Is There Space for Immunotherapy

in Non-Small Cell Lung Cancer?

Jean-Charles Soria, MD, PhD Gustave Roussy

Villejuif, France

U981

Lung Cancer: Most Common Malignancy and Leading Cause of Cancer-Related Mortality

1. Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11[Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr. Accessed September 2014; 2. Ferlay J, et al. Eur J Cancer. 2013;49(6):1374-1403.

0

500000

1000000

1500000

2000000

LungCancer

BreastCancer

ColorectalCancer

ProstateCancer

Incidence

Mortality

GLOBOCAN 2012 (worldwide, both sexes)1

1.59 million1

(1 in 5) estimated deaths worldwide

1.82 million1

estimated new cases worldwide

More people die from lung cancer than breast, colorectal and prostate

cancers combined1

Within Europe, ~1000 people die from lung cancer every day1,2

Classification Characteristics1

No

nsq

uam

ou

sc

Adenocarcinoma

(AC) 30% to 50%a

• Malignant epithelial tumors with glandular differentiation

• IASLC classification of invasive AC2:

• Lepidic, acinar, papillary, micropapillary, or solid pattern predominant

• Variants: Invasive mucinous AC, colloid, fetal, and enteric

Large cell

carcinoma 10%a

• Involves large cells (subtypes are giant cell, clear cell) with large nuclei

• No evidence of squamous or glandular differentiation

Sq

uam

ou

s

Squamous cell

carcinoma 30%b

• Involves cells of the squamous epithelium

• Two variants of clinicopathologic significance3

• Papillary variant

• Basaloid variant

Histologic Classification of NSCLC

aImage from www.surgical-pathology.com; bImage from www.lmp.ualberta.ca/resources/pathoimages/PC-S.htm; cOther less common subtypes of nonsquamous NSCLC include adenosquamous carcinoma and sarcomatoid carcinoma.3

IASCL, International Association for the Study of Lung Cancer; NSCLC, non-small cell lung cancer

1. Langer CJ, et al. J Clin Oncol. 2010;28(36):5311-5320. 2. Travis WD, et al. J Thorac Oncol 2011;4:244-285. 3. Travis WD, et al, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press: Lyon; 2004.

Metastatic NSCLC Today

NSCLC

Platinum

Doublet

Cisplatin

+

Pemetrexed

Doublet

+

Bevacizumab

SQUAMOUS ADENOCARCINOMA LARGE

CELL

EGFR mutated:

Gefitinib, Erlotinib,

Afatinib

ALK

translocated:

Crizotinib

Ceridinib

80%

No Clear Driver

or Oncogenic Event

20%

NSCLC

Oncogene

Addicted

24-36

Months

12

Months

ALK, anaplastic lymphoma kinase;

EGFR, epidermal growth factor receptor

First-line combination with chemotherapy

After failure of 1 prior chemotherapy

Maintenance treatment after First-line chemotherapy

First-line or unspecified setting single agent

1970 1980 1990 2000

Erlotinib 2004

Docetaxel 1999

Gefitinibb 2003

2010

Pemetrexedc 2004

Erlotinib 2010

Pemetrexedc 2009

Crizotinibd 2011 (US)/2012 (EU)

Erlotinibe 2013 Median Overall Survival (OS), months

12+

~8-10 ~6

~2-4

24-36

Carboplatina 1989

Gemcitabine 1996

Vinorelbine 1994

Docetaxel 2002

Bevacizumabc

2006

Pemetrexedc

2008

Paclitaxel 1998

nab-Paclitaxel

2012

Cisplatina 1978

Therapeutic Overview in NSCLC

aNot approved in NSCLC, but commonly used; bRestricted to patients participating in a clinical trial or continuing to benefit from treatment already initiated; cNonsquamous NSCLC only; dALK-positive NSCLC only; eEGFR exon 19 deletions or exon 21 (L858R) substitution mutations only; fAfatinib is approved for the treatment of patients with activating EGFR mutations but only progression-free survival (PFS) data have been published (May 2014).

US Food and Drug Administration. Available at: www.fda.gov. Accessed September 1, 2014. European Medicines Agency. Available at: www.ema.europa.eu. Accessed September 1, 2014. National Comprehensive Cancer Network. NCCN Guidelines®: Non-small cell lung cancer. v6.2015. Available at: https://www.nccn.org/store/login/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed May 14, 2015.

Afatinibe,f

2013 Year

Immunotherapy Strategies for NSCLC

. mAb, monoclonal antibody; PD, programmed death; PD-L, PD-ligand

National Institutes of Health. www.clinicaltrials.gov. Accessed September 1, 2014. National Comprehensive Cancer Network. NCCN Guidelines®: Non-small cell lung cancer. v6.2015. Available at: https://www.nccn.org/store/login/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Peters S, et al. Ann Oncol. 2012;23 Suppl 7:vii56-vii64.

Therapeutic vaccines

Enhancing immune

cell function

Adoptive Antitumor

mAbs

Bavituximab EGFR inhibition

Adoptive cell transfer

Modulate T-cell function

Cytokines

GSK1572932A TG4010

Belagenpumatucel-L Tergenpumatucel-L

Racotumomab L-BLP25 CIMAvax

Passive (adoptive) Designed to act at tumor;

immune-based mechanism

Active Designed to act on the immune system itself

Immunotherapy

Antigen dependent

Antigen independent

Immunecheckpoint

CTLA-4 inhibition PD-1 inhibition

PD-L1 inhibition

Immunotherapy Strategies for NSCLC

. mAb, monoclonal antibody; PD, programmed death; PD-L, PD-ligand

National Institutes of Health. www.clinicaltrials.gov. Accessed September 1, 2014. National Comprehensive Cancer Network. NCCN Guidelines®: Non-small cell lung cancer. v6.2015. Available at: https://www.nccn.org/store/login/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Peters S, et al. Ann Oncol. 2012;23 Suppl 7:vii56-vii64.

Therapeutic vaccines

Enhancing immune

cell function

Adoptive Antitumor

mAbs

Bavituximab EGFR inhibition

Adoptive cell transfer

Modulate T-cell function

Cytokines

GSK1572932A TG4010

Belagenpumatucel-L Tergenpumatucel-L

Racotumomab L-BLP25 CIMAvax

Passive (adoptive) Designed to act at tumor;

immune-based mechanism

Active Designed to act on the immune system itself

Immunotherapy

Antigen dependent

Antigen independent

Immunecheckpoint

CTLA-4 inhibition PD-1 inhibition

PD-L1 inhibition

Immune Checkpoint Inhibitors

Why Is Immunotherapy Intrinsically Unique?

Paradigm Shift in Cancer Therapy

Tumor Cell

Historic Paradigm:

Targeting Tumor Cells

Lymphocyte

New Paradigm:

Targeting Immune Cells

Courtesy A Marabelle

Specificities of ICB

Potential to Improve Clinical

Outcome

Targeting the immune system, not the tumor, offers the potential for activity across multiple

tumor types

Unique MoA of I-O therapies offers the

opportunity for combination

Immune adaptability, and memory offers

the potential for long-term survival

ICB, immune checkpoint blockade; I-O, immuno-oncology; MoA, mechanism of action

Big Hope—True for Lung Cancer?

[TITLE]

Sharpe A. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31 - June 3, 2013: Chicago, Illinois.

What Is an Immune Checkpoint?

But the concept is not limited to T cells (NK cells, macrophages)

-

Antibody Target Company Stage in Development

Ipilimumab CTLA-4 Bristol-Myers Squibb Phase III

Tremelimumab CTLA-4 MedImmune/Astra

Zeneca Phase II

BMS-936558

Nivolumab PD-1 Bristol-Myers Squibb Phase III/Approved USA

MK-3575

pembrozilumab PD-1 Merck Phase III

MPDL-3280A

Atezolizumab PD-L1 Genentech-Roche Phase III

Medi-4736

Durvalumab PD-L1

MedImmune/Astra

Zeneca Phase III

MSB0010718C

Avelumab PD-L1 Merck/Pfizer Phase II

BMS-936559 PD-L1 Bristol-Myers Squibb Phase I

AMP-224

Fc fusion

of PD-L2 GSK Phase I

Immune Checkpoint Inhibitors in NSCLC

Neo

adjuvant

Adjuvant

Metastatic

Preventive?

Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution?

Surgery

Locally

advanced

The earlier stage a drug can be used, the greater is the potential benefit

Late-stage disease

Benefit = a few months

Earlier stages of cancer

Benefit = many months

Adjuvant therapy

Benefit = months, years,

potential for cure (long-term remission)

Metastatic

Second-line and beyond

First-line monotherapy

In combination

Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution?

Immune Checkpoint Blockade

TKI

Chemo

Radiation Therapy Vaccines

Other Immune

Checkpoint Blockade

Rationale for Combination Survival

! me

controls

immune/checkpoint/blockade

Survival

! me

controls

conven5onal/therapies

Survival

! me

controls

combina5ons/conven5onal/therapies/

+/immune/checkpoint/blockade

Conventional

therapies

Controls

Survival

! me

controls

immune/checkpoint/blockade

Survival

! me

controls

conven5onal/therapies

Survival

! me

controls

combina5ons/conven5onal/therapies/

+/immune/checkpoint/blockade

Immune checkpoints

blockade

Controls

Ribas A, et al. Clin Cancer Res. 2012;18(2):336-341. Champiat S, et al.J Thorac Oncol. 2014;9(2):144-153.

Time Time

Conventional

therapies

Immune checkpoints

blockade

Controls

Ribas A, et al. Clin Cancer Res. 2012;18(2):336-341. Champiat S, et al.J Thorac Oncol. 2014;9(2):144-153.

Reported Immunomodulatory Effects of Conventional Agents

Immunogenic

cell death

CT, RT

Vaccines L-BLP25, MAGE-A3, EGF,

belagenpumatucel-L

tergenpumatucel-L

TG4010

Up-regulation

of MHCI paclitaxel,

gemcitabine,

erlotinib

DC maturation paclitaxel, docetaxel,

bevacizumab

Up-regulation

of PD-L1 paclitaxel,

etoposide

T-Reg

inhibition cisplatin,

paclitaxel,

bevacizumab

Down-regulation

of PD-L1 Pi3K? MEKi?

crizotininb

Champiat S, et al.J Thorac Oncol. 2014;9(2):144-153.

20%

NSCLC

Oncogene

Addicted

NCSLC

80%

No clear driver

or oncogenic event

platinum

doublet

cisplatin +

pemetrexed

doublet +

bevacizumab

SQUAMOUS ADENOCARCINOMAS LARGE

CELL

20%

NSCLC

Oncogene

Addicted

NCSLC

80%

No clear driver

or oncogenic event

platinum

doublet

cisplatin +

pemetrexed

doublet +

bevacizumab

SQUAMOUS ADENOCARCINOMAS LARGE

CELL

EGFR mutated

gefitinib,

erlotinib

afatinib

ALK, ROS

translocated

crizotinib

IMMUNOTHERAPY ?