Akynzeo+a+better+or+bitter+pill+for+the+prevention+of+cinv (1)

Nelson Origa, Pharm.D. Candidate Texas Tech University Health Sciences Center

School of Pharmacy | Dallas Campus February 4, 2015

Learning Objectives By the end of this presentation participants should be able to:1.Describe mechanisms of CINV2.Classify cancer drugs associated with CINV according to their emetogenicity3.Discuss current treatment recommendations for CINV4.Explain mechanism of action of Akynzeo® and its pharmacokinetics/pharmacodynamics5.Analyze trials that led to approval of Akynzeo® based on safety and efficacy

2

Abbreviations CINV-Chemotherapy-induced

nausea and vomiting 5-HT3-Serotonin type 3 receptor HEC-Highly emetogenic

chemotherapy MEC-Moderately emetogenic

chemotherapy AP-Area Postrema CTZ-Chemoreceptor trigger

zone NIDL-No Impact on Daily

Living FLIE-Functional Living Index-

Emesis

NK1 RA-Neurokinin 1receptor antagonist

NEPA-Netupitant + palonosetron EC-Emesis center CR-Complete Response CP-Complete protection NCCN-National comprehensive

cancer network MASCC-Multinational

Association of Supportive Care in Cancer

ASCO-American Society of Clincal Oncology

NTS-Nucleus tractus solitarius

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Chemotherapy-Induced Nausea and Vomiting: Definitions

Nausea: Inclination that vomiting is imminent

Vomiting: Expulsion of gastric contents due to contraction of muscles of abdomen and diaphragm

Retching: Movement of muscles of abdomen and thorax

CINV Acute 0-24 h Delayed 24-120 h Anticipatory

Learned response Breakthrough

During chemotherapy Refractory Occurs

despite use of antiemetics

4

CINV: Risk FactorsPatient Factors

Age: >6years or <50 Gender: Female>Male Vomiting Previous

cycle Low alcohol use Motion sickness Anxiety Expectation

Treatment factors Emetogenicity of drug Dose of drug Antiemetic

administered

Warr. Eur J Pharmacol. 2014;192-196. 5

CINV: Prevalence & Consequences67 Patients on HEC

60% delayed nausea 50% delayed emesis

231 Patients on MEC 52% delayed nausea 28% delayed emesis

Consequences of CINV↑Length of stay Poor adherence Diminished quality of

life

Jenelsins MC et al .Expert Opin Pharmacother. 2013;14(6):757-66.Grunberg SM et al.Cancer. 2004;100(10):2261-2268.

6

Chemotherapy Emetic Risk ClassificationHigh: > 90% frequency of emesis without antiemetics

Moderate: 31-90% frequency of emesis without antiemetics

Low: 10-30% frequency of emesis without antiemetics

Minimal: <10% frequency of emesis without antiemetics

Hesketh N. Engl J Med. 2008; 358:2482-24947

Emetogenic Potential of Cancer DrugsHigh Moderate Low Minimal

Intravenous Cisplatin Alemtuzumab Bortezomib Bevacizumab

Cyclophospha-mide≥1500

Cyclophosphamide<1500

Cetuximab Bleomycin

Gemcitabine Rituximab

Dacarbazine Doxorubicin Docetaxel Vinblastine

Carmustine Epirubicin Etoposide Vincristine

Oral Procarbazine Imatinib Capecitabine Hydroxyurea

Hexamethyl-melamine

Cyclophosphamide

Etoposide Methotrexate

8Affronti ML. Cancer Manag Res.2014; 6:329-337

Proposed Pathophysiology of CINVCentral & peripheral regions

Emetic/vomiting center (VC)-neurons in medulla oblongata-coordinate NV-primary structure

Chemoreceptor trigger zone(CTZ) in AP in floor of 4th ventricle of brain activated by chemotherapy

Vagal nerve afferents from GIT to nucleus tractus solitarius (NTS) & dorsal motor nucleus of the vagus nerve

GI tract releases 5-HT, SP,D2,H1 due to irritation, free radicals, damage, and necrosis of GI mucosa by chemo

Jenelsins MC .Expert Opin Pharmacother. 2013;14(6):757-66 Grunberg S. NEJM 1993.329:1790-1796

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Proposed Pathophysiology of CINV

NTS

Hesketh et al. N Engl J Med. 2008; 358:2482-2494.10

Neurotransmitters in CINV

GI, AP, NTS

Enterochromaffin Cells

Emetic Center

Area Postrema

GABACannabinoids

HistamineAcetylcholineEndorphins

Mustian KM. US Oncol Hematol. 2011 ; 7(2): 91–9711

CINV: Antiemetic Agents5-HT3 RA

Palonosetron(Aloxi®)Ondansetron(Zofran®)Granisetron(Sancuso®)Dolasetron(Anzemet®)

CorticosteroidsDexamethasone(Decadron®)Dopamine RAMetoclopramide(Reglan®)

NK-1 RAAprepitant(Emend®)Fosaprepitant(Emend®)Netupitant/palonosetron (Akynzeo®)

Benzodiazepines Lorazepam(Ativan®) Atypical Antipsychotic olanzapine(Zyprexa®)

Ettinger DS. NCCN Guidelines. Antiemesis.v 2.2014. 12

Antiemetic Agents: Adverse Effects5-HT3 RA

Headache Constipation QT prolongation (FDA

alert) Somnolence Dizziness Elevated transaminases

NK-1 RA Fatigue Hiccups Weakness Dizziness

Corticosteroids Euphoria Insomnia ↑Appetite Hyperglycemia Fluid retention

Ettinger DS. NCCN Guidelines. Antiemesis.v 2.2014. 13

CINV Prophylaxis The NCCN Guidelines for HEC

High Risk Low Risk 5-HT3 RA +Steroid+ NK-1 RA( or

olanzapine)

Palonosetron + dexamethasone + aprepitant

5-HT3 RA + dexamethasone + fosaprepitant

Dexamethasone or

Metoclopramide or Prochlorperazine or

Ondansetron or Dolasetron or Granisetron

Ettinger DS. NCCN Guidelines. Antiemesis.v 2.2014 14

CINV Prophylaxis NCCN Guidelines for MEC

Day 1 Days 2 and 3

5-HT3 RA + Steroid ±NK-1 RA 5-HT3 Monotherapy –No palonosetron Ondansetron 8mg po bid OR Steroid monotherapy: Dexamethasone 8mg po/iv daily OR NK-1 RA± Steroid

Palonosetron 0.25mg iv + Dexamethasone 12mg po/iv±Aprepitant 125mg po/fosaprepitant 150mg IV

OR OR

Olanzapine-based Regimen Olanzapine 10mg PO days 2-4 if given on day 1± Lorazepam 0.5mg-2mg PO/IV q 4h prn± HR2RA or proton pump inhibitor

Olanzapine 10mg po +Palonosetron 0.25mg iv +Dexamethasone 20mg iv

15Ettinger DS. NCCN Guidelines.Antiemesis.V2.2014.

CINV Treatment Summary

Mustian KM et al. US Oncol Hematol.2011;7(2):91-97. 16

Novel NK1 and 5-HT3 Antagonists

Netupitant Palonosetron Highly selective NK1 RA binds

NK1 in abdominal vagus nerve, brainstem, and AP→decreased emesis

Long t1/2~ 90 hours>90% brain receptor

saturation for long-96 hours Enhanced Substance P

inhibition when combined with palonosetron

Allosteric & positive cooperativity at 5-HT3 receptors

T1/2=40hours

5-HT3 receptor internalization= inhibition ↑and efficacy in acute & delayed CINV than 1st Gen 5-HT3 RA

High binding affinity/specificity to 5-HT3 receptors

Navari RM. Drug Design, Development and Therapy. 2015;9: 155-161 Hasketh . Ann Oncol.2014;25(7): 1340-1346 17

Novel NK1 and 5-HT3 Antagonists

Netupitant 300mg Palonosetron 0.5mgPK/PD:Onset 15 min-3h, Vd 1982±906L

99.5% protein binding Metabolized by CYP 3A4, 2C9, 2D6 to metabolites

Receptor occupancy: 92.5%(6h), 86.5%(24h)

Co-administration with netupitant 600mg /palonosetron 1.5mg: No significant effect on QTc intervalFixed-dose combination with netupitant offers: Synergy Convenience Potential guideline ↑ adherence

Akynzeo(R) [package insert]., SA, Lugano, Switzerland: Helsinn Healthcare; 2014. 18

Approved October 10, 2014

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Akynzeo: A Better or Bitter Pill for the Prevention of CINV ?Dosage: 300mg

netupitant/0.5mg palonosetron capsule

Administration- HEC 1 capsule po 1 hour before

chemotherapy + 12mg dexamethasone 30 minutes prior to chemotherapy on day 1, then 8mg days 2-4

Anthracyclines/Cyclophosphamide: Akynzeo 1 capsule po 1hour and 12mg dexamethasone 30 minutes prior to chemotherapy

Contraindication: NoneAdverse events≥3%:

Headache, constipation, dyspepsia, fatigue, asthenia

Akynzeo(R) [package insert]., SA, Lugano, Switzerland: Helsinn Healthcare; 2014.20

Akynzeo: A Better or Bitter Pill for the Prevention of CINV ?Drug interactions:Netupitant- moderate

inhibitor of CYP3A4 →dexamethasone, midazolam, docetaxel, cyclophosphamide

CYP 3A4 Inducers/Inhibitors

Pregnancy category C

Dose adjustment: Hepatic

Mild-moderate-No dose adjustment; severe- avoid

Renal Mild-moderate

impairment-No dose adjustment

Not studied in ESRD

Akynzeo(R) [package insert]., SA, Lugano, Switzerland: Helsinn Healthcare; 2014.21

NEPA Versus Aprepitant + PALOStudy of 413 patients on

HEC and MEC, NEPA showed small advantage (2-7%) over aprepitant/PALO in primary analysis: No emesis, no rescue therapy

Gralla RJ et al. Ann Oncol. 25(7):1333-1339.22

Study 1

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Study 1: Study DesignPhase II, Multicenter, Randomized, double blind,

double dummy, parallel group study694 chemotherapy naïve patients2008 29 sites-Russia 15 sites-Ukraine

Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.

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Study 1:Inclusion Criteria≥18 years oldDx of malignant tumorKarnofsky Performance

Scale score ≥70%Able to follow

procedures and complete patient diary

Naïve to chemotherapyScheduled cisplatin

therapy ≥50mg/m2 alone or in combination

Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346. 25

Study 1:Exclusion CriteriaScheduled to receive

HEC or MEC from day 2-5 post chemoModerate/highly emetogenic radiotherapy 1 week before day1

Bone marrow/stem cell transplant

Experienced vomiting, retching or >mild nausea in 24 h before day 1

History of serious CV conduction abnormalities except right bundle branch block


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Study 1:Exclusion CriteriaChronic use of CYP 3A4

substrates/inhibitor within 1 week

4 weeks of inducers before day 1

Use of CYP 3A4 substrate/inhibitor within 1 week


Study 1:Intervention5 Treatment groups:


Cisplatin ≥50mg/m2 administered

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Study 1: Intervention Cisplatin ≥50mg/m2 1-4 h infusion Blinding by matching placebos Rescue meds: For refractory/persistent nausea

and vomiting Treatment failure→ NEPA: 60 minutes before chemotherapy Dexamethasone: 30 minutes before

chemotherapy


Study 1: Efficacy EndpointsPrimary Endpoint Secondary Endpoints Complete Response(CR)

No EmesisNo Rescue medication during overall phase post-chemo (0-120h)

CR in acute phase (0-24h)CR during delayed phase(25-

120 h) No emesis No significant nausea:

Visual Analog Scale ≤25mmComplete Protection in all phases:

CR + No significant nausea


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Study 1: Statistical AnalysisIntention-to-treatAssumed overall CR

70% NEPA 50% PALO

1-sided α level=0.0166 129 patients/goup 85% →

powerRounded up to

136/group 680 patients →total

Logistic regression-Primary & secondary efficacy adjust for gender

Holm-Bonferroni-to adjust for multiple comparisons

Post hoc logistic regression-compare APR arm and PALO


Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.32

Study 1 Results: Efficacy Secondary Endpoint

NEPA300 more effective than palonosetron:No emesisNo significant nauseaComplete protection

All NEPA doses: Superior CR to palonosetron in overall phase

Primary Analysis-CR

CR, Overall 0-120hNNT= 100/[89.6-76.5]=8

Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.33

Study 1 Results Secondary Analysis

Hasketh PJ et al. Ann Oncol.2014;25(7): 1340-1346.34

Study 1: Safety DataAdverse Effects Authors’ Conclusion Most common Hiccups NEPA300 7(5.1%) NEPA 200 5(3.6% NEPA 100 5(3.7%) PALO 5(3.7%) Headache

NEPA 300 the most Effective dose combination

NEPA regimens significantly improved prevention of CINV in patients receiving cisplatin-based HEC

NEPA arms comparable to APR arm: adverse events & ECG changes


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Study 1: CritiqueStrengths WeaknessesRandomized, double blind Multicenter-44 sites Included patients with

different neoplasmsClinically important primary

endpoints

Conducted in one region only-Russia and Ukraine

Relied on patients ability to keep accurate diaries

Male > female yet female gender is a risk factor for CINV

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Study 2

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Study 2: Study Design Phase III, Multicenter,

Randomized, double blind, double dummy, parallel group study

1455 patientsApril 2011-November

2012177 sites, 15 countries

Countries:Argentina, Belarus, Brazil,

Bulgaria, Croatia, Germany, Hungary, India, Italy, Mexico, Poland, Romania, Russia, Ukraine, USA.

Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.

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Study 2: Treatment

Blinding: Matching PlaceboCyclophosphamide IV 500-1500mg/m2 + doxorubicin IV ≥60mg/m2 ORCyclophosphamide IV 500-1500mg/m2 + epirubicin IV ≥60mg/m2

Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.39

Study 2 Inclusion/Exclusion Criteria

Inclusion Criteria Exclusion Criteria

≥18 years oldNaïve to chemotherapyScheduled to receive first

AC MEC regimen for a solid malignant tumor

Eastern cooperative oncology group(ECOG) performance status of 0,1, or 2

Scheduled to receive: HEC from day 1-5 or

MEC from day 2-5 post chemo

Radiation therapy to abdomen/pelvis 1 week before day 1 or between day 1 and 5, or 3

Bone marrow/stem cell transplant


Study 2: Exclusion CriteriaExperienced vomiting, retching, mild nausea within

24 hours before day 1Serious cardiovascular abnormalities except

incomplete right bundle branch blockUse of CYP3A4 inducer within 4 weeks or

strong/moderate inhibitors within 1 week or scheduled to receive CYP 3A4 inhibitor/inducer/substrate


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Study 2: Assessments Each patient kept

diary starting day 1- morning of day 6

Emetic Episode: Timing Duration Rescue drug use

Severity of Nausea Visual Analog Scale Impact of CINV on

patients’ lives:Functional Living

Index-Emesis (FLIE)

9 Nausea domains 9 vomiting domains


Study 2: Efficacy EndpointsPrimary Efficacy Endpoints Secondary Efficacy Endpoints

Complete Response (CR) No emesis No rescue drug in

delayed phase of cycle 1

Complete Response(CR) Acute phase Overall phaseComplete Protection (CR + No significant

nausea) No emesis, no significant

nausea, during acute, delayed, and overall phases


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Study 2: Statistical AnalysisPrimary aim: Illustrate

superiority of NEPA over PALO based on CR during delayed phase of cycle 1

Cochran-Maentel-Haenszel (CMH) test to analyze primary efficacy outcome

Assumed responder rate 60% NEPA

50% PALO 2-Sided test of

difference, α level=0.05Sample size of 661

Patients/group 90% →power to detect 9% difference

Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333. 44

Study 2: Baseline Characteristics


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Study 2: Randomization


Study 2 Results: EfficacyPrimary Secondary Delayed Phase

NEPA superior to palonosetron- 76.9% Versus 69.5% (P=0.001)

Acute & Overall Phases

Significantly higher CR rates for NEPA than palonosetron

Delayed & Overall Phases

NEPA consistently more effective than palonosetron: No emesis

No significant nausea Complete protection


Study 2 Results: Primary Efficacy

NEPA superior to PALO in delayed Phase: CR of 76.9% Vs 69.5%NNT: Delayed 100/[76.9-69.5) = 14

CR:No EmesisNo Rescue drug

Study 2 Results: Primary Efficacy

48Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333

Study 2 Results: Impact on LifePatients with NIDL based on FLIE: Overall 0–120 h


Study 2 Results: Impact on Patients Life

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Study 2 Results Secondary Efficacy Endpoints


50Endpoints: No emesis, No rescue, CPNNT: No Emesis- Delayed=16

Study 2 Results: Adverse Events

ADRs comparable between treatment groups


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Study 2 Strengths

Randomized, double blind Intention-to-treat Clinically significant primary/secondary endpoints Patients with different neoplasms included Majority of patients fall within age bracket at higher

risk for CINV

LimitationsRelied on Patients to keep accurate diariesStudy included only chemotherapy naïve patients

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Study 2 Clinical Impact/Author’s Conclusion Akynzeo®, an oral fixed-dose drug, may help

overcome potential barriers to guideline adherence by providing convenience in a single day 1 dose of NEPA plus dexamethasone on day 1 only to prevent CINV for 5 days after therapy.

Akynzeo demonstrated superiority over palonosetron during 5-day period after chemotherapy.

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Akynzeo: A Better or Bitter Pill? Personal Conclusion

Results from efficacy studies indicate that Akynzeo® is a better pill for the prevention of CINV: It offers an easier to take fixed-dose oral capsule on day 1 of chemotherapy for prolonged prevention of CINV.

Akynzeo (netupitant/palonosetron) may offer better adherence to guidelines for CINV prevention hence improvement in outcomes for patients on HEC/MEC despite higher price.

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Acknowledgements Dr. Valerie Vuylsteke, Pharm.D., BCACP

Dr. Sachin Shah, PharmD., BCOP

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Bibliography 1. Warr. Prognostic factors for chemotherapy induced nausea and vomiting. Eur J Pharmacol.2014; 722:192-6.

2. Jenelsins MC, Tejani MA, Kamen C et al. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert Opin Pharmacother. 2013; 14(6):757-66.

3. Grunberg SM, Deuson RR, Mavros P,et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics .Cancer. 2004; 100 (10):2261-2268.

4. Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2008; 358:2482-2494.

5. Affronti ML, Bubalo J. Palonosetron in the management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy. Cancer Manag Res. 2014; 6: 329–337.

6. Mustian KM, Devine K, Ryan JL et al. Treatment of Nausea and Vomiting During Chemotherapy. US Oncol Hematol. 2011; 7(2): 91–97.

7. Grunberg SM, Hasketh PJ. Control of chemotherapy-induced emesis. NEJM. 1993.329:1790-1796.

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Bibliography8. National Comprehensive Cancer Network (NCCN). NCCN Clinical Guideline in Oncology Antiemesis version 2.2014.http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf

9. Navari RM. Profile of netupitant/palonosetron (NEPA) fixed dose combination and its potential in the treatment of chemotherapy-induced nausea and vomiting (CINV). Drug Design, Development and Therapy. 2015;9: 155-161

10. Hasketh P, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol.2014;25 (7): 1340-1346.

11. Akynzeo(R) [package insert]. SA, Lugano, Switzerland: Helsinn Healthcare; 2014.

12. Gralla R, Bosnjak S, Hontsa A, et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol.25(7):1333-1339

13. Aapro M, Rugo H, Rossi G, et al. 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. Ann Oncol.2014; 25(7): 1328-1333.

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Akynzeo+a+better+or+bitter+pill+for+the+prevention+of+cinv (1)

Healthcare

delayed nausea

frequency of emesis

chemotherapyinduced

cancer manag

chemotherapy refractory

receptor hec

thorax cinv acute

expert opin pharmacother