Goals & Objectives. Disclosure. Abbreviations. New and Emerging Chemotherapies 3/2/ Author has nothing to disclose

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1 Goals & Objectives New and Emerging Chemotherapies Luis Hernandez PGY-1 Pharmacy Resident University of Miami Hospital Distinguish key differences between new oral and parenteral chemotherapies Pharmacists: Discuss relevant side effects of new oral and parenteral chemotherapies Technicians: Discuss proper handling and storage of new oral and parenteral chemotherapies Learn about immunotherapies in Hematology/Oncology Pharmacists: Review recent FDA approvals of immunotherapies Technicians: Review preparation of recently approved immunotherapies Recognize and analyze the drugs and trends in the Hematology/Oncology pipeline Pharmacists, Technicians: Examine the most promising pipeline drugs 3 Disclosure Abbreviations Author has nothing to disclose 2 AE: Adverse event APC: Antigen presenting cell CA: Cancer CINV: Chemotherapy Induced Nausea & Vomiting CTLA-4: Cytotoxic T- lymphocyte-associated protein 4 GI: Gastrointestinal GM-CSF: Granulocyte macrophage colony stimulating factor PD-1: Programmed death receptor 1 PD-L1: Programmed death ligand 1 HR: Hormone receptor HSV: Herpes Simplex Virus IL: Interleukin NSCLC: Non small cell lung cancer PFUs: Plaque forming units TNF: Tumor necrosis factor 4 1

2 Immunotherapy AWP per vial Price of treatment for 1 year (70 kg pt) Darzalex (daratumumab) 100 mg/5 ml= $ mg/20 ml= $2,160 $149,000 New Chemotherapies Oral vs. Parenteral 5 Empliciti (elotuzumab) Imlygic (talimogene laherparepvec) 300 mg=$2, mg= $2,842 1,000,000 units/ml= $ ,000,000 units/ml= $5,280 $149,000 2 ml per visit for 6 months: ~$253,000 Unituxin (dinutuximab) 17.5 mg/5 ml= $9,000 **Peds pt w/ BSA= 1: $180,000 Oral chemos AWP for 30 day supply Price of treatment for 1 year Odomzo (sonidegib) $12,072 $144,864 Cotellic (cobimetinib) $7,274 $87,288 Ibrance (palbociclib) $12,411 $148,932 Tagrisso (osimertinib) $15,300 $183,600 Alecensa (alectinib) $14,793 $177,516 Lenvima (lenvatinib) $5,776 $69,312 Farydak (panobinostat) $8,800 (21 day cycle) $140,800 (16 cycles) Ninlaro (ixazomib) $10,404 $124, FDA Approvals Ibrance(palbociclib) Drug Indication Drug Indication Odomzo (sonidegib) Basal cell CA Alecensa (alectinib) NSCLC Ibrance (palbociclib) Breast CA Tagrisso (osimertinib) NSCLC Lonsurf (tipiracil/trifluridine) Yondelis (trabectedin) Imlygic (talimogene laherparepvec) Colorectal CA Liposarcoma or leiomyosarcoma Portrazza (necitumumab) NSCLC Unituxin (dinutuximab) Neuroblastoma Melanoma Lenvima (lenvatinib) Thyroid CA Cotellic (cobimetinib) Melanoma Varubi (rolapitant) CINV Farydak (panobinostat) Multiple Myeloma Empliciti (elotuzumab) Multiple Myeloma Ninlaro (ixazomib) Multiple Myeloma Darzalex (daratumumab) Multiple Myeloma Advanced breast cancer (HR+, HER-2 negative) o First-line in combination with Femara (letrozole) o Second-line with Faslodex (fulvestrant) 125 mg PO daily for 21 days, then 7 off (with food) Bone marrow suppression, GI toxicity, infections and thromboembolic events Major CYP3A4 substrate FDA Novel Drug Approvals for [ONLINE] Available at: [Accessed 2/4/16]. 6 Ibrance (palbociclib) [prescribing information]. New York, NY: Pfizer Labs; February

3 Ibrance(palbociclib) Farydak(panobinostat) m/buy-ibrance-palbociclibbreast-cancer-pfizer.html. Accessed 2/12/16 /drug/34436/. Accessed 2/12/16 Accessed 2/12/ &course=181&nocredit=1&token=33d2a02765b2ed16e7848cbdcf98ea0a. Accessed 2/12/ Farydak(panobinostat) Multiple Myeloma (with bortezomib, dexamethasone) 20 mg PO every other day for 3 doses/week (D1, 3, 5, 8, 10, 12) of weeks 1, 2 of each 21-day cycle x 8 cycles Boxed Warnings: Diarrhea & cardiovascular events Moderate emetogenic potential CYP3A4 substrate; moderate CYP2D6 inhibitor Ninlaro(ixazomib) Multiple Myeloma (with lenalidomide, dexamethasone) 4 mg POweekly on Days 1, 8, 15 of each 28-day cycle Take 1 hour prior or 2 hours after eating CrCl < 30 ml/min or dialysis-decrease dose to 3 mg Hematologic, dermatologic, GI toxicities, neuropathies Farydak (panobinostat) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; February Ninlaro (ixazomib) [prescribing information]. Cambridge, MA: Takeda Pharmaceutical Company Limited; November

4 Ninlaro(ixazomib) Empliciti (elotuzumab) o-ixazomib-treatment-multiplemyeloma/. Accessed 2/12/16 ticles/112247/ /fda -gives-approval-to-bloodcancer-drug-empliciti.htm. Accessed 2/12/16 Accessed 2/12/ Accessed 2/12/16 15 Empliciti (elotuzumab) Darzalex (daratumumab) Multiple myeloma (relapsed/refractory) with lenalidomide and dexamethasone Cycle 28-Day Cycles 1 & 2 28-Day Cycles 3+ Day of Cycle Empliciti (mg/kg) IV Lenalidomide (25 mg) PO Days 1-21 Days 1-21 Dexamethasone (mg) PO Dexamethasone (mg) IV Interferes with serological testing Higher incidence of second primary malignancies Empliciti (elotuzumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; November Multiple Myeloma (relapsed/refractory): Single agent 16 mg/kg IV weekly (1-8), q2 weeks (9-24), q4 weeks Delayed infusion reactions Prophylaxis for Herpes Zoster Virus is recommended: 1 week prior and for 3 months after treatment Refrigerate for up to 24 hours and protect from light Interferes with serological testing Darzalex (daratumumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc.; November

5 Darzalex (daratumumab) Imlygic (talimogene laherparepvec) Do not administer to immunocompromised, pregnant Store and transport at -90 C to -70 C Protect from light Accessed 2/12/16 Common adverse events: fatigue, chills, pyrexia, nausea Limitation: Has not been shown to improve overall survival or have an effect on visceral metastases Accessed 2/12/16 17 Imlygic (talimogenelaherparepvec) [prescribing information]. Thousand Oaks, CA: BioVex, Inc; October Imlygic (talimogene laherparepvec) Imlygic(talimogene laherparepvec) Genetically modified, live attenuated, herpes simplex virus 1 oncolytic virus Indication: Unresectable melanoma Dosing: o Initial visit: Inject up to 4 ml of 10 6 PFUs/ml intralesionally o Second visit: Inject up to 4 ml of 10 8 PFUs/ml intralesionally (3 weeks after initial) o Future visits: Inject up to 4 ml of 10 8 PFUs/ml intralesionally every 2 weeks for at least 6 months Imlygic (talimogenelaherparepvec) [prescribing information]. Thousand Oaks, CA: BioVex, Inc; October

6 Initiation of Immune Response The Future of Cancer Treatment: Immunotherapies Antigen Antigen fragments Naive T-cell Antigen receptors Effector cells: 1. Activate other immune cells 2. Kill target cells Antigen presenting cell (APC) Activated T-cell Memory cells: 1. Circulate for months years 2. Ready to rapidly respond to same antigen again Antigen Activated recognition APC Activation T-cell interaction T-cell activation Replication of antigenspecific T-cells T-cells become specialized Lymphoid Organs 21 Abbas AK, Lichtman AH. Basic Immunology. 3rd ed Peripheral Tissues 23 Cancer Pathogenesis Immune Cells in Tumors Deregulating cellular energetics Avoiding immune destruction Evading growth suppressors Hallmarks of Cancer Pathogenesis (2011) Activating invasion and metastasis Enabling replicative immortality OS (%) T-cell infiltration within tumors is associated with overall survival (OS) in patients with different cancers Kaplan-Meier Curve for OS in Advanced Ovarian Cancer 1 P<0.001 Intratumoral T cells (n=102) Median OS = 50.3 months Sustaining proliferative signaling Resisting cell death Inducing angiogenesis 25 0 No intratumoral T cells (n=72) Median OS = 18 months n=102 Month Hanahan D, Weinberg RA. Cell. 2011;144(5): Zhang L, Coukos G, et al. N Engl J Med. 2003;348(3):

7 What is Immunotherapy? Treatment to boost or restore the ability of the immune system to fight cancer, infections, and other diseases Examples in cancer: 1) Checkpoint inhibitors 2) Monoclonal antibodies 3) Therapeutic cancer vaccines 4) Cytokines Immunotherapy: Treatment Considerations Relative efficacy may be greater with lower tumor burden Patient given immunotherapy earlier in disease may have better outcomes Tumor Burden A B Tumor Growth Rate Expected clinical outcome if no treatment is provided A B Death Patient given a vaccine earlier Patient given a vaccine later Time National Cancer Institute. Cancer terms. Accessed 1/15/ Gulley JL, Drake CG. ClinCancer Res. 2011;17(12): Cancer Type Checkpoint Inhibitors Monoclonal Antibodies Cancer Vaccines Oncolytic Virus Bladder Brain Breast Cervical Colorectal Esophageal Head and Neck Kidney Leukemia Liver Lung Lymphoma Melanoma *** Multiple Myeloma Ovarian Pancreatic Prostate Sarcoma Adapted from Checkpoint Inhibition Accessed 2/2/

8 OPDIVO (nivolumab) Takes the foot off the brakes YERVOY (ipilimumab) Accessed 2/2/ KEYTRUDA (pembrolizumab) Immune-Mediated Adverse Effects Rare immune-mediated side effects: o Pneumonitis o Colitis o Hepatitis o Nephritis and Renal Dysfunction o Hypothyroidism and Hyperthyroidism Treatment: o Hold or permanently discontinue depending on severity o Steroids (prednisone 1-2 mg/kg daily or equivalent) expression-can-id-best-responders-mercks-anti-pd-1. Accessed 2/12/

9 Monitoring Parameters 1) Hepatic and renal function tests (baseline, periodic) 2) Thyroid function tests (baseline and every 6 weeks) 3) Blood glucose (hyperglycemia) 4) Rash, diarrhea, adrenal insufficiency 5) CBC, platelets 100,000, ANC 1.5(baseline, weekly) 6) Infusion reactions Nivolumab Infusion Vials must be refrigerated and protected from light Prepared in NS or D5W; 10 mg/ml vial 1-10 mg/ml 3 mg/kg IV q2weeks; 1 mg/kg IV q3weeks x 4 with ipilimumab; no premedicationsrequired Storage after preparation: Room temperature-no more than 4 hours Refrigeration- no more than 24 hours IV line musthave a sterile, non-pyrogenic, low protein binding micron in-line filter; infuse over 60 mins 33 Opdivo (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; January Pembrolizumab Infusion Vials must be refrigerated and protected from light Prepared in NS or D5W; 100 mg/4ml vial 1-10 mg/ml 2 mg/kg IV q3weeks; no premedicationsrequired Storage after preparation: Room temperature-no more than 6 hours Refrigeration- no more than 24 hours IV line musthave a sterile, non-pyrogenic, low protein binding micron in-line filter; infuse over 30 mins Ipilimumab Infusion Vials must be refrigerated and protected from light Prepared in NS or D5W; 5 mg/ml vial 1-2 mg/ml 3 mg/kg IV q3weeks x 4 doses MAX Storage after preparation: no more than 24 hours IV line musthave a sterile, non-pyrogenic, low protein binding micron in-line filter; infuse over 90 mins Opdivo (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; January Yervoy (ipilimumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; October

10 Patient Case Management of Diarrhea 55 year old woman with metastatic melanoma Started Opdivo (Nivolumab) 3 mg/kg IV q2weeks She comes to clinic 4 weeks later complaining of diarrhea, which was occasionally bloody She took some Imodium (loperamide) for several days with no results 37 O Day, et al. Cancer 2007;110: Patient Case Managing Adverse Events How do you proceed? a) Refer her to the emergency department for IV hydration and steroids; dicontinue nivolumab b) Counsel patient that this is normal and may be related to her diet; continue nivolumab c) Obtain a full history of the diarrhea and recommend a strict diet, oral hydration; continue nivolumab d) Recommend oral steroids x 5 days, followed by a month long taper; continue nivolumab e) Discontinue nivolumab and the diarrhea will stop 38 Any Grade 1 AE or isolated hypothyroidism Symptom management or replacement therapy for hypothyroidism Continue PD-1 treatment and monitor Nivolumab immune mediated adverse reactions management guide. d?file=00pi000000gl6roeal. Accessed February A Guide to Monitoring Patients During Treatment with Pembrolizumab: A Resource for Adverse Reaction Management. Available at: Accessed February 2016 Grade 2 colitis, nephritis, hepatitis or pneumonitis Symptomatic hypophysitis Any Grade 3 AE Hold PD-1 treatment and administer steroids Improve to Grade 1: Taper steroids for 1+ month Resume if: Grade 0/1 AE after steroid taper Permanently discontinue if: No improvement within 12 weeks Cannot taper steroids 40 within 12 weeks 10

11 Managing Adverse Events Grade 3 or 4 pneumonitis or nephritis Grade 3 or 4 infusion reaction Any life-threatening or Grade 4 adverse event Any severe or recurrent Grade 3 adverse event What does the future hold? Initiate steroids and permanently discontinue checkpoint inhibitor Nivolumab immune mediated adverse reactions management guide. vlet.filedownload?file=00pi000000gl6roeal. Accessed February A Guide to Monitoring Patients During Treatment with Pembrolizumab: A Resource for Adverse Reaction Management. Available at: Accessed February 2016 Hepatitis with: AST/ALT > 5x ULN AST/ALT 50% from baseline Total bilirubin> 3x ULN Key Role for Pharmacists Discuss Med Rec findings with physician (monitor autoimmune disease and/or immunosuppression) Monitor toxicities, especially dermatologic and GI Anticipate drug-drug interactions Evaluate costs/acquisition Immunotherapy takes time to work Selinexor SINE (selective inhibitor of nuclear export) Oral agent active in highly aggressive lymphomas Inhibits I-ĸB export Other applications: o HIV, influenza o Autoimmune diseases o Surgical wound healing 42 Multiple Myeloma Research Foundation What is Selinexor (KPT-330)?. [ONLINE] Available at: [Accessed 2/10/16] Image:

12 Acalabrutinib 2 nd -generation inhibitor of Bruton styrosine kinase (BTK) for relapsed CLL 95% overall response rate; 100% in 17p deletion More selective, irreversible inhibition of BTK Improved safety profile compared to ibrutinib: o No major hemorrhage, AFib, tumor lysis, pneumonitis o Headache, diarrhea and weight gain were most common Byrd JC, Harrington B, O Brien S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med Jan 28;374(4): Take Home Points There were 16 Hematology/Oncology drugs approved by the FDA in 2015 Although only 20% of patients respond to immunotherapy, responses are long lasting Immune mediated reactions from PD-1 and CTLA-4 inhibitors can be managed with steroids Starting immunotherapy earlier in the disease course leads to better outcomes 47 Multikine (Leukocyte Interleukin, Injection) Combination of cytokines (IL-1, IL-2, IL-6, TNF-α, etc.) Combination immunotherapy: Has both active and passive immunity with no outside antigens required Currently in global Phase III trial for head & neck cancer o First-line treatment for 3 weeks immediately after diagnosis o Before any standard of care therapies o Phase 2 results: reduced or eliminated all signs of tumor before surgery, radiation and/or chemotherapy True/False Questions 1) The trend toward immunotherapies in Hematology/Oncology describes medications that boost the immune system to fight against malignancy 2) Orally administered chemotherapies are safer than those administered intravenously 3) Imlygic (talimogene laherparepvec) is a first in class oncolytic virus that uses HSV-1 along with GM-CSF and is injected directly into melanoma lesions 4) Imlygic (talimogene laherparepvec) should be stored in a refrigerator (2 C - 8 C) CEL-SCI What is the investigational therapy Multikine (Leukocyte Interleukin, Injection)?. [ONLINE] Available at: [Accessed 2/12/16]