newly-diagnosed CD33 positive acute myeloid leukemia (AML) in adults and for treatment of relapsed or refractory CD33 positive AML in adults and in pediatric patients 2 years and older. Dosing: 3 mg/m2 for newly diagnosed AML in combination with daunorubicin and cytarabine on days 1, 4 and 7 Gemtuzumab ozogamicin product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf

Gemtuzumab Ozogamicin (Mylotarg ) Common AE: hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis Warning: Severe or fatal hepatic veno-occlusive disease Infusion related reactions Gemtuzumab ozogamicin product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf

Bosutinib (Bosulif ) Approved in December 2017 (accelerated approval) Mechanism: a tyrosine kinase inhibitor. Bosutinib inhibits BCR- ABL kinase that promotes CML Indication: newly diagnosed Philadelphia chromosome positive CML in chronic phase Dosing: Daily dosing of 400 mg recommended to be taken with food Common AE: diarrhea, nausea/vomiting, thrombocytopenia, abdominal pain, rash, anemia, pyrexia, and fatigue Bosutinib product information 2017 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203341s009lbl.pdf

Potential Future Treatment Options for AML in Trial Phase Crenolanib: a tyrosine kinase inhibitor, potent inhibitor of FLT3-ITD Quizartinib: a tyrosine kinase inhibitor, a FLT3-ITD inhibitor showing results as a monotherapy Gliteritinib: a tyrosine kinase inhibitor, for treatment in adults with FLT3 positive relapsed/refractory AML Ivosidenib: small molecule inhibitor for high-risk relapsed or refractory AML patients with an IDH1 mutation