Update on antiemetics, what is new and future directions. Karin Jordan University of Halle

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1 Update on antiemetics, what is new and future directions Karin Jordan University of Halle

2 History of Antiemetics

3 Controlling Chemotherapy-Induced EMESIS: Progress Over The Past 30 Years: Efficacy 5-Day Complete Control: 5HT 3 RA + Steroids Added NK 1 RA 100% - 85% 75% 75% - 50% - 50% 50% 60% 50% 25% - 0% 10% Cisplatin (Highly Emetic) AC Chemotherapy

4 Pathophysiology of Emesis

5 Time course of cancer therapy induced Therapy Emesis Acute Emesis Delayed Emesis 24 h after Therapy mainly Serotonin/ 5-HT 3 RAs 2-5 days after Therapy mainly Substance P/ NK-1 antagonists

6 Neurotransmitters and Antiemetics Dolasetron Granisetron Ondansetron Palonosetron Tropisetron and others Serotonin / 5-HT 3 RAs Metoclopramide Haloperidol Dopamine / D 2 RAs Emetic reflex Histamine Endorphins Aprepitant Netupitant Rolapitant Substance P / NK 1 RAs GABA Cannabinoids Acetylcholine D 2, dopamine; GABA, gamma-aminobutyric acid; NK, neurokinin; Ras, receptor antagonists, 5-HT3: 5-hydroxytryptamine3 Gralla RJ, et al. J Clin Oncol. 1999;17(9): Grunberg SM, et al. N Engl J Med. 1993;329(24): Hesketh PJ. Support Care Cancer. 2001;9(5):

7 Risk factors and Emetogenicity of chemotherapeutic agents

8 Female Gender Young age Individual Risk Factors for the development of CINV History of chemotherapy Anxious personality Minimal alcohol use (Caveat 5 drinks week is protective) History of emesis during pregnancy History of motion sickness Roila F, J Clin Oncol 1991; 4: 675-8, Morrow G, Support Care Cancer 2002; 10: , Warr D, Support Care Cancer 2010, Jordan K et al. Oncologist Sep;12(9):1143-5

9 Emetogenic Potential: i.v. Agents Chemotherapy Risk Examples High > 90% Cisplatin, streptozocin, carmustine, dacarbazine, Antrazyclin/cyclophosphamid based regimen Moderate 30 90% Low 10 30% Carboplatin, cyclophosphamide, doxorubicin, ifosfamide, oxaliplatin, irinotecan, alemtuzumab, azacitidine, bendamustine Etoposide, gemcitabine, 5-FU, docetaxel, paclitaxel, cetuximab, catumaxomab, panitumumab Minimal < 10% Vinca alkaloids, bleomycin, bevacizumab - Aapro M, et al. MASCC/ESMO Antiemetic Guideline, version Available at: - Basch E, et al. J Clin Oncol 2011;29: Hesketh PJ, et al. J Clin Oncol 2016;34: Available at:

10 Emetogenic Potential: oral Agents HIGH Hexamethylmelamine Procarbazine MODERATE Bosutinib Ceritinib Cyclophosphamide Imatinib Vinorelbine Crizotinib Temozolomide LOW Afatinib Axatinib Capecitabine Dabrafenib Dasatinib Everolimus Etoposide Fludarabine Ibrutinib Idelalisib Lapatinib Lenalidomide Olaparib Nilotinib Pazopanib Ponatinib Regorafenib Sunitinib Tegafur Uracil Thalidomide Vandetanib Vorinostat MINIMAL Chlorambucil Erlotinib Gefitinib Hydroxyurea Melphalan Methotrexate L-Phenylalanine mustard Pomalidomide Ruxolitinib Sorafenib 6-Thioguanine Vemurafenib Vismodegib Aapro M, et al. MASCC/ESMO Antiemetic Guideline, version Available at:

11 Antiemetic drugs

12 Antiemetic Agents Class Drug examples Mode of action Predominant efficacy 5-HT 3 rec.- antagonists NK 1 rec.-antagonists ondansetron, granisetron, tropisetron, palonosetron, PA Aprepitant, fosaprepitant, NE, rolapitant 5-HT 3 receptor acute delayed (+) + NK 1 receptor + ++ Steroids Dexamethasone Multiple + + Benzamides Metoclopramide DA D 2 /5HT 3 receptor (+) (+) Benzodiazepines GABA-chloride channel complex GABA-chloride channel complex (+) (+) Classical Neuroleptics Haloperidol Mainly D 2 receptor (+) (+) Atypical neuroleptics Olanzapine Multiple receptors* + + Cannabinoids Antihistamines Dronabinol, nabilone Diphenhydramine, hydroxyzine CB1-Receptor Agonism, (CB2-Receptor) Muscarinic/ cholinergic receptor (+) (+) - - Ginger Ginger At least: 5-HT 3 receptor (+) (+) *(D1, D2, D3, D4), serotonergic (5-HT2A, 5-HT2C, 5-HT3, 5-HT6), adrenergic (á1), histaminergic, (H1), and muscarinic (m1, m2, m3, m4)

13 Serotonin receptor antagonists

14 Principles of Antiemetic Therapy: 5-HT 3 Receptor Antagonists Lowest fully effective dose should be used Once all relevant receptors are saturated, higher doses do not enhance any aspect of activity Once daily is enough Single dose is as active as multiple-dose regimens Gralla RJ, et al. J Clin Oncol. 1999;17(9): Basch E, et al. J Clin Oncol 2011;29: Hesketh PJ, et al. J Clin Oncol 2016;34: Available at:

15 Steroids Mode of action is not known Efficacy is often underestimated

16 Neurokinin-1 receptor antagonists

17 Recommended NK 1 RA Dosing Acute emesis Delayed emesis Aprepitant 125 mg orally, once on the day of chemotherapy 80 mg orally, once daily for the 2 days after chemotherapy (only if used on Day 1) Fosaprepitant 150 mg IV, once on the day of chemotherapy NE PA Rolapitant 300 mg/ 0,5 mg netupitant/ palonosetron orally, once on the day of chemotherapy* 180 mg orally, once on the day of chemotherapy * Combined in one capsule

18 NEPA: key features Dosing: netupitant 300 mg / palonosetron 0.5 mg in one capsule Approved in USA: October 2014 and in Europe: May 2015 under the trade name Akynzeo Three phase 3 trials with more than 2,500 patients Moderate inhibitor of CYP3A4: dexamethasone has to be reduced CYP3A4: cytochrome P450 3A4; HEC: highly emetogenic chemotherapy; MEC: moderately emetogenic chemotherapy Aapro M, et al. Ann Oncol. 2014;25: Gralla RJ, et al. Ann Oncol. 2014;25: Hesketh PJ, et al. Ann Oncol. 2014;25:

19 Netupitant: Chemical structure and main features NETU 300 mg Aprepitant Half-life (h) Binding Affinity (pki) high 2 90% Striatum Receptor Occupancy YES 4 YES 2 reached at C max Potent and selective NK 1 RA Competitively binds to and blocks activity of human substance P receptors which results in the prevention or alleviation of CINV High binding affinity, long half-life High and long-lasting (for up to 96 hours) brain receptor saturation after single oral dose NETU: netupitant; NK1: neurokinin-1; RA: receptor antagonist ; PK: pharmacokinetics h: hours; pki: the negative logarithm to base 10 of the equilibrium dissociation constant; Cmax: maximum plasma concentration * the first agent available in the NK1 receptor antagonist drug class (Navari RM. Drugs. 2013;73: ) 1. Lorusso V et al. Future Oncol Oct 31:1-13; 2. Emend (aprepitant) prescribing information, 2008; 3. Rizzi A et al. Peptides. 2012;37:86 97; 4. Spinelli T et al. J Clin Pharmacol Jan;54(1):

20 Drug - Drug Interaction Aprepitant/Fosaprepitant and Netupitant are moderate inhibitors of CYP3A4 Similar to grapefruit juice or diltiazem The oral dexamethasone dose should be reduced by approximately 50% Interactions with other chemotherapeutic agents Aprepitant: Either no interaction or no clinically relevant interaction exists with chemotherapeutic agents (intravenous cyclophosphamide, docetaxel, intravenous vinorelbine) Majumdar AK et al. Clin Pharmacol Ther. 2003;74: Akynzeo. Package Insert: Woodcliff Lake, NY: Esai, Inc., 2014 Aapro, M. Ann Oncol 2010

21 Key Phase III Data NEPA

22 A Randomized Phase III Study Evaluating the Efficacy and Safety of NEPA, a Fixed-Dose Combination of Netupitant and Palonosetron, for Prevention of Chemotherapy-Induced Nausea and Vomiting Following Moderately Emetogenic Chemotherapy Matti Aapro 1, Rugo H 2, Rossi G 3, Borroni ME 3, Bondarenko I 4, Sarosiek T 5, Oprean C 6, Cardona-Huerta S 7, Lorusso V 8, Karthaus M 9, Schwartzberg L 10, Grunberg S 11 1 Clinique de Genolier, Genolier, Switzerland; 2 Comprehensive Cancer Center, University of California San Francisco, USA; 3 Corporate Clinical Development, Statistics and Data Management, Helsinn Healthcare, Lugano, Switzerland; 4 Department of Oncology, Dnepropetrovsk Medical Academy, Dnepropetrovsk, Ukraine; 5 Nzoz Magodent, Warsaw, Poland; 6 Oncomed SRL, Timisoara, Romania; 7 Hospital Universitario, Universidad Autonoma de Nuevo León, Monterrey, Mexico; 8 National Cancer Institute Giovanni Paolo II, Bari, Italy; 9 Department of Hematology, Oncology and Palliative Medicine, Staedt. Klinikum Neuperlach and Harlaching, München, Germany; 10 The West Clinic, Memphis; 11 Fletcher Allen Health Care, Burlington, USA Aapro M, et al. Ann Oncol. 2014;25(7):

23 Methods and Study Design This was a phase III, multinational, randomized, double-blind study in chemotherapy-naïve patients undergoing anthracycline-cyclophosphamide chemotherapy Patients were randomized to receive one of the following treatments prior to chemotherapy on day 1: Randomized 1:1 Oral NEPA + Oral DEX 12 mg (NEPA = NETU 300 mg + PALO 0.50 mg) N = 1455 Oral PALO 0.50 mg* + Oral DEX 20 mg (*PALO 0.50 mg oral formulation is bioequivalent to 0.25 mg PALO IV) NEPA or PALO were ingested 60 minutes prior to chemotherapy; DEX was taken 30 minutes prior to chemotherapy On days 2-5 no other antiemetic was planned, in particular no dexamethasone was given Patients were allowed to participate in a multiple-cycle extension if they met enrollment criteria after completion of cycle 1. Aapro M, et al. Ann Oncol. 2014;25(7):

24 Percent of Patients Complete Response (CR) Rates P =.047 P =.001 P =.001 CR: No emesis, no rescue medication Aapro M, et al. Ann Oncol. 2014;25(7):

25 Patients (%) No Significant Nausea (NSN) rates (cycle 1) Nausea was well controlled with a single dose of NEPA Significantly improved control was observed with NEPA + DEX compared with PALO + DEX in the delayed and overall phases ,3 87,9 * * NEPA + DEX Oral PALO + DEX 80 76,9 71,3 74,6 69, Acute NSN Delayed NSN Overall NSN * p Based on efficacy population. Acute: 0 24 h; delayed: h; overall: h. Aapro M, et al. Ann Oncol. 2014;25:

26 Antiemetic Guidelines (focused update) 2016 MASCC: Multinational Association of Supportive Care in Cancer

27 2016 V.1.1 ANTIEMETIC GUIDELINES: MASCC/ESMO 27 ACUTE Nausea and Vomiting: SUMMARY EMETIC RISK GROUP ANTIEMETICS High Non-AC 5-HT 3 + DEX + NK 1 High AC 5-HT 3 + DEX + NK 1 Carboplatin 5-HT 3 + DEX + NK 1 Moderate (other than carboplatin) 5-HT 3 + DEX Low 5-HT 3 or DEX or DOP Minimal No routine prophylaxis 5-HT 3 = serotonin 3 receptor antagonist DEX = DEXAMETHASONE NK 1 = neurokinin 1 receptor antagonist such as APREPITANT or FOSAPREPITANT or ROLAPITANT or NEPA (combination of netupitant and palonosetron) DOP = dopamine receptor antagonist NOTE: If the NK 1 receptor antagonist is not available for AC chemotherapy, palonosetron is the preferred 5-HT 3 receptor antagonist.

28 2016 V.1.1 ANTIEMETIC GUIDELINES: MASCC/ESMO 28 DELAYED Nausea and Vomiting: SUMMARY EMETIC RISK GROUP High Non-AC DEX ANTIEMETICS or (if APR 125mg for acute: ( MCP + DEX ) or APR ) High AC None or (if APR 125mg for acute: DEX or APR ) Carboplatin Oxaliplatin, or anthracycline, or cyclophosphamide Moderate (other) None or (if APR 125mg for acute: APR ) DEX can be considered No routine prophylaxis Low and Minimal No routine prophylaxis DEX = DEXAMETHASONE MCP = METOCLOPRAMIDE APR = APREPITANT

29 In highly emetogenic chemotherapy: no real surprise and in moderate emetogenic chemotherapy? Carboplatin Moderate emetogenic chemotherapy: Risk of emesis: 30% to 90% Broad range of chemotherapeutic agents Irinotecan Alemtuzumab Azacitidine

30 NK 1 RA regimen in patients receiving carboplatin Overall (0 120 hours) No emesis rate APR + 5-HT 3 RA + DEX 5-HT 3 RA + DEX Absolute difference Gralla (N = 192) 84% 70% 14% Overall (0 120 hours) Complete response NK 1 RA + 5-HT 3 RA + DEX 5-HT 3 RA + DEX Absolute difference Tanioka (N = 91) 62% 52% 10% Ito (N = 134) 80% 67% 14% Yahata (N = 324) 62% 47% 15% Hesketh (N = 401) 80% 65% 15% Adapted from Jordan K, et al. Ann Oncol. 2015;26: , 1. Gralla R, et al. J Clin Oncol 2010;28(Suppl):abstract 9057., 2. Tanioka M, et al. Br J Cancer., 2013;109(4): , 3. Ito Y, et al. Lung Cancer. 2014;84(3): , 4. Yahata H, et al. Ann Oncol. 2014;25(Suppl 4):abstract 1481PD., 5. Hesketh PJ, et al. J Clin Oncol. 2015;33(Suppl):abstract 9622.

31 Antiemetic Guidelines ASCO Guidelines Focused update

32 Antiemetic prophylaxis, ASCO 2016 Emetic risk group Risk (% pts) Acute prevention Delayed prevention High and AC combinations >90% - 5-HT 3 RA + DEX + NK 1 RAs - NEPA + DEX - DEX + NK 1 RA* - DEX Moderate 30-90% PALO + DEX DEX Low 10-30% DEX Minimal <10% No routine prophylaxis No preventive measures No preventive measures 5HT 3 RA: 5-hydroxytryptamine 3 serotonin receptor antagonist; DEX: dexamethasone; PALO: Palonosetron; AC, anthracyclinecyclophosphamide; NK 1 RA: neurokinin-1 receptor antagonist. * when aprepitant administered on day 1. Basch E, et al. J Clin Oncol 2011;29: Hesketh PJ, et al. J Clin Oncol 2016;34: Available at:

33 International Guidelines updated recommendations for NK1-RAs Chemotherapy Regimen Regimen including NK1-RAs HEC Regimens AC-based (HEC) chemotherapy Carboplatin-MEC Non-carboplatin MEC Multi-day chemotherapy Pediatric HEC/MEC N/A Last Updated February 2016 Interim update Nov 2015 March 2016

34 Conclusion Prophylactic guideline-based antiemetic treatment is the major goal Zero tolerance strategy Evidence-based antiemetic regimens help maintain quality of life and assist in the use of the most effective anticancer agents The new NK 1 RA enhances the prophylactic antiemetic armamentarium NEPA: the combination offers an opportunity to improve guideline adherence