Development therapeutics

in 2018

Christophe MASSARD, MD PhD

U 981

CLUB Phase 1, 23 NOV 2017

christophe.massard@gustaveroussy.fr

• Participation to advisory boards, speaker or investigator for: Amgen, Astellas, Astra Zeneca, Bayer, Celgene, Genentech, Ipsen, Jansen, Lilly, Novartis, Pfizer, Roche, Sanofi, Orion, MedImmune, New Oncology, DebioPharm

• I am a PI of Eli Lilly and Company trial with NOTCH inhibitor

• I will not discuss off label use in my presentation

• I will discuss investigational use in my presentation

Disclosure

• I am a medical oncologist

• I am a Phase 1 PI, and a strong believer in Precision medicine programs

Disclosure

Outline

• Changes in the classical drug development paradigm

• Example1: « oldman »phase 1

• Example2: Precision medicine

• Example3: Immunotherapy

Outline

• Changes in the classical drug development paradigm

– quoi faire des essais cliniques en 2018?

• Example1: « oldman »phase 1

• Example2: Precision medicine

• Example3: Immunotherapy

PURPOSE

EMPHASIS

ENDPOINT

Registration value

Find MTD

Safety

20-60

Null

Define Activity

N (patients)

Toxicity (DLT)

Activity

Response (ORR)

20-200

Limited

Efficacy

Compare with SOC

Survival (PFS, OS)

200-2000

Major

Classical drug development paradigm before 2000

PURPOSE

EMPHASIS

ENDPOINT

Registration value

Define MTD and Activity

Safety & Activity & Biomarkers

100-1000 + N (patients)

Toxicity & Response (all and selected) & Preliminary Survival

Efficacy

Compare with SOC

Survival (PFS, OS)

200-2000

Major (confirmatory)

The revolution in drug development is a change in nature and goals of early phases

Real (conditional, breakthrough)

Postel-Vinay S et al, Annals of Oncology 2014

Postel-Vinay S et al, Annals of Oncology 2014

FDA approval on phase I/II data

DITEP Main Indicators of Activity

Patients

Referral of patients to DITEP for inclusion in early clinical studies

Patients recruited in our studies & patients treated in early clinical trials

9

Tubingen University – Gustave Roussy Meeting Monday, June 19th, 2017

DITEP Main Indicators of Activity

Patients

1838 patient’s referrals for inclusion in early clinical trials in 2016

443 patients with various tumor types treated in early clinical trials in 2016

Focus 2016

10

Tubingen University – Gustave Roussy Meeting Monday, June 19th, 2017

Outline

• Changes in the classical drug development paradigm

• Example1: « oldman »phase 1

– EGFR mAB

• Example2: Precision medicine

• Example3: Immunotherapy

Treatment advances in mCRC

0 5 10 15 20 25

Overall survival (months) 30

5 Scheithauer, 1993

12.6 Saltz, 2000

14.1 Douillard, 2000 5-FU/LV infusion

5-FU/LV bolus

BSC

17.4 Douillard, 2000

19.5 Goldberg, 2004 FOLFOX

22.6 Falcone, 2007 FOLFOXIRI

20.3 Hurwitz, 2004 IFL + bevacizumab

21.3 Saltz, 2008 XELOX/FOLFOX + bevacizumab

23.5 Van Cutsem, 2011 FOLFIRI + cetuximab

Douillard, 2011 FOLFOX + panitumumab 23.9

22.8 Bokemeyer, 2011 FOLFOX + cetuximab

30 30 Alan P. Venook, 2014

FOLFIRI + bevacizumab cetuximab

28.7

25 Heinemann, 2014

FOLFIRI + cetuximab bevacizumab

Chemotherapy + bevacizumab cetuximab / cetuximab bevacizumab

FOLFIRI

Cunningham N Engl J Med

2004;351:337

IRINOTECAN + CETUXIMAB in 2nd LINE : BOND TRIAL

Cunningham N Engl J Med 2004;351:337

Membrane

P

Ligand

EGFR

P PIP3

AKT1/2

mTOR

PIP2

PDK1/2

eIF4E

4EBP1

p70S6K GSK3

Voie

PI3K/AKT

Voie

Ras/MAPK

transcription Inhibition apoptose Proliferation Angiogenèse Migration

PI3K

PTEN

Grb

hSOS

MEK1

ERK1/2

Ras

Raf1

Prolifération cellulaire

Inhibition apoptose

PLC DAG PKC

IP3

Voie PLC

STAT

STAT

Voie STAT

La voie de l’EGFR

KRAS Status Responders* Non

responders*

Total

KRAS mutation (%) 0 (0) 13 (100) 13

Wildtype (%) 11 (65) 6 (35) 17

p=0.0003

Lièvre A et al. Cancer Res 2006.

KRAS Mutation and Anti-EGFR therapy

in advanced colorectal cancer

* Response according to RECIST criteria

Wildtype

mutated KRAS

Overall survival according to KRAS mutation

16.3 months

6.9 months p=0.016

0

25

50

75

100

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Months

Pe

rce

nt

surv

ival

20-30 pts

Escalation Expansion

Classical Phase I

Phase I/II trial

Escalation Expansion

Phase I design modifications

Combo with A

Combo with B

Combo with C

Combo with D

20-30 pts

20-30 pts

20-30 pts

20-30 pts

20-30 pts

Escalation Expansion

Classical Phase I

Phase I/II trial

Escalation Expansion

Phase I design modifications

Combo with A

Combo with B

Combo with C

Combo with D

20-30 pts

20-30 pts

20-30 pts

20-30 pts

RADIATION COMBO

HEMATOLOGICAL DISEASE

Outline

• Changes in the classical drug development paradigm

• Example1: « oldman »phase 1

• Example2: Precision medicine

– We are still believers

• Example3: Immunotherapy

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

Emile E. Voest and Rene Bernards Jan 2016

September 29, 2016

8 SEPTEMBER 2016 | VOL 537 | NATURE | S63

Conceptual evolution of Cancer treatment

Few therapeutic options to treat

tumors:

- Surgery

- Radiotherapy

- Few chemotherapies

Increase on therapeutic options

allowed specific treatments for

different tumor types:

-Combined chemo-radiation

-Specific protocols

Disease guided

approach

Pathological guided

approach

Clinical Oncology Pathological Oncology Molecular Oncology

Targeted agents that work in specific

molecular alterations:

-Broad knowledge of molecular tumor

biology and immune context

Molecular & immune

approach

Nowadays

Immune Oncology

Modified f rom J Rodon

SANGER sequencing

RT-PCR Sequenom/ SNAPshot NGS

Technology has improved…

WES/RNAseq

MacConaill L E , Garraway L A JCO 2010;28:5219-5228

Decreasing costs

Molecular profiling

Identification of the molecular alteration

Targeted therapy according to the molecular profile

Tumor Specimen

Precision Medicine: To identify and hit the target A virtuous circle (I)

Can molecular profiling improve patient outcome ?

MOSCATO: MOlecular Screening for CAncer Treatment Optimization

Selected Molecular Profiling Initiatives and Genotype-Matching to Clinical Trials

Group Sample Size

Platform Fresh Biopsy vs FFPE

Germ-line Control

Number and % of “Matched” Patients in Genotype-Matched Clinical Trials

Gustave Roussy MOSCATO

1,035 40-75 gene panels (Life) + CGH (Agilent) + RNA Seq

Fresh biopsy Yes 199/1035 = 19%

Institut Curie 741 46 gene panel (Life) + CNA (Affymetrix) +IHC

Fresh biopsy No 195 randomized/741 = 26%

BCCA 100 Whole genome Fresh biopsy Yes 1/100 = 1%

MD Anderson 2,000 11-50 gene panels (Life)

FFPE No 83/2000 = 4%

Princess Margaret

1,640 23-48 gene panels (Ilumina, Life)

FFPE Yes 92/1640 = 5.6%

24

Massard et al. Cancer Dis 2017; LeTourneau et al. Lancet Oncol 2015; Laskin et al. Cold Spring Harb Mol Stud 2015; Meric-Bernstam et al. J Clin Oncol 2015; Stockley, Bedard et al. Genome Med 2016.

CNA = Copy number alterations; IHC = Immunohistochemistry

Courtesy J Rodon

Courtesy A Bardelli

20-30 pts

Escalation Expansion

Classical Phase I

Phase I/II trial

X 100 selected pts Molecular enrichment

Escalation Expansion

Phase I design modifications

Outline

• Changes in the classical drug development paradigm

• Example1: « oldman »phase 1

• Example2: Precision medicine

• Example3: Immunotherapy

PD-1/ PD-L1

Blockade

Mel RCC NSCLC

Bladder

HNSCC

Gastric

Hodgkin

B-Cell NHL

MSI CRC

Ovarian TNBC

Mesothelioma

HCC

Eso phageal

SCLC

Biliary Tract

Anal

MCC

Thymic Carcinoma

MMRd GBM

US approvals

Courtsey A Marabelle

20-30 pts

Escalation Expansion

Classical Phase I

Multiple parallel expansion cohorts in Phase I Long-term follow-up

100-1000 patients +/- immune enrichment

Escalation Expansion

Phase I design modifications

Challenge #1: How do we identify sensitive disease?

Challenge #2: How do we overcome resistance to immune checkpoint blockade therapy?

?

Challenge #3: new patterns of response/progression?

Inclusion :

Novembre 2012

Decembre 2012

Janvier2013

Février 2013

Mars 2013

Juillet 2013

Pseudoprogression in melanoma patients

Identifier les candidats: Biomarqueurs

06/10/2015 30/11/2015

And progression?

Hyperprogressive disease (HPD): a new pattern of progression

Champiat et al, Clin Cancer Res 2016

Challenge #4: How do we combine IO?

“We are not on the right path,” Khleif tells me. “Currently there are a lot of combination clinical trials

and some of those trials are not based on science.”

Aknowledgements: MOSCATO Team Steering Committee Jean-Charles Soria (PI) Fabrice André Gilles Vassal Alexander Eggermont

Investigators Christophe Massard Antoine Hollebecque Charles Ferte Rastislav Bahleda Eric Angevin Andreea Varga Anas Gazzah Sophie Postel-Vinay Jean-Marie Michot Eric Deutsch Caroline Even Jean-Pierre Armand

Radiologists Thierry de Baere Frédéric Deschamps Lambros Tselikas Vania Tacher

Pathologists Jean Yves Scoaezec Philippe Vielh Cécile Charpy

Statistics Marie-Cécile Le Deley

Dorota Gajda

Aljosa Celebic

Silvia Rosellini

Study Coordinator Maud Ngo-Camus

Fanny Wunder

Aurélie Abou Lovergne

Lisa Lambert

Siham Gouissem

Felicien Vanié

Biologists Ludovic Lacroix

Nathalie Auger

Valérie Koubi-Pick

Benoush Abedi

Romy Chen Min Tao

Vladimir Lazar

Catherine Richon

Clément Mazoyer

Bastien Job

Equipe Médecine personnalisée

Equipe ET EXTRA

Funded by

Philantropy and French Grants

And Industrial partnerships

• SANOFI-AVENTIS

• Genentech

Acknowledgements Jean-Charles Soria

Vincent Ribrag

Eric Deutsch

Antoine Hollebecque

Andrea Varga

Aurélien Marabelle

Sophie Postel-Vinay

Eric Angevin

Rastislav Bahleda

Anas Gazzah

Jean-Marie Michot

Capucine Baldini

Patricia Martin

Jessica Menis

Stéphane Champiat

Yolla El Dakdouki

Loic Verlingue

Benjamin Besse