Anna Maria Di GiacomoMedical Oncology and Immunotherapy

Center for Immuno-Oncology

SIENA, ITALY

Immunologia e Cancro: Differenze di Genere

Cancer immunotherapy, a very long standing concept

Venuti A. J Exp Clin Cancer Res. 2009.

The concept that a vaccine could be useful in the treatment of cancer is a long-held

hope coming from the observation that patients with cancer who developed bacterial

infections experienced remission of their malignancies.

The earliest mention of cancer-fighting infections dates to a

citation from Ebers papyrus (1550 B.C.) attributed to the Egyptian

physician Imhotep (2600 B.C.), who recommended to treat

tumors (swellings) with a poultice followed by an incision which

would result in infection of the tumor and therefore its regression.

In 1896, the surgeon William Coley locally injected streptococcal

broth cultures to induce erysipelas in an Italian patient (Mr. Zola)

with an inoperable neck sarcoma, obtaining a tumour regression.

Although therapy was toxic, the patient's tumour ultimately

regressed, and he lived disease-free for 8 years before

succumbing to his cancer.

Hallmarks of cancer2000: immune mechanisms not recognized

Hanahan D, Weinberg RA, Cell 2000; 100: 57-70

The cancer immunoediting concept

R D Schreiber et al. Science 2011

Hallmarks of cancer2011: immune mechanisms recognized

Hanahan D, Weinberg RA, Cell 2011; 144: 646-674

Surgery

Radiotherapy

Chemotherapy

Evolving Therapeutic Options for

Cancer Treatment

Surgery

Radiotherapy

Chemotherapy

Immunotherapy

Evolving Therapeutic Options for

Cancer Treatment

8

Adapted from Pardoll DM 2012.

APC/

TumorT cell

CD40 CD40L

CD137

OX40

CD137L

OX40L

Activation

Activation

Activation

PD-1

B7-1 (CD80)

PD-L1

PD-L2

LAG-3

MHC

CD28 ActivationB7-2 (CD86)

B7-1 (CD80) CTLA-4 Inhibition

TCR

Inhibition

Inhibition

Inhibition

These pathways can be

blocked via I-O agents to

counteract tumor-

mediated inhibition

These pathways can be

activated via I-O agents to

counteract tumor-mediated

inhibition

APC=antigen-presenting cell; CTLA-4=cytotoxic T-lymphocyte antigen-4; LAG-3=lymphocyte activation gene-3; MHC=major

histocompatibility complex;

PD-1=programmed death-1; PD-L1=PD ligand-1; PD-L2=PD ligand-2; TCR=T-cell receptor.

Pardoll DM. Nat Rev Cancer. 2012;12:252-264.

T-cell Checkpoint and Co-stimulatory Pathways

Tissue

samples

readily

accessible

Adaptable to

tissue culture

Amenable to

testing of

novel

therapies

Melanoma as a tool for cancer research

0 1 2 3 4 5 6 7 8 9 10

100

90

80

70

60

0

50

40

30

20

10

Overa

ll S

urv

ival (%

)

Years

IPI (Pooled analysis)1

NIVO Monotherapy (Phase 3 Checkmate 066)3

N=210

NIVO Monotherapy (Phase 1 CA209-003)2

N=107

N=1,861

11

Immune Checkpoint Inhibitors Provide Durable Long-

term Survival for Patients with Advanced Melanoma

1. Schadendorf et al. J Clin Oncol 2015;33:1889-1894; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 2015 International Congress.

Immune Checkpoint Pathways

CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4 ; MHC = major histocompatibility complex; PD-1 = programmed death-1;

PD-L1 = programmed death ligand 1; TCR = T-cell receptor.

CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)

Wolchok JD et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1709684

Kaplan–Meier Estimates of Survival.

A

B

C

D

**

F

* * *

*

C E

Baseline 3 weeks after the first dose 20 weeks after the first dose

Baseline 9 weeks after the first dose 20 weeks after the first dose

Danielli R et al, unpublished

Immunotherapy in solid tumors with

immunomodulating antibodies

www.ImmunOncologia.org

ASCO 2016

CheckMate 017 and CheckMate 057 Study Designs

17

LCSS = Lung Cancer Symptom Scale; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; TKI = tyrosine kinase inhibitor

CheckMate 017 (NCT01642004; N = 272)

CheckMate 057 (NCT01673867; N = 582)

Docetaxel 75 mg/m2 IV Q3W

until PD or

unacceptable toxicity

(n = 290)

Key eligibility criteria

•Stage IIIB/IV SQ NSCLC

•ECOG PS 0–1

•One prior platinum-based chemotherapy

•Pretreatment (archival or fresh) tumor

samples required for PD-L1 analysis

Key eligibility criteria

•Stage IIIB/IV non-SQ NSCLC

•ECOG PS 0–1

•One prior platinum-based chemotherapy

•Pretreatment (archival or fresh) tumor

samples required for PD-L1 analysis

•Prior maintenance therapy allowed

•Prior TKI therapy allowed for known ALK

translocation or EGFR mutation Ran

do

miz

e 1

:1R

an

do

miz

e 1

:1

Endpoints

• Primary‒ OS

• Additional‒ ORR‒ PFS‒ Efficacy by tumor PD-L1 expression‒ Safety‒ Quality of life (LCSS)

Endpoints

• Primary‒ OS

• Additional‒ ORR‒ PFS‒ Efficacy by tumor PD-L1 expression‒ Safety‒ Quality of life (LCSS)

Nivolumab 3 mg/kg IV Q2W

until PD or

unacceptable toxicity

(n = 292)

Docetaxel 75 mg/m2 IV Q3W

until PD or

unacceptable toxicity

(n = 137)

Nivolumab 3 mg/kg IV Q2W

until PD or

unacceptable toxicity

(n = 135)

ASCO 201618

CI = confidence interval; HR = hazard ratio

Kaplan–Meier Estimates of OS(3 Years Minimum Follow-up)

29

2

19

4

14

8

11

2

82 58 49 39 7 0

29

0

19

5

11

2

67 46 35 26 16 1 0

13

5

86 57 38 31 26 21 16 8 0

13

7

69 33 17 11 10 8 7 3 0

CheckMate 057 (non-SQ NSCLC)CheckMate 017 (SQ NSCLC)

No. of patients at risk

Nivolumab

Docetaxel

No. of patients at risk

Nivolumab

Docetaxel

0 6 12 18 24 30 36 42 48 54

Δ10%

Nivolumab (n = 135)

Docetaxel (n = 137)

1-y OS = 42%

2-y OS = 23%

3-y OS = 16%1-y OS = 24%

2-y OS = 8%3-y OS = 6%

HR (95% CI): 0.62 (0.48, 0.80)

100

80

60

40

20

0

OS

(%

)

Months

Δ18%

Δ15%

0 6 12 18 24 30 36 42 48 54

Months

1-y OS = 51%

2-y OS = 29%

3-y OS = 18%

1-y OS = 39%

2-y OS = 16%

3-y OS = 9%

Nivolumab (n = 292)

Docetaxel (n = 290)

HR (95% CI): 0.73 (0.62, 0.88)

100

80

60

40

20

0O

S (

%)

Δ12%

Δ13%

Δ9%

Felip E, ESMO 2017

ASCO 2016

5-Year Estimates of OS

Median OS (95% CI), mo

Overall (N = 129) 9.9 (7.8, 12.4)

100

80

60

40

20

0

0 1 2 3 4 5 6 7 8

129 49 27 20 17 16 3 1 0

YearsNo. at Risk

OS

(%

)

1 y OS, 42%

2 y OS, 24%3 y OS, 18% 5 y OS, 16%

aThere were 3 deaths between 3 and 5 years, all due to disease progression; 1 surviving patient was censored for OS prior to 5 years (OS: 58.2+ months)

AACR 2017

BMS CA209-003: phase 1 dose finding study in NSCLC

BMS HIGHLY CONFIDENTIAL. For internal use only.

Herbst, Lancet, 2016

Garon, ASCO 2016

Keynote 010

All PD-L1 PD-L1 ≥ 50%

PD-L1 = 1-49%

KEYNOTE-024 Study Design (NCT02142738)

Presented By Julie Brahmer at 2017 ASCO Annual Meeting

Kaplan-Meier Estimate of PFS2

Presented By Julie Brahmer at 2017 ASCO Annual Meeting

Kaplan-Meier Estimate of OS: <br />Updated Analysis

Presented By Julie Brahmer at 2017 ASCO Annual Meeting

Jun 16, 2016

Ph. III Anti-PD1/PD-L1 combination trials in first line advanced NSCLC

Immunotherapy in solid tumors with immunomodulating antibodies

www.ImmunOncologia.org

Design of phase III CheckMate 025 study

Motzer RJ, et al. N Engl J Med 2015;373:1803–13.

Patient

eligibility

• aRCC with

clear-cell

component

• KPS ≥70%

• One or two

prior anti-

angiogenic

therapies

• Progression

within 6

months prior

to enrollment

Nivolumab

3 mg/kg

intravenously

every 2 weeks

Everolimus

10 mg orally

once daily

Ra

nd

om

ize

1:1

Study

endpoints

• Primary

– OS

• Secondary

– ORR

– PFS

– Safety

– HRQoL

10

Survival by subgroups in phase III CheckMate 025 study

Nivolumab

N = 410

Everolimus

N = 411

Median OS, months (95%CI)1 25.0 (21.8–NE) 19.6 (17.6–23.1)

Median OS by MSKCC risk group,

months (95%CI)2

Favorable NR 29.0 (26.9–NE)

Intermediate 21.8 (18.3–NE) 18.4 (16.1–23.1)

Poor 15.3 (9.6–22.4) 7.9 (5.4–9.7)

Median OS by KPS, months (95%CI)2

90 or 100 NR (26.7–NE) 29.0 (24.3–NE)

≤70a or 80 18.1 (14.3–22.2) 10.1 (7.9–12.8)

Median OS by response, months

(95%CI)3,b

CR/PR NR (24.1–NE) NR (12.4–NE)

SD NR (22.7–NE) 25.0 (22.9–NE)

PD 14.0 (11.3–16.9) 9.8 (6.1–12.2)

aAll patients had a KPS of 70 at time of study entry but this may have decreased at randomization.bAll treated patients evaluable for best overall response by 4 months.

1. Motzer RJ, et al. N Engl J Med 2015;373:1803–13. 2. Motzer RJ, et al. J Clin Oncol 2016;34(suppl 2S):abstr 498. 3. Motzer RJ, et al.

ASCO 2016 Abstract 4552.

Minimum follow-up was 14.0 months

11

Summary of safety in phase III CheckMate 025 study

Nivolumab

N = 406

Everolimus

N = 397

Any

grade

Grade

3–4

Any

grade

Grade

3–4

Treatment-related

AEs, %78.6 18.7 87.9 36.5

Treatment-related

AEs leading to

discontinuation, %

7.6 4.7 13.1 7.1

12Motzer RJ, et al. N Engl J Med 2015;373:1803–13.

CheckMate 214: Study design

IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; Q3W, every 3 weeks

Treatment until

progression or

unacceptable

toxicity

• Treatment-naïve

advanced or

metastatic clear-cell

RCC

• Measurable disease

• KPS ≥70%

• Tumor tissue

available for PD-L1

testing

TreatmentPatients

Randomize 1:1

Arm A

3 mg/kg nivolumab IV +

1 mg/kg ipilimumab IV Q3W

for four doses, then

3 mg/kg nivolumab IV Q2W

Arm B

50 mg sunitinib orally once

daily for 4 weeks

(6-week cycles)

Stratified by

•IMDC prognostic score

(0 vs 1–2 vs 3–6)

•Region (US vs

Canada/Europe vs Rest

of World)

ORR and DOR: IMDC intermediate/poor risk

N = 847

Outcome

NIVO +

IPI

N = 425

SUN

N = 422

Confirmed ORR,a % (95%

CI)

42 (37–

47)

27 (22–

31)

P < 0.0001

Confirmed BOR,a %

Complete response

Partial response

Stable disease

Progressive disease

Unable to determine/not

reported

9b

32

31

20

8

1b

25

45

17

12

aIRRC-assessed ORR and BOR by RECIST v1.1; bP < 0.0001

SUN

NIVO + IPI

No. at Risk

177 146 120 55 3

112 75 52 17 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24Months

Du

rati

on

of

Resp

on

se (

Pro

bab

ilit

y)

Co-primary endpoint: ORR

Median duration of

response, months

(95% CI)

Patients with

ongoing

response, %

NIVO +

IPI

NR (21.8–

NE)72

SUN18.2 (14.8–

NE)63

OS: IMDC intermediate/poor risk

Hazard ratio (99.8% CI), 0.63 (0.44–0.89)

P < 0.0001

Median OS, months (95%

CI)

NIVO +

IPI

NR (28.2–NE)

SUN 26.0 (22.1–NE)

Ov

era

ll S

urv

ival (P

rob

ab

ilit

y)

425 399 372 348 332 318 300 241 119 44 2 0

422 387 352 315 288 253 225 179 89 34 3 0

No. at Risk

NIVO + IPI

SUN

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

18 21 24 27 30 3315129630

Co-primary endpoint

1970s 1980s 1990s 2010s

Spontaneous regressions in

melanoma: immune component?

1st tumour associated

antigen cloned

IL-2 approved in the US for melanoma

(1992)

IFN adjuvant

melanoma US (1995)

2011Ipilimumab approved

for advanced melanoma

2015–2017Anti-PD-1/-PD-L1

for metastatic melanoma, NSCLC,

RCC, Bladder, HNSCC, Hodgkin, Merkel, MSI-H.

Ipilimumab in adjuvant

melanoma. Nivolumab +

ipilimumab, T-VEC in melanoma

2010 Provenge US

Coley in 1891: observation of a

tumour regression in a pt who developed a

post-op infection

A historical view of immunotherapy…

Italy 2017

Anti-PD-1 in: RCC

HodgkinMelanoma

NSCLC……….………..

2017

The theoretical right patient for immunotherapy?

• Low tumor burden ?

• Slow progressive disease ?

• Untreated ?

• Younger ?

• Gender ?

• Normal biohumoral parameters (e.g. LDH) ?

• Molecularly addicted ?

Individuality and Variation of Personal Regulomes

in Primary Human T Cells

Qu et al., 2015, Cell Systems

KEYNOTE-006

Overall 19/3558/86

0.35 (0.19–0.64)0.62 (0.39–0.98)

Age Category<65

≥65

8/1734/4911/1824/37

0.26 (0.11–0.64)0.72 (0.40–1.29)0.50 (0.21–1.19)0.54 (0.26–1.12)

GenderMale

Female

7/1626/4212/1932/44

0.45 (0.18–1.12)0.47 (0.24–0.94)0.27 (0.12–0.61)0.80 (0.44–1.48)

Baseline ECOG Performance Status0

1

12/2437/587/10

21/28

0.33 (0.16–0.69)0.52 (0.30–0.91)0.41 (0.13–1.25)0.83 (0.37–1.86)

M Stage at Study EntryM1c 12/22

36/530.37 (0.17–0.84)0.54 (0.29–1.00)

Baseline LDH≤ULN

>ULN

9/1827/4310/1729/41

0.22 (0.09–0.54)0.43 (0.23–0.82)0.45 (0.19–1.07)0.71 (0.36–1.40)

Checkmate 067- PFS by Subgroups

39

Hazard Ratio (95% CI)Events/patients NIVO+IPI NIVO

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

NIVO or NIVO+IPI better IPI better

BMS HIGHLY CONFIDENTIAL. For internal use only.

CTLA-4PD1-PDL1CTLA-4/PD1

Combos/Sequences

MelanomaLung cancer

Novel targets

4-1BB

OX-40ICOS KIR

TIM-3

LAG-3CD40

IDO

Renal

Other tumors

Mesothelioma Urothelial

Colorectal

Glioblastoma

Head-Neck

Ovarian

BreastMSI-H Tumors

• Maresa Altomonte• Erika Bertocci• Luana Calabrò• Ornella Cutaia• Riccardo Danielli• Anna Maria Di Giacomo• Carolina Fazio• Ester Fonsatti• Carla Chiarucci• Gianluca Giacobini• Andrea Lazzeri

Medical Oncology and ImmunotherapyCenter for Immuno-Oncology

University Hospital of Siena - Italy

• Francesca Colizzi• Sandra Coral• Alessia Covre• Elisabetta Fratta• Hugues Nicolay• Luca Sigalotti• Maria Lofiego• Patrizia Tunici• Antonello Lamboglia• Monica Valente• Armida D’Incecco