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Dr Christophe Massard

SIOG 2016 Milan, 19 NOV 2016

Immunotherapy

Hot topics in geriatric oncology• 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

• 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 Systemic anti-cancer therapies

CHEMOTHERAPYTARGETED THERAPIES

IMMUNOTHERAPIES

Outline

• Background

• Immunecheckpoints

• Drugs in development

• Perspectives

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Outline

• Background

• Immunecheckpoints

• Drugs in development

• Perspectives

Paradigm Shift in Cancer Therapy

Tumor Cell

Historical Paradigm:

Targeting Tumor Cells

Lymphocyte

New Paradigm:

Targeting Immune Cells

Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun

6;486(7401):16.

Illustration with anti-PD-1 / anti-PD-L1 mAbs

Initially sold as a simple paradigm !

Outline

• Background

• Immunecheckpoints

• Drugs in development

– CTLA-4 inhibitors

– PD1/PDL1 inhibitors

• Perspectives

Nivolumab

(BMS)

&

Pembrolizumab

(MSD)

Durvalumab (AZ/Medimmune)

Avelumab (Pfizer)

Anti-PD-1 Anti-PD-L1

Approved

Tremelimumab

(AZ)

Anti-CTLA-4

Approved

Know your Immune Checkpoint Antibodies

Ipilimumab

(BMS)

Approved

Atezolizumab (Roche/Genentech)

PD-1/ PD-L1

Blockade

MelNSCLC

Bladder

RCC

HNSCC

Gastric

Hodgkin

B-Cell NHL

MSI High CRC

OvarianTNBC

Mesothelioma

HCC

Oesoph

SCLC

Biliary Tract

Anal

MCC

Thymic

MSI GBM

Spectrum of activity of anti PD1/PDL1

Adapted from A Marabelle

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PD-1/ PD-L1

Blockade

Mel RCC

NSCLC

Bladder

HNSCC

Gastric

Hodgkin

B-Cell NHL

MSI CRC

OvarianTNBC

Mesothelioma

HCC

Eso phageal

SCLC

Biliary Tract

Anal

MCC

ThymicCarcinoma

MMRdGBM

US approvals

Courtsey A Marabelle

Outline

• Background

• Immunecheckpoints

• Drugs in development

• Perspectives

[TITLE]

Presented By Arlene Sharpe, MD, PhD at 2013 ASCO Annual Meeting

What is an immune checkpoint ?

���� But the concept is not limited to T-cells (NK cells, Macrophages)

T-cell co-stimulatory targets in the clinic

T-cellAPC T-cellAPC

T-cell co-inhibitory targets in the clinic

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Immune Checkpoint Blockade

for Therapeutic Action

against Multiple Cancer Clones

ααααPD-1

ααααPD-L1

ααααCTLA4

ααααOX40

αααα4-1BB

ααααCD47

ααααKIR

ααααCD40

ααααLAG-3

ααααTIM-3

ααααGITR

• Cutaneous

• Gut and liver

• Cardiovascular

• Nephrolgical

• Neurological

• Lung

• Bone and arthritis

• Endocrinological

• Ophtalmological

- Side effects are the testominy of biological activity,

- ON or OFF target

- Learning to deal with side-effects is a key-issue >>>long term toxicity

Immunotherapy toxicities managment Immunotherapy toxicities managment Immunotherapy toxicities managment Immunotherapy toxicities managment (acute/chronic phase)(acute/chronic phase)(acute/chronic phase)(acute/chronic phase)

GASTROINTESTINAL

Diarrhea

Abdominal pain Colitis

PancreatitisBowel perforationIleus

LIVERAbnormal liver function tests

(AST, ALT)or total bilirubin elevation

SKINPruritus

RashDermatitis

Psoriasis

NEUROLOGICNeuropathy

MyelopathyGuillain Barré

MeningitisEncephalitisMyasthenia

ENDOCRINEThyroiditis

Hyper or hypothyroidismHypohysitis

Pan-hypopituitarismAdrenal insufficiency Diabetes

OTHER ADVERSE REACTIONS …

adapted from YERVOY FDA-approved Risk Evaluation and Mitigation Strategy (REMS)

RESPIRATORYCough

DyspneaPneumonitis

Sarcoidosis

PD1-induced psoriasis

PD1-induced psoriasis

Patient treated with topical steroids & oral retinoid

7 months after anti PD1 discontinuation

Hyperprogressive disease (HPD):

a new pattern of progression

Champiat et al, Clin Cancer Res 2016

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Hyperprogressive disease (HPD):

a new pattern of progression

Champiat et al, Clin Cancer Res 2016

Take home messagesTake home messagesTake home messagesTake home messages• Cancer Immunotherapy is « drug of the year »

– Anti-PD1 and PDL1 in phase I>>>III and FDA approved

• Antitumor activity in different tumor types

– Melanoma, Kidney

– NSCLC (a « non-immunogenic » tumor!!!!)

– And other cancers…

• Monotherapies blocking PD-1/PDL1 may be more effective in combination

• There is a need to enrich phase I/II trials in patients presenting target alteration

– To identify predictors for sensitivity

Thank you…

Dr Aurélien Marabelle

Dr Caroline Robert

Dr Bernard Escudier

Dr Laurence Albiges

Pr Jean-Charles Soria

Gustave Roussy Phase 1 Unit, DITEP