vii simposio getthi

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...

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100

200

300

400

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600

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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

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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

ISG15 silencing suppresses CSC phenotype

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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