1
Osteosarcoma: The addition of Osteosarcoma: The addition of muramyl tripeptide to chemotherapy muramyl tripeptide to chemotherapy improves overall survival: A report improves overall survival: A report
from the Children’s Oncology Groupfrom the Children’s Oncology Group
Osteosarcoma: The addition of Osteosarcoma: The addition of muramyl tripeptide to chemotherapy muramyl tripeptide to chemotherapy improves overall survival: A report improves overall survival: A report
from the Children’s Oncology Groupfrom the Children’s Oncology Group
Paul A. Meyers, MD, Cindy Schwartz, MD, Mark Krailo, PhD, John H. Healey, MD, Mark Bernstein,
MD, Donna Betcher, Ernest Conrad, MD*, William S. Ferguson, MD, Mark C. Gebhardt, MD, Allen Goorin, MD, Michael Harris, MD, Eugenie Kleinerman, MD, Michael Link, MD, Helen Nadel, MD, Michael Nieder, MD, Judith Sato, MD*, Gene P. Siegal, MD, Michael
Weiner, MD, Robert Wells, MD, Richard Womer, MD, Holcombe Grier, MD
Paul A. Meyers, MD, Cindy Schwartz, MD, Mark Krailo, PhD, John H. Healey, MD, Mark Bernstein,
MD, Donna Betcher, Ernest Conrad, MD*, William S. Ferguson, MD, Mark C. Gebhardt, MD, Allen Goorin, MD, Michael Harris, MD, Eugenie Kleinerman, MD, Michael Link, MD, Helen Nadel, MD, Michael Nieder, MD, Judith Sato, MD*, Gene P. Siegal, MD, Michael
Weiner, MD, Robert Wells, MD, Richard Womer, MD, Holcombe Grier, MD
2
Spacer
Muramyl Tripeptide-Phosphatidyl Muramyl Tripeptide-Phosphatidyl Ethanolamine (MTP-PE)Ethanolamine (MTP-PE)Muramyl Tripeptide-Phosphatidyl Muramyl Tripeptide-Phosphatidyl Ethanolamine (MTP-PE)Ethanolamine (MTP-PE)
MTP
MDP PE
2005.01
3
L-MTP-PEL-MTP-PEL-MTP-PEL-MTP-PE
2003.03
MTP-PE
MTP-PE
4
Cytosol
Macrophage
Administration of MTPAdministration of MTPAdministration of MTPAdministration of MTP
NOD2
MDPMTP MTPMTPMTP
1 hour 5 hours
IL- 1
IL- 8
IL- 6
TNFa
Adapted from Strober W., Nature Rev Immunol, 6:9-20, 2006
5
MTP Induces Infiltration of Inflammatory MTP Induces Infiltration of Inflammatory Macrophages into Lung MetastasesMacrophages into Lung MetastasesMTP Induces Infiltration of Inflammatory MTP Induces Infiltration of Inflammatory Macrophages into Lung MetastasesMacrophages into Lung Metastases
Kleinerman Kleinerman et al.et al., , Cancer Immunol. ImmunotherCancer Immunol. Immunother., 1992., 1992
Without MTP With MTP
2006.01
6MacEwen EG et al. J Natl Cancer Inst. 1989;81:935-938.2119.02
MTP for Osteosarcoma in DogsMTP for Osteosarcoma in Dogs
0
20
40
60
80
100
0 100 200 300 400 500 600 700 800 900 1000
Days Post Surgery
Cu
mu
lati
ve P
rop
ort
ion
in
R
emis
sio
n (
%)
Liposomal MTP-PE
Placebo liposomes
7
Phase 2 Results in Relapsed Osteosarcoma Phase 2 Results in Relapsed Osteosarcoma with Lung Metastaseswith Lung MetastasesPhase 2 Results in Relapsed Osteosarcoma Phase 2 Results in Relapsed Osteosarcoma with Lung Metastaseswith Lung Metastases
2025.04 Kleinerman ES et al, Am.J. Clin. Onc. 18:93, 1995
Dis
ease
-Fre
e S
urvi
val
1.01.0
0.80.8
0.60.6
0.40.4
0.20.2
00
Years
FailTotal
Historical control2021
Cohort 21116
Cohort 11212
00 101088664422 1212
8
Phase 3 Study DesignPhase 3 Study DesignPhase 3 Study DesignPhase 3 Study Design
A Cisplatin
DoxorubicinHDMTX
2028.03
BIfosfamide
DoxorubicinHDMTX
INDUCTION INDUCTION
Cisplatin, Ifosfamide, Doxorubicin, HDMTXCisplatin, Ifosfamide, Doxorubicin, HDMTX
2020 36362727WeeksWeeks
Cisplatin, Doxorubicin, HDMTXCisplatin, Doxorubicin, HDMTX
MAINTENANCE MAINTENANCE
A
B
Cisplatin, Doxorubicin, HDMTX, Cisplatin, Doxorubicin, HDMTX, MTPMTP
Cisplatin, Ifosfamide,Cisplatin, Ifosfamide, Doxorubicin, HDMTX, Doxorubicin, HDMTX, MTPMTP
A+
B+
DEFINITIVE
SURGERY
DEFINITIVE
SURGERY
9
678337341Totals
338171167MTP
340166174No MTP
Totals
B: CDDP+Dox+MT
X +IFS
A: CDDP+Dox+MTX
(no IFS)
IDMITT
678337341Totals
338171167MTP
340166174No MTP
Totals
B: CDDP+Dox+MT
X +IFS
A: CDDP+Dox+MTX
(no IFS)
IDMITT
Phase 3 – 2x2 Study EnrollmentPhase 3 – 2x2 Study EnrollmentPhase 3 – 2x2 Study EnrollmentPhase 3 – 2x2 Study Enrollment
2096.02
Chemotherapy Regimens
A B
CisplatinDoxorubicin
HDMTX
IfosfamideCisplatin
Doxorubicin
HDMTXTotal
Patients
No MTP 168 163 331
MTP 163 168 331
Total patients 331 331 662
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n S
urvi
ving
0 5 10Year
I
IIAIIBIII
IV
Necrosis Grading
Survival From DS by Necrosis Grading
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n
0 5 10 15Year
SurvivalEFS
Outcome
Outcome
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n E
vent
-Fre
e
0 5 10 15Year
A-A+B-B+
Regimen
EFS by Randomized Regimen
Analysis of interactionAnalysis of interaction
Interaction between assigned Interaction between assigned chemotherapy and MTP was assessed chemotherapy and MTP was assessed using the proportional hazards regression. using the proportional hazards regression. A p-value of 0.10 level or less was A p-value of 0.10 level or less was considered evidence of a significant considered evidence of a significant interaction.interaction.
1 2 120| , c m c mt c m t e
1 2 120| , c m c mt c m t e
1 2 120| , c m c mt c m t e
Analysis of InteractionAnalysis of Interaction
Event free survival: Test of the hypothesis Event free survival: Test of the hypothesis of no interaction (p = 0.102)of no interaction (p = 0.102)
MTP Hazard ratio MTP Hazard ratio [95% CI][95% CI]
Regimen ARegimen A 0.99 [0.69, 1.4]0.99 [0.69, 1.4] Regimen BRegimen B 0.65 [0.45, 0.65 [0.45,
0.93]0.93] All patientsAll patients 0.80 [0.62, 1.0]0.80 [0.62, 1.0]
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n E
vent
Fre
e
0 5 10 15Year
AB
Chemotherapy Regimen
EFS by Chemotherapy Assignment
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n E
vent
Fre
e
0 5 10 15Year
YesNo
Assigned MTP
EFS by MTP Assignment
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n S
urvi
ving
0 5 10 15Year
A-A+B-B+
Regimen
Survival by Randomized Regimen
Analysis of InteractionAnalysis of Interaction
Overall survival: Test of the hypothesis of Overall survival: Test of the hypothesis of no interaction (p = 0.60)no interaction (p = 0.60)
MTP Hazard ratio [95% CI]MTP Hazard ratio [95% CI] Regimen ARegimen A 0.76 [0.49, 1.2]0.76 [0.49, 1.2] Regimen BRegimen B 0.66 [0.43, 1.0]0.66 [0.43, 1.0] All patientsAll patients 0.71 [0.52, 0.71 [0.52,
0.96]0.96]
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n S
urvi
ving
0 5 10 15Year
AB
Chemotherapy Regimen
Survival by Chemotherapy Assignment
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n S
urvi
ving
0 5 10 15Year
YesNo
Assigned MTP
Survival by MTP Assignment
21
Osteosarcoma: Overall SurvivalOsteosarcoma: Overall SurvivalSEER and COG 2006 Data (All Patients)SEER and COG 2006 Data (All Patients)Osteosarcoma: Overall SurvivalOsteosarcoma: Overall SurvivalSEER and COG 2006 Data (All Patients)SEER and COG 2006 Data (All Patients)
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10 12Years
MTP
No MTP
SEER 1993-2002SEER 1987-1992
SEER 1981-1986SEER 1975-1980
22
Validity of Survival Endpoint Validity of Survival Endpoint Validity of Survival Endpoint Validity of Survival Endpoint
Threats to the validity of survival– asymmetric follow-up – asymmetric application of effective post relapse
intervention
Post-relapse intervention for osteosarcoma– No chemotherapy effect on post-relapse survival– No survival post relapse without surgical resection
Post-relapse intervention INT-0133– no between-arm differences
2121.01
23
ConclusionsConclusionsConclusionsConclusions
The addition of ifosfamide in this dose schedule to cisplatin, doxorubicin, and HDMTX did not improve EFS or overall survival
The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.
The survival for patients treated with MTP and chemotherapy was superior to SEER results for the last twenty years.
24years from relapse
20181614121086420
su
rviv
al
1,0
,9
,8
,7
,6
,5
,4
,3
,2
,1
0,0
59%
23% 18%
N=576; 149 alive
Median Follow-up All: 1.2 yearsSurvivors: 4.2 years
38%
15%
Recurrent Osteosarcoma:
Overall SurvivalKempf-Bielack B et al. J Clin Oncol. 2005;23:559-568.
Years From Relapse
Su
rviv
al
25
Recurrent Osteosarcoma:Recurrent Osteosarcoma:
Complete Surgery?Complete Surgery?KeKempf-Bielack B et al. J Clin Oncol. 2005;23:559-568.
years after relapse
20181614121086420
su
rviv
al
1,0
,8
,6
,4
,2
0,0
Yes (CR#2) n=339
No (macroscopic rest) n=229
P<.0001
0%
38%
Years After Relapse
Su
rviv
al
26
Postrelapse Survival in Postrelapse Survival in Osteosarcoma of the Extremities: Osteosarcoma of the Extremities: Prognostic Factors for Long-Term Prognostic Factors for Long-Term SurvivalSurvival
Postrelapse Survival in Postrelapse Survival in Osteosarcoma of the Extremities: Osteosarcoma of the Extremities: Prognostic Factors for Long-Term Prognostic Factors for Long-Term SurvivalSurvival
1st Relapses N 5-Year Survival
Total 162 28%
Surgery complete 114 39%
Surgery incomplete 48 0% (at 3 years)
27years since relapse
20181614121086420
su
rviv
al
1,0
,9
,8
,7
,6
,5
,4
,3
,2
,1
0,0
Multidrug chemo n=333
None or single agent n=216
P=.012
26%
21%
Recurrent Osteosarcoma:Recurrent Osteosarcoma:
Chemotherapy?Chemotherapy?KeKempf-Bielack B et al. J Clin Oncol. 2005;23:559-568.
Years Since Relapse
Su
rviv
al
28
Data for post relapse therapy by study armData for post relapse therapy by study armData for post relapse therapy by study armData for post relapse therapy by study arm
Regimen Reg A without MTP
Reg A with MTP
Reg B without MTP
Reg B with MTP
Number of patients with relapse
62 58 71 49
Number of patients with data available
51 48 65 43
Data available for 86% of relapse patients
29
Site of first metastatic diseaseSite of first metastatic diseaseSite of first metastatic diseaseSite of first metastatic disease
Relapse limited to the lungs
Reg A without MTP
Reg A with MTP
Reg B without MTP
Reg B with MTP
YES 18
(38%)
23
(50%)
33
(52%)
20
(48%)
NO 30
(63%)
23
(50%)
30
(48%)
22
(52%)
p= 0.45
30
Surgery following relpaseSurgery following relpaseSurgery following relpaseSurgery following relpase
Reg A without MTP
Reg A with MTP
Reg B without MTP
Reg B with MTP
Relapse surgery
13
(24%)
16
(31%)
21
(31%)
9
(20%)
No relapse surgery
41
(76%)
36
(69%)
47
(69%)
35
(80%)
p= 0.22