Newly approved nausea and vomiting due to chemotherapy

1. Nelson Origa, Pharm.D. Candidate
Texas Tech University Health Sciences Center
School of Pharmacy | Dallas Campus
February 4, 2015

2. Learning Objectives
By the end of this presentation
participants should be able to:
1.Describe mechanisms of CINV
2.Classify cancer drugs associated with CINV
according to their emetogenicity
3.Discuss current treatment recommendations
for CINV
4.Explain mechanism of action of Akynzeo®
and
its pharmacokinetics/pharmacodynamics
5.Analyze trials that led to approval of Akynzeo®
based on safety and efficacy
2

3. 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
3

4. 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

5. CINV: Risk Factors
Patient 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

6. CINV: Prevalence & Consequences
67 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

7. Chemotherapy Emetic Risk Classification
High: > 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; 358:2482-2494
7

8. Emetogenic Potential of Cancer Drugs
High Moderate Low Minimal
Intravenous Cisplatin Alemtuzumab Bortezomib Bevacizumab
Cyclophospha-
mide≥1500
Cyclophospha
mide<1500
Cetuximab Bleomycin
Gemcitabine Rituximab
Dacarbazine Doxorubicin Docetaxel Vinblastine
Carmustine Epirubicin Etoposide Vincristine
Oral Procarbazine Imatinib Capecitabine Hydroxyurea
Hexamethyl-
melamine
Cyclophospha
mide
Etoposide Methotrexate
8
Affronti ML. Cancer Manag Res.2014; 6:329-337

9. Proposed Pathophysiology of CINV
Central & 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
9

10. Proposed Pathophysiology of
CINV
NTS
Hesketh et al. N Engl J Med. 2008; 358:2482-2494.
10

11. Neurotransmitters in CINV
GI, AP, NTS
Enterochromaffin Cells
Emetic
Center
Area Postrema
GABA
Cannabinoids
Histamine
Acetylcholine
Endorphins
Mustian KM. US Oncol Hematol. 2011 ; 7(2): 91–97
11

12. CINV: Antiemetic Agents
5-HT3 RA
Palonosetron(Aloxi®
)
Ondansetron(Zofran®
)
Granisetron(Sancuso®
)
Dolasetron(Anzemet®
)
Corticosteroids
Dexamethasone(Decadron®
)
Dopamine RA
Metoclopramide(Reglan®
)
NK-1 RA
Aprepitant(Emend®
)
Fosaprepitant(Emend®
)
Netupitant/palonosetron
(Akynzeo®
)
Benzodiazepines
Lorazepam(Ativan®
)
Atypical Antipsychotic
olanzapine(Zyprexa®
)
Ettinger DS. NCCN Guidelines. Antiemesis.v 2.2014. 12

13. Antiemetic Agents: Adverse Effects
5-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

14. 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

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

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

17. 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

18. Novel NK1 and 5-HT3 Antagonists
Netupitant 300mg Palonosetron 0.5mg
PK/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
interval
Fixed-dose combination with
netupitant offers:
Synergy Convenience
Potential guideline↑
adherence
Akynzeo(R) [package insert]., SA, Lugano, Switzerland: Helsinn Healthcare; 2014. 18

19. Approved October 10,
2014
19

20. 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/Cycloph
osphamide: Akynzeo 1
capsule po 1hour and
12mg dexamethasone 30
minutes prior to
chemotherapy
Contraindication: None
Adverse events≥3%:
Headache, constipation,
dyspepsia, fatigue,
asthenia
Akynzeo(R) [package insert]., SA, Lugano, Switzerland: Helsinn Healthcare; 2014.
20

21. 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

22. NEPA Versus Aprepitant + PALO
Study 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

23. Study 1
23

24. Study 1: Study Design
Phase II, Multicenter, Randomized, double blind,
double dummy, parallel group study
694 chemotherapy naïve patients
2008
29 sites-Russia
15 sites-Ukraine
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.
24

25. Study 1:Inclusion Criteria
≥18 years old
Dx of malignant tumor
Karnofsky Performance
Scale score ≥70%
Able to follow
procedures and
complete patient diary
Naïve to chemotherapy
Scheduled cisplatin
therapy ≥50mg/m2
alone
or in combination
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346. 25

26. Study 1:Exclusion Criteria
Scheduled to receive
HEC or MEC from day
2-5 post chemo
Moderate/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
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.
26

27. Study 1:Exclusion Criteria
Chronic 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
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346. 27

28. Study 1:Intervention
5 Treatment groups:
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.
Cisplatin ≥50mg/m2
administered
28

29. 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
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.
29

30. Study 1: Efficacy Endpoints
Primary Endpoint Secondary Endpoints
 Complete Response(CR)
No Emesis
No 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 ≤25mm
Complete Protection in
all phases:
CR + No significant nausea
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.
30

31. Study 1: Statistical Analysis
Intention-to-treat
Assumed overall CR
70% NEPA
50% PALO
1-sided α level=0.0166
129 patients/goup 85%→
power
Rounded 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.
31

32. Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.
32

33. Study 1 Results: Efficacy
Secondary Endpoint
NEPA300 more effective
than palonosetron:
 No emesis
 No significant nausea
 Complete protection
All NEPA doses:
Superior CR to
palonosetron in
overall phase
Primary Analysis-CR
CR, Overall 0-120h
NNT= 100/[89.6-76.5]=8
Hasketh PJ et al . Ann Oncol.2014;25(7): 1340-1346.
33

34. Study 1 Results
Secondary Analysis
Hasketh PJ et al. Ann Oncol.2014;25(7): 1340-1346.
34

35. Study 1: Safety Data
Adverse 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
35

36. Study 1: Critique
Strengths Weaknesses
Randomized, double blind
 Multicenter-44 sites
Included patients with
different neoplasms
Clinically 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
36

37. Study 2
37

38. Study 2: Study Design
Phase III, Multicenter,
Randomized, double
blind, double dummy,
parallel group study
1455 patients
April 2011-November
2012
177 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.
38

39. Study 2: Treatment
Blinding: Matching Placebo
Cyclophosphamide IV 500-1500mg/m2
+
doxorubicin IV ≥60mg/m2
OR
Cyclophosphamide IV 500-1500mg/m2
+ epirubicin
IV ≥60mg/m2
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
39

40. Study 2
Inclusion/Exclusion Criteria
Inclusion Criteria Exclusion Criteria
≥18 years old
Naïve to chemotherapy
Scheduled 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
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
40

41. Study 2: Exclusion Criteria
Experienced vomiting, retching, mild nausea within
24 hours before day 1
Serious cardiovascular abnormalities except
incomplete right bundle branch block
Use of CYP3A4 inducer within 4 weeks or
strong/moderate inhibitors within 1 week or
scheduled to receive CYP 3A4
inhibitor/inducer/substrate
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
41

42. 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
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
42

43. Study 2: Efficacy Endpoints
Primary 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 phase
Complete Protection
(CR + No significant
nausea)
 No emesis, no significant
nausea, during acute,
delayed, and overall phases
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
43

44. Study 2: Statistical Analysis
Primary 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=0.05
Sample size of 661
Patients/group 90%→
power to detect 9%
difference
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
44

45. Study 2: Baseline Characteristics
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
45

46. Study 2: Randomization
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
46

47. Study 2 Results: Efficacy
Primary 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
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
47

48. 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 Emesis
No Rescue drug
Study 2 Results: Primary Efficacy
48
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333

49. Study 2 Results: Impact on LifePatients with NIDL based on FLIE:
Overall 0–120 h
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
Study 2 Results: Impact on Patients Life
49

50. Study 2 Results
Secondary Efficacy Endpoints
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
50Endpoints: No emesis, No rescue, CP

51. Study 2 Results: Adverse Events
ADRs
comparable
between
treatment
groups
Aapro M. et al. Ann Oncol.2014;25(7): 1328-1333.
51

52. 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
Limitations
Relied on Patients to keep accurate diaries
Study included only chemotherapy naïve patients
52

53. 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.
53

54. 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.
54

55. Acknowledgements
Dr. Valerie Vuylsteke, Pharm.D., BCACP
Dr. Sachin Shah, PharmD., BCOP
55

56. 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.
56

57. Bibliography
8. 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.
57