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