ANTIEMETIC RESEARCH AND PROGRESS: Richard J. Gralla, MD, FACP Professor of Medicine Albert Einstein College of Medicine Bronx, New York

THE FUTURE OF ANTIEMETICS Fausto Roila Medical Oncology, Terni, Italy

Steven Grunberg (1950-2013)

DISCLOSURES: A 30 Year Perspective Research support, consultancy or honoraria: Abeille AH Robbins American Cancer Society American Home Products Aventis Beecham BMS Eisai Eli Lilly Glaxo Glaxo Wellcome GSK Helsinn HMR Lauder Foundation Merrill Dow Marion Merrill Dow Merck MGI National Cancer Institute Pfizer Rhone Poulenc Roche RPR Sancuso Sandoz Sanofi Sanofi-Aventis Schering Plough Smith Kline Beecham Solvay Takeda Tesoro Wyeth No employment, stock or other ownership

THE MULTIPLE ROLES FOR SUPPORTIVE CARE IN CANCER Enhance the use of the most effective anti-neoplastic agents Reduce or eliminate associated symptoms and side-effects Preserve or improve quality of life Permit safe out-patient treatment

How can we identify targets*? Expression Possible target Expression + activation Promising target Expression + activation + mechanism A major target for a clinical trial Expression + activation + mechanism + drug A potentially valuable therapy * J Fletcher. Sarcoma State of the Science Meeting, June 2002, Bethesda, MD

Chemotherapy-induced nausea and vomiting (CINV): Impact on Quality of Life Before chemotherapy (day 1) After chemotherapy (day 3) 130 120 115 (N=122) 122 121 Mean FLIE scores 110 100 90 * 85 80 70 Patients experiencing CINV Patients without CINV * p=0.001 Functional Living Index Emesis (FLIE): Adapted from CM Lindley et al. Qual Life Res. 1992;1:331 340; used with permission from Kluwer Academic Publishers 1992.

ISSUES IN THE CONTROL OF EMESIS FUTURE AND RESEARCH Complete elimination of vomiting and nausea ENHANCING EMETIC CONTROL IN PRACTICE The Role of Corticosteroids The Choice of Serotonin Antagonist The Use of NK1 Antagonists THE ROLE AND VALUE OF GUIDELINES

THE EFFECT OF ADDING DEXAMETHASONE TO 5-HT 3 ANTAGONISTS ON ACUTE EMESIS Jantunen et al, Eur J Cancer 1997; 33: 66

RANDOMIZED TRIAL TESTING DEXAMETHASONE IN DELAYED EMESIS: CTX / ANTHRA (Aapro, Ann Oncol 2010) DAY 1: All patients: Palonosetron 0.25 mg IV + Dexamethasone 8 mg IV RANDOMIZE DAYS 2 & 3: N = 151 n = 149 PLACEBO DEX 4 mg orally 2x / day 5 DAY CR: 54% p = 0.487 54% ACUTE: 70% 69% DELAYED: 62% 66% All women: met breast ca; med age 52. ENDPOINT: 5 DAY CR Noninferior < 15% No nausea (delayed) favored DEX (62% vs 55%); no diff in FLIE (p=0.64) or side effects

Aprepitant versus dexamethasone for preventing delayed emesis induced by anthracyclines+ cyclophosphamide chemotherapy in breast cancer patients: a double-blind, multicenter, randomized study Roila F, et al. J Clin Oncol 2013; 31: 603s, abstr. 9614

Binding Affinity of 5-HT 3 Receptor Antagonists 5-HT 3 Antagonist: pk i (nm): Granisetron 1 8.4 Ondansetron 1 8.1 Dolasetron 1 7.6 1 Van Wijngaarden I et al. Eur J Pharm Mol Pharmacol. 1990;188:301 312. 2 Miller RC et al. Drug Dev Res. 1993;28:87 93.

SINGLE DOSE 5-HT 3 ANTAGONIST STUDIES - Randomized Comparison Trial (N = 973): Cisplatin 50 mg / M 2-100 80 79.3 79.1 60 40 20 0 Acute Emesis Ondansetron + Dex Granisetron + Dex For acute emesis: Dexamethasone 20 mg IV; Ondansetron 8 mg IV, Granisetron 3 mg IV Ref: Roila IGAR, Proc ASCO 1995, Ann Oncol 1996

ASCO Practice Guideline Update: 2011 Ondansetron may increase the risk of developing abnormal changes in the electrical activity of the heart, which can result in a potentially fatal abnormal heart rhythm Please visit the FDA website for additional information. Reference: Basch et al. J Clin Oncol 29: 4189-4198, 2011

Binding Affinity of 5-HT 3 Receptor Antagonists 5-HT 3 Antagonist: pk i (nm): Palonosetron 1 10.4 Granisetron 2 8.4 Ondansetron 2 8.1 Dolasetron 3 7.6 1 Wong EH et al. Br J Pharmacol. 1995;114:851 859. 2 Van Wijngaarden I et al. Eur J Pharm Mol Pharmacol. 1990;188:301 312. 3 Miller RC et al. Drug Dev Res. 1993;28:87 93.

PALONOSETRON EFFICACY: TWO RANDOMIZED TRIALS - Moderately Emetic Chemotherapy (n = 754) - Complete Response (%) 80 70 60 50 40 30 20 * 72 60.6 * 64 46.8 Palonosetron 0.25 mg Ondansetron/dolasetron * p 0.025 10 0 0 24 h 24 120 h Rubenstein E. Proc ASCO. 2003 (approved palonosetron dose shown, 3-arm trials, 754 of 1132 patients )

RANDOMIZED-DOUBLE BLIND TRIAL COMPARING: PALONOSETRON + DEX versus GRANISETRON + DEX in EITHER CISPLATIN OR AC / EC (N = 1114) R a n d o m i Z e Palonosetron 0.75 mg IV + Dexamethasone 16 mg IV - Versus - Granisetron 40 ug / kg IV + Dexamethasone 16 mg IV Delayed emesis: Dexamethasone days 2 & 3: 8mg IV (Cisplatin), 4 mg PO (AC / EC) Reference: Saito et al. Lancet Oncol, 10; 115-124, 2009

RANDOMIZED-DOUBLE BLIND TRIAL COMPARING: PALONOSETRON + DEX versus GRANISETRON + DEX in EITHER CISPLATIN OR AC / EC (N = 1114) Complete Control: Palonosetron 0.75mg + Dexamethasone Granisetron 40ug/kg + Dexamethasone 100% - NS p = 0.0001 p = 0.0001 75% - 50% - 75.3% 73.3% 56.8% 44.5% 51.5% 40.4% 25% - ACUTE DELAYED OVERALL Reference: Saito et al. Lancet Oncol, 10; 115-124, 2009 Dex: 16mg IV day 1, then 8mg IV (Cis) / 4mg PO (AC) days 2 & 3

PALONOSETRON + DEX + APREPITANT versus GRANISETRON + DEX + APREPITANT WITH CISPLATIN (N = 842) Complete Response: 100% - 75% - Palonosetron + Dex + Aprep Granisetron NS p = 0.01 p = 0.053 91.8% 91.8% 67.2.% 59.1% 65.7% 59.1% + Dex + Aprep 50% - 25% - ACUTE DELAYED OVERALL Reference: Hashimoto et al. Proc ASCO, 2013 abstract #9621

RISK FACTORS FOR EMESIS AND CONTROL - Clinical Factors and Personalization - Chemotherapy Regimen Gender Age Chronic Alcohol Intake History

EMETIC CONTROL: MOLECULAR STUDIES - Effect of Deletion Variant of the 5-HT 3B Gene on Emetic Response - Number of Emetic Episodes * 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 5 1.5 0.8 wt / wt wt / del del / del -100_-102AAG Deletion Variant Genotype * Number of episodes over 24 hours Tremblay et al, J Clin Oncol 21: 2147, 2003

NEUROTRANSMITTERS AND EMESIS Dopamine/ DA RAs Histamine Serotonin/ 5-HT 3 RAs Substance P/ NK-1 RAs Emetic reflex Endorphins Acetylcholine GABA Cannabinoids DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin; RAs = receptor antagonists

Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Blockade of NK 1 receptors after aprepitant dosing Tracer Binding Low High Hargreaves R. J Clin Psychiatry 2002; 63( Suppl.1): 18-24.

Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Blockade of NK 1 receptors after aprepitant dosing Low Tracer Binding Brain NK 1 Receptor Occupancy (%) 100 90 80 70 60 50 40 30 20 10 0 Mean (± SD) Plasma Trough Concentrations of the Aprepitant 3-Day Regimen 0 1 10 100 1000 10000 Aprepitant Plasma Trough Concentration (ng/ml) High Hargreaves R. J Clin Psychiatry 2002; 63( Suppl.1): 18-24.

Aprepitant randomized trials: The role of aprepitant addition in patients receiving cisplatin R A N D O M I S E Ondansetron32 mg IV * + Dexamethasone 20 mg po (then 8 mg bid x 3 days) vs. Ondansetron32 mg IV * + Dexamethasone 12 mg po (then 8 mg bid x 3 days) + Aprepitant 125 mg po (then 80 mg po x 2 days) Heskethet al. J ClinOncol2003; Poli-Bigelli, et al. Cancer2003. * NOTE: 32 mg is NO longer an approved Ondansetron dose

Phase III combined data from both Phase III trials: Complete response: high risk chemotherapy (Cisplatin) Acute Emesis Delayed Emesis Aprepitant regimen Ondansetron + Dex 100 80 60 86% p<0.001 73% 100 80 60 72% p<0.001 40 40 51% 20 20 0 N= 520 523 0 N= 520 523 Hesketh et al. J Clin Oncol 2003; Poli-Bigelli, et al. Cancer 2003.

Phase III combined data from both Phase III trials: Complete response: high risk chemotherapy (Cisplatin) Acute Emesis Delayed Emesis Aprepitant regimen Ondansetron + Dex 100 80 60 p<0.001 86% 73% 100 80 60 72% p<0.001 40 40 51% 20 20 0 N= 520 523 0 N= 520 523 Hesketh et al. J Clin Oncol 2003; Poli-Bigelli, et al. Cancer 2003.

TESTING THE ADDITION OF APREPITANT IN A 5-DAY CISPLATIN TRIAL (GERM CELL) Aprepitant 125 mg Day 3, then 80 mg Days 4-7 5 HT 3 on Days 1-5 R a n d o m i Z e Dexamethasone 20mg Days 1+2, 4mg bid days 6-7 Placebo Day 1, then days 4-7 5 HT 3 on Days 1-5 With Crossover On 2 nd Cycle Dexamethasone 20mg Days 1+2, 4mg bid days 6-7 PATIENTS: 69 men, Median age 32. BEP Chemo 93% (no prior in 83%) Albany C, et al. J Clin Oncol 2012; 30: 3998-4003

TESTING THE ADDITION OF APREPITANT IN A 5-DAY CISPLATIN TRIAL (GERM CELL) APREPITANT PLACEBO P NO EMESIS: DAYS 1-5 80% 52% <0.0001 DAYS 6-8 92% 78% <0.0005 COMPLETE RESPONSE: DAYS 1-5 47% 15% <0.0001 DAYS 6-8 63% 35% <0.0004 DAYS 1-8 42% 13% <0.0001 Albany C, et al. JCO 2012; Preference strongly favored Aprepitant

METHODS - A randomized double-blind study comparing aprepitant versus dexamethasone was carried out in naive breast cancer patients treated with anthracyclines + cyclophosphamide - Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 8 mg plus oral aprepitant 125 mg - On days 2 and 3 patients randomly received oral dexamethasone 4 mg bid or aprepitant 80 mg qd Primary endpoint was rate of complete response (no vomiting, no rescue treatment) from days 2-5 after chemotherapy

RESULTS IN THE ACUTE PHASE (551 PTS) Dexamethasone Aprepitant No. of patients (%) 273 (%) 278 (%) RESPONSES complete response 239 (87.6) 236 (84.9) complete protection 179 (65.6) 170 (61.2) total protection 142 (52.0) 147 (52.9) no vomiting 253 (92.7) 251 (90.3) no nausea 142 (52.0) 149 (53.6) no significant nausea (VAS < 25 mm) 84 (30.8) 77 (27.7) mean number of emetic episodes (sd)* 3.8 (3.3) 5.7 (3.2) mean maximum severity of nausea (sd) 39.7 (24.6) 48.7 (26.6) mean duration of nausea, hours (sd) 4.9 (5.8) 6.0 (6.5) *evaluated in patients who vomited; evaluated in patients who had nausea; sd = standard deviation; Complete Response: No vomiting, no rescue treatment; Complete Protection = No vomiting, no rescue treatment, no significant nausea (VAS < 25 mm); Total Protection = No vomiting, no nausea.

RESULTS IN THE DELAYED PHASE (551 PTS) Dexameth. Aprepit. P Value No. of patients (%) 273 (%) 278 (%) Complete response 217 (79.5) 221 (79.5) n.s. Complete protection 164 (60.1) 152 (54.7) n.s. Total control 131 (48.0) 120 (43.2) n.s. No vomiting 250 (91.6) 248 (89.2) n.s. No nausea 134 (49.1) 122 (43.9) n.s. No significant nausea 174 (63.7) 158 (56.8) n.s. Mean number of emetic episodes (sd)* 5.7 (6.5) 9.2 (9.4) n.s. Mean maximum severity of nausea (sd) 42.8 (25.9) 45.5 (24.1) n.s. Mean duration of nausea, hours (sd) 14.1 (18.4) 16.6 (21.4) n.s. * in patients who had delayed vomiting (dexamethasone: 23 patients; aprepitant: 30 patients) in patients suffering from delayed nausea (dexamethasone: 139 patients; aprepitant: 156 patients)

ADVERSE EVENTS IN DELAYED PHASE Dexamethasone Aprepitant P Value No. of patients (%) 273 (%) 278 (%) Headache 55 (20.1) 49 (17.6) n.s. Diarrhea 2 (0.7) 5 (1.8) n.s. Constipation 52 (19.1) 40 (14.4) n.s. Hiccup 4 (1.5) 6 (2.2) n.s. Asthenia 90 (33.0) 98 (35.3) n.s. Epigastric pain 37 (13.6) 24 (8.6) n.s. Sedation 13 (4.7) 23 (8.3) n.s. Tremors 6 (2.2) 4 (1.4) n.s. Insomnia 8 (2.9) 1 (0.4) 0.02 Agitation 7 (2.6) 8 (2.9) n.s. Face erythema 34 (12.5) 23 (8.3) n.s. Heartburn 22 (8.1) 10 (3.6) 0.03 Anorexia 8 (2.9) 18 (6.5) n.s. Sweating 7 (2.6) 3 (1.1) n.s. Hyperglicemia 2 (0.7) 1 (0.4) n.s. Tachycardia 9 (3.3) 6 (2.2) n.s.

ANTIEMETIC TREATMENT Goals with Chemotherapy: All Major Guideline Groups The Strategy is to Prevent Nausea and Vomiting, rather than Treat Complete control in all settings No side-effects Convenient and easy to use

NK 1 RECEPTOR ANTAGONIST AGENTS Approved or Under Investigation for Use as Antiemetics Aprepitant (oral) Fos-aprepitant (IV) Netupitant * (and NEPA) * Rolapitant * * Agents under investigation

NEPA Clinical Trials Presented in 2013 MEETINGS: ASCO ECCO MASCC SABC ASH PRESENTERS: Aapro Gralla Hesketh Jordan Rugo Schwartzberg

NEPA RANDOMIZED PHASE II TRIAL TO ESTABLISH THE NETUPITANT DOSE FOR PHASE III STUDIES Eligibility: No prior chemotherapy Karnofsky Performance Status 70% First course of cisplatin ( 50 mg/m 2 ), with or without other chemotherapy Subjects Enrolled: 694 patients were randomized 677 (98%) received study treatment and the protocol-required Highly Emetic Chemotherapy

Treatment Schema: Group Day 1 Days 2 and 3 Day 4 PALO PALO 0.5 mg + DEX 20 mg + Placebo DEX 8 mg BID DEX 8 mg BID NEPA 100 NETU 100 mg + PALO 0.5 mg + DEX 12 mg DEX 4 mg BID DEX 4 mg BID NEPA 200 NETU 200 mg + PALO 0.5 mg + DEX 12 mg DEX 4 mg BID DEX 4 mg BID NEPA 300 NETU 300 mg + PALO 0.5 mg + DEX 12 mg DEX 4 mg BID DEX 4 mg BID APR + OND APR 125 mg + OND 32 mg + DEX 12 mg APR 80 mg + DEX 4 mg BID DEX 4 mg BID PALO = palonosetron, NEPA = fixed dose combination of PALO + netupitant, APR = aprepitant, DEX = dexamethasone, OND = ondansetron. PALO, NEPA, APR, DEX were oral; OND was IV PALO, NEPA and APR administered 60 min prior to HEC Day 1; APR in morning on Days 2-3 OND was 50 ml IV infusion 15 min duration prior to HEC DEX administered 30 min prior to HEC Day 1 then in the morning and evening on days 2-4

Complete Response Rates: Overall (0-120h hr) P = 0.018 P = 0.017 P = 0.004 P = 0.027 PALO NEPA 100 NEPA 200 NEPA 300 APR+OND *p value from logistic regression vs PALO ** p value from a post-hoc logistic regression analysis vs PALO

Complete Response Rates: Acute (0-24 hr) and Delayed (25-120 hr) % Patients p-value PALO (N = 136) NEPA 100 (N = 135) NEPA 200 (N = 137) NEPA 300 (N = 135) Acute (0-24 hr) 89.7% 93.3% 0.278 92.7% 0.383 98.5% 0.007 Delayed (25-120 hr) 80.1% 90.4% 0.018 91.2% 0.010 90.4% 0.018 p value from logistic regression vs PALO

No Significant Nausea (Maximum VAS < 25 mm) (Acute, Delayed, and Overall) PALO NEPA 100 NEPA 200 NEPA 300 * P 0.05 compared with PALO; not adjusted for multiple comparisons

NEPA PHASE III TRIAL IN AC CHEMO Study Design Phase III, multinational, randomized, double-blind study in chemotherapy-naïve patients undergoing Anthracycline - CTX chemo Patients randomized to receive one of the following regimens, on Day 1 only (no continued steroids): N = 1455 Randomized 1:1 Oral NEPA + Oral DEX 12 mg (NEPA = NETU 300 mg + PALO 0.50 mg) Oral PALO 0.50 mg + Oral DEX 20 mg NEPA (netupitant + palo) or PALO were administered 60 minutes prior to chemotherapy; DEX was given orally at 30 minutes prior to chemotherapy No other antiemetic was given as part of either study regimen after Day 1

NEPA PHASE III TRIAL IN AC CHEMO Complete Response Rates P = 0.047 P = 0.001 P = 0.001 Percent of patients CR: no emesis, no rescue medication Based on full analysis set of 1449 patients

Overview of Treatment Emergent Adverse Events and Most Common ( 2% Incidence) Treatment-Related Adverse Events Adverse Event NEPA + DEX (N = 725) Palonosetron + DEX (N = 725) Patients with at least one treatment emergent Adverse Event 551 (76%) 507 (69.9%) Patients with any treatmentrelated Adverse Event 59 (8.1%) 52 (7.2%) Headache Constipation 24 (3.3%) 15 (2.1%) 22 (3.0%) 15 (2.1%)

MULTI-CYCLE NEPA RANDOMIZED TRIAL Phase III, multicenter, multinational, randomized, active controlled, double-blind, double-dummy, parallel group study Patients had not received prior chemotherapy Patients received Highly ( HEC ) or Moderately Emetic Chemo ( MEC ) Group Day 1 Days 2 and 3 Day 4 N = 413 Randomized 3:1 NEPA NEPA (NETU 300 mg + PALO 0.5 mg) + DEX 12 mg (HEC & MEC) HEC: DEX 8 mg MEC: none HEC: DEX 8 mg MEC: none 75/25 % MEC/HEC APR + PALO APR 125 mg + PALO 0.5 mg + DEX 12 mg (HEC & MEC) HEC: APR 80 mg + DEX 8 mg MEC: APR 80 mg HEC: DEX 8 mg MEC: none NEPA, PALO, APR, DEX were all oral Day 1: NEPA and APR administered 60 min prior to chemotherapy, Dexamethasone (DEX) administered 30 min prior to CT

Complete Response Rates: Overall (0-120 hr) Over 6 Cycles Percent of patients (%) NEPA N = 309 280 259 233 156 124 APR + PALO N = 103 96 90 81 57 44 Similar results observed for both the HEC and MEC subsets No formal statistical comparisons were performed

NEPA CONCLUSIONS FROM RANDOMIZED TRIALS Netupitant at 300 mg is an appropriate NK 1 RA to add to palonosetron in an all oral combination. This dose was associated with few side effects and high efficacy The addition of netupitant significantly improves the efficacy of palonosetron NEPA as a single dose regimen given only prior to chemotherapy (with dexamethasone on day 1) is effective: In patients receiving Anthracycline + Cyclophosphamide / Moderately Emetic Chemotherapy (MEC) as for breast cancer and requires no further antiemetic agents after day 1 In patients receiving Highly Emetic Chemotherapy (HEC), such as cisplatin, with only dexamethasone continued after day 1 NEPA has few side effects and maintains efficacy over repeated cycles of chemo NEPA provides a straight-forward strategy to enhance the use of guideline-based antiemetic regimens and is maximally convenient to improve patient adherence

THREE-DRUG PHASE II TRIAL SINGLE DAY* - Palonosetron + Aprepitant + Dexamethasone (N = 41) - Single Dose Regimen Only (All given once shortly before Chemotherapy): Palonosetron 0.25 mg IV Dexamethasone 20 mg PO Aprepitant 285 mg PO Women: 98% No Prior Chemo: 100% Median Age: 51 Anthracycline + CTX: 95% Acute Emesis Delayed Emesis Overall (5 days) No Nausea or Mild** 78% 68% 66% No Emesis 100% 95% 95% ** Nausea < 26 on a VAS Grunberg et al. Supportive Care in Cancer 2009 * Preliminary Investigative Trial

Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III study Navari RM, et al. J Support Oncol 2011; 9: 188-195

DESIGN OF THE STUDY (241 pts) g. 1 g. 2 g. 3 g. 4 Aprepitant po 125 mg 80 mg 80 mg - Palonosetron iv 0.25 mg - - - Dexamethasone 12 mg 4mg bid 4mg bid 4mg bid Olanzapine po 10 mg 10 mg 10 mg 10 mg Palonosetron iv 0.25 mg - - - Dexamethasone 20 mg - - - dexamethasone iv on day 1 and orally on day 2-4

RESULTS (% COMPLETE RESPONSES) OPD APD p Day 1 97.0 87.0 n.s. Day 2-5 77.0 73.0 n.s. Day 1-5 77.0 73.0 n.s.

It is an open study SHORTCOMINGS Due to the small sample size, the study was only powered to investigate large differences such as a 15% difference in complete response on day 1-5. It was not stated if the study was designed as a superiority, non inferiority or equivalence study. An unplanned interim analysis was carried out but the significance level was not modified according to Bonferroni s inequality.

MASCC/ESMO Antiemetic Guideline 2013 Multinational Association of Supportive Care in Cancer Third Major Guideline Update by MASCC over a 15 Year Period Recommendations: Published Ann Oncol 2010 and www.mascc.org with periodic web updates the latest in April 2013

GUIDELINES AND EVIDENCE-BASED MEDICINE Approaches in Guideline Development Evidence - based Opinion (Consensus) - based Economically - based

SUMMARY ACUTE NAUSEA AND VOMITING EMETIC RISK GROUP High Anthracycline + Cyclophosphamide (AC) Moderate (other than AC) ANTIEMETICS + + + + + + 5HT3 DEX APR or FOS 5HT3 DEX APR 5HT3 DEX APR or FOS + + + DEX 5HT3 DEX APR PALO Low PALO DEX OR + DEX 5HT3 OR DRA Minimal No routine DEXprophylaxis 5HT3 = serotonin receptor antagonist DEX = DEXAMETHASONE APR = APREPITANT; FOS= FOSAPREPITANT PALO = PALONOSETRON DRA = dopamine receptor antagonist * NOTE: If the NK1 receptor antagonist is not available for AC chemotherapy, palonosetron is the preferred 5-HT3 receptor antagonist. The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer. - Ann Oncol 2010; www.mascc.org. 2013 Multinational Association of Supportive Care in Cancer TM All rights reserved worldwide.

SUMMARY DELAYED NAUSEA AND VOMITING EMETIC RISK GROUP ANTIEMETICS High DEX* + APR* 5HT3 + DEX + APR Anthracycline + APR or none** Cyclophosphamide (AC) 5HT3 DEX APR Moderate (other than AC) Low Minimal PALO + + DEX + DEX No routine prophylaxis DEX No routine prophylaxis DEX = DEXAMETHASONE APR= APREPITANT The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer. Ann Oncol 2010; www.mascc.org. 2013 Multinational Association of Supportive Care in Cancer TM All rights reserved worldwide.

Reported and Actual Application of National and International Antiemetic Guidelines Percentage of European and US Oncologists reporting that they frequently or always use major national or international antiemetic guidelines: 50% 70% Percentage of patients receiving highly or moderately emetic chemotherapy actually given guideline consistent antiemetics in a 991 patient observational study: 29% Aapro, Molassiotis, Dicato et al Proc MASCC 2011

Pan European Emesis Registry ( PEER ) Study Design Primary Objective: To compare Complete Response rates over 5 Days postchemotherapy among patients receiving: Guideline consistent Antiemetic prophylaxis (GCCP) with those receiving: Guideline inconsistent Antiemetic prophylaxis (GICP) Aapro, Molassiotis, Dicato et al Proc MASCC 2011

Complete Response, 5 Days (cycle 1): PEER Study P=0.104 80% 71.4% P=0.010 75% 69.2% GCCP 70% 65% 60% 55% 50% 54.2% 48.9% P=0.549 44.5% P=0.027 57.8% 59.9% 50.7% GICP 45% 40% 35% 30% HEC (N=189) Female AC (N=463) MEC (N=339) Overall (N = 991) P-values are derived from multivariate model

Resource Utilization (cycle 1): PEER Study All Antiemetic Risk Groups Parameter Visit to: Primary Care Physician, or Specialist, or ER GCCP ( Compliant ) ( N = 287 ) GICP ( Not Compliant ) ( N = 704 ) Total ( N = 991 ) N Percent N Percent N Percent 14 4.9% 40 7.7% 66 6.6 Hospital days 5 1.7 10 1.4 15 1.5 Note: In a busy practice treating 100 patients per day, the rate with non-compliance with Antiemetic Guidelines results in 700 additional urgent visits per year

ISSUES IN THE CONTROL OF EMESIS FUTURE AND RESEARCH Complete elimination of vomiting and nausea ENHANCING EMETIC CONTROL IN PRACTICE Effectiveness = Efficacy THE ROLE AND VALUE OF GUIDELINES Enhancing incorporation of guidelines into practice

Multiple roles for supportive care in cancer Reduce or eliminate associated symptoms and side-effects Preserve or improve quality of life Enhance the use of the most effective anti-neoplastic agents Positively affect survival and the quality of that survival Cancer patients are living longer and better lives, thanks to better symptom control, more effective therapies, and a deeper understanding of cancer Dr. Harold Varmus, Director NCI, PBS Newshour, September 24, 2012

P. Hetzel, MD

Palonosetron Dosing in 8 Studies - Individual Patient Data Meta-analysis: Overall Complete Response TOTAL HEC MEC Grunberg RR= 1.00 (CI 0.83, 1.2) RR= 1.202 (CI 0.88, 1.641) RR= 0.903 (CI 0.718, 1.135) Eisenberg-2 Oral HEC Gralla Eisenberg Aapro Masuda Tabei 0.1 1 10 Favors 0.25 mg Odds Ratio Favors 0.75 mg References: Lesser et al, Proc IASLC 2009; Raftopoulos et al, Proc ASCO 2009