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Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival: A report from the Children’s

Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival: A report from the Children’s Oncology Group.

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Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival: A report from the Children’s

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  1. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival: A report from 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

  2. Muramyl Tripeptide-Phosphatidyl Ethanolamine (MTP-PE) MTP MDP PE Spacer 2005.01

  3. MTP-PE MTP-PE L-MTP-PE 2003.03

  4. Macrophage MTP MTP MTP Cytosol NOD2 MDP 1 hour 5 hours IL- 8 IL- 1 TNFa IL- 6 Administration of MTP MTP Adapted from Strober W., Nature Rev Immunol, 6:9-20, 2006

  5. MTP Induces Infiltration of Inflammatory Macrophages into Lung Metastases Without MTP With MTP Kleinerman et al., Cancer Immunol. Immunother., 1992 2006.01

  6. MTP for Osteosarcoma in Dogs MacEwen EG et al. J Natl Cancer Inst. 1989;81:935-938. 2119.02

  7. 1.0 Total Fail 12 12 Cohort 1 16 11 Cohort 2 0.8 21 20 Historical control 0.6 Disease-Free Survival 0.4 0.2 0 0 2 4 6 8 10 12 Years Phase 2 Results in Relapsed Osteosarcoma with Lung Metastases Kleinerman ES et al, Am.J. Clin. Onc. 18:93, 1995 2025.04

  8. A+ Cisplatin, Doxorubicin, HDMTX, MTP Cisplatin, Ifosfamide,Doxorubicin, HDMTX, MTP B+ Phase 3 Study Design INDUCTION DEFINITIVESURGERY MAINTENANCE A Cisplatin Doxorubicin HDMTX A Cisplatin, Doxorubicin, HDMTX Cisplatin, Ifosfamide, Doxorubicin, HDMTX B Ifosfamide Doxorubicin HDMTX B 20 27 36 Weeks 2028.03

  9. A: CDDP+Dox+MTX (no IFS) A: CDDP+Dox+MTX (no IFS) B: CDDP+Dox+MTX +IFS B: CDDP+Dox+MTX +IFS Totals Totals No MTP No MTP 174 174 166 166 340 340 IDM ITT IDM ITT MTP MTP 167 167 171 171 338 338 Totals Totals 341 341 337 337 678 678 Phase 3 – 2x2 Study Enrollment 2096.02

  10. Analysis of interaction • Interaction between assigned chemotherapy and MTP was assessed using the proportional hazards regression. A p-value of 0.10 level or less was considered evidence of a significant interaction.

  11. Analysis of Interaction • Event free survival: Test of the hypothesis of no interaction (p = 0.102) • MTP Hazard ratio [95% CI] • Regimen A 0.99 [0.69, 1.4] • Regimen B 0.65 [0.45, 0.93] • All patients 0.80 [0.62, 1.0]

  12. Analysis of Interaction • Overall survival: Test of the hypothesis of no interaction (p = 0.60) • MTP Hazard ratio [95% CI] • Regimen A 0.76 [0.49, 1.2] • Regimen B 0.66 [0.43, 1.0] • All patients 0.71 [0.52, 0.96]

  13. MTP No MTP SEER 1987-1992 SEER 1993-2002 SEER 1981-1986 SEER 1975-1980 Osteosarcoma: Overall SurvivalSEER and COG 2006 Data (All Patients)

  14. 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

  15. Conclusions • 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.

  16. Recurrent Osteosarcoma:Overall Survival Kempf-Bielack B et al. J Clin Oncol. 2005;23:559-568. Median Follow-up All: 1.2 years Survivors: 4.2 years Survival 59% 38% 23% 18% 15% N=576; 149 alive Years From Relapse

  17. Yes(CR#2)n=339 No(macroscopic rest) n=229 Survival 38% 0% P<.0001 Years After Relapse Recurrent Osteosarcoma: Complete Surgery? Kempf-Bielack B et al. J Clin Oncol. 2005;23:559-568.

  18. Postrelapse Survival in Osteosarcoma of the Extremities: Prognostic Factors for Long-Term Survival (at 3 years)

  19. Recurrent Osteosarcoma: Chemotherapy? Kempf-Bielack B et al. J Clin Oncol. 2005;23:559-568. Multidrug chemo n=333 None or single agent n=216 Survival 26% 21% P=.012 Years Since Relapse

  20. Data for post relapse therapy by study arm Data available for 86% of relapse patients

  21. Site of first metastatic disease p= 0.45

  22. Surgery following relpase p= 0.22

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