JRN HERRSTEDT, M'D'

1
ANTIEMETICSSTANDARDS OF CARE

• JØRN HERRSTEDT, M.D.
• COPENHAGEN UNIVERSITY HOSPITAL
• HERLEV, DENMARK

2
STANDARDS OF CARE
1979 A corticosteroid is superior to
placebo. 1981 High-dose metoclopramide (hd-MCP)
is effective. 1984 A corticosteroid improves
effect of hd-MCP. 1987 First clinical trial with
a serotonin receptor antagonist (5-HT3-RA).
1991 A corticosteroid improves the effect of
5-HT3-RAs (HEC). 1993 A dopamine antagonist
improves the effect of a 5-HT3-RA. 1995 A
corticosteroid improves the effect of 5-HT3-RAs
(MEC). 1997 First clinical trial with a
neurokinin1-receptor antagonist
(NK1-RA). 2003 NK1-RA improves effect of 5-HT3-RA
plus corticosteroid (HEC). 2005 NK1-RA improves
effect of 5-HT3-RA plus corticosteroid (MEC).
Baker et al., NEJM 1979. Gralla et al., NEJM
1981. Allan et al., BMJ 1984.
Leibundgut and Lancranjan, The Lancet 1987.
Roila et al., JCO 1991.
Herrstedt et al., NEJM 1993. IGAR, NEJM 1995.
Kris et al., JNCI 1997.
Hesketh et al., JCO 2003. Poli-Bigelli
et al., Cancer 2003. Warr et al., JCO 2005.
3
Gralla RJ et al. N Engl J Med 1981305.905-909.
4
Natural History of Delayed Nausea and Vomiting
Kris MG. J Clin Oncol 198531379-1384.
5
STANDARDS OF CARE
1979 A corticosteroid is superior to
placebo. 1981 High-dose metoclopramide (hd-MCP)
is effective. 1984 A corticosteroid improves
effect of hd-MCP. 1987 First clinical trial with
a serotonin receptor antagonist (5-HT3-RA).
1991 A corticosteroid improves the effect of
5-HT3-RAs (HEC). 1993 A dopamine antagonist
improves the effect of a 5-HT3-RA. 1995 A
corticosteroid improves the effect of 5-HT3-RAs
(MEC). 1997 First clinical trial with a
neurokinin1-receptor antagonist
(NK1-RA). 2003 NK1-RA improves effect of 5-HT3-RA
plus corticosteroid (HEC). 2005 NK1-RA improves
effect of 5-HT3-RA plus corticosteroid (MEC).
Baker et al., NEJM 1979. Gralla et al., NEJM
1981. Allan et al., BMJ 1984.
Leibundgut and Lancranjan, The Lancet 1987.
Roila et al., JCO 1991.
Herrstedt et al., NEJM 1993. IGAR, NEJM 1995.
Kris et al., JNCI 1997.
Hesketh et al., JCO 2003. Poli-Bigelli
et al., Cancer 2003. Warr et al., JCO 2005.
6
5-HT3-receptor antagonists

• Azasetron Y-25130
• Batanopride BMY-25801
• Bemesetron MDL 72222
• Dazopride AHR-5531
• Dolasetron MDL 73,147EF
• Eusetron RG 12915
• Granisetron BRL 43694
• Itasetron DAU 6215
• Lerisetron F-0930
• Ondansetron GR 38032
• Palonosetron RS 25259-197
• Pancopride LAS 30451
• Ramosetron YM060
• Renzapride BRL 24924
• Tropisetron ICS 205-930
• Zacopride AHR-111906
• Zatosetron LY 277359

7
5-HT3-receptor antagonists

• Azasetron Y-25130
• Batanopride BMY-25801
• Bemesetron MDL 72222
• Dazopride AHR-5531
• Dolasetron MDL 73,147EF AnzemetR
• Eusetron RG 12915
• Granisetron BRL 43694 KytrilR
• Itasetron DAU 6215
• Lerisetron F-0930
• Ondansetron GR 38032 ZofranR
• Palonosetron RS 25259-197 AloxiR
• Pancopride LAS 30451
• Ramosetron YM060
• Renzapride BRL 24924
• Tropisetron ICS 205-930 NavobanR
• Zacopride AHR-111906
• Zatosetron LY 277359

8
Ondansetron versus granisetron both combined with
dexamethasone in the prevention of
cisplatin-induced emesis

• IGAR. Ann Oncol 19956805-10.

No emesis Day 1

n 966
9
Presence of acute nausea and vomiting as a
prognostic factor for delayed N/V
ACUTE
ACUTE
NO ACUTE
NO ACUTE
IGAR. Support Care Cancer 19998229-232.
10
STANDARDS OF CARE
1979 A corticosteroid is superior to
placebo. 1981 High-dose metoclopramide (hd-MCP)
is effective. 1984 A corticosteroid improves
effect of hd-MCP. 1987 First clinical trial with
a serotonin receptor antagonist (5-HT3-RA).
1991 A corticosteroid improves the effect of
5-HT3-RAs (HEC). 1993 A dopamine antagonist
improves the effect of a 5-HT3-RA. 1995 A
corticosteroid improves the effect of 5-HT3-RAs
(MEC). 1997 First clinical trial with a
neurokinin1-receptor antagonist
(NK1-RA). 2003 NK1-RA improves effect of 5-HT3-RA
plus corticosteroid (HEC). 2005 NK1-RA improves
effect of 5-HT3-RA plus corticosteroid (MEC).
Baker et al., NEJM 1979. Gralla et al., NEJM
1981. Allan et al., BMJ 1984.
Leibundgut and Lancranjan, The Lancet 1987.
Roila et al., JCO 1991.
Herrstedt et al., NEJM 1993. IGAR, NEJM 1995.
Kris et al., JNCI 1997.
Hesketh et al., JCO 2003. Poli-Bigelli
et al., Cancer 2003. Warr et al., JCO 2005.
11
Neurokinin (NK)1 receptor antagonists

• CI-1021
• CJ 11,974 Ezlopitant
• CP 99,994
• CP 122,721
• FK 888
• GR 203040
• GR 205171 Vofopitant
• GW 597599
• GW 679769 Casopitant
• HSP-117
• L-741671
• L-743310
• L-754,030 Aprepitant
• L-758,298
• LY306740
• RO-0673189 Netupitant
• RP-67580
• RPR-100893 Dapitant
• SCH 619734

Previously PD-154075 Not investigated as an
antiemetic Prodrug to L-754030
12
Neurokinin (NK)1 receptor antagonists

• CI-1021
• CJ 11,974 Ezlopitant
• CP 99,994
• CP 122,721
• FK 888
• GR 203040
• GR 205171 Vofopitant
• GW 597599
• GW 679769 Casopitant
• HSP-117
• L-741671
• L-743310
• L-754,030 Aprepitant EmendR
• L-758,298
• LY306740
• RO-0673189 Netupitant
• RP-67580
• RPR-100893 Dapitant
• SCH 619734

Previously PD-154075 Not investigated as an
antiemetic Prodrug to L-754030
13
HEC - Aprepitant Phase III Trials
Treatment Groups (n 1099)
Days 2-3
Day 4
Day 1
D
O
D
A
D
A
8 P
32
12
125
80
8 P
APR
32
20
8 x 2
P
8 x 2
P
CONT
Oondansetron Ddexamethasone Aaprepitant
Pplacebo
1. Hesketh PJ et al. JCO 2003214112-19. 2.
Poli-Bigelli S et al. Cancer 2003973090-98.
14
HEC - Aprepitant Phase III Trial
Treatment Groups (n 489)
Days 2-3
Day 4
Day 1
D
O
D
A
D
A
O
O
8 P
32
12
125
80
8 P
P x 2
P x 2
APR
32
20
8 x 2
P
8 x 2
8 x 2
8 x 2
P
CONT
Oondansetron Ddexamethasone Aaprepitant
Pplacebo
Schmoll HJ et al. Ann Oncol 2006171000-1006.
15
HEC Studies Cycle 1 Primary Endpoint Complete
Response (0-120 h)
p0.003
plt0.001
plt0.001
Percentage of Patients
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MEC - Aprepitant Phase III Trial
Treatment Groups (n 866)
Day 1
Days 2-3

APR
OND
DEX
APR
OND
8 mg x 2
12 mg
125 mg
Placebo
80 mg
APR
8 mg x 2
CONT
20 mg
Placebo
8 mg x 2
Placebo
OND ondansetron p.o.
Anthracycline plus DEX
dexamethasone p.o.
Cyclophosphamide APR aprepitant p.o. CONT
placebo-controlled arm
Warr DG et al. J Clin Oncol 2005232822-2830.
17
MEC study Cycle 1 Primary Endpoint Complete
Response (0-120 h)
100
Primary Efficacy Analysis
plt0.001
90
pns
76
80
p0.015
70
59
59
56
60
51
50
42
Percentage of Patients
40
30
20
10
0
Complete Response (CR)
No Rescue Therapy
No Vomiting
Components of CR
Warr DG et al. J Clin Oncol 2005232822-2830.
18
STANDARDS OF CAREDIFFERENT PROBLEMS

• Nausea
• Multiple-day
• Refractory N V
• Breakthrough N V
• High-dose chemotherapy
• Multiple cycles
• Defining the dose of dexamethasone
• Physicians/nurses underestimate N V

19
MEC study Cycle 1 Primary Endpoint Complete
Response (0-120 h)
100
Primary Efficacy Analysis
plt0.001
90
pns
76
80
p0.015
70
59
59
56
60
51
50
42
Percentage of Patients
40
30
20
10
0
Complete Response (CR)
No Rescue Therapy
No Vomiting
Components of CR
Warr DG et al. J Clin Oncol 2005232822-2830.
20
Sustained No Vomiting Rate
Aprepitant Regimen
80
Standard Regimen
76
70
67
63
60
59
48
42
Percentage of Patients
40
39
Log-rank test, plt0.001
20
0
1
2
3
4
Number at Risk Aprepitant Regimen 432
296 258
234 Standard Regimen 424 224
168 139
Time (Cycle) since First Chemotherapy
Herrstedt J et al.
Cancer 2005

1041548-55.

21
Dose-finding study of dexamethasoneAcute nausea
and vomiting from HEC

• Patients Cisplatin gt 50 mg/m2 /- others
• All received ondansetron 8 mg IV
• Randomized to receive single IV doses of DEX

Dexamethasone N No Emesis No Nausea 4
mg 133 69 61 8 mg 136 69 61 12
mg 130 79 67 20 mg 131 83 71
Conclusions Dexamethasone 20 mg should be the
standard. No difference in adverse
effects.
IGAR. JCO 1998162937-42.
22
Dose-finding study of dexamethasoneAcute nausea
and vomiting from MEC

• Patients Anthracyclines, carboplatin or
  cyclophosphamide
• All received ondansetron 8 mg IV
• Randomized to receive different doses of DEX

Dexamethasone N No Emesis No Nausea 8 mg
iv 195 89.2 61.0 24 mg iv 195 83.6 56.9 8
mg iv 4 mg x 4 195 84.6 66.7
Conclusions Dexamethasone 8 mg iv should be the
standard. No difference in adverse
effects.
IGAR. JCO 200422725-9.
23
Perception vs Reality Moderately Emetogenic
Chemotherapy
Grunberg SM et al. Cancer 20041002261-8.
24
STANDARDS OF CARE ACUTE NAUSEA AND VOMITING
The Antiemetic Subcommittee of MASCC. Ann Oncol
20061720-28. ESMO Minimum Clinical
Recommendations. Ann Oncol in press.

25
STANDARDS OF CARE DELAYED NAUSEA AND VOMITING
The Antiemetic Subcommittee of MASCC. Ann Oncol
20061720-28. ESMO Minimum Clinical
Recommendations. Ann Oncol in press.