Is the current design of precision medicine studies the right one: - - PowerPoint PPT Presentation

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Is the current design of precision medicine studies the right one: - - PowerPoint PPT Presentation

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Is the current design of precision medicine studies the right one: lessons from the SHIVA trial PRO Christophe Le Tourneau, MD, PhD Institut Curie Paris & Saint-Cloud France Department of Medical Oncology Head of Early Phase

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Is the current design of precision medicine studies the right one: lessons from the SHIVA trial PRO

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

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  • Nothing to disclose

Conflicts of interest

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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

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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

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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

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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

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  • CUSTOM trial (Advanced thoracic malignancies)

Introduction

Lopez-Chavezet al. JCO 2015;33:1000-7

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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

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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

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  • WINTHER

Introduction

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Introduction

  • M-PACT
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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 YES NO 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

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Le Tourneau et al. Lancet Oncol 2015;16:1324-34

Introduction

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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?

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Is the current design of precision medicine studies the right one? PRO

Outline

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Is the current design of precision medicine studies the right one? PRO

1) The SHIVA trial asked a real-life question

Outline

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Real-life question

Ciriello et al. Nature Genet 2013;45:1127-33

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  • Pilot study by von Hoff et al.

Real-life question

von Hoff et al. JCO 2010;28:4877-83

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Real-life question

von Hoff et al. JCO 2010;28:4877-83

  • 18/66 patients (27%): PFS ratio>1.3
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Real-life question

Tsimberidou et al. CCR 2012;18:6373-83 Patients receiving matched targeted therapy Patients receiving no matched targeted therapy

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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

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>

?

Real-life question

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Is the current design of precision medicine studies the right one? PRO

1) The SHIVA trial asked a real-life question 2) The SHIVA trial was designed to evaluate a specific prespecified treatment algorithm

Outline

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Treatment algorithm

Molecular profile

Molecular alteration

Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent Targeted agent

= TREATMENT ALGORITHM

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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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 Amplification Dasatinib

HORMONE RECEPTOR PATHWAY PI3K/AKT/mTOR PATHWAY RAF/MEK PATHWAY

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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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

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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

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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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 Amplification Dasatinib

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Treatment algorithm

PFS – Hormone receptor pathway

Le Tourneau et al. Lancet Oncol 2015;16:1324-34

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Treatment algorithm

  • 72 yo female AR+ breast cancer

M0 Abiraterone M14

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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 Amplification Dasatinib

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Treatment algorithm

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Treatment algorithm

PFS – PI3K/AKT/mTOR pathway

Le Tourneau et al. Lancet Oncol 2015;16:1324-34

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Treatment algorithm

  • 41 yo female PI3KCA-mutated cervical ca

M0 Everolimus M3

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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 Amplification Dasatinib

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Treatment algorithm

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Le Tourneau et al. Lancet Oncol 2015;16:1324-34

PFS – RAF/MEK pathway

Treatment algorithm

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Treatment algorithm

Le Tourneau et al. JNCI [epub ahead of print on November 23, 2015]

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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
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Is the current design of precision medicine studies the right one? PRO

1) 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

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Cross-over data

Le Tourneau et al. ASCO 2016 (#2535) 25% =25/100 72% =70/97

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Cross-over data

Le Tourneau et al. ASCO 2016 (#2535)

N PFS ratio >1.3 PFS ratio >2 TPC  MTA

Hormone receptor pathway PI3K/AKT/mTOR pathway RAF/MEK pathway

68

31 30 7

41%

35% 38% 54%

25%

20% 19% 18%

MTA  TPC 25 56% 28%

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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

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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