vii simposio getthi
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VII SIMPOSIO GETTHI
Sesión 1: Del síndromeHereditario a la diana terapéutica
Los pilares para una carrera profesional más allá de la asistencia en oncología
Javier Martin-Broto, Fundacion Jimenez Diaz University Hospital
4 de noviembre de 2021 - Formato virtual
Los pilares para una carrera profesional más allá de la
asistencia en oncología
Dr. Javier Martin-BrotoFundación Jimenez Diaz University Hospital
VII SIMPOSIO GETTHI
• Consulting or Advisory Role
✓ PharmaMar, GSK, Novartis, Amgen, Bayer, Lilly
• Speakers' Bureau
✓ PharmaMar
• Research Funding
✓ Novartis, Eisai, PharmaMar, Lilly, GSK
• Clinical trials
✓ Lyxte, Karyopharm, Celgene, Pfizer, BMS, Blueprint, Deciphera, Nektar,
Forma, Amgen, Daichii
VII SIMPOSIO GETTHI
• Introduction: Quo Vadis
• Research: Power of transforming
• Research type: Clinical, Translational, Preclinical
• A Small piece of Strategy
A Good Physician means…
This is not about Care Giver vs Researcher
We must pursue an excellent training in all the oncologic tumors
As Oncologist we need to participate in research
Research offer the probability to transform
The way is long and hard
MSKCC is not attractive because they are performing Good anamnesis there but because they are researchers.
Invest in Training
Invest in English
Invest in TravelInvest in Character
Invest in how to publish
Invest in how to apply in a call
BachelorDegree
Master Degree
GainExperience
PursueCertifications
Consider a Doctorate
Teaching skillsScientific writtingAdvanced StatisticsPublic Speaking
Foreign lenguage
Research Assistant
Clinical ResearchAssociateCertified Principal investigator
CommunicationData AnalysisCritical thinkingInterpersonal skillsStrong attention to detailLong-suffering
1-year stage
▪ Advances start benefiting some patients
▪ Series of little advances will eventually entail bigger changes
▪ The mortality rate in cancer decreased for first time in the
2000, after several cumulative hits.
▪ These changes were fueled by research
N Engl J Med. 2012 Jun 7;366(23):2207
Cellularorigin oftumors
Seed & Soilhypothesiss
Chromosomalmutationsin cancer
Little by Little steps will transform the reality
N Engl J Med. 2012 Jun 7;366(23):2207
Virchow 1863
Paget 1889
Boveri 1914
DNA transmitsCellularinformation
Avery 1944
Watson & Crick 1953
DNA Structure
Geneticcode fromDNA to RNA
Nirenberg1961
Bacterialand DNA restrictionsites
Smith & Wilcox1970
APC & colorectalcancer
Nishisho1991
Tumor stromalinteraction
Provenzano 2006
YOU 2021
?
35%
50%
68%
% OS in
Cancer
✓1983: Mazur and Clark introduced new term GIST✓1960-1980: Ultraestructural and IHC showed absence of smooth muscle differenti
✓1930-1950: classified as leimyomas, leiomyosarcomas o leiomyoblastomas
✓1998: Kindblom y cols. Precusor Intersticial Cajal Cells Ckit+
✓1998: Hirota y cols. Gain-of-function in KIT mutations
✓ 2001: Joensuu y cols. Described 1st GIST case treated with IMATINIB
✓ 1992: Alexander Levitzki suggested that inhibiting ABL with small molecules called tyrphostins
✓ 1911: Ramón y Cajal described the myenteric plexus of the rabbit intestine (ICC) looking for a simpler neuronal network
✓1994-95: Mesenchymal origen with positivity for CD34
Life expectancy from < 1y → > 5 y
EUR Phase III- Accrual...
0
100
200
300
400
500
600
700
800
900
1000
June01 Sept01 Dec01 March02 June02 Dec02
Tirosin kinase Inhibitors Vertiginous Clinical Development
N Engl J Med. 2001 Apr 5;344(14
Ripretinib
6.3 84.3(6m OS)
Avapritinib in D842v
• 4 LINES OF TARGETD THERAPIES
APPROVED
• Resistant D842V mutant overcome
Independent prognostic factors for RFS in GIST patients
Multivariate analysis
Factors RR 95%CI p
Miettinen-Lasota Risk Categories:
Intermediate 5.97 2.09-17.06 0.001
High 11.45 4.40-29.76 <0.001
Critical Mutations 557 or 558 3.05 1.59-5.85 0.001
PDGFRa mut
Del 557/558 mut
Other
J Martin-Broto et al. J Clin Oncol 2005 Sep 1;23(25):6190-8. J Martin-Broto et al, Ann Oncol. 2010 Jul; 21(7):1552-7
Cancer surpassing cardiovascular disease as the leading cause of mortality in high income populations
BMJ 2017;357:j2765 doi: 10.1136/bmj
1971 --//→ 1991 19981999 2003 2005
AISLADO
1996 2001 2002 2004 2005
FASE 2
FASE 3
M1
DOSIS
FASE 3
M0+
FASE 3
M0?
AISLADO
NEJM
FASE 1
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FASE 1
GIST
FASE 2
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FASE 3
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FASE 12
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Sunitinib
Imatinib
TAXANES IN BREAST CANCER
TK INH IN GIST
Tirosin kinase InhibitorsVertiginous Clinical Development
▪ Clinical trials is the only way to approve drugs for certain indications
▪ There are still myths around clinical trials: • Treated like a guinea pig• Placebo instead of real drug• Is the latter option, after I have exhausted all the options• Clinical trials are more dangerous• The investigators have financial interest
▪ The time from bench (isolated experimental drug) to bedside lasts 12 years as a median
▪ From every 25.000 compounds in the LAB, 25 are tested in humans, 5 make it to market and just 1 recoups what was invested.
▪ This drug journey up to the market has a global cost of 1.5 billion of pounds.
IS THERE A SURVIVAL BENEFIT FOR PATIENTS ENROLLED IN CLINICAL TRIALS?
Survival by tumor type of center with high-volume of clinical trials is significantly better than centers with low volume.
(Arch. Intern. Med. 168(6), 657–662 (2008))
Hawthorne effect is the improvement in survival detected in enrolled patients just for the fact of the higher
surveillance (BMC Med. Res. Methodol. 7, 30 (2007).)
There is no evidence that participating in clinical trials will entail significant survival benefits. In the recruitment
process we rather should emphasize the patient volunteering to give an altruistic contribution. (BMC Cancer. 2020
May 8;20(1):401. )
In any case, most trial participants found trial participation worth (74%), would it again (85%) and would recommend
others (85% of patients). (2012 ASCO Annual, Meeting. Chicago, IL, USA, 1–5 June 2012)
1400 new compounds approved by FDA over time 100 companies with at least one drug approved
The Pharmaceutical Journal, May 2015;Online:DOI:10.1211/PJ.2015.20068196
Definition:
Clinical trials instigated by academic researchers, aimed at acquiring scientific knowledge
and evidence to improve patient care. This investigation deals with potential treatment
innovations that do not attract or could even be against commercial interest.
Examples:
Proof-of-concept trials
Studies on orphan diseases
Comparison of treatment interventions
Novel indications for registered drugs
Investigator-driven trials in rare tumors: even more difficult
Eur J Cancer 2011 Nov;47(17):2493-511
Survival Rare vs Common Cancers
Key Issues of Poor Outcome of Rare Tumors
Lancet Oncol. 2016 Feb;17(2):136-138
❑Difficulties or delay in diagnostic procedure
❑Limited Access to centers with clinical expertise in Rare Cancer
❑ Inadequate funding for clinical research programs
❑Few interest of Pharma Companies in clinical research programs
Investigator-driven trials in rare tumors: even more difficult
Key Milestones for Academic Research Trials for Network
It was not enough just to overcome the first 5 steps, we run aground in the last one
18 INVESTIGATOR-DRIVEN CLINICAL TRIALS ID (69.2%)
8 PHARMA-DRIVEN CLINICAL TRIALS PD (30.8%)
Investigator-driven trials in rare tumors: even more difficult
Study Design:
TYPICAL SFT
MALIGNANT SFT
EXTRASKELETAL MYXOID CHONDROSARCOMA
GEIS 32
CLOSED 34
First Stage 12/23 Up to 31
ALREADY CLOSED 24
❑ Simon 2-Stage phase II❑ Main endpoint:
Response (Choi)❑ Pathologic Review &
Radiological Assessmentwere Centralized
❑ CT scans every 8 weeks
Investigator-driven trials in rare tumors: even more difficult
IDEA
Early 2013
GSK meeting
October 2013 Sept 2014 June 2019
Kick off meeting Data locked
Pazopanib as upfront line of antiangiogenic
Investigator-driven trials in rare tumors: even more difficult
- Global CRO: GEIS/SOFPROMED
- Monitoring at National Level
- Central Pathology review pre Enrolment
at national level
- Central supranational Pathology review at
the end
- Central radiological assessment at the
end
- Translational at the end
Choi RECIST
PartialResponse PR
18 (58%) 2 (6%)
Stable DiseaseSD
12 (39%) 29 (94%)
ProgressiveDisease PD
1 (3%) 0
CENTRAL RADIOLOGICAL ASSESSMENTPat #93
• BASELINE (June 2018)
L1: Hepatic lesion: 45mm, 98HU
• December 2018
L1: Hepatic lesion: 33mm, 43HU
RECIST: SD (decrease 26%)
CHOI PR (decrease 56%)
Investigator-driven trials in rare tumors: even more difficult
Lancet Oncol. 2019 Jan;20(1):134-144.
Investigator-driven trials in rare tumors: even more difficult
TYPICAL COHORT
MALIGNANT COHORT
Median follow-up 18 m (IQR 14-34) 27 m (IQR 16-31)
Median PFS (Central Choi) 9.8 m (7.2-12.3) 5.57 m (4.51–6.62)
Median PFS (Central RECIST) 12.1 m (2.6-21.7) 5.57 m (4.29–6.84)
6-month PFS rate (Choi) (%) 77% (61-93) 40% (24-56)
Median OS (CI95%) 49.8 Not Reached
OS at 24 months 57% (36-78) 73% (58–88)
Events of Progress. (Choi) 20 (61%) 32 (91%)
Events of Death 11 (35%) 10 (29%)
CHEMOTHERAPY ANTIANGIOGENIC
SECONDARY ENDPOINT: SURVIVAL IN CONTEXT
3.5-4.6 m (local) 4.7-6.0 m (local)
20-28% (RECIST) 45% (RECIST)
11.5-13.3 m 16 m
Lancet Oncol. 2019 Jan;20(1):134-144.
- Imatinib, Gefitinib & Trastuzumab started the era of personalized medicine
- The Increase of molecular testing allows focusing on different drivers
- Great emergence of Molecular biomarkers for a better prediction or fo a better prognostic grouping
Relevant milestone in translational Oncology Research
Nat Rev Clin Oncol 11, 649–662 (2014)
MAXSTAT cut-off value for RDW:1.03
INFLAMMATORY INDICES: IMPACT OF PLR IN OUTCOME
MAXSTAT cut-off value for PLR: 242
Peripheral inflammatory indexes in GEIS-32 enrolled patients
J Clin Oncology 2021 39:15_suppl, 11511-11511
Lancet Oncol. 2019 Jan;20(1):134-144.
1.7 months [95% CI 0–3.9] vs 7.1 months [4.5–9.8], p<0.0001) and worse 2-year overall survival (20% [95% CI 0–55] vs 86% [71–100], p<0.0001
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• To test drugs & combinations
• To validate biomarkers
• To explore signaling pathways in
different tumor context
• To find new targets
• To explore components of
microenvironment
Inhibitory effect in MRP-1 and P-gp effluxactivity
SK-UT-1 CP0024
CFDA Rho-123 CFDA Rho-123
• Patient derived xenograft (PDX)
Informed Consentsigned
Project approvedby IRB
Samplingcollection and
implant
• Plataforma de modelos PDX grupo TERABIS*
Subtype N=33
Adamantinoma 1
Alveolar soft-part sarcoma 2
Chondrosarcoma 1
Clear Cell Sarcoma 2
DD Liposarcoma 1
Epithelioid Sarcoma 1
Ewing Sarcoma 4
GIST 2
Leiomyosarcoma 5
MPNST 2
Myxoid Liposarcoma 1
Myxofibrosarcoma 2
Osteosarcoma 2
Rhabdomyosarcoma 3
Sclerosing Epithelioid Fibrosarcoma 1
Solitary Fibrous Tumor 1
Undifferentiated pleomorphic sarcoma 2
Trabectedin increases the expression of cell cycle markers involved in the
regulation of G1/S (Cyclin D3) or G2/M (AurKB) transition:
Potentiates an unsynchronized induction of proliferation
Daño de ADN post-trabectedin
Multi-institutional European phase I/II trial of trabectedin plus radiotherapy in metastatic soft tissue sarcoma (STS) patients. A Collaborative Spanish (GEIS),
Italian (ISG) and French (FSG) Sarcoma Groups study
Martin-Broto J1, Lopez-Pousa A2, Hindi N1, Cruz J3, Peinado J1, Morosi C4, Isern J2, Dolado MC3, Alvarez R5, Alvarez A5, Grignani G6, Gatti M7, Luna Fra P8, Alastuey I8, Blay JY9, Sunyach MP9, Rincon I1, Gronchi A10, Romero J11
1 Virgen del Rocio University Hospital, Institute of Biomedicine Research (IBIS)/CSIC/Universidad de Sevilla, Seville, Spain; 2H de laSanta Creu i Sant Pau, Barcelona, Spain; 3H Universitario de Canarias, Santa Cruz De Tenerife, Spain; 4Department of Radiology,Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 5H Universitario Gregorio Marañón, Madrid, Spain; 6Sarcoma Unit,Division of Medical Oncology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy; 7Radiotherapy Unit, Candiolo CancerInstitute, FPO, IRCCS, Candiolo, Italy; 8H Universitario Son Espases, Palma De Mallorca, Spain; 9Centre Léon Bérard, Lyon, France;10Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 11H Puerta de Hierro, Madrid, Spain
JAMA Oncol 2020 Apr 1;6(4):535-541
41 y.o male SYNOVIAL SARCOMA (4th line)
4/JAN/2018 5/JUL/2018
58 y.o male PLEOMORPHIC RHABDOMYOSARCOMA (3rd line)
12/APR/2018 14/JUN/2018
55 y.o female LEIOMYOSARCOMA (2nd line)
25/JAN/2018 17/MAY/2018
150.3 + 15.3 = 165.5 138 + 11.5 = 149.5 53 + 13 = 66
2 NOV 2017 15 JAN 2018 17 JULY 2018
TRABECTEDIN +RT
Concurrent exposures to trabectedin and radiotherapy (RT) appeared to be synergistic in preclinical experiments; ** Phase I/II; Martin-Broto J et al JAMA Oncol
2020 Apr 1;6(4):535-541. doi: 10.1001/jamaoncol.2019.6584.
GEIS STRATEGIC PLAN
✓ RESOURCES
✓ ORGANIZATION
✓ THEIR RELATIONSHIP WITH STAKEHOLDERS
✓ ACTIVITIES
ANALYSES OF SIMILAR INITIATIVES
✓ SARCOMA COOPERATIVE GROUPS (SCG): Scientific Association
✓ SCG (most of them) have their own structure for Clinical Trials
✓ Sub Committees by Pathology and Speciality
✓ Research, Teaching and Clinical Assistance
STRATEGIC PLAN
CLINICAL RESEARCH CENTER- GEISC/Diego de Leon 47, Madrid
Melissa Fernández- Project Coordinator
Susana Vitorino- Project Coordinator
Beatriz Suarez Senior CRA
Beatriz Llorente- Senior CRA
Maria Cuaresma - Senior CRA
+ Freelance Statistician: Ivan Arribas
Adriana Rojo- Data Center Coordinator
J Manuel Escandell- Senior CRA
Home based Data Center based
✓ It is NECESSARY go beyond clinical care in medicine, especially in ONCOLOGY
✓For an Oncologist, it is FEASIBLE to develop a research career even in Spain
✓ There is a time for PLANTING, and a time for HARVEST
✓ACADEMIC TRIALS (investigator-driven) are crucial for rare tumors
✓Prospectively designed TRANSLATIONAL studies (correlatives) give insights to
the investigation.
✓PRECLINICAL team devoted to especific tumor is DESIRABLE
✓Altogether, the previous investigation has the power of TRANSFORMING
David MouraSerena LacerenzaNadia HindiMaria LópezJosé MondazaPaloma SánchezElena BlancoRubén AmiánMª José Acosta
Irene GarcíaCarlos TorradoLeo Talafiggo
J Martin-Broto
Angela Gavilán Cristina Gonzalez-AguileraPaula MartinezSofia RubioCristina TousIrene FelipeRicardo MenendezAna SalinasLaura MiguelezEmilio CarmonaPaloma SánchezLorena Alonso
Amancio CarneroMarco Pérez
Carolina Castilla
Joaquín DopazoMaría PeñaDaniel López López
GEIS NetworkEURACAN Network
Jonathan Fletcher, Harvard UniversityAdrián Mariño
Consorcio SELNET
Patricia MonteroBeatriz EsquinasM Mar TorresJacki AguinagaldeCeli Rodriguez
•VII SIMPOSIO GETTHI
jmartin@atbsarc.org
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