Supportive Care for Induced Nausea & (CINV): The next steps in improving outcomes

Dr Richard Berman FRCP Supportive Care Physician Honorary Senior Lecturer in Cancer Sciences The Christie NHS Foundation Trust

This session is sponsored by TESARO UK who selected the speaker and reviewed the slides, which may contain promotional content Funding Source and Conflicts of Interest

• Consultations: Grunenthal, Astra Zeneca, Chugai

• Honoraria for lectures: Tesaro, Kyowa Kirin, Chugai

The content and interpretation of this presentation are the views and comment of the speaker and not of Tesaro. The Christie NHS Foundation Trust Supportive care [in cancer] is the prevention and management of the adverse effects of cancer and cancer treatment The landscape of cancer is changing More and more people are living longer with cancer Proactive supportive care can improve survival

1. Early Palliative Care for Patients with Metastatic Non–Small-Cell Lung Cancer, Temel JS et al, N Engl J Med 2010; 363:733- 742 August 19, 2010. 2. Palliative and Supportive Care: Early Versus Delayed Initiation of Concurrent Palliative Oncology Care: Patient Outcomes in the ENABLE III Randomized Controlled Trial - Marie A. Bakitas, Journal of Clinical Oncology May 1, 2015:1438-1445; published online on March 23, 2015; DOI:10.1200/JCO.2014.58.6362 3. Effect of Early Palliative Care on Chemotherapy Use and End-of-Life Care in Patients With Metastatic Non–Small-Cell Lung Cancer; Joseph A. Greer, JCO; Feb 1 2012, vol 30, no 4, 394-400) 4. Overall Survival Results of a Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment, Basch E, JAMA; Jul 11 2017;318(2):197-198

Chemotherapy-induced nausea and vomiting (CINV) Quality matters in CINV | Audit methods

Disease sites Head & neck n=360 patients Breast Prospective study of case notes and Colorectal e-prescribing records Followed through 3 cycles of chemotherapy Ovarian Data was collected on  Severity of nausea and vomiting  Anti-emetic use  Hospital admission  Concordance with international guidelines

Supportive Care Team, The Christie NHS Foundation Trust, CINV baseline audit, 2013-14 Quality matters in CINV | Headline results

Disease Head & neck Breast Colorectal Ovarian sites N=59 N=101 N=100 N=100

• Males n =102, Females n=258 • Age range 27-86, mean 56, median 58 years • Concordance with MASCC guidelines ranged from 88% (Head and Neck) to 0% (colorectal and ovarian) • 57% of the total cohort reported nausea and 32% vomiting • 11% of patients were admitted to hospital with CINV a contributory factor • Aprepitant was added at a later cycle in 15% patients, which resulted in better symptom control (no further admissions in this group)

Supportive Care Team, The Christie NHS Foundation Trust, CINV baseline audit, 2013-14 CLINICAL GUIDELINES

FOR THE PREVENTION AND MANAGEMENT OF CHEMOTHERAPY AND RADIOTHERAPY INDUCED NAUSEA AND VOMITING IN ADULTS

Supportive Care Team, The Christie NHS Foundation Trust, CINV clinical guidelines, 2015 What is the burden of CINV?

CINV adversely impacts patients' quality of life

Before chemotherapy (day 1) After chemotherapy (day 3) 130 (N = 122) 122 121 120 115

110

100

90

85 Mean FLIEscores Mean 80

70 Patients experiencing CINV Patients without CINV (n = 68) (n = 54) FLIE, Functional Living Index–Emesis . Adapted from CM Lindley et al. Qual Life Res. 1992;1:331-40. Who is more at risk?

• Female gender • Young age • Anxious personality • Minimal alcohol use (caveat ≥ 5 drinks/week is protective) • History of emesis during pregnancy • History of motion sickness • History of previous CINV

Morrow GR, et al. Support Care Cancer. 2002;10:96-105. Why optimal CINV treatment and prevention is important

• Nausea and vomiting are common and feared symptoms among cancer patients

• Up to 80% of patients will experience chemotherapy-induced nausea and vomiting (CINV) without prophylactic therapy

• Nausea and vomiting can lead to deteriorated nutritional status

• Inadequate emesis control may lead to anticipatory sickness

Aziz F. Ann Palliat Med 2012;1(2):130-136; Laszlo J. N Engl J Med 1981;305:948-9; Morran C. Br Med J 1979;1:1323-4; Wilcox PM. Cancer Treat Rep 1982;66:1601-4 Why does CINV occur? Physiology and neuropharmacology of chemotherapy-induced emesis

5-HT3, 5-hydroxytryptamine receptor type 3; chemo, chemotherapy; CTZ, chemoreceptor trigger zone; GI, gastrointestinal; NK1, neurokinin 1; VC, vomiting centre. Artist rendering based on work of Paul Andrews and others. NEUROTRANSMITTERS AND PATHWAYS: Targeting Key Pathways to Influence Emetic Control

Dopamine / Histamine D2 RAs

Serotonin / Endorphins 5-HT3 RAs Emetic reflex Substance P / Acetylcholine NK1 RAs

GABA Cannabinoids

DA =v dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin RAs = receptor antagonists Efficacy in controlling chemotherapy-induced emesis has progressed over the past 30 years

5-HT3 RA Added 5-day complete control: + steroids NK1 RA

100 85 (highly emetic) “AC” chemotherapy 75 75 60 50 50 50

50 %

25 10 0

1980 1990 2000 2010 Year AC, anthracycline + cyclophosphamide; RA, receptor antagonist.

Gralla R, personal communication. Binding affinity of different 5-HT3 receptor antagonists

5HT3 antagonist pKi (nM) Palonosetron1 10.4 Granisetron2 8.4 Ondansetron2 8.1 Dolasetron3 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. NK-1 receptor antagonists: How do they work?

• NK1 receptors antagonists exert their strongest antiemetic properties through central inhibition of the emesis pattern generator

• This is one of the final common mechanisms involved in activation and coordination of the vomiting reflex

• There is substantial evidence for involvement of substance P throughout the CINV response

• NK1 – RAs prevent the sensitisation of NK1 receptors by substance P

• This decreases the likelihood of vomiting

• NK-1 RAs also increase the efficacy of steroids and 5-HT3 antagonists

Saito R, Takano Y, Kamiya HO. Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87- 94. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001;111:106S-112S in 2018: practical issues

1. Good – if not perfect – antiemetic agents are available

2. Quality evidence exists that should guide all oncologists in preventing “CINV”

3. Still, many patients experience emesis

4. So do evidence-based guidelines actually work?

CINV, chemotherapy-induced nausea and vomiting. Controlling emesis in chemotherapy:

What’s new? Controlling Emesis during Chemotherapy: New findings which can affect Practice

• New Agents • New Data • Updated Guidelines • Resource Utilisation Developing new antiemetic agents: what would be ‘the ideal’ / where are ‘the gaps’?

• Better control during the ‘delayed phase’

• Single dose day 1

• Effective control over multiple chemotherapy cycles

• Flexibility: Agents with different metabolic pathways to avoid drug-drug interactions Controlling Emesis during Chemotherapy: New agents

• Rolapitant

– NK1 receptor antagonist with different metabolic pathway – Highly selective agent • NEPA

– Fixed-dose combination of netupitant (NK1 receptor antagonist) + palonosetron (5HT3 receptor antagonist) – Highly selective agents

• Olanzapine – A non-specific, non-selective, neuroleptic agent – Antiemetic and anti-nausea properties – Questions persist regarding dose and role Controlling Emesis during Chemotherapy: New Agents

• Rolapitant

– NK1 receptor antagonist with different metabolic pathway – Highly selective agent

• NEPA

• Fixed-dose combination of netupitant (NK1 receptor antagonist) + palonosetron (5HT3 receptor antagonist) • Highly selective agents

• Olanzapine • A non-specific, non-selective, neuroleptic agent • Antiemetic and anti-nausea properties • Questions persist regarding dose and role F C Rolapitant Background 3 O N H O CF3 N H

. . HCl H2O

Selective, long-acting NK-1 receptor antagonist with reduced risk of drug interaction: not an inducer or inhibitor of CYP3A4

Single oral dose, give day 1 prior to chemo

–Long t1/2 (~180 h) suggests a single dose may be sufficient to prevent CINV during the entire 5-day (0–120 h) at risk period

–180mg dose achieved >90% NK-1 receptor occupancy in the brain and maintained level for up to 5 days post a single dose

Wang X et al. Clin Pharmacol Ther 2017; 102(2):332-339 Rolapitant Phase III Trial Efficacy in Highly Emetic Chemotherapy (“HEC”)

Rolapitant group achieved significantly higher CR rates in the primary endpoint of delayed phase (>24–120 h) compared to the control group in HEC studies

HEC1 (mITT Population) HEC2 (mITT Population)

p=0.005 p=0.233 p<0.001 p=0.001 p=0.043 p=0.084

Rapoport BL et al. Lancet Oncol. 2015 Rolapitant Phase III Trial: Efficacy in Moderately Emetic Chemotherapy

mITT Population

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% p = 0.143

(

e t

a 83.5% R

p < 0.001 80.3%

e s

n p < 0.001 o

p 71.3%

s 68.6%

e

R

e

t 61.6% e

l 57.8%

p

m

o C

Delayed Phase Acute Phase Overall Phase (>24–120 hr) (0–24 hr) (0–120 hr)

Control (n=666) Rolapitant 200 mg (n=666)

Chemotherapy: One or more of the following: cyclophosphamide, doxorubicin, epirubicin , carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, cytarabine. More than 50% of patients received anthracycline + cyclophospamide (AC) chemotherapy. Primary endpoint = Complete Response in delayed emesis Schwarzberg et al Lancet Oncol 2015;16: 1071-8

Schwartzberg LS et al. Lancet Oncol. 2015 Controlling Emesis during Chemotherapy New Agents

• Rolapitant

– NK1 receptor antagonist with different metabolic pathway – Highly selective agent • NEPA

– Fixed-dose combination of Netupitant (NK1 receptor antagonist) + Palonosetron (5HT3 receptor antagonist) – Highly selective agents

• Olanzapine – A non-specific, non-selective, neuroleptic agent – Antiemetic and anti-nausea properties – Questions persist regarding dose and role Background of Netupitant and “NEPA”

• NEPA is a fixed-dose combination of oral netupitant and oral palonosetron. It is designed to improve antiemetic control by: – Administration as an all oral combination agent – A single dose schedule given on the day of chemotherapy only

• Palonosetron is a widely used 5-HT3 RA with: a long plasma half-life, demonstrated activity both orally and IV, and an good safety profile – Palonosetron is specifically recommended in key antiemetic settings in major evidence-based guidelines – Palonosetron does not prolong QTc intervals

• Netupitant is a NK1 RA with a long plasma half-life and a long duration of receptor occupancy 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):

Randomized Oral NEPA + Oral DEX 12 mg 1:1 (NEPA = NETU 300 mg + PALO 0.50 mg) N = 1455 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

Reference: Aapro M et al. Ann Oncol. 2014; 25:1328-33 NEPA PHASE III TRIAL IN AC CHEMO Complete Response Rates

CR (no emesis, no rescue medication)

* p = 0.047. ** p = 0.001. Aapro M, et al. Ann Oncol. 2014;25:1328-33. Complete Response Rates: Overall (0-120h) 6 cycles

NEPA 100 91 90 92 91 86 87 88 86 86 APR + PALO 81 81 80 76

60

40 Patients (%) Patients Full analysis population. 20 CR (no emesis, no rescue medication) 0 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6

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 Ref: Gralla RJ et al. Ann Oncol. 2014; 25:1333 – 1339 Controlling Emesis during Chemotherapy: New Agents

• Rolapitant

– NK1 receptor antagonist with different metabolic pathway – Highly selective agent

• NEPA

• Fixed-dose combination of netupitant (NK1 receptor antagonist) + palonosetron (5HT3 receptor antagonist) • Highly selective agents • Olanzapine • A non-specific, non-selective, neuroleptic agent • Antiemetic and anti-nausea properties • Questions persist regarding dose and role OLANZAPINE AS AN ANTIEMETIC*: Background and Overview

• Olanzapine is an antipsychotic agent available orally

• Phase II and phase III trials have indicated antiemetic activity

• Affects a variety of neurotransmitter receptors

– Different to most modern antiemetics

– Implications: possible benefit with broader spectrum…but potential of more side- effects

*Olanzapine does not have marketing authorisation for this indication OLANZAPINE 4-AGENT PHASE III Alliance 221301 TRIAL - Randomized, Double-Blind Study-

• Cisplatin ≥ 70 mg/M2 or Cyclophosphamide / Doxorubicin (600 / 60 mg/M2)

• Antiemetics: 3 Drugs for All: 1) Aprepitant or Fos-aprepitant + 2) Dexamethasone x 3

days + 3) 5HT3 Receptor Antagonist of choice. All antiemetics given orally PLUS either: Olanzapine 10 mg / day on days 1 – 4, OR Placebo on days 1 - 4

• Results: 3-Drugs + 3-Drugs + Olanzapine Placebo (n = 192) (n = 188) p No Nausea: Acute / Delayed 74% / 42% 45% / 24% <0.01 Complete Response: Acute / Delayed 86% / 67% 65% / 52% <0.01

Not Sedation on day 2**: > 5 (scale 0 – 10) 20% 7% Reported • Side Effects: Grade 3 or 4 Adverse Events: Olanzapine 6%; Placebo 2%

•* CR = No emesis and no use of rescue ** Day of maximal sedation. • Reference : Navari et al. N Engl J Med 2016 Olanzapine as an Antiemetic in CINV: Overview and issues

• What is its role?:

– As the 4th drug in a combination1, or 2 – Initial therapy as a replacement for an NK1RA , or – For patients who have not done well during the prior cycle

• What is the dose?: – 10 mg per day (US trials)1, 5 mg per day (Japanese trial)3

1. Navari RM, et al. New Engl J Med. 2016; 375: 134-142 2. Navari RM, et al. J Clin Oncol. 2015; 33(suppl): Abst 9502 3. Hashimoto H, et al. J Clin Oncol. 2016; 34 (suppl): Abst 10111 Controlling Emesis with Chemotherapy: Findings which can affect Practice

• New Agents • New Data What’s New? • Updated Guidelines • Resource Utilisation MASCC 2017 Systematic review and individual patient data based meta-analysis of Palonosetron trials for chemotherapy-induced nausea and vomiting

DEXAMETHASONE FOR 3 DAYS VERSUS DEXAMETHASONE FOR 1 DAY ALONE

Aapro M, Celio L, Okada Y, Oba K, Furukawa N, Kosaka Y, Yuki S, Komatsu Y The Trials in This Meta-Analysis (Dexamethasone sparing)

Trial Aapro Celio Komatsu Furukawa Kosaka published year 2010 2011 2015 2015 2016

N 300 324 308 82 80 Design Double blind Open-label Open-label Open-label Open-label multicenter multicenter multicenter multicenter multicenter Placebo Placebo controlled controlled Location Europe Europe Japan Japan Japan sex Women both both Women Women Mean age 51 57 64 59 53 Chemotherapy: AC 300 (100%) 87 (27%) 0 0 80 (100%) MEC 0 237 (73%) 308 (100%) 82 (100%) 0 Alcohol drinking 14 (6%) 131 (40%) 138 (47%) 7 (9%) 5 (6%)

44 Conclusions: Dexamethasone sparing meta-analysis

• Dexamethasone-sparing regimens – after Day 1 - are not associated with a significant loss in overall antiemetic control in MEC or AC-containing chemotherapy

• These findings allow for easier antiemetic regimens with fewer side-effects Controlling Emesis with Chemotherapy: Findings which can affect Practice

• New Agents • New Data What’s New? • Updated Guidelines • Resource Utilisation Focus on:MASCC/ESMO antiemetic guidelines vers. 1.2 2016

Summary of Acute and Delayed Prevention Emetic risk group Risk (% pts) Acute prevention Delayed prevention DEX If aprepitant: Non-AC HEC DEX + APR or HEC >90% 5-HT RA + DEX + NK RA 3 1 DEX + Metoclopramide None AC HEC If aprepitant: APR or DEX None

MEC (Carboplatin) 5-HT3RA + DEX + NK1RA If aprepitant: APR MEC (with known MEC delayed CINV 30-90% DEX potential) 5-HT RA + DEX MEC (without known 3 delayed CINV No routine prophylaxis potential)

LEC Low 10-30% 5-HT3RA or DEX or DRA No routine prophylaxis MiEC Minimal <10% No routine prophylaxis No routine prophylaxis

NOTE: If the NK1 receptor antagonist is not available for AC HEC chemotherapy, PALO is the preferred 5-HT3 RA Olanzapine is recommended for nausea prevention Recommended single agents NK1RAs: Aprepitant, Fosaprepitant, Netupitant (administered with palonosetron as part of the fixed-dose oral combination agent NEPA), Rolapitant Recommended DRAs: Metoclopramide ESMO: European Society of Medical Oncology; MASCC: Multinational Association of Supportive Care in Cancer.

HEC: highly emetogenic chemotherapy; MEC: moderatly emetogenic chemotherapy; LEC: low emetogenic chemotherapy; MiEC: minimal emetogenic chemotherapy; 5HT3 RA: 5-hydroxytryptamine 3 serotonin receptor antagonist; NK1RA: neuokinin-1 receptor antagonist; DEX: Dexamethasone; NETU: Netupitant; PALO: Palonosetron; APR: Aprepitant; FOS: Fosaprepitant; PALO: Palonosetron; AC: Anthracycline + Cyclophosphamide.47 • Roila F. et al. Ann Oncol. 2016 Sep;27(suppl 5):v119-v133. MASCC/ESMO Antiemetic Guideline 2016 V.1.2. Available at: http://www.mascc.org/ Focus on: NCCN antiemesis guidelines, v.1 2017

Recommendations for the Control of CINV

Emetic risk Risk Acute prevention Delayed prevention group (%pts) (day 1) (days 2-4 for HEC; 2-3 for MEC)

- 5-HT3RA + APR + DEX - APR + DEX - 5-HT3RA + FOS + DEX - DEX High and AC - 5-HT RA + ROL + DEX* - DEX >90% 3 combinations° - NEPA + DEX - DEX - OLA + PALO + DEX - OLA

- OLA + 5-HT3RA + DEX + APR / FOS - OLA + DEX + APR - 5-HT3RA (PALO or GRA preferred) + DEX - 5-HT3RA or DEX + + - 5-HT3RA + APR + DEX - APR + DEX + + - 5-HT3RA + FOS + DEX - + DEX Moderate 30-90% + + - 5-HT3RA + ROL + DEX* - + DEX - NEPA + DEX - + DEX - OLA + PALO + DEX - OLA - DEX or prochlorperazine or metoclopramide Low 10-30% No preventive measures or 5-HT3RA

° Also Carboplatin (at AUC > 4) Recommended 5-HT3 RAs: Palonosetron, , Ondasetron, Dolasetron. Palonosetron and granisetron extended-release injection formulation are the preferred 5-HT3 RAs in moderately antiemetic regimens without an NK1 RA Recommended single agents NK1 RAs: Aprepitant, Fosaprepitant, Rolapitant. * Rolapitant should not be administered at less than 2-week intervals and DEX dosage from day 2-4 has not to be reduced + for select patients with additional risk factors or who have failed previous therapy with 5-HT3 antagonist plus steroid

NCCN: National Comprehensive Cancer Network; 5HT3RA: 5-hydroxytryptamine 3 serotonin receptor antagonist; DEX: dexamethasone; PALO: Palonosetron; AC, anthracycline-cyclophosphamide; GRA: granisetron extended-release injection; OLA: olanzapine. NCCN Clinical Practice Guidelines in Oncology; Version 1.2017. Available at: www.nccn.org . 48 Focus on: ASCO Antiemesis Guidelines 2017

Summary of Acute and Delayed Prevention Risk Delayed prevention Emetic risk group Acute prevention (% pts) (Days 2-3)

NK1 RA*+ DEX** + Non-AC HEC ‡ 5-HT3RA + DEX + OLA*** HEC >90% ‡‡ NK1RA + OLA AC-HEC NK1 RA* + OLA** MEC - Carboplatin

(at AUC > 4 5-HT3RA + DEX + NK1RA - mg/mL/min) MEC MEC (with delayed CINV 30-90% DEX potential)*** 5-HT RA + DEX MEC others 3 (including Carboplatin - AUC < 4 mg/mL/min)

LEC Low 10-30% 5-HT3RA or DEX -

MiEC Minimal <10% - - ‡‡ APR / FOS / NEPA / ROL ‡ Granisetron (oral or transdermal patch or subcutaneous) / PALO / Dolasetron / Tropisetron / Ramosetron * If APR on day 1 ** from day 2 to 4 *** Oxaliplatin, Cyclophosphamide, Doxorubicin,..

HEC: highly emetogenic chemotherapy; MEC: moderatly emetogenic chemotherapy; LEC: low emetogenic chemotherapy; MiEC: minimal emetogenic chemotherapy; 5HT3 RA: 5-hydroxytryptamine 3 serotonin receptor antagonist; NK1RA: neuokinin-1 receptor antagonist; DEX: Dexamethasone; NEPA: fix combination of netupitant and palonosetron; PALO: Palonosetron; APR: Aprepitant; FOS: Fosaprepitant; OLA: Olanzapine; AC: Anthracycline + Cyclophosphamide.49 • Hesketh PJ, et al. J Clin Oncol 2017 Jul 31:JCO2017744789. doi: 10.1200/JCO.2017.74.4789. [Epub ahead of print]; Available at: www.asco.org/guidelines/antiemetics A Modest Proposal for Updating Antiemetic Risk Categories by Chemotherapy for Guideline Use: ACUTE PHASE

EMETIC RISK GROUP ANTIEMETICS

High 5HT3 + DEX + NK1 Moderately-High (60% - 5HT3 + DEX + APR 90%)…ie AC, Carbo, Oxali, 5HT3 + DEX + NK1 more… 5HT3 + DEX + APR Moderate (other than 5HT3 * + DEX AC) PALO + DEX Low DEX OR 5HT3 OR DRA DEX Minimal No routine prophylaxis

5HT3 = NK1 = DRA = DEX = serotonin receptor neurokinin receptor dopamine receptor DEXAMETHASONE antagonist antagonist antagonist * Some groups / experts prefer palonosetron Based on: Roila F, et al. Ann Oncol. 201627(suppl 5):v119-v133. Basch E, et al. J Clin Oncol. 2016;34(6):557-565. www.nccn.org

Consider Olazapine in: The highest risk groups (Cisplatin/AC…especially in younger women, and in those who did not do well with the initial chemotherapy A Modest Proposal for Updating Antiemetic Risk Categories by Chemotherapy for Guideline Use: DELAYED PHASE

EMETIC RISK GROUP ANTIEMETICS

High DEX + NK1* or none 5HT3 + DEX + APR Moderately-High (60% - 90%)…ie…AC, Carbo, Oxali, more… NK1* or none ±DEX 5HT3 + DEX + APR Moderate (other than AC) ± DEX Low PALO No+ routineDEX prophylaxis

Minimal No routineDEX prophylaxis

NK1 = neurokinin receptor DEX = DEXAMETHASONE antagonist

* NOTE: if NEPA (with netupitant), rolapitant, aprepitant 165 mg or fos-aprepitant 150mg used on Day 1 – no further NK1 but, continue NK1 if 3-day aprepitant regimen is used Controlling Emesis during Chemotherapy: Findings which can affect Practice

• New Agents • New Data What’s New? • Updated Guidelines • Resource Utilisation Studies Examining the Effectiveness of Guidelines: Some Definitions

• Primary Objective:

• To compare Complete Response rates over 5 Days post- chemotherapy among patients receiving:

Guideline consistent Antiemetic prophylaxis (GCCP) th those receiving: Guideline inconsistent Antiemetic prophylaxis (GICP)

Aapro et al Ann Oncol 2012; Gilmore et al J Oncol Practice 2014; O’Kane et al Proc MASCC 2009 Pan European Emesis Registry (“PEER”) study: design and patients using MASCC guidelines

Parameter: Patients (N) 991 Where conducted 8 European countries (including UK) Women (%) 73 Median age (years) 57 HEC/AC/MEC (%) 19/47/34 Guideline compliant (%) 29 Guideline non-compliant (%) 71

Aapro M, et al. Ann Oncol. 2012;23:1986-92. Pan European Emesis Registry (“PEER”) study: results using MASCC guidelines

Guideline Guideline p value/ Parameter compliant non-compliant odds ratio Patients (N) 287 704 – Complete responsea (%) 60 51 0.008/1.43 No emesis (%) 63 59 0.154/1.18 No nauseab (%) 48 41 0.031/1.37 No CINV (%) 43 34 0.016/1.41

a No emesis or rescue therapy. b Defined as nausea scored < 5 on the VAS. VAS, visual analogue scale.

Aapro M, et al. Ann Oncol. 2012;23:1986-92. Antiemetic Guidelines: Good value?

• Evidence-based guidelines are the best tool to help:

– Avoid over-use and under-use of antiemetics – Achieve prevention of emesis ANTIEMETIC THERAPY Evidence based benefit of current antiemetic therapy

• Antiemetics continue to be crucial in patients receiving most combination chemotherapy regimens: – Preserve quality of life – Permit safe out-patient treatment – Reduce or eliminate associated symptoms and side-effects – Enhance use of the most effective antineoplastic agents • Newer antiemetics and new trials indicate significant improvement in controlling both acute and delayed emesis: – Development based on targeting identified key receptors – Emesis prevention based on individual risk indicated by all major guideline groups 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