Efficacy of Netupitant-Palonosetron (NEPA) in chemotherapy-induced nausea and vomiting prevention

1. Dr Chandan K Das
Assistant Professor Medical Oncology
PGIMER, Chandigarh
NEPA: Deep Dive…
(NEtupitant + PAlonosetron)

2. Chemotherapy-induced nausea
and vomiting (CINV)
Background

3. CINV is a frequent complication in patients undergoing emetogenic chemotherapy1
Nausea and vomiting is a life saving mechanism that has an important role in evolution
When the body detects toxins, it organizes a complex reaction to eliminate them as soon as possible by
emptying the stomach content2
Nausea and vomiting are two of the most frequent and troubling side effects patients experience
during chemotherapy, interfering with compliance with cancer therapies and quality of life2
 While newly available treatments have improved our ability to manage nausea and vomiting, anticipatory
and delayed nausea and vomiting are still major problems for patients receiving chemotherapy2
 The etiology of nausea and vomiting is multifactorial, very complicated, and not completely understood3
 The relevant pathways often involve multiple neurotransmitters and receptors4
3
CINV: chemotherapy-induced nausea and vomiting
1. Aapro M et al. Ann Oncol. 2012 Aug;23(8):1986-92. Epub 2012 Mar 6;
2. Janelsins MC et al. Expert Opin Pharmacother. 2013 April ; 14(6): 757–766.
3. Lorusso V et al. Future Oncol. 2014 Oct 31:1-13.
4. Frame DG. J Support Oncol. 2010 Mar-Apr;8(2 Suppl 1):5-9.
Chemotherapy-induced nausea and vomiting
Overview

4. CINV classification is widely agreed upon the antiemetic community:1
 Acute
> Occurs within a few minutes up to 24 hours after chemotherapy2,3
 Delayed
> Occurs more than 24 hours after chemotherapy (usually 24-120 hours)2,3
 Anticipatory
> Occurs before a cycle of chemotherapy, as conditioned response2,3
 Breakthrough
> Occurs despite prophylactic treatment and/or requires rescue antiemetic agents2,3
 Refractory
> Occurs during subsequent treatment cycles when antiemetic prophylaxis and/or rescue have failed in earlier
cycles2,3
Treatment of these separate conditions may differ, and poor control of acute nausea and vomiting pIays an
important role in ultimate control of deIayed CINV3
4
CINV: chemotherapy-induced nausea and vomiting.
1. Jordan K et al. Eur J Pharmacol. 2013 Jan 5;722:197-202.
2. Curran MP et al. Drugs. 2009;69(13):1853-78
3. Viale PH. Clin J Onc Nurs. 2005;9(1):77-84
Chemotherapy-induced nausea and vomiting
Classification

5. Uncontrolled and/or prolonged CINV has a potential to cause:
 Dehydration and electrolyte imbalance1
 Muscular effects and mental consequences1
 Malnutrition and esophageal tears1
 Impaired health-related quality of life2
> Negative impact on activities of daily living2
 Discontinuation of anticancer therapy3
 Increases in morbidity, mortality4
 Delays in discharge from hospital1
 Increased costs to health care system5
These side effects can interfere with treatment compliance: patients sometimes delay
chemotherapy cycles and contemplate refusing future treatments because of fear of further CINV
CINV: chemotherapy-induced nausea and vomiting.
1. Curran MP et al. Drugs. 2009;69(13):1853-78
2. Aapro M et al. Ann Oncol. 2012 Aug;23(8):1986-92. Epub 2012 Mar 6.
3. Janelsins MC et al. Expert Opin Pharmacother. 2013 April ; 14(6): 757–766.
4. Burke TA et al. Support Care Cancer. 2011 Jan;19(1):131-40.
5. Turini M. et al. Drugs Context 2015; 4: 212285
Chemotherapy-induced nausea and vomiting
Effects and consequences
Costs could be offset by
optimizing the management of
CINV episodes, by providing
education to patients in order to
limit hospital access and by
improving utilization of existing
antiemetic agents and new, more
efficacious treatments. Such
approaches can help to achieve
not only an improvement in patient
well-being but also a significant
reduction of the budgetary impact
of CINV on NHS5

6. Known individual risk factors for the development of CINV:
Tailoring CINV treatments to the patient based on individual risk factors will greatly
enhance the potential of antiemetics and to eliminate CINV4
1. Gregory RE, et al. Drugs. 1998;55:173-189
2. Jordan K et al. Oncologist. 2007 Sep;12(9):1143-50.
3. Hesketh PJ, et al. J Clin Oncol. 1997;15:103-109
4. Janelsins MC et al. Expert Opin Pharmacother. 2013 April ; 14(6): 757–766. CINV: chemotherapy-induced nausea and vomiting.
Chemotherapy-induced nausea and vomiting
Risk Factors
Patient-related risk factors1,2: Treatment-related risk factors:1,3
> Younger age (<50 years)
> No/minimal prior history of alcohol and
tobacco use
> Susceptibility to motion sickness
> Prior CINV
> Anxiety
> Emesis during pregnancy
> Impaired performance status
> Previous exposure to chemotherapy
> Emetogenic potential of chemotherapy agents or
regimens (Hesketh classification)3
> Chemotherapy dose and schedule 1
> Use of multiple chemotherapy agents3
Several efforts ongoing to increase awarness on that among the international medical comunity

7. CINV Hesketh classification- NCCN 2019
High emetic risk
(>90% frequency of emesis)b,c
• AC combination defined as any
chemotherapy regimen that
contains an anthracycline and
cyclophosphamide
• Carboplatin AUC ≥4
• Carmustine >250 mg/m2
• Epirubicin >90 mg/m2
• Cisplatin • Ifosfamide ≥2 g/m2
per dose
• Cyclophosphamide >1,500 mg/m2
• Mechlorethamine
• Dacarbazine• Streptozocin
• Doxorubicin ≥60 mg/m2
Moderate emetic risk
(>30%–90% frequency of
emesis)b,c
• Aldesleukin >12–15 million IU/m2
• Amifostine >300 mg/m2
• Arsenic trioxide
• Azacitidine
• Bendamustine
• Busulfan
• Carboplatin AUC <4d
• Carmustined
≤250 mg/m2
• Clofarabine
• Cyclophosphamide ≤1500 mg/m2d
• Cytarabine >200 mg/m2
• Dactinomycind
• Irinotecan (liposomal)
• Daunorubicind
• Melphalan
• Dual-drug liposomal encapsulation • Methotrexated
≥250 m
cytarabine and daunorubicin • Oxaliplatind
• Dinutuximab • Temozolomide
• Doxorubicind
<60 mg/m2
• Trabectedind
• Epirubicind
≤90 mg/m2
• Idarubicin
• Ifosfamided
<2 g/m2
per dose
• Interferon alfa ≥10 million IU/m2
• Irinotecand

8. Chemotherapy-induced nausea
and vomiting (CINV)
Physiology and treatment considerations

9. Chemotherapy-induced nausea and vomiting
Physiology
NK1 RA
5-HT3 RA
Adapted from:
Navari RM and Aapro M. N
Engl J Med 2016;374:1356-67 NK1: neurokinin-1;
5-HT3: 5-hydroxytryptamine 3.
VC controls:
- Salivation
- Respiratory
Rates
- Pharyngeal, GI
and Abdominal
Muscles
contractions

10. Adapted from: Navari RM. Drugs. 2013;73:249–262.
Frame DG. J Support Oncol. 2010 Mar-Apr;8(2 Suppl 1):5-9.
Lorusso V et al. Future Oncol. 2014 Oct 31:1-13. DA: dopamine; GABA: gamma-aminobutyric acid; NK1: neurokinin-1 RAs: receptor antagonists; 5-HT3: 5-hydroxytryptamine3.
Chemotherapy-induced nausea and vomiting
Neurotransmitters involved in the emetic reflex
Emetic
Reflex
Histamine
Endorphins
AcetylcholineDopamine
Substance P
GABA
Cannabinoids
Serotonin
NK1 RAs 5-HT3 RAs
DA RAs

11. The physiopathology of CINV is multifactorial involving several neurotransmitters and receptors1
Combination antiemetic regimens targeting multiple molecular pathways associated with
emesis have become the standard of care for prevention of CINV1
Compelling clinical research and antiemetic guidelines recommend a prophylactic combination of
different antiemetic agents
CINV: chemotherapy-induced nausea and vomiting
Frame DG. J Support Oncol. 2010 Mar-Apr;8(2 Suppl 1):5-9.
Cancer Supportive Care Goal (II)

12. Antiemetics Available for CINV Prevention
Overview
 Most commonly used classes of antiemetics:
> 5-HT3 Receptor Antagonists (palonosetron, dolasetron, granisetron, ondansetron, tropisetron):
– inhibit serotonin, 5-HT3 mediated activation of the vagal afferent fibers in the stomach and the central CTZ and
vomiting centre through the 5-HT3 receptor1,6
> Corticosteroids (dexamethasone, methylprednisolone,..):
– unknown mechanism but increase the 5-HT3 RA antiemetic efficacy2,6
> NK1 Receptor Antagonists (netupitant, aprepitant, rolapitant):
– inhibition of the SP-mediated activation of the vomiting centre3,4,6
> D2 Receptor antagonist (metoclopramide):
– Inhibition of both the 5-HT3 and dopamine receptors
 Other agents less frequently used due to unwanted side effects or limited antiemetic effect
are antihistamines, anticholinergics, atypical antipsychotics5,6,7
5-HT3: 5-hydroxytryptamine 3; CTZ: chemoreceptor trigger zone; CINV: chemotherapy-induced nausea and vomiting; RA: receptor antagonist; NK1: neurokinin-1; SP: substance P; DA: dopamine.
1. Hesketh PJ. Support Care Cancer. 2004 Aug;12(8):550-4. Epub 2004 Jun 30; 2. Janelsins MC et al. Expert Opin Pharmacother. 2013 April; 14(6): 757–766; 3. Hesketh PJ. Support Care Cancer. 2001 Jul;9(5):350-4;
4. Rizzi A et al. Peptides. 2012 Sep;37(1):86-97; 5. Frame DG. J Support Oncol. 2010 Mar-Apr;8(2 Suppl 1):5-9; 6. Navari RM. Drugs. 2013;73:249–262., 7. Pi Olanzapine pi.lilly.com/us/zyprexa-pi.pdf
International Antiemetic Guidelines recommendations

13. International Guidelines for
Antiemetic Treatment

14.  Objective: prevent rather than treat nausea and vomiting
 Treatment recommendations are regularly updated
> New clinical trials are studied and worked up into recommendations that are consistent, easy
to use, and based on compelling clinical data
There are 4 principal sets of internationally recognized guideline recommendations
with regard to antiemetic treatment:
International Guidelines for Antiemetic Treatment
Overview
* Now together
1. 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/ ; 2. NCCN Clinical Practice Guidelines in Oncology; Version 1.0
2016. Available at: www.nccn.org; 3. Basch E, et al. J Clin Oncol 2011;29:4189–98. 4. Hesketh PJ, et al. J Clin Oncol 2016;34:381–6. Available at: www.asco.org/guidelines/antiemetics
> Multinational Association of Supportive Care in Cancer (MASCC)1*
> European Society for Medical Oncology (ESMO)1*
> National Comprehensive Cancer Network (NCCN)2
> American Society of Clinical Oncology (ASCO)3,4

15. Emetic risk groups Antiemetics
High (non-AC)
High: anthracycline +
cyclophosphamide (AC)a
Carboplatinb
Moderatec
Low
Overview of NCCN / ASCO / MASCC-ESMO guidelines
for acute nausea and vomiting
* The addition of OLA is recommended in HEC by ASCO, is one possible option in HEC and MEC by NCCN and only when nausea is an issue by MASCC/ESMO
a If an NK1 RA is not available for AC chemotherapy, palonosetron is the preferred 5-HT3 RA for MASCC/ESMO.
b Carboplatin is considered as “high-MEC” by ASCO (here only AUC > 4) and MASCC/ESMO, and reclassified as HEC by NCCN (when AUC >4): an NK1 RA
should be added in all cases.
c An NK1 RA is recommended as option in MEC for selected patients with additional risk factors or who have failed previous therapy with 5-HT3 antagonist plus
steroid by NCCN.
d Palonosetron and granisetron extended-release injection formulation are the preferred 5-HT3 RAs in MEC regimens without an NK1 RA by NCCN.
e Not for ASCO.
5-HT3 RA =
serotonin receptor
antagonist
DEX =
dexamethasone
NK1 RA= neurokinin 1
receptor antagonist
PALO =
palonosetron
DRA =
dopamine receptor
antagonist
5-HT3 RA DEX NK1 RA
5-HT3 RA DEX NK1 RA
DEX
DEX5-HT3 RA DRAe
+ +
OR
+
+
OR
+
+
+ OLA*
OLA*
+ OLA*
5-HT3 RA DEX NK1 RA+ +
OLA =
Olanzapina
5-HT3 RAd

16. Overview of NCCN / ASCO / MASCC-ESMO guidelines
for delayed nausea and vomiting
Emetic risk groups Antiemetics
High (non-AC)
High: anthracycline +
cyclophosphamide (AC)
Carboplatinb
Moderatec
Low -
DEX
DEX**
+ OLA*
+ OLA*
a NK1 RA (aprepitant 80 mg) only if aprepitant 125 mg was used on Day 1. Other NK1 RAs, netupitant, rolapitant, aprepitant 165 mg or fosaprepitant 150 mg do not
need repeat doses.
* The addition of OLA is recommended in HEC by ASCO, is one possible option in HEC and MEC by NCCN and only when nausea is an issue by MASCC/ESMO.
** DEX is recommended in AC by NCCN and, If APR on D1, APR or DEX by MASCC/ESMO.
b Carboplatin: DEX is recommended only by NCCN over AUC >4
c Only for regimens with known delayed CINV potential by MASCC/ESMO and ASCO.
NK1 RAa
NK1 RAa
+
NK1 RAa +
OLA*
OLA*
+
DEX +

17. DAY 1: Select option A, B, or C (order does not imply preference) DAYS 2, 3, 4:
All are category 1, start before chemotherapy:j
A
• NK1 RA (choose one):
Aprepitant 125 mg PO once
Aprepitant injectable emulsion 130 mg IV oncem
Fosaprepitant 150 mg IV once
Netupitant 300 mg / palonosetron 0.5 mg (available as fixed combination product only) PO oncen
Fosnetupitant 235 mg / palonosetron 0.25 mg (available as fixed combination product only) IV oncen
Rolapitant 180 mg PO onceo
• 5-HT3 RA (choose one):p,q
Dolasetron 100 mg PO once
Granisetron 10 mg SQ once,r or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV once, or 3.1 mg/24-h transdermal patch applied 24–48 h
prior to first dose of chemotherapy.
Ondansetron 16–24 mg PO once, or 8–16 mg IV once
Palonosetron 0.25 mg IV once
• Dexamethasone 12 mg PO/IV onces,t
A
• Aprepitant 80 mg PO daily on
days 2, 3
(if aprepitant PO used on day 1)
• Dexamethasone 8 mgs,t PO/IV
daily on days 2, 3, 4
B
• Olanzapine 5–10 mg PO onceu
• Palonosetron 0.25 mg IV once
• Dexamethasone 12 mg PO/IV onces,t
B
• Olanzapine 5–10 mg PO daily on
days 2, 3, 4u
C
• Olanzapine 5–10 mg PO onceu,v,w
• NK1 RA (choose one):
Aprepitant 125 mg PO once
Aprepitant injectable emulsion 130 mg IV oncem
Fosaprepitant 150 mg IV once
Netupitant 300 mg / palonosetron 0.5 mg (available as fixed combination product only) PO oncen
Fosnetupitant 235 mg / palonosetron 0.25 mg (available as fixed combination product only) IV oncen
Rolapitant 180 mg PO onceo
• 5-HT3 RA (choose one):p,q
Dolasetron 100 mg PO once
Granisetron 10 mg SQ once,r or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV once, or 3.1 mg/24-h transdermal patch
applied 24–48 h prior to first dose of chemotherapy.
Ondansetron 16–24 mg PO once, or 8–16 mg IV once
Palonosetron 0.25 mg IV once
• Dexamethasone 12 mg PO/IV onces,t
C
• Olanzapine 5–10 mg PO daily
on days 2, 3, 4u
• Aprepitant 80 mg PO daily on
days 2, 3
(if aprepitant PO used on day 1)
• Dexamethasone 8 mgs,t PO/IV
daily on days 2, 3, 4

18. D
• 5-HT3 RA (choose one):
Dolasetron 100 mg PO once
Granisetron 10 mg SQ oncer (preferred), or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV
once, or 3.1 mg/24-h transdermal patch applied 24–48 h prior to first dose of
chemotherapy.
Ondansetron 16–24 mg PO once, or 8–16 mg IV once
Palonosetron 0.25 mg IV once (preferred)
• Dexamethasone 12 mg PO/IV onces,t
D
• Dexamethasone 8 mgs,t PO/IV daily on days 2,
3
OR
• 5-HT3 RA monotherapyx:
Granisetron 1–2 mg (total dose) PO daily or
0.01 mg/kg (max 1 mg) IV daily on days 2 and 3
Ondansetron 8 mg PO twice daily or 16 mg PO
daily or 8–16 mg IV daily on days 2, 3
Dolasetron 100 mg PO daily on days 2, 3
E
• Olanzapine 5–10 mg PO onceu
• Palonosetron 0.25 mg IV once
• Dexamethasone 12 mg PO/IV onces,t
E
• Olanzapine 5–10 mg PO daily on days 2, 3u
F
Note: An NK1 RA should be added (to dexamethasone and a 5-HT3 RA regimen) for select
patients with additional risk factors or previous treatment failure with a corticosteroid + 5-HT3
RA alone.
• NK1 RA (choose one):
Aprepitant 125 mg PO once
Aprepitant injectable emulsion 130 mg IV oncem
Fosaprepitant 150 mg IV oncen
Netupitant 300 mg / palonosetron 0.5 mg (available as fixed combination product only) PO
oncen
Fosnetupitant 235 mg / palonosetron 0.25 mg (available as fixed combination product only)
IV oncen
Granisetron 10 mg SQ once,r or 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV
once, or 3.1 mg/24-h transdermal patch applied 24–48 h prior to first dose of
chemotherapy.
Ondansetron 16–24 mg PO once, or 8–16 mg IV once
Palonosetron 0.25 mg IV once
• Dexamethasone 12 mg PO/IV onces,t
F
• Aprepitant 80 mg PO daily on days 2, 3
(if aprepitant PO used on day 1)
• ± Dexamethasone 8 mgs,t PO/IV daily on days 2,
3

19. NEPA : Molecular action
...offers Additive or Synergistic effects??

20. Netupitant
 S: selective neurokinin type 1 receptor
antagonist (NK1 RA)1 With Competitive
binding & blocking of human substance P
receptors1
 P: High (>90% receptor occupancy), long-
lasting (>96 h) brain receptor saturation
after single oral dose1
Palonosetron
 Q: Higher binding affinity and longer half-
life than other 5-HT3 RAs3,4;
 S: Selective for 5-HT3 & exhibits distinctly
different receptor binding (allosteric
binding, positive cooperativity)5
 P: Results in long-lasting inhibition of 5-
HT3 receptor function5
5-HT3: 5-hydroxytryptamine-3; NK1: neurokinin 1; RA: receptor antagonist
1. Spinelli T, et al. J Clin Pharmacol 2014;54:97–108. 2. Rizzi A, et al. Peptides 37 2012;37:86–97. 3. Constenla, M. Ann Pharmacother 2004;38:1683–91. 4. Wong EHF, et al. Br J Pharmacol 1985;114:851–9.
5. Rojas C et al. Eur J Pharmacol. 2010;626:193–9. 6. Rojas C, et al. J Pharmacol Exp Ther 2010;335:362–8. 7. 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/ 8. NCCN: National Comprehensive Cancer Network; NCCN Clinical Practice Guidelines in Oncology; Version 2.0 2017. Available at: www.nccn.org.
Aapro M, et al. Journal of Clinical Oncology 2014;32(15_Suppl.):9502 (incl. oral presentation contents), presented at ASCO 2014.
Pharmacologic Rationale for combining NETU and PALO
…act on Complimentary sites!!
21
Palonosetron …. A well trusted Setron
Palonosetron …. Referred as the preferred 5HT3 RA by NCCN

21. Palonosetron …offers benefits
22
Rojas C et al. Eur J Pharmacol. 2014 Jan 5;722:26-37

22. The 5-HT3 RA can displace serotonin-inhibiting signal transduction
Cell membrane
Competitive binding
Rojas C et Slusher BS. Eur J Pharmacol. 2012 Jun 5;684(1-3):1-7.
PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3; RA: receptor antagonist.
5-HT3 receptor serotonin5-HT3 RAs Signal transduction
5-HT3 RA administration
5-HT3 RA and Serotonin Receptor Binding Characteristics
Competitive binding

23. Serotonin can displace the 5-HT3 RA and reactivate signal transduction
Cell membrane
Rojas C et Slusher BS. Eur J Pharmacol. 2012 Jun 5;684(1-3):1-7.
PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3; RA: receptor antagonist.
5-HT3 receptor serotonin Signal transduction
Competitive binding
Serotonin and the 5-HT3 RA compete for the same binding site.
5-HT3 RAs
5-HT3 RA and Serotonin Receptor Binding Characteristics
Competitive binding

24. PALO binding to the allosteric site causes a conformational change that increases the affinity for
a second molecule of PALO to bind
Cell membrane
Rojas C et Slusher BS. Eur J Pharmacol. 2012 Jun 5;684(1-3):1-7.
PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3.
Allosteric binding and positive cooperativity
PALO can displace serotonin and has a stronger binding affinity compared to other
setrons such as ondansetron and granisetron
5-HT3 receptor serotonin Signal transductionPALO
PALO and Serotonin Receptor Binding Characteristics
Allosteric binding and positive cooperativity

25. PALO caused a longer inhibition of 5-HT3 receptor function vs granisetron & ondansetron
after the drug was removed
p<0.001
30
40
50
60
70
80
90
100
Control Cells Pretreated With
PALO
Cells Pretreated with
Granisetron
Cells Pretreated with
Ondansetron
RelativeResponse
Impact on 5HT3 Receptor Function
Ca2+ Influx as Indicator of 5-HT3 Receptor Function
Rojas C et al. Anesth Analg. 2008 Aug;107(2):469-78.
PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3.
p<0.005
P value in comparison with control.
Incubate HEK 293 cells (expressing 5-HT3 receptor) with PALO, granisetron or ondansetron for 24 hours. Remove
antagonists. Allow 150 minutes recovery with additional media changes to “wash out” antagonists. “Challenge” the
system with serotonin (5-HT). Measure 5-HT-induced Ca2+ influx:
Low Ca2+ influx is an indicator that the 5-HT3 RA is working to disable normal 5-HT3 receptor function

26. PALO triggers 5-HT3 receptor internalization which may lead to prolonged inhibition of receptor function
5-HT3 receptor serotonin palonosetron
PALO Impact on 5-HT3 Receptor Function
Allosteric Binding and 5-HT3 Receptor Internalization
Rojas C et al. Eur J Pharmacol. 2010 Jan 25;626(2-3):193-9.
Allosteric binding and 5-HT3 receptor internalization:

27. PALO Mechanism of action
Summary
Grunberg SM, Hesketh PJ.
N Engl J Med 1993; 329(24): 1790-6.
Rojas C. et al.
Anesth Analg 2008; 107: 469–78
Rojas C, Thomas AG, Alt J, et al Eur J
Pharmacol. 2010; 626(2–3): 193-9.
Conformational change
All 5-HT3RAs
Competitive Binding Allosteric Binding Receptor Internalization
Palonosetron
5-HT3 receptor serotonin palonosetron Substance P NK1 receptor5-HT3 RAs

28. Netupitant
 Next Generation NK1RA
 S: selective neurokinin type 1 receptor
antagonist (NK1 RA)1 With Competitive
binding & blocking of human substance P
receptors1
 P: High (>90% receptor occupancy), long-
lasting (>96 h) brain receptor saturation
after single oral dose1
Palonosetron
 Q: Higher binding affinity and longer half-
life than other 5-HT3 RAs3,4;
 S: Selective for 5-HT3 & exhibits distinctly
different receptor binding (allosteric
binding, positive cooperativity)5
 P: Results in long-lasting inhibition of 5-
HT3 receptor function5
5-HT3: 5-hydroxytryptamine-3; NK1: neurokinin 1; RA: receptor antagonist
1. Spinelli T, et al. J Clin Pharmacol 2014;54:97–108. 2. Rizzi A, et al. Peptides 37 2012;37:86–97. 3. Constenla, M. Ann Pharmacother 2004;38:1683–91. 4. Wong EHF, et al. Br J Pharmacol 1985;114:851–9.
5. Rojas C et al. Eur J Pharmacol. 2010;626:193–9. 6. Rojas C, et al. J Pharmacol Exp Ther 2010;335:362–8. 7. 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/ 8. NCCN: National Comprehensive Cancer Network; NCCN Clinical Practice Guidelines in Oncology; Version 2.0 2017. Available at: www.nccn.org.
Aapro M, et al. Journal of Clinical Oncology 2014;32(15_Suppl.):9502 (incl. oral presentation contents), presented at ASCO 2014.
Pharmacologic Rationale for combining NETU and PALO
…act on Complimentary sites!!
29
…Inhibits cross-talk between the 5-HT3 and NK1 receptor pathways6

29. Receptor response
without cross-talk activity
Receptor response
with cross-talk activity
Adapted from: Rojas C et al. J Pharmacol Exp Ther. 2010 Nov;335(2):362-8.
1 2 1 2
1 12 2
PALO Impact on NK1 Receptor Function
Crosstalk inhibition
Receptor cross-talk is defined as activation of one receptor by its ligand affecting cellular responses
to another receptor system(s).

30. PALO
PALO inhibits
cross-talk activity
Receptor response
with cross-talk activity
Serotonin
NK1: neurokinin-1; 5-HT3: 5-hydroxytryptamine 3; PALO: Palonosetron;Adapted from: Rojas C et al. J Pharmacol Exp Ther. 2010 Nov;335(2):362-8.
Substance P Substance P
PALO Impact on NK1 Receptor Function
Crosstalk inhibition
PALO inhibits cross-talk between the 5-HT3 and NK1 receptor pathways
5-HT3 receptor NK1 receptor Serotonin SPPALO

31. NEPA: Superior ‘Reduction of Sub P ≈ NK-1 R binding’!

32. PALO + NETU Mechanism of action
Synergistic effect on SP-response inhibition
Stathis M et al. Eur J Pharmacol. 2012 Aug 15;689(1-3):25-30. NK1: neurokinin-1; 5-HT3: 5-hydroxytryptamine 3; PALO: Palonosetron; SP: Substance P; NETU: Netupitant.
Inhibition of SP response by
NETU and PALO is dose
dependent and synergistic

33.  NETU and PALO show long half-lives of both agents support prolonged receptor
occupancy and efficacy during both the acute (0–24 h) and delayed (25–120 h)
phases post-chemotherapy, following a single dose of NEPA1
> No accumulation is expected when NEPA is administered with chemotherapy regimens
every 2 or 3 weeks (at least 95% or 99% of the dose, respectively, would be eliminated by
next dose)
 NETU and PALO have no drug-drug interactions at a metabolic, binding, or
excretory level
> Different CYP metabolizing enzymes, elimination routes, and large differences in plasma
protein binding
> This minimizes the potential for increased adverse events when administered in
combination
34
Pharmacologic Rationale for combining NETU and PALO
…PK/PD synergy!!
CYP: cytochrome P450; DEX: dexamethasone; NEPA: oral fixed combination of netupitant (300 mg) and palonosetron (0.50 mg); NETU: netupitant; PALO: palonosetron; PK: pharmacokinetics
1. McBride A, et al. ASHP 2015 Summer Meetings Professional Poster abstracts archive Abs. 34-T
Gilmore J. et al. ASHP 2015 Summer Meetings Professional Poster abstracts archive Abs. 34-M (including poster contents), presented at ASHP 2015.
Gilmore J. et al. J Oncol Pharm Pract, April 2016; vol. 22, 2 suppl: pp. 1-29 (including poster contents) presented at HOPA 2016

34. 36
Pharmacologic Rationale for combining NETU and PALO
Roles of the Substance P and Serotonin Pathways in CINV
Chemotherapy
CINV
Substance P Serotonin
NK1 receptors 5-HT3 receptors
• Predominantly in the
delayed phase of CINV
• Primarily in the brain
• Predominantly in the acute
phase of CINV
• Primarily in the GI tract
NK1 RAs 5-HT3 RAs
Central Pathway Peripheral Pathway
5-HT3: 5-hydroxytryptamine-3; CINV: chemotherapy-induced nausea and vomiting; GI: gastrointestinal; NK1: neurokinin-1; RA: receptor antagonist
Gilmore J. et al. ASHP 2015 Summer Meetings Professional Poster abstracts archive Abs. 34-M (including poster contents), presented at ASHP 2015
Gilmore J. et al. J Oncol Pharm Pract, April 2016; vol. 22, 2 suppl: pp. 1-29 (including poster contents) presented at HOPA 2016
The similar and complementary PK profiles of NETU and PALO, combined with
the synergistic effects on receptor antagonism, support the rationale for the
clinical use of the NEPA fixed combination

35. NEPA
Pharmacology

36. PK: pharmacokinetics; PALO: Palonosetron;5-HT3: 5-hydroxytryptamine 3; RA: receptor antagonist; h: hours; pKi: the negative logarithm to base 10 of the equilibrium dissociation constant; NK1: neurokinin-1; SP: substance P
1. Constenla, M., 2004 Ann Pharmacother . 38, 1683-1691. 2. Wong E.H. et al. Br J Pharmacol. 1995;114:851-859. 3.Rojas C et al. Anesth Analg. 2008 Aug;107(2):469-78.
4. Rojas C et al. Eur J Pharmacol. 2010 25;626(2-3):193-9. 5. Rojas C et al. J Pharmacol Exp Ther. 2010 335(2):362-8. 6.Saito M et al. Lancet Oncol. 2009 10(2):115-24. 7.Janelsins MC et al. Expert Opin Pharmacother. 2013;14(6):
757–766.
NEPA Combination Overview
Palonosetron: pharmacology
PALO Ondansetron Granisetron
Half life (h)1 > 40 5-6 11.6
Binding affinity (pKi)2 10.45 8.39 8.91
Positive cooperativity3 YES NO NO
Inhibition of receptor function4 Long lasting Short lasting Short lasting
Receptor internalization4 YES NO NO
Inhibition of 5-HT3/NK1 receptor cross-talk5 YES NO NO
- Distinct inhibition of the SP response associated with delayed emesis
(not observed with ondansetron or granisetron)5-7
- Unique efficacy of PALO against delayed emesis observed in the clinic
as a superior to earlier 5HT3 RAs5-7
PALO chemical structure and main features versus other 5-HT3 RAs:

37.  Potent and selective NK1 RA
 Competitively binds to and blocks activity of human substance P receptors
 High binding affinity, long half-life
 High and long-lasting (for up to 96 hours) brain receptor occupancy after single oral dose
 Metabolized by CYP3A4
 Moderate inhibitor of CYP3A4
PK: pharmacokinetics; NETU: netupitant; NK1: neurokinin-1; RA: receptor antagonist. h: hours; pKi: the negative logarithm to base 10 of the equilibrium dissociation constant; Cmax: maximum plasma concentration; RO:
Receptor Occupancy .
1. Lorusso V et al. Future Oncol. 2014 Oct 31:1-13. 2. Emend® (aprepitant) prescribing information, 2008. 3. Rizzi A. et al. Peptides 37 (2012) 86–97. 4. Spinelli T et al. J Clin Pharmacol. 2014 Jan;54(1):97-108.
5. Varubi™ (rolapitant) prescribing information, 2015; 6. Bernareggi A. and Spinelli T.. Support Care Cancer (2015) 23 (Suppl 1):S1–S388; 7. Van Laer K, et al. Clin Pharmacol Ther. 2012;92(2):243–250.
NEPA Combination Overview
Netupitant: pharmacology
Netupitant chemical structure and main features versus other NK1 RAs:
N
O
CF3
NN
N
CF3
NETU 300 mg Aprepitant
Half-life (h) 961 9-132
Binding Affinity (pKi) 9.03 6.22
Striatum RO reached at Cmax 90%4 90%2
Striatum RO reached at 120 hours 75%6 37-66%7

38. NEPA
Main Features

39. NEPA Convenience and Benefit (I)
Potential to reduce the number
of doses of antiemetic in CINV
prophylaxis2
Potential to reduce mistakes
in antiemetic prophylaxis
administration3
Potential of flexibility in timing
of antiemetic prophylaxis
dosing4
Potential to improve
antiemetic guidelines
adherence1
1. Hesketh et al., Ann Oncol 2014;25:1340-6
2. Lorusso V. Ther Clin Risk Manag. 2016 Jun 7;12:917-25
3. Ruffo et al. Support Care Cancer (2016) 24 (Suppl 1):S1–S249
4. Schwartzberg L, et al. Support Care Cancer (2015) 23, (suppl1):S136–7
A single capsule of NEPA has:
NEPA: oral fixed combination of netupitant (300 mg) and palonosetron (0.50 mg)

40. Lorusso V. Ther Clin Risk Manag. 2016 Jun 7;12:917-25.
NEPA Convenience and Benefit (II)
Potential to reduce the number of doses of antiemetic for CINV prophylaxis
Please note that at the time of this publication AC was still considered as MEC from MASCC/ESMO antiemetic guidelines
Lorusso V. Ther Clin Risk Manag. 2016 Jun 7;12:917-25.

41. NEPA Convenience and Benefit (III)
Potential to reduce mistakes in the administration of antiemetic prophylaxis
NEPA: oral fixed combination of netupitant (300 mg) and palonosetron (0.50 mg)
Ruffo et al. Support Care Cancer (2016) 24 (Suppl 1):S1–S249
 Patients’ non-compliance to antiemetic treatments represents an important issue to
oncologists
 A total of 35% of patients were reported to have compliance issues during home
administration of antiemetics
 The main reasons for antiemetic treatment failure were:
> Underestimating the emetogenic risk of chemotherapy
> Administering weaker antiemetic regimens than required
> Patients making mistakes with administration of antiemetics at home
 Adherence to antiemetic guidelines and awareness of the emetogenic potential of
chemotherapeutic agents and their combinations in the context of patient-related risk
factors may be key for the optimal selection of individualized antiemetic treatments
Simplification of antiemetic treatment with an effective single-dose combination agent
(ie, NEPA) may offer the potential to increase treatment compliance and consequently
improve CINV control

42.  NEPA is an efficacious antiemetic combination with the added convenience of a single dose
 A NK1-RO of 92.5% was reached in the striatum within 6 h of dosing with NEPA
 The 90% NK1-RO threshold in the striatum, that has historically been associated with
antiemetic efficacy, was predicted to be reached following NEPA by 2.9 h
The RO data and efficacy results suggest that shifting the timing of administration of
NEPA closer to the time of chemotherapy initiation would not result in loss of efficacy
 The flexibility in timing of dosing may further enhance the convenience of this new antiemetic
combination (however this hypothesis should be validated in a clinical trial)
46
NEPA: oral fixed combination of netupitant (300 mg) and palonosetron (0.50 mg); NK1: neurokinin 1; RO: receptor occupancy
Schwartzberg L, et al. Support Care Cancer (2015) 23, (suppl1):S136–7 (incl. poster contents), presented at MASCC 2015.
NEPA Convenience and Benefit (IV)
Potential of flexibility in timing of antiemetic prophylaxis dosing
Poster presented by : Schwartzberg L, et al. Support Care Cancer (2015) 23, (suppl1):S136–7
(incl. poster contents), presented at MASCC 2015.

43. Since the incidence of cancer patients with cardiovascular-related diseases is growing,
especially in the elderly population, the cardiac safety profile of drugs used for supportive
care has been investigated1:
 NEPA combination has no significant effects on QTcl, HR, PR, QRS interval duration, or
cardiac ECG morphological patterns, even at supratherapeutic doses, compared with
placebo2
 No indications that exposure to netupitant or palonosetron induced changes in QTc
parameters2
 Administration of different doses of NEPA was well tolerated in healthy subjects2
These results should predict a lack of cardiac safety concerns in clinical practice2
1. Data on file; 2.Spinelli et al. SpringerPlus 2014, 3:389
NEPA Pharmacology and PK
NEPA: Cardiac Safety in healthy subjects

44. NEPA ...Finding a place!!
Pivotal CTs

45.  Primary target product profile:
> Prevention of acute and delayed nausea and vomiting associated with highly and moderately
emetogenic cancer chemotherapy (HEC/MEC)
 All studies are multicenter, randomized, double-blind, active-control
 Pivotal Clinical trials:
1. HEC: NETU 07-07 (Phase II, NEPA + DEX superiority vs oral Palo + DEX, N = 694; dose-ranging)
– Hesketh et al. Annals of Oncology 2014
2. AC: NETU 08-18 (Phase III, NEPA + DEX superiority vs oral Palo + DEX, N = 1455)
– Aapro et al. Annals of Oncology 2014
3. Safety Study in HEC/MEC: NETU 10-29 (Phase III, NEPA + DEX safety vs aprepitant + PALO +
DEX, N = 413)
– Gralla et al. Annals of Oncology 2014
Clinical Development Program: Overview

46. A randomized Phase 3 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
Phase 3 study in patients receiving MEC
M Aapro, H Rugo, G Rossi, G Rizzi, ME Borroni,
IT Bondarenko, C Sarosiek, S Oprean, S Cardona-Huerta,
V Lorusso, M Karthaus, L Schwartzberg, S Grunberg.
A randomized Phase 3 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: 1328–1333

47. Objective
 This large, registration study was designed to demonstrate the superiority of NEPA over
PALO in chemotherapy-naïve patients receiving AC-based moderately emetogenic
chemotherapy (MEC) and to evaluate the safety of NEPA
Design
 Phase 3, multicenter, randomized, double-blind, double-dummy, parallel group study
conducted at 177 sites in 15 countries
56
Study objective, design, patients
Aapro et al., Ann Oncol 2014; 25: 1328–1333
 Patients were randomly assigned (1:1) to receive either PALO or NEPA , as shown in the
table
 After completion of cycle 1, patients had the option to participate in a multiple-cycle
extension, receiving the same treatment as assigned in cycle 1
> There was no pre-specified limit of the number of repeat consecutive cycles

48.  NEPA was significantly superior to PALO during the acute, delayed and overall phases
Complete Response (No Emesis, No Rescue Medication)
Primary End point: Complete Response – acute, delayed,
overall phases
0
20
40
60
80
100
88.4 85
76.9
69.5
74.3
66.6
Patients(%)
Acute (0-24 hr) Delayed (25-120 hr) Overall (0-120 hr)
NEPA+DEX
PALO+DEX
* ††
Aapro et al., Ann Oncol 2014; 25: 1328–1333
PALO = palonosetron, NEPA = fixed combination of PALO + netupitant (NETU), DEX = dexamethasone.
* P=0.047
† P=0.001

49. NEPA was statistically superior to PALO
during the acute, delayed and overall phases
No Emesis - acute, delayed, overall
phases
0
20
40
60
80
100
90.9 87.3
81.8
75.6
79.8
72.1
Patients(%)
Acute (0-24 hr) Delayed (25-120 hr) Overall (0-120 hr)
NEPA+DE
X
PALO+DE
X
‡†*
Aapro et al., Ann Oncol 2014; 25: 1328–1333
PALO = palonosetron, NEPA = fixed combination of PALO + netupitant (NETU), DEX = dexamethasone.
* P=0.025
† P=0.004
‡ P<0.001
0
20
40
60
80
100
87.387.9
76.9
71.3 74.6
69.1
Patients(%)
Acute (0-24 hr) Delayed (25-120 hr) Overall (0-120 hr)
NEPA+D
EX
PALO+D
EX
‡†*
* P=0.747
† P=0.014
‡ 0.020
NEPA was statistically superior to PALO
during the delayed and overall phases
No Significant Nausea - acute, delayed,
overall phases
No Emesis and No Significant Nausea - acute, delayed,
overall phases

50.  A greater proportion of NEPA-treated patients reported no impact on daily living (NIDL)
based on FLIE for the nausea, vomiting and combined domains compared with PALO
FLIE assessment: nausea and vomiting
0
20
40
60
80
100
71.5
65.8
90.1
84.4
78.5
72.1
Patients(%)
Nausea domain Vomiting domain Overall combined
NEPA+DEX
PALO+DEX
‡†*
59
Aapro et al., Ann Oncol 2014; 25: 1328–1333
* P=0.015
† P=0.001
‡ P=0.005
PALO = palonosetron, NEPA = fixed combination of PALO + netupitant (NETU), DEX = dexamethasone.

51. DEX, dexamethasone; CR, complete response; NEPA: oral fixed combination of netupitant (300 mg) and palonosetron (0.50 mg); PALO, palonosetron
Aapro M. et al. Journal of Clinical Oncology, 2014 ASCO 32,15_suppl, 2014: 9502
Higher CR Rates with NEPA Maintained Across 4 Cycles of
Chemotherapy
0
10
20
30
40
50
60
70
80
90
100
74
80
84 84
67 67 70
75
Patients(%)
NEPA + DEX
Oral PALO + DEX
Cycle 2 Cycle 4Cycle 3Cycle 1
N= 724
N= 725
NEPA + DEX
Oral PALO + DEX
598
606
635
651
551
560
CR Rates (Overall 0–120 h) for During the First 4 Treatment Cycles
*
** ** **
* P= 0.001
* * P < 0.0001

52. A Phase 3 study evaluating the safety and
efficacy of NEPA, a fixed-dose combination of
netupitant and palonosetron, for prevention of
chemotherapy-induced nausea and vomiting
(CINV) over repeated cycles of chemotherapy
Phase 3 Safety study: multiple cycles in
patients receiving HEC and MEC
R Gralla, S Bosnjak, A Hontsa, C Balser, G Rizzi, G Rossi,
ME Borroni, K Jordan.
A Phase 3 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 2014; 25: 1333–1339

53. Objective
 The study was designed to assess the safety of NEPA with a secondary objective of
evaluating the efficacy of NEPA over multiple cycles of HEC and MEC
Design
 This was a Phase 3, multinational, multicenter, randomized, double-blind, double-
dummy, parallel-group study conducted at 59 sites in 10 countries
Study objective, design, patients
Gralla et al. Ann Oncol 2014; 25: 1333–1339
 Patients were randomly allocated (stratified by HEC/MEC and gender) 3:1 NEPA or APR
+ PALO
 The DEX dose/schedule was based on the emetogenicity of the chemotherapeutic regimen
and according to antiemetic guidelines
> HEC: 12 mg Day 1 and 8 mg Days 2-4; MEC: 12 mg Day 1
 There was no pre-specified limit to the number of consecutive chemotherapy cycles for
patients

54. Patients randomized and cycles completed
Table 3
NEPA APR + PALO
Randomized 309 104
Completed Cycle 1
303
(98.1%)
102
(98.1%)
Completed Cycle 2
278
(90.0%)
94
(90.4%)
Completed Cycle 3
255
(82.5%)
88
(84.6%)
Completed Cycle 4
230
(74.4%)
81
(77.9%)
Completed Cycle 5
156
(50.5%)
57
(54.8%)
Completed Cycle 6
122
(39.5%)
43
(41.3%)
PALO = palonosetron, NEPA = fixed combination of PALO + netupitant (NETU), APR = aprepitant, HEC = highly emetogenic chemotherapy, MEC = moderately emetogenic chemotherapy excluding breast cancer
patients receiving AC (anthracycline plus cyclophosphamide).
Gralla et al. Ann Oncol 2014; 25: 1333–1339

55. Complete Response in the Overall Phase (0-120 hour)
0
20
40
60
80
100
81
76
86
81
91
87 90 88
92
86
91
86
Patients(%)
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
NEPA
APR+PALO
 The overall CR rates were high and antiemetic efficacy was maintained over repeated cycles for both
treatment groups with NEPA
 In the NEPA group the proportion of patients with an overall CR across cycles was similar for patients
receiving HEC and MEC. In the APR + PALO group, CR rates were slightly lower in the HEC than in the
MEC subgroup
Full Analysis Population
Complete Response (No
Emesis, No Rescue Medication)
PALO = palonosetron,
NEPA = fixed combination of
PALO + netupitant (NETU),
APR = aprepitant.
Gralla et al. Ann Oncol 2014; 25: 1333–1339
*
**
*p<0.05

56. Adverse events over multiple cycles
There was no indication that the frequency of adverse events increased with the number of
treatment cycles
Gralla et al. Ann Oncol 2014; 25: 1333–1339
There were no cardiac safety concerns based on AEs and ECGs
 Changes from baseline in 12-lead ECGs at 5 and 24 hours post-dose were similar between
the groups, with any QTc interval prolongation being transient and returning to pre-dose
measurements within 120 hour post-dose across all cycles
 The percentage of patients who developed ECG abnormalities was comparable for the
treatment groups throughout the study, with no concern
 Mean LVEF was comparable at screening and at the end of the study with small changes in
both groups

57. Nausea control with NEPA
NEPA…for CIN??

59. NEPA…for Multiday chemotherapy??

60. NEPA in multiday chemotherapy
Regimen received : Epirubicin (EPI) 35 mg/m2 days 1–3 and Ifosfamide (IFO) 3000
mg/m2 days 1– 3 every 21 days
For antiemetic prophylaxis, all patients received a single dose of NEPA on day 1
only and dexamethasone 12 mg on days 1, 2, and 3.
• A dose escalation of dexamethasone was done, 4 mg/bid on days 4, 5, and 6
and 2 mg/bid on days 7, 8, and 9.

61. Results : Complete response

62. Result : No nausea
Study Conclusion : Benefit of NEPA to prevent CINV in sarcoma patients
receiving MD chemotherapy.

63. NEPA: Cost effectiveness??

64. Cost effectiveness of NEPA
• Purpose : To assess, the cost-effectiveness of chemotherapy-induced nausea and vomiting (CINV) prophylaxis
using a single dose of netupitant and palonosetron in a fixed combination (NEPA) versus aprepitant plus
granisetron (APR + GRAN), each in combination with dexamethasone, in chemotherapy-naïve patients receiving
highly emetogenic chemotherapy (HEC).
• Methods : Patient-level outcomes over a 5-day post-HEC period from a randomized, double-blind, phase 3 clinical
trial of NEPA (n = 412) versus APR + GRAN (n = 416).
• Costs and CINV-related utilities were assigned to each subject using published sources. Parameter uncertainty
was addressed via multivariate probabilistic sensitivity analyses (PSA)

65. Results : Cost-effectiveness analyses results

66. NEPA is highly cost-effective (and in fact
cost-saving) versus an aprepitant-based
regimen in post-HEC CINV prevention
Conclusion

67.  Approved & recommended by FDA or EMA for CINV since 2014
 Approved for initial or repeated chemotherapy cycles but not limited to HEC regimens
 NEPA offers ‘Synergistic’ benefits or control of Sub P signaling during Delayed Emesis
 NEPA benefits
1. Convenient, single dosage form
2. Dual MOA for Control for Central & Peripheral pathways
3. Favorable side effect profile for pts undergoing multiple chemotherapy cycles or
High-risk patients with ‘AC’ exposure
4. Dosing flexibility for ease of administration
NEPA: Summary