Professor Bruce Morland Birmingham, UK - PowerPoint Presentation

1. Professor Bruce MorlandBirmingham, UKOsteogenic sarcoma protocol

2. Osteosarcoma1. Meyers PA, Gorlick R. Pediatr Clin North Am 1997;44(4):973-990. 2. Bone sarcomas: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25(3): iii113-iii123. 3. Mascarenhas L et al. SEER AYA Monograph 2002;8:97-109 (Table 8.1). 4. Stiller CA et al. Eur J Cancer 2013;49:684-695. 5. Grimer RJ. Lancet Oncol 2005:6:85-92.Disease of children and young adults1Most common between ages of 10-20 years1Incidence: 0.2-0.3 per 100,000 population in Europe2Affects approximately 450 patients under 24 years of age in the U.S. each year3Estimated 1,135 new cases every year in Europe4Relapse rate in newly diagnosed patients can be as high as 30%1Most recurrences occur as lung metastases5

3. History of osteosarcoma treatmentAnninga JK et al. Eur J Cancer 2011;47(16):2431-45.Before the 1970s patients underwent amputation and no chemotherapyLong term overall survival was <20%Introduction of chemotherapy in the early 1970s significantly improved outcomesBy the mid 1980s long term overall survival up to 50-60%Some studies showed better rates, but overall little significant improvement for over three decades

4. Minimal improvement in osteosarcoma survival since 1980sHistorical:Surgery aloneIntroduction of chemotherapyAttempted refinement of chemotherapyAdapted from: 1. Anninga JK et al. Eur J Cancer 2011;47(16):2431-45

5. Osteosarcoma: 5-Year Survival in EuropeStiller CA et al. Eur J Cancer 2006;42:2124-25.n 391 492 460 495

6. Osteosarcoma: 5 year survival (SEER data)Smith MA et al JCO 2010;28(15):2625-2634.The Surveillance, Epidemiology, and End Results (SEER) Program of the US National Cancer Institute (NCI) collects and publishes cancer incidence and survival data from population-based cancer registries

7. How are patients treated today?1. Abed R, Grimer R. Cancer Treatment Reviews 2010; 36: 342-347. 2. Bone sarcomas: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25(3): iii113-iii123. 3. Gorlick R, Meyers PA. J Pediatr Hematol Oncol, 2003;25:840-185% of patients can now have their tumour removed without amputation due to1:Better imaging techniquesGreater surgical skillResponsiveness of tumours to chemotherapyAdvances in biomedical engineering Chemotherapy involving doxorubicin, cisplatin, high dose methotrexate and ifosfamide (+/- etoposide) administered before and after surgery2Actually no formal proof that giving chemotherapy pre-operatively improves outcome1The concept originally stemmed from the need for time to construct endoprosthesis3

8. First let us not forget the basics!

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10. Osteosarcoma

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12. ThemesEmphasis on surgical expertise with full range of reconstructive techniquesMAP chemotherapy upfrontSurgery the mainstay of recurrent disease (thoracotomy)Role of 2nd line chemo unproven (ifos/etop)Poor post-relapse prognosis

13. More than anything else I say today this probably saves more lives!Get the patients to specialists EARLYMetastatic disease at presentation is BAD newsStage and diagnose the patient accuratelyRecognise the treatment of osteosarcoma is multidisciplinaryTeam members MUST communicate effectivelyThis MAY be facilitated by limited specialised bone sarcoma centres

14. Strategies to Improve OutcomesSince the 1980s strategies to improve outcomes have focused on attempting to refine both pre-operative and post-operative chemotherapy e.g.Salvage: adapt adjuvant chemotherapy based on histological responseIncrease proportion of good respondersMore chemotherapy Increase chemotherapy dose intensityRisk-adapted chemotherapyAddition of a new agent

15. Is tumor response improved by more chemotherapy? Thanks to Stefano Ferrari

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17. Histologic response/primary chemotherapyRizzoli/ISG experiencePrimary treatment> 90% Tumor necrosisIOR/OS-1MTX-CDDP I.A.52%IOR/OS-2MTX-CDDP I.A.-DOX71%IOR/OS-3MTX-CDDP I.A.-DOXMTX-CDDP I.V.-DOX64%43%IOR/OS-4MTX-CDDP I.A/I.V.-DOX-IFO69%ISG/SSG-1MTX-CDDP I.V.-DOX-HDIFO63%

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19. How about increasing dose-intensity?

20. EOILewis 2000lowintermediatehigh

21. Is dose intensification by G-CSF beneficial? European Osteosarcoma Intergroup Trial EOI-80931

22. Chemotherapy at standard or increased dose intensity in patients with operable osteosarcoma of the extremity - MRC BO06 EORTC 80931

23. MRC BO06 EORTC 80931

24. Conclusion:Dose / Dose-Intensity importance remains unprovenG-CSF for interval compression not useful in osteosarcoma

25. MTX DOX DDP IFODoes it matter how many of these drugs are used?

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27. MTX DOX DDP IFOWhich and how many of these drugs should be used?Personal Opinion at least 3 of these drugs should be used it may not really matter which of the 3 addition of a 4th drug may not improve outcomes, but: adding a 4th may allow to reduce cumulative toxicities „optimal“ conventional chemotherapy remains to be defined (but will it ever be????)

28. Can outcomes be improved for poor responders?

29. “Salvage”-Question: Stats3y EFS: good  75% poor  50% Significance 5% Power 80% 50  60%needed:  700 randomized poor responders   1.400 patients willing to be randomized  > 2.000 patients overall

30. COG Childrens’ Oncology GroupCOSSCooperative Osteosarcoma Study GroupEOIEuropean Osteosarcoma IntergroupSSGScandinavian Sarcoma GroupEuropean and American Osteosarcoma Study

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32. EURAMOS Recruitment 04/05 – 06/11Thanks to EURAMOS-CDC, MRC London2.260 patientsfrom 326 institutions in 17 countries

33. Design and eligibilityBiopsy-proven diagnosis of resectable osteosarcomaREGISTERMAP (induction)SurgeryHistological response assessmentPoorGoodRANDOMIZERANDOMIZEMAPMAPIEMAPMAPifnRegistrationResectable high-grade osteosarcomaExtremity or axialLocalized or metastaticAge ≤40yrNo pretreatment for osteosarcomaNo previous chemo for any diseaseNo contraindication to treatmentRegistration & chemo ≤30day after biopsyWritten informed consent

34. DesignPrimary tumor resectionRAP MMIE MA MMwk 1-10wk 11wk 12-40Ai Mwk 12-29x2AP MMA MMAP MMAP MMIE MAP MMIE MAi MMMAPIEMAPInduction MAPEligibility for randomisationPoor histological response to induction MAP≥10% viable tumor in resected specimenComplete resection of primary tumorNo progressionRecovered from prior therapyPoor ResponseDosing MMethotrexate 12gm/m2ADoxorubicin75mg/m2PCisplatin120mg/m2IIfosfamide 14g/m2iIfosfamide 9g/m2EEtoposide500mg/m2

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36. MAPIE vs. MAP in Poor RespondersEvent-Free Survival

37. MAPIE vs. MAP in Poor RespondersOverall Survival

38. MAPIE more toxic than MAPMAPIE: More grade III/IV toxicity (examples) febrile neutropenia 73% vs. 50% infection 83% vs. 65% hypophosphatemia 29% vs. 19%MAPIE: More secondary leukemias - MAPIE ≥7/307 vs. MAP 2/308

39. EURAMOS-1 Conclusions Poor ResponseAdding ifosfamide and etoposide to MAP is associated with additional morbidity and has no effect on survival outcomes.

40. EURAMOS-1 Conclusions Poor ResponseContinue with MAPDo NOT add IFO/ETO!

41. Add something new?

42. Might results be improved by “immunotherapy”?

43. Design and eligibilityRandomizationGood response <10% viable tumorAssessment by reference pathologist if possibleAge ≥ 5 yrs No disease progressionIf mets, complete removal feasibleRecovery from prior therapyRandomization ≤ 35 days post-opWritten informed consentBiopsy-proven diagnosis of resectable osteosarcomaREGISTERMAP (induction)SurgeryHistological response assessmentPoorGoodRANDOMIZERANDOMIZEMAPMAPIEMAPMAPifnEURAMOS-1; Bielack et al., ASCO 2013

44. InterventionsPrimary tumor resectionRifn MAPMAPMAMAMAPMAPMAMAMAPMAPwk 1-10wk 11wk 12-29wk 30-104M Methotrexate 12gm/m2A Doxorubicin 75mg/m2P Cisplatin 120mg/m2Pegylated interferon -2bTimingWeekly after chemo until wk 104DosingStarting at 0.5 μg/kg/wk s.c. (max. 50 μg) x 4 wks if well toleratedEscalation to 1.0 μg/kg/wk s.c. (max. 100 μg) Protocol guidelines for

45. EFS - intention to treat 74% at 3yr77% at 3yrMAP (n=358)MAPifn (n=357)Events, n (%)93 (26%)81 (23%)3 year EFS74% (69%-79%)77% (72%-81%)Hazard ratio* (95%CI)p-value0.82 (0.61-1.11) p=0.201*Cox model adjusted for data center, metastases status, site and location of tumor on bone

46. Interferon treatment

47. EURAMOS-1 Conclusions Evidence from EURAMOS-1 does not support adaptation of postoperative chemotherapy based on histological response!

48. Sophie Piperno-Neumann, Marie-Cécile Le Deley, Françoise Rédini, Hélène Pacquement, Perrine Marec-Bérard, Philippe Petit, Hervé Brisse, Cyril Lervat, Jean-Claude Gentet, Natacha Entz-Werlé, Antoine Italiano, Nadège Corradini, Emmanuelle Bompas, Nicolas Penel, Marie-Dominique Tabone, Anne Gomez-Brouchet, Jean-Marc Guinebretière, Eric Mascard, François Gouin, Aurélie Chevance, Naïma Bonnet, Jean-Yves Blay, Laurence Brugières Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trialLancet OncologyVolume 17, No. 8, p1070–1080, August 2016

49. Mifamurtide?

50. Summary: Phase I and II StudiesMifamurtide stimulatesmonocyte tumouricidal activity the production of cytokinesthe influx of activated macrophages into osteosarcoma lung nodulesRelapsed patients treated with mifamurtide had a superior disease-free and overall survivalCombining Mifamurtide with chemotherapy did not interfere with its immune activityMepact (mifamurtide) is not licensed for use in patients with relapsed/metastatic osteosarcoma

51. Phase III Study DesignAdapted from:Meyers PA et al. J Clin Oncol 2005;23:2004-2011Meyers PA et al. J Clin Oncol 2008;26:633-638A CisplatinDoxorubicinHDMTXBIfosfamideDoxorubicinHDMTXINDUCTIONIfosfamide, Cisplatin, Doxorubicin, HDMTX203627WeeksCisplatin, Doxorubicin, HDMTX MAINTENANCEA-Cisplatin, Doxorubicin, HDMTX, MTP (Mepact)Ifosfamide, Cisplatin, Doxorubicin, HDMTX, MTP (Mepact)DEFINITIVESURGERYRegimens A and B: Doxorubicin x 6 ea (25 mg/m2/day x 3), Cisplatin x 4 ea (120 mg/m2), and Methotrexate x 12 ea (12 g/m2)Regimen B only: Ifosfamide x 5 ea (1.8 g/m2/day x 5)HDMTX = High-Dose Methotrexate;RANDOMISATIONHISTOLOGICAL EVALUATIONA+B-B+

52. POG/CCGMeyers et al2005

53. Event-free Survival by Chemotherapy Assignmentp=0.91Meyers PA et al. J Clin Oncol 2008;26:633-638

54. Overall Survival and Event-free Survival by Mifamurtide Assignmentp=0.03, HR 0.71(CI: 0.52, 0.96)p=0.08, HR 0.8(CI: 0.62, 1.00)Meyers PA et al. J Clin Oncol 2008;26:633-638

55. What about metastatic disease?

56. What is the best management for metastases?Avoid getting them in the first place!SurgerySurgerySurgerySurgeryChemotherapy

57. Mifamurtide?Cancer 2009;115:5339-48

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59. PatientSexAgeDiagnosedPrimary siteSurgeryMetsCompleted treatmentAliveDeadDate of 1st post op MAPDate of first MifamurtideNotesIZF13Jun-11L humerusEPRJul-12A19.9.1122.12.111st patient started when drug approved. HeadachesGPF12Mar-12R femurEPRMar-13A18.7.1223.7.12HBF8Apr-12L femurEPRJun-13A13.8.1231.8.12HEM7Apr-12R femurEPRJun-13A8.10.128.11.12JRM14Jun-12R tibiaFibula graftJul-13A24.10.1229.10.12JBF14Jul-12L tibiaEPRLungAug-13DOD22.10.1222.11.12Funding delayed start of Mepact. Nearly completed all Mepact doses when relpase detectedBTF12Sep-12L tibiaAmputationSep-14A2.12.139.12.13Emergency amputation after first Cis/Dox dose receivedRJF14Jul-13R tibiaEPRMay-14A20.11.1327.2.14Prolonged wound infection post-op. MTX-induced encephalopathy after 2nd dose of MepactNJM13Nov-13R femurEPRDec-14A31.3.143.4.14Omitted final 2 doses of Dox for reduced FS, replaced with 2 extra doses of MTXJMF13May-14R femurAmputationJuly-15A1.9.1411.9.14MTX-induced leukoencephalopathyBCM10Sep-14R femurEPROct-15A5.1.1516.1.15RMM12Feb-15L femurEPRMar-16A15.6.1518.6.15HMM14May-16R tibiaEPRJun-17A28.9.1629.9.16

60. What about new agents?

61. New agentsZoledronateData from France suggesting worse outcomeAnti-GD2 MoAbDenosumabTyrosine kinase inhibitorsM-Tor pathway inhibitorsPDL-1CAR T-cells

62. The challengesGenetically chaotic tumourUnlikely single pathway will be effective therapeuticallyCombination with chemotherapy challengingHow to determine if the agents workLumps of “chalk” don’t shrink? PFS end points, but reliable controls…..Patients often very end stage when come to Phase I/II

63. ConclusionsWe are stuck!“Gold standards”At least 3 chemotherapy drugs (+/- Mepact)Complete surgical resection of all diseaseIncludes metastasesNew molecularly targeted therapies likely to have limited benefit on a genetically chaotic tumourImmune therapies may hold some promise?

64. תודה