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Keep Calm and Love France
Robin L Jones
Royal Marsden Hospital
Institute of Cancer Research
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
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
• Treatment – Less adjuvant/ neoadjuvant chemotherapy
• United States of America:
• Care not centralized – Insurance system (complex) – Geography – Financial incentive
• Collaboration
– SARC – Collaborative groups: Alliance, SWOG
• Resources – Federal – Donors
• Treatment – Trabectedin NOT approved in 2010 – Neoadjuvant chemotherapy – Doxorubicin/ Ifosfamide
Importance of Centralised Care
• Rarity
• Heterogeneity
• Diverse anatomic primary sites
• Cumulative experience required for expertise in all aspects of care
• Consultation exercise lead to publication of guidance in 2006 covering early referral, diagnosis, centralisation of care and all aspects of multidisciplinary management http://guidance.nice.org.uk/CSGSarcoma
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
Criteria for urgent referral for a patient with a suspicious lump
• >5cm
• Increasing size
• Deep to deep fascia
• Painful
Pathology: Discrepancies Soft Tissue Tumor DiagnosisYear Author Country Number Diagnosis Grade
1978 Baker et al USA 130 32 -
1984 Tetu et al Canada 260 35 -
1986 Presant et al US SECSG 216 28 24
1986 Coindre et al FR Panel 25 30 25
1989 Alvegaard et al SSG 240 25 40
1989 Shiraki et al US ECOG 488 26 -
1991 Harris et al UK 376 24 -
1995 Prescott et al UK 17 29 -
1999 Meis-Kindblom et al SSG 1000 20 25
2004 Randall et al US 104 37 25
2004 Van Dalen et al NE rpl 143 24 36
2009 Thway et al UK 349 22 23
2010 Lurkin et al France 366 25 19
2012 Ray-Coquard et al France/ Italy 1463 44 -
2014 Thway et al UK 348 28 11
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
NETSARC Data
• Overall: 37% presented prior to initial Dx
• 2010 – 2015: – 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<0.0001
• Biopsy prior to resection – 87% vs 55%, p<0.0001
Blay JY et al ESMO 2016
NETSARC Data
• Secondary Resections1
• NETSARC review before first surgery – 99 (5.5%) secondary resections
• NETSARC review after first surgery
– 1125 (15.3%) • P<0.0001
• Median Follow-up 26 months – NETSARC discussion before first
surgery • Significantly better local recurrence-
free survival • P<0.0001
• Metastasis-free survival1
• No significant difference • NETSARC review before and after
surgery – P=0.15
• Long-term risk of recurrence2
– 5.8% late metastatic disease
1Blay JY et al ESMO 2016 2Toulmonde M et al. Cancer 120; 3003-3006: 2014
Networks
• NETSARC: • Impressive organisational
structure
• Importance MDT discussion prior to first surgery1
– Pre-operative imaging + biopsy
– Local recurrence free survival
• Multi institutional Tumour Boards2: – 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 2016 2Attia S et al. CTOS 2015
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
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
Clinical Practice Guidelines• 2005-2007
– 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
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…
Experience in USA
• Immunotherapy
• Olaratumab
• Trabectedin
• Chemotherapy – Neoadjuvant chemotherapy
– Doxorubicin/ ifosfamide
Courtesy of Brian van Tine
Bone Marrow Transplantation: Replace cancer + stem cells Donated healthy cells engraft patient bone marrow establish cancer free blood + immune system
Immunotherapy in Cancer
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); 199–220: 1891
Coley’s toxins
• Lack of known mechanism of action
• Not easy to induce – 1st 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
Robbins P F et al. JCO 29; 917-924: 2011
Mel
anom
aS
ynov
ial s
arco
ma
• 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
Despite Low MHC, NY-ESO-1 Specific T Cells Can Induce Clinical Responses in SS Patients
• 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
• Frequently map to chromosome X and exist as multigene families
• In vitro activation by hypomethylation and/or histone deacetylase inhibition
A: MAGE-A4 in tests; B: MAGE-C1 in fetal ovary C: MAGE-A in trophoblastic placenta; D: NY-ESO-1 in bladder cancer
CANCER TESTIS ANTIGENS ARE ATTRACTIVE IMMUNOTHERAPEUTIC TARGETS
Pollack et al. Cancer 118(18); 4564-70: 2012
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); 4564-70: 2012
Step 1: Leukapharesis
Step 2: PBMC derived DC’s
Step 3: 2 stimulations with peptide pulsed DC’s + IL21, IL2 and IL7.
CD25 depletion or CD8 selection
Step 4: Clinical grade sorting.
Rapid Expansion
Generation of Autologous NY-ESO-1 specific CD8+ CTL lines
Pollack SM et al. J Immunother Cancer 2(1); 36: 2014
Day +2: low dose IFN γ
Day 0: Cell infusion 1010/m2
Day +9: low dose IFN γ
Day -5: low dose IFN γ
Day -12: begin low dose IFN γ
Day -3, -2: CY 2/g/m2/d
Low dose (250,000 U/m2) BID IL-2
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
Pre-infusion 4 weeks post infusion
Response: Large lung tumor in patient with pre-treated metastatic synovial sarcoma
Adoptive T cell Therapy
• Infrastructure
• Cost
• Durability of clinical benefit
– Repeat infusions?
– Combinations?
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
Protocol 9079: ID-LV305 is a DC targeted lentivus encoding NY-ESO-1
Somaiah N et al. ASCO 2016; Abstract 3093
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
• With radiation – Drive TAM to M1 phenotype-
encourage inflammation – Causing strong T cell response
• Phase I trial: • G100 (TLR4 agonist) +
radiation • Accessible tumours injected
• Endpoints: – Safety – Efficacy distant sites – Changes in tumour infiltrates
Pollack S, et al. ASCO 2016; Abstract 11017
• Two genetically “simple” STS subtypes: liposarcoma + synovial
• Two highly mutated, genetically complex subtypes: UPS + LMS
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
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
Follow on trials
• Phase I gemcitabine + pembrolizumab – NCT03123276
– Royal Marsden
• Doxorubicin + pembrolizumab
– NCT02888665
– Fred Hutchinson Cancer Research Center
Phase I Pembrolizumab/ Gemcitabine Trial
• Objectives – Safety/ tolerability
– Recommended dose
– Efficacy
– Exploratory
• Inclusion Criteria
– Pleomorphic sarcoma/ leiomyosarcoma
– Disease that is amenable to serial biopsy
Phase I Pembrolizumab / Gemcitabine Trial
Phase I Pembrolizumab / Gemcitabine Trial
Olaratumab: Open-label, Phase 1b/2 Trial
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
RANDOMIZE
Olaratumab monotherapy until progression
Olaratumab 15 mg/kg D1,8 +
Dox 75 mg/m2 D1 × 8 cycles (21 days)*
Optional olaratumab monotherapy after
progressionDox 75 mg/m2 D1
× 8 cycles
• Same entry criteria as Phase 1b • Stratification:
• PDGFRα (IHC) • Lines of prior treatment • ECOG PS • Histology (leiomyosarcoma,
synovial sarcoma, other)
Phase 2
* During Cycles 5-8, patients receiving Dox could receive dexrazoxane, at the investigator’s discretion.
Tap W et al. Lancet 388(10043); 488-497: 2016
Progression-Free Survival (ITT) (Phase 2)
Tap W et al. Lancet 388(10043); 488-497: 2016
Olaratumab: Overall Survival (ITT) (Phase 2)
Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Ov
era
ll S
urv
ival
0.0
0.2
0.4
0.6
0.8
1.0Olaratumab + DoxDox
Olaratumab
+ Dox DoxN 66 67Event 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 0.0004Hazard ratio (95% CI) 0.441 (0.277, 0.702)
Tap W et al. Lancet 388(10043); 488-497: 2016
Olaratumab TrialsPhase NCT Drugs Geographic
Location
III NCT02451943 Doxorubicin + olaratumab vs doxorubicin + placebo
USA/ Europe/ Asia
I/ II Doxorubicin/ ifosfamide + olaratumab
USA, Europe
I/ II NCT02659020 Gemcitabine/ docetaxel + olaratumab
USA, Europe
Ib NCT02783599 Pre-operative olaratumab + doxorubicin
USA, Europe
I NCT03126591 Pembrolizumab + olaratumab
USA, Europe
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 sarcomas1-5 • PDGFRα expression is associated with increased metastatic potential5,6 • PDGFRα functions via autocrine and paracrine growth of tumor cells7,8
• Direct Stromal effect
• PDGF stimulation of PDGFRα-positive stromal cells enhances tumor growth 9,10 • PDGFRα signaling on tumor stromal cells can contribute to angiogenesis9
1Carvalho et al. Breast Cancer Res 7(5); R788-95: 2005
2Ramos et al. Cancer Biol Ther 8(21);2042-50: 2009
3Corless et al. J Clin Oncol 23(23); 5357-64: 2005
4Cancer Genome Atlas Network. Nature 455(7216); 1061-8: 2008
5Dolloff et al. Oncogene 24(45); 6848-54: 2005
6Fitzer-Attas et al. Oncogene 15(13); 1545-54: 1997 7LaRochelle et al. Cell Growth Differ 4(7); 547-53: 1993 8Keating and Williams. Science 239(4842); 914-16: 1998 9 Dong et al. EMBO J 23(14); 2800-10; 2004 10Skobe and Fusenig. Proc Natl Acad Sci USA 95(3); 1050-5: 1998
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
Progression-free survival (PFS), Overall Response Rate (ORR), Duration of Response (DOR), Safety,
Patient-Reported Outcomes (PRO)
Overall Survival (OS)
Randomized Phase 3 Study of Trabectedin vs Dacarbazine (ET743-SAR-3007): Study Design and Status at Interim Analysis
Randomization
Dexamethasone 20 mg IV pre-medication
Dacarbazine 1g/m2 20-120 min q3wks
(N=173*)
2:1
Trabectedin 1.5 mg/m² 24h q3wks
(N=345*)
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
N=518*
•Conducted at 85 sites in 4 different countries (94% of patients were enrolled at US sites)
*Numbers reflect randomizations
at time of Interim Analysis
Primary Endpoint
Secondary Endpoints
Demetri G, et al. JCO 34(8): 786-93; 2016
HR (95% CI) = 0.55 (0.436,0.696) p<0.0001
PFS events: 329 (63.5% of 518 patients) mPFS Trabectedin: 4.2 months mPFS Dacarbazine: 1.5 months
Phase III Trial Trabectedin: PFS (Investigator Assessed)
Unstratified analysis
Demetri G, et al. JCO 34(8): 786-93; 2016
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=0.3741
Interim Analysis of Overall Survival
Demetri G, et al. JCO 34(8): 786-93; 2016
Elderly Patients• European estimated yearly incidence of STS
• 5 cases per 100,000 people1
• Over 40% of STS are diagnosed in people older than 65 years2
• Highest incidence of sarcomas in patients aged 75-84 years (∼16%)1
• Advancing age has been shown to be an
– Independent prognostic factor for poor survival in metastatic STS2
• Older patients present worse prognosis with
• Higher grade and larger tumors at presentation1
• Localized STS: Elderly receive less intensive care compared with younger patients1
• Lower use of adjuvant chemotherapy, radiotherapy and • Definitive surgery with an increased risk of positive surgical margins1
• Often excluded or very poorly represented in clinical trials1
1Garbay D, et al. Ann Oncol 24; 1924-30: 2013 2Yousaf N, et al. Clinical Sarcoma Res 5; 10: 2015
Trabectedin in Elderly Patients
Time (months)
p-value = 0.4427 HR: 0.9 95% CI (0.687-1.179)
Progression Free Survival
Cum
ulat
ive
prob
abili
ty
Cum
ulat
ive
prob
abili
ty
p-value = 0.1216 HR: 0.8
95%CI: 0.61-1.06
Time (months)
Overall Survival
• 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; 1717-1724: 2013
Trabectedin vs DTIC: Elderly Patients
• 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=0.1813
• 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=0.0002
Jones RL et al. ESMO 2015
Neoadjuvant Chemotherapy
• Controversial topic
• Widely used in USA – Doxorubicin/ ifosfamide also widely used in metastatic
setting
• Interesting recent data1 – Epriubicin + ifosfamide vs histology tailored
• Trial participation should be encouraged
1Gronchi A et al. Lancet Oncol 2017
Pazopanib
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
R A N D O M I Z E
Placebo
Neoadjuvant Pazopanib Trial Schema
14 Day Run-in
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
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
NETSARC: Primary SurgeryResection NETSARC review before first
treatmentNETSARC 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<0.0001Blay JY et al ESMO 2016
Focused Clustering Analysis• 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
Pollack S et al. Cancer 2017
