ONCOLOGY DRUG UPDATE 3/31/2017 DISCLOSURES OBJECTIVES OUTLINE QUIZ DRUG PIPELINE. I do not have any conflicts of interest or disclosures to make

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1 DISCLOSURES I do not have any conflicts of interest or disclosures to make ONCOLOGY DRUG UPDATE Mark Wagner, PharmD, BCOP April 8 th, OBJECTIVES Identify the new medications that were approved in 2016 OUTLINE Drug Pipeline Recall the key points of each drug (i.e. indication, administration, pre-meds, side effects) List the updated indications for already approved medications New Drugs New Indications Daratumumab Recap QUIZ How many new oncology medications were approved in 2016? A) 5 B) 8 C) 13 D) 18 DRUG PIPELINE 6 What we can expect in the future 5 1

2 DRUG DEVELOPMENT TREND RECENT YEARS Year Parenteral Chemo PO Chemo Olaratumab OLARATUMAB Atezolizumab New Oncology Drugs Venetoclax Indication Soft Tissue Sarcoma 1 st line with doxorubicin Not curable with radiation or surgery Mechanism of action Platelet derived growth factor receptor inhibitor (PDGFRi) 9 Rucaparib Defibrotide 10 DOSING/PREPARATION 15 mg/kg IV on days 1 and 8 every 21 days 190 mg/19 ml and 500 mg/50 ml vials 0.9% sodium chloride Total volume = 250 ml Doxorubicin 75 mg/m 2 day 1 every 21 days Max of 8 cycles PROBLEM??? ADMINISTRATION Diphenhydramine + Dexamethasone Cycle 1 Day 1 ONLY IV infusion over 1 hour Only compatible with NS (flush line after infusion w/ NS) Dexrazoxane may be added on day 1 of cycles

3 TOXICITIES Infusion reactions Myelosuppression GI toxicity Others Fatigue, neuropathy, hyperglycemia, electrolyte imbalance, muscle/skeletal pain QUIZ Which of the following would you give as pretreatment, in addition to antiemetics, for Cycle 3 Day 8 Olaratumab treatment? A) Diphenhydramine B) Dexamethasone C) Diphenhydramine + Dexamethasone D) No pre-treatment needed ATEZOLIZUMAB Indications Urothelial (Bladder) Carcinoma Locally advanced/metastatic Progression during/following platinum agent HOW IT WORKS! PD-L1 Inhibitor = Immunotherapy SOUND FAMILIAR??? Nivolumab and Pembrolizumab are PD-1 Inhibitors Different mechanism of action Metastatic NSCLC Progression during/following platinum agent TUMOR DEFENSE SYSTEM ATTACKING THE TUMOR B7.1 B7.1 PD-1 PD-1 Tumor inhibits T-cells by having PD-L1 binding to PD-1 & B7.1 receptors on T-cells 17 Blocks PD-L1 resulting in active T-cells allowing the binding and destruction of the tumor 18 3

4 MOA SUMMARY DOSING/ADMINISTRATION 1200 mg IV every 3 weeks Atezolizumab binds to PD-L1 on tumor cells Stops binding of PD-L1 on tumor cells to PD-1 & B7.1 receptors on T-cells Restores T-cell activity T-cells can target and destroy tumor cells Prepare in 250 ml 0.9% sodium chloride Do not shake! Infusion Rate 1 st dose: 60 minutes Subsequent doses: 30 minutes Stable for 6 hours at room temperature 19 Stable for 24 hours under refrigeration 20 TOXICITIES Think -itis Pneumonitis L: liver E: endocrine Thyroid, pituitary, adrenal G: gastrointestinal Colitis, pancreatitis S: skin LEGS MORE TO COME Ongoing studies in: Kidney Breast Colorectal Melanoma MDS Lymphoma Multiple Myeloma VENETOCLAX Indication Chronic Lymphocytic Leukemia (CLL) with deletion 17p and at least 1 prior therapy MOA BCL-2 Inhibitor Restores normal apoptosis Oral chemotherapy DOSING Ramp Up Phase Week Daily Dose # of Tablets 1 20 mg 2 (10 mg) 2 50 mg 1 (50 mg) mg 1 (100 mg) mg 2 (100 mg) mg 4 (100 mg)

5 COUNSELING POINTS Take tablet(s) with a meal and water at the same time each day L of water/day start Day -2 THE SEVILLE ORANGE Type of bitter orange typically used to make marmalades and some liqueurs If miss dose within 8 hours = Take it!!! Frequent lab monitoring Anti-hyperuricemic prophylactic medication Avoid Seville oranges, grapefruit, and starfruit TUMOR LYSIS SYNDROME (TLS) RISK ASSESSMENT TLS PROPHYLAXIS/MONITORING Tumor burden CT scan Absolute lymphocyte count (ALC) Renal function CrCl <80 ml/min Labs Potassium, phosphorus, calcium Uric acid Normal ALC: /L 27 Risk (Tumor burden) LOW All LN <5 cm & ALC <25 x10 9 /L MEDIUM 1+ LN 5 to <10cm OR ALC >25 x10 9 /L HIGH 1+ LN >10 cm OR 1+ LN >5 cm & ALC >25 x10 9 /L Oral Hydration L/day Oral Hydration L/day +/- IV hydration Prophylaxis Oral Hydration L/day + IV hydration at ml/hr Allopurinol Allopurinol Allopurinol +/- rasburicase Setting/Lab Monitoring Outpatient: Pre-dose, 6-8, & 24 hours post 1 st dose of 20 mg & 50 mg. Pre-dose all subsequent ramp-up doses Above + consider inpatient if CrCl <80 ml/min for 1 st dose of 20 mg and 50 mg (see below for hospital monitoring) Inpatient for 20 mg & 50 mg initial doses: Pre-dose, 4, 8, 12, & 24 hours post 20 mg & 50 mg initial dose. Outpatient for subsequent ramp-up doses: Pre-dose, 6-8, & 24 hours post 1 st dose. 28 OTHER SIDE EFFECTS QUIZ Neutropenia 41% had Grade ¾ Consider supportive measures NO Live attenuated vaccines Which of the following side effects is most likely to occur within the first 2 weeks of treatment with venetoclax? Diarrhea (35%) URT infection (22%) A) Nausea/Vomiting Thrombocytopenia (22%) B) Tumor Lysis Syndrome Fatigue (21%) C) Neutropenia Pneumonia (5%) Pyrexia (3.3%) D) Infusion Reaction

6 RUCAPARIB Indication Advanced Ovarian Cancer BRCA mutation 2+ prior lines of chemotherapy DOSING/ADMINISTRATION 600 mg PO twice daily two 300 mg tablets With or without food Mechanism of Action PARP inhibitor Poly-ADP ribose polymerase 1 DNA repair enzyme Dose Reduction Dose 1 st 500 mg twice daily (300 mg tablet mg tablet) 2 nd 400 mg twice daily (two 200 mg tablets) 3 rd 300 mg twice daily (300 mg tablet) TOXICITIES Nausea/Vomiting/Diarrhea/Constipation Increased SCr & LFTs Myelosuppression Dysgeusia Dyspnea Decreased appetite Increased cholesterol MDS/AML (0.5%) DEFIBROTIDE Indication Treatment of adult or pediatric hepatic venoocclusive disease (VOD) aka sinusoidal obstruction syndrome (SOS) with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) WHAT IS VOD/SOS??? Definition Small veins of liver become obstructed Cause: High-Dose Chemo before BMT = SOS Symptoms Weight gain d/t fluid retention Hepatomegaly Increased bilirubin HOW IT WORKS Breaks up fibrin clots Increased prostaglandin I2 Relaxes smooth muscle of blood vessels

7 DOSING/ADMINISTRATION 6.25 mg/kg every 6 hours Use baseline weight 2 hour IV infusion 0.2 micron in-line filter Duration: >21 days Flush line with NS or D5W before & after administration No other drugs MONITORING/TOXICITY Bleeding Avoid anticoagulants or fibrinolytics Nose bleeds Hypersensitivity Reaction Hypertension N/V/D NIVOLUMAB Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck Progressed on or after platinum based therapy 39 NEW INDICATIONS Old dogs learning new tricks Hodgkin s Lymphoma Relapsed/progressed after Autologous HSCT and post-transplantation brentuximab vedotin Dosing Change 240 mg flat dose Renal cell carcinoma, metastatic melanoma, and 40 NSCLC PEMBROLIZUMAB 1 st line Metastatic NSCLC PD-L1 Expression >50% CABOZANTINIB Advanced Renal Cell Carcinoma Prior anti-angiogenic therapy Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck Progressed on or after platinum based therapy PD-L1 Expression >1% CRIZOTINIB (XALKORI ) Metastatic NSCLC ROS1 Positive

8 OBINUTUZUMAB Relapsed Follicular Lymphoma Relapsed/refractory to rituximab regimen With bendamustine followed by monotherapy PALBOCICLIB HR+, HER2-, advanced/metastatic breast cancer Disease progression following endocrine therapy With fulvestrant ERIBULIN Unresectable/Metastatic Liposarcoma Prior anthracycline containing regimen DARATUMUMAB Indication Multiple Myeloma Dexamethasone and lenalidomide or bortezomib Failed 1 prior therapy Single agent Failed 3+ prior therapies Proteasome inhibitor Immunomodulatory agent 2015 DRUG RECAP 45 Daratumumab 46 DOSING SCHEDULE Monotherapy or w/ lenalidomide + dexamethasone Weeks 1-8: weekly Weeks 9-24: every 2 weeks Weeks 25+: every 4 weeks DOSE/ADMINISTRATION 16 mg/kg actual body weight Pre-meds Steroid, acetaminophen, antihistamine W/ bortezomib + dexamethasone Weeks 1-9: weekly Weeks 10-24: every 3 weeks Weeks 25+: every four weeks Dilution Initial rate Volume 1 st Infusion 1000 ml 50 ml/hr 2 nd Infusion 500 ml 50 ml/hr Subsequent 500 ml 100 ml/hr Infusions Rate increment 50 ml/hr every hour Max Rate 200 ml/hr

9 LOGISTICS Stability 15 hours at room temperature including infusion time Chair Time 1 st dose 7 hours minimum 2 nd dose 4.5 hours minimum 3 rd + doses 3.75 hours minimum TOXICITY INFUSION REACTIONS!!! Type & screen patient s Myelosuppression Musculoskeletal pain/spasms Outpatient vs. Observation REFERENCES REFERENCES (CONT.) Lartruvo [package insert]. Eli Lilly and Company, Indianapolis, IN; February 2017 Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043): Tecentriq [package insert]. Genentech, Inc., South San Francisco, CA; October 2016 Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030): doi: /S (16) Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a singlearm, multicentre, phase 2 trial. Lancet. 2016;387: doi: /S (16) Venclexta [package insert]. AbbVie Inc., North Chicago, IL and Genentech USA, Inc., South San Francisco, CA; April 2016 Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4): Rubraca [package insert]. Clovis Oncology, Inc., Boulder, CO; December 2016 Defitelio [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA; March 2016 Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127(13): REFERENCES (CONT.) QUESTIONS U.S. Food and Drug Administration. (2017, March 27). Hematology/Oncology (Cancer) Approvals & Safety Notifications. Retrieved March 28, 2017, from htm Darzalex [package insert]. Janssen Biotech, Inc., Horsham, PA; November 2016?

10 ONCOLOGY DRUG UPDATE 2016 Mark Wagner, PharmD, BCOP April 8 th,