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
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
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.
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
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
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
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
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
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
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
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
Notas del editor
Warr. Prognostic factors for chemotherapy induced nausea and vomiting. Eur J Pharmacol. 2014 Jan 5;722:192-6. doi: 10.1016/j.ejphar.2013.10.015. Epub 2013 Oct 21.
63,761 hospital discharges for cancer and chemo in US in 1996:↑Length of stay: CINV 9.1 No CINV 7.0 –Grunberg 2000.
CINV most distressing adverse effects of chemotherapy
Poor chemotherapy adherence
↑Length of stay: CINV 9.1 No CINV 7.0 (P=0.0001) –Grunberg 2000.Anxiety/depression
Grunberg 2004. CANCER May 15, 2004 / Volume 100 / Number 10
Paul J. Hesketh, M.D.,Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008; 358:2482-2494June 5, 2008DOI: 10.1056/NEJMra0706547
Jenelsins MC et al.Expert Opin Pharmacother. 2013 Apr;14(6):757-66. doi: 10.1517/14656566.2013.776541
Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients.
Janelsins MC1, Tejani MA, Kamen C, Peoples AR, Mustian KM, Morrow GR.
Hasketh 2008
Karen M Mustian, PhD, MPH, Katie Devine, PhD, Julie L Ryan, PhD, MPH, Michelle C
Janelsins, PhD, Lisa K Sprod, PhD, Luke J Peppone, PhD, MPH, Grace D Candelario, MD,
Supriya G Mohile, MD, MPH, and Gary R Morrow, PhD, MS
James P Wilmot Cancer Center, University of Rochester School
US Oncol Hematol. 2011 ; 7(2): 91–97.
Grunberg S. NEJM 1993.329:1790-1796
David G. Frame, PharmD, Best Practice Management of CINV
in Oncology Patients: I. Physiology
and Treatment of CINVThe Journal of Supportive Oncology,Volume 8, Supplement 1 ■ March/April 2010
US Oncol Hematol. 2011; 7(2): 91–97:Karen M Mustian, PhD, MPH, Katie Devine, PhD, Julie L Ryan, PhD, MPH, Michelle C
Janelsins, PhD, Lisa K Sprod, PhD, Luke J Peppone, PhD, MPH, Grace D Candelario, MD,
Supriya G Mohile, MD, MPH, and Gary R Morrow, PhD, MS
James P Wilmot Cancer Center, University of Rochester School
PALO: receptor internalization
Receptor Occupancy: 92.5%(6h),86.5%(24h) after administration of 300mg
Ann Oncol. Jul 2014; 25(7): 1333–1339.
R. J. Gralla,1,* S. M. Bosnjak,2 A. Hontsa,3 C. Balser,4 G. Rizzi,5 G. Rossi,6 M. E. Borroni,6 and K. Jordan7
Elaborate on Karnofsky PS score!!
VAS=visual analog scale: Explain this!!
Emetic episode=≥ 1 continuous vomiting or retching; severity of nausea: Visual analog scale(VAS)-0mm-no nausea; 100mm-nausea as bad as it could be.
FLIE: 9 nausea domain and 9 vomiting domain questionaire completed in day 6 to assess impact of CINV on patients lives.
No significant nausea: VAS score≤25mm; safety-adverse events, clinical labs, physical examination, vital signs, electrocardiogram(ECG)
NEPA was to be declared superior to PALO if 2-sided p-value was ≤0.05 and in favor of NEPA. CMH-treatment, age class, and region as strata.
Assumption: Responder rate of 60% NEPA and 50% PALO in delayed phase.
CMH: to analyze prim endpt: No emesis, CP, No significant nausea, and FLIE
661 increased to 730/group to ensure adequate # of assessable patients.
CR: No emesis, No rescue med; NEPA superior to PALO in delayed
Phase: CR of 76.9% Vs 69.5%
NIDL: proportion of patients with no impact on daily living; FLIE=Functional Living Index-Emesis. Overall 0-120 hours
NEPA&gt;Effective than PALO in Delayed
& Overall phases for Secondary Endpoints
a=those considered by investigator to be possibly, probably or definitely related to study drug. 85%=mild/moderate intensity.
95% NEPA treated with severe ADRs only 5(0.7%) had severe tmt related ADRs. Most common ADRs: Headache and constipation. &lt;0.7% tmt d/c with NEPA for severe ADRs/death. 12-lead change in ECG similar between treatment groups.