Keep Calm and Love France. Robin L Jones Royal Marsden Hospital Institute of Cancer Research

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1 Keep Calm and Love France Robin L Jones Royal Marsden Hospital Institute of Cancer Research

2 Plan Parallels between France - UK - USA Importance of centralized care Improving Outcome Guidance (IOG) in UK/ Paediatric European Reference Networks (ERNs) Guidelines Will Brexit impact the European Sarcoma Community? Experience in USA Immunotherapy Olaratumab Trabectedin Chemotherapy Neoadjuvant chemotherapy: Pre-operative studies Doxorubicin/ Ifosfamide Conclusion

3 Parallel Experience France/ UK: Centralized care Collaboration Trials/ EORTC/ ESMO ERNs Leading into the future Minimize impact of Brexit? French Sarcoma Group Trials Retrospective studies Pathology/ Translational Research Resources Less in UK United States of America: Care not centralized Insurance system (complex) Geography Financial incentive Collaboration SARC Collaborative groups: Alliance, SWOG Resources Federal Donors Treatment Less adjuvant/ neoadjuvant chemotherapy Treatment Trabectedin NOT approved in 2010 Neoadjuvant chemotherapy Doxorubicin/ Ifosfamide

4 Importance of Centralised Care Rarity Heterogeneity Diverse anatomic primary sites Cumulative experience required for expertise in all aspects of care

5 Consultation exercise lead to publication of guidance in 2006 covering early referral, diagnosis, centralisation of care and all aspects of multidisciplinary management guidance.nice.org.uk/ CSGSarcoma

6 NICE IOG: Key Recommendations All sarcoma patients must be managed by a sarcoma MDT Designated Diagnostic Centres Provisional sarcoma diagnosis must be reviewed by specialist sarcoma pathologist Treatment Centre must manage: 100 new cases of soft tissue sarcoma a year 50 for bone sarcomas Implications for numbers of surgeons and other staff Sarcoma operations must be done by appropriately experienced surgeons In sarcoma MDT or specialist MDT in consultation

7 Criteria for urgent referral for a patient with >5cm a suspicious lump Increasing size Deep to deep fascia Painful

8 Pathology: Discrepancies Soft Tissue Tumor Diagnosis Year Author Country Number Diagnosis Grade 1978 Baker et al USA Tetu et al Canada Presant et al US SECSG Coindre et al FR Panel Alvegaard et al SSG Shiraki et al US ECOG Harris et al UK Prescott et al UK Meis-Kindblom et al SSG Randall et al US Van Dalen et al NE rpl Thway et al UK Lurkin et al France Ray-Coquard et al France/ Italy Thway et al UK

9 Surgery: Impact of Referral to Specialist Centers Canadian study Limb STS patients referred to centre within 3 months of diagnosis Had improved OS and reduced risk amputation Swedish study Limb/ trunk STS patients referred to specialist centre before surgery had Improved DSS but not OS Five studies 1 UK, 1 France and 3 Sweden compared surgical margins 4 found adequate margins more likely for patients treated at specialist centres Consistent evidence of reduced risk of local recurrence at specialist centres

10 NETSARC Data Overall: 37% presented prior to initial Dx : Increase % reviewed prior to surgery 30.3% to 41.6% NETSARC prior to first treatment: Adequate imaging prior to treatment 87.9% vs 67.8%, p< Biopsy prior to resection 87% vs 55%, p< Blay JY et al ESMO 2016

11 NETSARC Data Secondary Resections 1 NETSARC review before first surgery 99 (5.5%) secondary resections NETSARC review after first surgery 1125 (15.3%) P< Metastasis-free survival 1 No significant difference NETSARC review before and after surgery P=0.15 Long-term risk of recurrence 2 5.8% late metastatic disease Median Follow-up 26 months NETSARC discussion before first surgery Significantly better local recurrencefree survival P< Blay JY et al ESMO Toulmonde M et al. Cancer 120; : 2014

12 Networks NETSARC: Impressive organisational structure Importance MDT discussion prior to first surgery 1 Pre-operative imaging + biopsy Local recurrence free survival Multi institutional Tumour Boards 2 : Collaboration Shared care Rare cancers Low/ middle income countries: Logistical hurdles Specialist surgical/ radiation expertise Cost of novel systemic therapies Available resources 1Blay JY et al ESMO Attia S et al. CTOS 2015

13 European Reference Networks (ERNs) EU directive: 2011/24 Tackle rare diseases requiring specialist care Reference centres: Knowledge/ research hubs for other EU countries Rights of EU patients to cross-border healthcare Ensure availability treatment facilities

14 Value of Guidelines Guidelines cover referral pathways, diagnosis and management Early referral The larger the tumour the worse the outcome Accurate diagnosis Surgery Radiation Chemotherapy Follow-up

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16 Clinical Practice Guidelines 472 cases of soft tissue sarcoma Adherence to guidelines for surgery Strongest independent prognostic factor of Progression-free survival with Age, gender, grade + tumor size Multivariate Analysis for OS Adherence to guidelines for surgery Strong independent prognostic factor Derbel O et al. PLOS One 2017

17 Impact of Brexit on European Sarcoma Community? Hopefully minimal Will impact research funding in UK ERNs Guidelines ESMO EORTC/ clinical trials Uncertain time in the UK

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19 Experience in USA Immunotherapy Olaratumab Trabectedin Chemotherapy Neoadjuvant chemotherapy Doxorubicin/ ifosfamide

20 Courtesy of Brian van Tine

21 Immunotherapy in Cancer Bone Marrow Transplantation: Replace cancer + stem cells Donated healthy cells engraft patient bone marrow establish cancer free blood + immune system

22 Coley s toxins Beef tea culture media Erysipelas and Bacillus prodigiosus, i.e. Group A Streptococcus Serratia marcescens Material injected directly into tumor Sarcoma, lymphosarcoma : Hodgkin disease, NHL Coley WB. Ann Surg 14(3); : 1891

23 Coley s toxins Lack of known mechanism of action Not easy to induce 1 st patient injected numerous times Infecting patients with pathogenic bacteria Risks: Potentially life threatening ASCO: Not reproducible Inconsistent Ineffective therapy in sarcoma Guide to Complementary and Alternative Cancer Methods, ASCO, 2000

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26 Despite Low MHC, NY-ESO-1 Specific T Cells Can Induce Clinical Responses in SS Patients Treated 6 Synovial Sarcoma patients with NY-ESO-1 specific T cells Used intensive conditioning regimen including high dose Cyclophosphamide, Fludarabine and high dose IL-2 4 of 6 patients had partial responses though all ultimately progressed Melanoma Synovial sarcoma Robbins P F et al. JCO 29; : 2011

27 CANCER TESTIS ANTIGENS ARE ATTRACTIVE IMMUNOTHERAPEUTIC TARGETS Proteins expressed in testis and many cancers Not expressed in other normal tissues Immunogenic in cancer patients Includes NY-ESO-1, LAGE-1, PRAME, MAGE family antigens A: MAGE-A4 in tests; B: MAGE-C1 in fetal ovary C: MAGE-A in trophoblastic placenta; D: NY-ESO-1 in bladder cancer Pollack et al. Cancer 118(18); : 2012 Frequently map to chromosome X and exist as multigene families In vitro activation by hypomethylation and/or histone deacetylase inhibition

28 Myxoid Liposarcomas Express NY-ESO-1, Usually Homogenously 25 cases tested, all positive >70% of cases, homogenous Myxoid liposarcoma cell lines can lysed by NY-ESO specific effectors No other disease expresses NY-ESO-1 with this frequency Pollack et al. Cancer 118(18); : 2012

29 Generation of Autologous NY-ESO-1 specific CD8+ CTL lines CD25 depletion or CD8 selection Step 1: Leukapharesis Step 2: PBMC derived DC s Pollack SM et al. J Immunother Cancer 2(1); 36: 2014 Step 3: 2 stimulations with peptide pulsed DC s + IL21, IL2 and IL7. Step 4: Clinical grade sorting. Rapid Expansion

30 Phase I Study To Determine the Safety of Cellular Adoptive Immunotherapy Using Autologous NY-ESO-1 Specific CD8 + Cells For Patients With Advanced Myxoid liposarcoma and Synovial Sarcoma with Cyclophosphamide Conditioning and Post-Infusional Low Dose IL-2 both In Combination with Low Dose Weekly IFNγ Day 0: Cell infusion /m 2 Low dose (250,000 U/m 2 ) BID IL-2 Day -12: begin low dose IFN γ Day -5: low dose IFN γ Day -3, -2: CY 2/g/ m 2 /d Day +2: low dose IFN γ Day +9: low dose IFN γ

31 Response: Large lung tumor in patient with pre-treated metastatic synovial sarcoma Pre-infusion 4 weeks post infusion

32 Adoptive T cell Therapy Infrastructure Cost Durability of clinical benefit Repeat infusions? Combinations?

33 NY-ESO-1 vaccine LV305 Hybrid viral vector Target dendritic cells Induce expression of NY- ESO-1 Potentially generate + expand anti cancer cytotoxic T cells Phase I Advanced/ Metastatic cancer NY-ESO-1 expression CMB305: designed to generate + expand anti-ny- ESO-1 cells LV305 G305 (NY-ESO-1 recombinant protein) GLA-SE (TLR-4 agonist) 3 month PFS Synovial 74% Myxoid 75% 1-year survival Synovial 86% Myxoid 100% Somaiah N et al. ASCO 2016; Abstract 3093 Somaiah N et al. ASCO 2017; Abstract 11006

34 Protocol 9079: ID-LV305 is a DC targeted lentivus encoding NY-ESO-1 Somaiah N et al. ASCO 2016; Abstract 3093

35 Tumour Associated Macrophages (TAM) Important role in immune evasion by sarcomas Could these ineffective antigen presenting cells be made to work more effectively? G100 (TLR4 agonist) Stimulate immunity Cytokine production Increase inflammation Phase I trial: G100 (TLR4 agonist) + radiation Accessible tumours injected Endpoints: Safety Efficacy distant sites Changes in tumour infiltrates With radiation Drive TAM to M1 phenotypeencourage inflammation Causing strong T cell response Pollack S, et al. ASCO 2016; Abstract 11017

36 Two genetically simple STS subtypes: liposarcoma + synovial Two highly mutated, genetically complex subtypes: UPS + LMS

37 T-cell infiltration + Clonality in Sarcomas Undifferentiated pleomorphic + leiomyosarcoma High expression levels of genes related to Antigen presentation T-cell infiltration Undifferentiated pleomorphic sarcoma Higher levels of PD-L1 (p 0.001) PD-1 (p 0.05) Highest T cell infiltration (based on T-cell receptor sequencing) T-cell infiltrates in undifferentiated pleomorphic sarcoma More oligoclonal compared to Synovial Liposarcoma (p 0.05) For all sarcomas T-cell infiltration + clonality highly correlated with PD-1 + PD-L1 expression levels (p 0.01) Pollack S et al. Cancer 2017

38 T-cell infiltration + Clonality in Sarcomas Undifferentiated pleomorphic sarcoma Provoke substantial immune response Well suited to therapy with checkpoint inhibitors Synovial/ liposarcoma Express immunogenic self antigens Strategies to improve Antigen presentation + T-cell infiltration Pollack S et al. Cancer 2017

39 Follow on trials Phase I gemcitabine + pembrolizumab NCT Royal Marsden Doxorubicin + pembrolizumab NCT Fred Hutchinson Cancer Research Center

40 Phase I Pembrolizumab/ Gemcitabine Trial Objectives Safety/ tolerability Recommended dose Efficacy Exploratory Inclusion Criteria Pleomorphic sarcoma/ leiomyosarcoma Disease that is amenable to serial biopsy

41 Phase I Pembrolizumab / Gemcitabine Trial

42 Phase I Pembrolizumab / Gemcitabine Trial

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44 Olaratumab: Open-label, Phase 1b/2 Trial Phase 2 Same entry criteria as Phase 1b Stratification: PDGFRα (IHC) Lines of prior treatment ECOG PS Histology (leiomyosarcoma, synovial sarcoma, other) RANDOMIZE Olaratumab 15 mg/kg D1,8 + Dox 75 mg/m 2 D1 8 cycles (21 days)* Dox 75 mg/m 2 D1 8 cycles Olaratumab monotherapy until progression Optional olaratumab monotherapy after progression Primary endpoint: Progression-free survival (PFS) (predefined statistical significance: 2-sided alpha = 0.2) Secondary end points: Overall survival (OS), objective response rate, PFS at 3 months Biomarker: PDGFRα (IHC) and related ligands * During Cycles 5-8, patients receiving Dox could receive dexrazoxane, at the investigator s discretion. Tap W et al. Lancet 388(10043); : 2016

45 Progression-Free Survival (ITT) (Phase 2) Tap W et al. Lancet 388(10043); : 2016

46 Olaratumab: Overall Survival (ITT) (Phase 2) Overall Survival Olaratumab + Dox Dox N Event 34 (51.5) 50 (74.6) Censored 32 (48.5) 17 (25.4) Median OS (95% CI) 25.0 (20.9, 30.9) 14.7 (9.2, 18.0) Stratified p-value Hazard ratio (95% CI) (0.277, 0.702) Olaratumab + Dox Dox Months Tap W et al. Lancet 388(10043); : 2016

47 Olaratumab Trials Phase NCT Drugs Geographic Location III NCT Doxorubicin + olaratumab vs doxorubicin + placebo I/ II Doxorubicin/ ifosfamide + olaratumab I/ II NCT Gemcitabine/ docetaxel + olaratumab Ib NCT Pre-operative olaratumab + doxorubicin I NCT Pembrolizumab + olaratumab USA/ Europe/ Asia USA, Europe USA, Europe USA, Europe USA, Europe

48 Platelet Derived Growth Factor Receptor (PDGFR) α/ β Cell surface receptor tyrosine kinase (α,β) activated by PDGF (A-D) family of ligands PDGF/PDGFR signaling plays a significant role in normal mesenchymal biology: Mesenchymal stem cell differentiation, growth mesenchymal cells, angiogenesis/ wound healing Direct Tumor Effect PDGFRα genetically altered +/or overexpressed in multiple tumors including sarcomas 1-5 PDGFRα expression is associated with increased metastatic potential 5,6 PDGFRα functions via autocrine and paracrine growth of tumor cells 7,8 Direct Stromal effect PDGF stimulation of PDGFRα-positive stromal cells enhances tumor growth 9,10 PDGFRα signaling on tumor stromal cells can contribute to angiogenesis 9 1Carvalho et al. Breast Cancer Res 7(5); R788-95: Ramos et al. Cancer Biol Ther 8(21); : Corless et al. J Clin Oncol 23(23); : Cancer Genome Atlas Network. Nature 455(7216); : Dolloff et al. Oncogene 24(45); : Fitzer-Attas et al. Oncogene 15(13); : LaRochelle et al. Cell Growth Differ 4(7); : Keating and Williams. Science 239(4842); : Dong et al. EMBO J 23(14); ; Skobe and Fusenig. Proc Natl Acad Sci USA 95(3); : 1998

49 Olaratumab Phase Ib trial Phase II olaratumab trial Analysis PDGFRα expression: exploratory end point Precise mechanism of action unknown Phase Ib pre-operative window study Ascertain mechanism of action of antibody Identify putative biomarkers Sequential biopsies/ blood samples/ imaging Single agent olaratumab 1 cycle Doxorubicin + olaratumab

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51 Randomized Phase 3 Study of Trabectedin vs Dacarbazine (ET743-SAR-3007): Study Design and Status at Interim Analysis Stratification: Prior lines chemotherapy (1 vs 2+) ECOG PS (0 vs 1) Sarcoma subtype (LPS vs LMS) Key Criteria: Histologically proven LPS or LMS Previous therapy with an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen Adequate bone marrow, renal and liver function Randomization 2:1 N=518 * Trabectedin 1.5 mg/m² 24h q3wks (N=345*) Dexamethasone 20 mg IV pre-medication Dacarbazine 1g/m min q3wks (N=173*) Conducted at 85 sites in 4 different countries (94% of patients were enrolled at US sites) Primary Endpoint * Numbers reflect randomizations at time of Interim Analysis Overall Survival (OS) Secondary Endpoints Progression-free survival (PFS), Overall Response Rate (ORR), Duration of Response (DOR), Safety, Patient-Reported Outcomes (PRO) Demetri G, et al. JCO 34(8): ; 2016

52 Phase III Trial Trabectedin: PFS (Investigator Assessed) PFS events: 329 (63.5% of 518 patients) mpfs Trabectedin: 4.2 months mpfs Dacarbazine: 1.5 months HR (95% CI) = 0.55 (0.436,0.696) p< Unstratified analysis Demetri G, et al. JCO 34(8): ; 2016

53 Interim Analysis of Overall Survival OS events = 189 (64% subjects censored) mos Trabectedin: 12.4 months mos Dacarbazine: 12.9 months HR (95% CI)=0.87 (0.644, 1.181) p= Demetri G, et al. JCO 34(8): ; 2016

54 Elderly Patients European estimated yearly incidence of STS 5 cases per 100,000 people 1 Over 40% of STS are diagnosed in people older than 65 years 2 Highest incidence of sarcomas in patients aged years ( 16%) 1 Advancing age has been shown to be an Independent prognostic factor for poor survival in metastatic STS 2 Older patients present worse prognosis with Higher grade and larger tumors at presentation 1 Localized STS: Elderly receive less intensive care compared with younger patients 1 Lower use of adjuvant chemotherapy, radiotherapy and Definitive surgery with an increased risk of positive surgical margins 1 Often excluded or very poorly represented in clinical trials 1 1Garbay D, et al. Ann Oncol 24; : Yousaf N, et al. Clinical Sarcoma Res 5; 10: 2015

55 Trabectedin in Elderly Patients Cumulative probability p-value = HR: % CI ( ) Progression Free Survival Cumulative probability Overall Survival p-value = HR: %CI: Time (months) Time (months) Pooled analysis of data from 5 phase II trials Assessed the effects of age on the efficacy and safety of trabectedin in 350 sarcoma patients < 60 years of age, n=267 (76%). Median age: 48 (19-59) years 60 years, n=83 (24%). Median age: 65 (60-81) years No differences in median PFS and similar OS showed in patients <60 vs. 60 years Le Cesne A et al. Br J Cancer 109; : 2013

56 Trabectedin vs DTIC: Elderly Patients Median PFS: 4.9 months in trabectedin group vs. 1.5 months in dacarbazine group A 60% reduction in disease progression risk or death HR=0.40 and p= Median OS : 15.1 months in trabectedin group vs. 8.1 months in dacarbazine group Non-significant trend towards improved OS HR=0.72 and p= Jones RL et al. ESMO 2015

57 Neoadjuvant Chemotherapy Controversial topic Widely used in USA Doxorubicin/ ifosfamide also widely used in metastatic setting Interesting recent data 1 Epriubicin + ifosfamide vs histology tailored Trial participation should be encouraged 1Gronchi A et al. Lancet Oncol 2017

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59 Neoadjuvant Pazopanib Trial Schema R A N D O M I Z E Pazopanib Placebo 14 Day Run-in Doxorubicin + Ifosfamide 2-4 cycles Surgery Pazopanib One year (for responders to neoadjuvant pazopanib) Pre-therapy Biopsy PET/CT MRI or CT VEGF PET/CT MRI or CT VEGF PK PET/CT MRI or CT VEGF Pathological response

60 Neoadjuvant Pazopanib Trial Objectives FDG-PET changes in SUV Correlation pazopanib activity + exposure RECIST + pathological response Safety/ tolerability Recurrence-free + overall survival Inclusion Criteria Localised extremity/ chest wall High grade 5 cm

61 Conclusions UK has more in common with France than USA Continued collaboration ERN, ESMO, EORTC Essential to minimise impact of Brexit on European Sarcoma Community More systemic options for patients with metastatic sarcoma Trabectedin, Olaratumab, Pazopanib, Eribulin Discussion regarding neoadjuvant chemotherapy Patients with high-risk extremity/ trunk STS Clinical trials + translational studies

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63 Thank you!

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65 NETSARC: Primary Surgery Resection NETSARC review before first treatment NETSARC review after first treatment R0 53.0% 34.2% R1 26.8% 32.7% R2 9.1 % 17.6% R (unknown/ not evaluable) 11.0% 15.5% P< Blay JY et al ESMO 2016

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67 Focused Clustering Analysis Pollack S et al. Cancer 2017 Genes included if p 0.05 difference for at least one subtype 367/760 genes Regions defined based on dendrogram clustering Most striking separation for genes related to antigen presentation + T cell infiltration