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Is the current design of precision medicine studies the right one:
lessons from the SHIVA trialPRO
Christophe Le Tourneau, MD, PhD
Institut Curie – Paris & Saint-Cloud – France
Department of Medical Oncology
Head of Early Phase Clinical Trials
Versailles-Saint-Quentin-en-Yvelines University
WIN symposium – Paris – June 27, 2016
• Nothing to disclose
Conflicts of interest
Precision medicine trials
Stratified trials Algorithm-testing trials
Molecularly-
stratified
Histology-
stratified
Non-
randomized
Randomized
Tumor types 1 N 1 or N
Molecular
Alterations
N 1 or N N
Treatments N 1 N
Test Test drugs efficacy Test algorithm efficiency
Le Tourneau et al. Chin Clin Oncol 2014;3:13
Introduction
Precision medicine trials
Stratified trials Algorithm-testing trials
Molecularly-
stratified
Histology-
stratified
Non-
randomized
Randomized
Tumor types 1 N 1 or N
Molecular
Alterations
N 1 or N N
Treatments N 1 N
Test Test drugs efficacy Test algorithm efficiency
Le Tourneau et al. Chin Clin Oncol 2014;3:13
Introduction
Precision medicine trials
Stratified trials Algorithm-testing trials
Molecularly-
stratified
Histology-
stratified
Non-
randomized
Randomized
Tumor types 1 N 1 or N
Molecular
Alterations
N 1 or N N
Treatments N 1 N
Test Test drugs efficacy Test algorithm efficiency
Le Tourneau et al. Chin Clin Oncol 2014;3:13
Introduction
Precision medicine trials
Stratified trials Algorithm-testing trials
Molecularly-
stratified
Histology-
stratified
Non-
randomized
Randomized
Tumor types 1 N 1 or N
Molecular
Alterations
N 1 or N N
Treatments N 1 N
Test Test drugs efficacy Test algorithm efficiency
Le Tourneau et al. Chin Clin Oncol 2014;3:13
Introduction
• CUSTOM trial (Advanced thoracic malignancies)
Introduction
Lopez-Chavezet al. JCO 2015;33:1000-7
Precision medicine trials
Stratified trials Algorithm-testing trials
Molecularly-
stratified
Histology-
stratified
Non-
randomized
Randomized
Tumor types 1 N 1 or N
Molecular
Alterations
N 1 or N N
Treatments N 1 N
Test Test drugs efficacy Test algorithm efficiency
Le Tourneau et al. Chin Clin Oncol 2014;3:13
Introduction
Precision medicine trials
Stratified trials Algorithm-testing trials
Molecularly-
stratified
Histology-
stratified
Non-
randomized
Randomized
Tumor types 1 N 1 or N
Molecular
Alterations
N 1 or N N
Treatments N 1 N
Test Test drugs efficacy Test algorithm efficiency
Le Tourneau et al. Chin Clin Oncol 2014;3:13
Introduction
• WINTHER
Introduction
Introduction
• M-PACT
R
Targeted therapy based on molecular
profiling
Conventional therapy at
physicians‘ choice
NGS+
Cytoscan HD
+IHC
Bioinformatics
Tumor biopsy
Informed
consent
signed
Specific
therapy
available
Molecular
biology
board
YESNO
Non eligible
patient
Eligible
patient
Informed
consent
signed
Patients with refractory
cancer (all tumor types)
Imatinib
Everolimus
Sorafenib
Erlotinib
Dasatinib
Lapatinib
Trastuzumab
Vemurafenib
Tamoxifen
Letrozole
Abiraterone
Cross-over
Le Tourneau et al. Lancet Oncol 2015;16:1324-34
Le Tourneau et al. Lancet Oncol 2015;16:1324-34
Introduction
Precision medicine trials
Stratified trials Algorithm-testing trials
Molecularly-
stratified
Histology-
stratified
Non-
randomized
Randomized
Tumor types 1 N 1 or N
Molecular
Alterations
N 1 or N N
Treatments N 1 N
Test Test drugs efficacy Test algorithm efficiency
Le Tourneau et al. Chin Clin Oncol 2014;3:13
Introduction
Was the design of the SHIVA trial the right one?
Is the current design of precision
medicine studies the right one? PRO
Outline
Is the current design of precision
medicine studies the right one? PRO1) The SHIVA trial asked a real-life question
Outline
Real-life question
Ciriello et al. Nature Genet 2013;45:1127-33
• Pilot study by von Hoff et al.
Real-life question
von Hoff et al. JCO 2010;28:4877-83
Real-life question
von Hoff et al. JCO 2010;28:4877-83
• 18/66 patients (27%): PFS ratio>1.3
Real-life question
Tsimberidou et al. CCR 2012;18:6373-83
Patients receiving matched targeted therapy Patients receiving no matched targeted therapy
Real-life question
Tsimberidou et al. CCR 2012;18:6373-83
Failure-free survival Overall survival
Patients receiving matched targeted
therapy
Patients receiving matched
targeted therapy
Patients receiving no matched targeted therapy
>?
Real-life question
Is the current design of precision
medicine studies the right one? PRO1) The SHIVA trial asked a real-life question
2) The SHIVA trial was designed to evaluate a specific
prespecified treatment algorithm
Outline
Treatment algorithm
Molecular
profile
Molecular
alteration
Targeted agentTargeted agentTargeted agentTargeted agent Targeted agent Targeted agent Targeted agent
= TREATMENT ALGORITHM
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
Targets Molecular alterations MTAs
ER, PR Protein expression >10% IHC Tamoxifen or Letrozole
AR Protein expression >10% IHC Abiraterone
PI3KCA, AKT1
AKT2/3, mTOR, RICTOR, RAPTOR
PTEN
STK11
INPP4B
Mutation/Amplification
Amplification
Homozygous deletion
Heterozygous deletion + mutation or IHC
Homozygous deletion
Heterozygous deletion + mutation
Homozygous deletion
Everolimus
BRAF Mutation/Amplification Vemurafenib
KIT, ABL1/2, RET Mutation/Amplification Imatinib
PDGFRA/B, FLT3 Mutation/Amplification Sorafenib
EGFR Mutation/Amplification Erlotinib
HER-2 Mutation/Amplification Lapatinib + Trastuzumab
SRC
EPHA2, LCK, YES1
Mutation/Amplification
AmplificationDasatinib
HORMONE
RECEPTOR PATHWAY
PI3K/AKT/mTOR
PATHWAY
RAF/MEK
PATHWAY
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
• Variants of interest:
- validated hotspots mutations* frequency: >4% for SNVs and >5% for indels
* coverage: >30X for SNVs and >100X for indels
- non targeted variants* outside a hotspot
* frequency >10%
* no synonymous mutations
* no polymorphisms
Treatment algorithm
• Amplifications:
- Gene copy number* diploid tumor: >6
* tetraploid tumor: >7
- Amplicon size* <1 Mb
* <10 Mb if protein overexpression/or loss of expression
is validated in IHC
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
Targets Molecular alterations MTAs
ER, PR Protein expression >10% IHC Tamoxifen or Letrozole
AR Protein expression >10% IHC Abiraterone
PI3KCA, AKT1
AKT2/3, mTOR, RICTOR, RAPTOR
PTEN
STK11
INPP4B
Mutation/Amplification
Amplification
Homozygous deletion
Heterozygous deletion + mutation or IHC
Homozygous deletion
Heterozygous deletion + mutation
Homozygous deletion
Everolimus
BRAF Mutation/Amplification Vemurafenib
KIT, ABL1/2, RET Mutation/Amplification Imatinib
PDGFRA/B, FLT3 Mutation/Amplification Sorafenib
EGFR Mutation/Amplification Erlotinib
HER-2 Mutation/Amplification Lapatinib + Trastuzumab
SRC
EPHA2, LCK, YES1
Mutation/Amplification
AmplificationDasatinib
Treatment algorithm
PFS – Hormone receptor pathway
Le Tourneau et al. Lancet Oncol 2015;16:1324-34
Treatment algorithm
• 72 yo female AR+ breast cancer
M0 Abiraterone M14
Treatment algorithm
Targets Molecular alterations MTAs
ER, PR Protein expression >10% IHC Tamoxifen or Letrozole
AR Protein expression >10% IHC Abiraterone
PI3KCA, AKT1
AKT2/3, mTOR, RICTOR, RAPTOR
PTEN
STK11
INPP4B
Mutation/Amplification
Amplification
Homozygous deletion
Heterozygous deletion + mutation or IHC
Homozygous deletion
Heterozygous deletion + mutation
Homozygous deletion
Everolimus
BRAF Mutation/Amplification Vemurafenib
KIT, ABL1/2, RET Mutation/Amplification Imatinib
PDGFRA/B, FLT3 Mutation/Amplification Sorafenib
EGFR Mutation/Amplification Erlotinib
HER-2 Mutation/Amplification Lapatinib + Trastuzumab
SRC
EPHA2, LCK, YES1
Mutation/Amplification
AmplificationDasatinib
Treatment algorithm
Treatment algorithm
PFS – PI3K/AKT/mTOR pathway
Le Tourneau et al. Lancet Oncol 2015;16:1324-34
Treatment algorithm
• 41 yo female PI3KCA-mutated cervical ca
M0 Everolimus M3
Treatment algorithm
Targets Molecular alterations MTAs
ER, PR Protein expression >10% IHC Tamoxifen or Letrozole
AR Protein expression >10% IHC Abiraterone
PI3KCA, AKT1
AKT2/3, mTOR, RICTOR, RAPTOR
PTEN
STK11
INPP4B
Mutation/Amplification
Amplification
Homozygous deletion
Heterozygous deletion + mutation or IHC
Homozygous deletion
Heterozygous deletion + mutation
Homozygous deletion
Everolimus
BRAF Mutation/Amplification Vemurafenib
KIT, ABL1/2, RET Mutation/Amplification Imatinib
PDGFRA/B, FLT3 Mutation/Amplification Sorafenib
EGFR Mutation/Amplification Erlotinib
HER-2 Mutation/Amplification Lapatinib + Trastuzumab
SRC
EPHA2, LCK, YES1
Mutation/Amplification
AmplificationDasatinib
Treatment algorithm
Le Tourneau et al. Lancet Oncol 2015;16:1324-34
PFS – RAF/MEK pathway
Treatment algorithm
Treatment algorithm
Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]
Treatment algorithm
• Multiple molecular alterations:- DNA alterations were considered of a higher impact than
hormone receptors expression
- If AR and ER/PR were both overexpressed, the hormone
receptor with the highest expression level was taken into
account
- If >2 DNA alterations were identified, clinically validated
alterations prevailed (i.e. HER-2 amplification)
- Erlotinib was not given in case of KRAS mutation
Is the current design of precision
medicine studies the right one? PRO1) The SHIVA trial asked a real-life question
2) The SHIVA trial was designed to evaluate a specific
prespecified treatment algorithm
3) The cross-over data of the SHIVA trial suggest that
taking each patient as his/her own control is a relevant
strategy for precision medicine studies
Outline
Cross-over data
Le Tourneau et al. ASCO 2016 (#2535)
25% =25/100
72% =70/97
Cross-over data
Le Tourneau et al. ASCO 2016 (#2535)
N PFS ratio >1.3 PFS ratio >2
TPC MTAHormone receptor pathway
PI3K/AKT/mTOR pathway
RAF/MEK pathway
6831
30
7
41%35%
38%
54%
25%20%
19%
18%
MTA TPC 25 56% 28%
Conclusions
• The current design of precision medicine
studies is relevant
• Using the PFS ratio as a primary end point
might be a relevant strategy for precision
medicine trials
• Treatment algorithms will need to be
refined to further improve patients’ outcome
Acknowledgments• Direction
Thierry Philip
Claude Huriet
Pierre Teillac
Daniel Louvard
• ICGEX
Olivier Delattre
Thomas Rio Frio
Virginie Bernard
• UGEC
Patricia Tresca
Sebastien Armanet
Fabrice Mulot
• Biostatistics
Xavier Paoletti
Lisa Belin
Corine Plancher
Cécile Mauborgne
• Pathology
Anne Salomon
Odette Mariani
Frédérique Hammel
Xavier Sastre
Didier Meseure
• Translational research
Maud Kamal
David Gentien
Sergio Roman-Roman
• Radiology
Vincent Servois
Daniel Szwarc
• Bioinformatics
Philippe Huppé
Nicolas Servant
Julien Romejon
Emmanuel Barillot
Philippe La Rosa
Alexandre Hamburger
Pierre Gestraud
Fanny Coffin
Séverine Lair
Bruno Zeitouni
Alban Lermine
Camille Barette
• Comunication
Céline Giustranti
Catherine Goupillon-Senghor
Cécile Charre
• Genetics
Ivan Bièche
Gaëlle Pierron
Etienne Rouleau
Céline Callens
Marc-Henri Stern
• Surgery
Thomas Jouffroy
José Rodriguez
Angélique Girod
Pascale Mariani
Virginie Fourchotte
Fabien Reyal
• Foundation
Hélène Bongrain- Meng
Ifrah El-Alia
Véronique Masson
Agnès Hubert
• Clinical research
Malika Medjbahri
• Sampling
Solène Padiglione
• Pharmacy
Laurence Escalup
• Oncology
Alain Livartowski
Suzy Scholl
Laurent Mignot
Philippe Beuzeboc
Paul Cottu
Jean-Yves Pierga
Véronique Diéras
Valérie Laurence
Sophie Piperno-Neumann
Catherine Daniel
Wulfran Cacheux
Bruno Buecher
Emmanuel Mitry
Astrid Lièvre
Coraline Dubot
Etienne Brain
Barbara Dieumegard
Frédérique Cvitkovic