Oncorete: Sharing and Innovation System

Anna Maria Di Giacomo Center for Immuno-Oncology

SIENA, ITALY

Immunoterapia Oncologica:

attese del paziente e opportunità di cura

Oncorete: Sharing and Innovation SystemFirenze, 25 Febbraio 2019

Surgery

Radiotherapy

Chemotherapy

Immunotherapy

Evolving Therapeutic Options for

Cancer Treatment

Pioneering cancer immunotherapy researchers awardedNobel Prize in medicine 2018

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

Overall Survival for Metastatic Melanoma

Survival data from 42 Phase II

trials with over 2,100 stage IV

patients1:

12 month OS: 25.5 %, median

OS: 6.2 months

(stage IV melanoma including

patients with brain metastases)

1Korn EL et al. J Clin Oncol 2008;26(4):527-34.2Dummer R, Hauschild A, Jost L. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment

and follow-up. Ann Oncol 2008;19 Suppl 2:ii86-8.

Time (months)

Pro

po

rtio

n a

live

Due to the lack of efficacious therapy, the preferred treatment

for metastatic melanoma remains the inclusion in a clinical

trial2

Adapted from Korn 2008

0 1 2 3 4 5 6 7 8 9 10

100

90

80

70

60

0

50

40

30

20

10

Ove

rall

Su

rviv

al (%

)

Years

IPI (Pooled analysis)1

N=1,861

Immune Checkpoint Inhibitors Provide Durable Long-

term Survival for Patients with Advanced Melanoma

Anti-CTLA Pooled analysis

LONG-TERM BENEFITS OF IPILIMUMAB IN ADVANCED MELANOMA:THE CENTER FOR IMMUNO-ONCOLOGY OF SIENA EXPERIENCE

mOS=9.9 months (95% CI: 6.8-12.9)

mean OS was 34.5 months (95% CI:

27.1-40.9)

Kaplan–Meier analysis of OS among 167 patients receiving

ipilimumab

Di Giacomo AM et al., Unpublished

NO therapy after ipilimumab: median OS= 7.3 months

YES therapy after ipilimumab: median OS= 16.8 months

Kaplan–Meier analysis of OSafter subsequent systemic therapies for all patients

0 1 2 3 4 5 6 7 8 9 10

100

90

80

70

60

0

50

40

30

20

10

Ove

rall

Su

rviv

al (%

)

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

Immune Checkpoint Inhibitors Provide Durable Long-

term Survival for Patients with Advanced Melanoma

Anti-CTLA Pooled analysis

Anti-PD-1 pretreated melanoma

Anti-PD-1 untreated melanoma

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)

NIVO+IPI (n = 314) NIVO (n = 316) IPI (n = 315)

Median OS, mo (95% CI)NR

(38.2, NR)36.9

(28.3, NR)19.9

(16.9, 24.6)

HR (95% CI) versus IPI0.54

(0.44, 0.67)0.65

(0.53, 0.79) –

HR (95% CI) versus NIVOa 0.84 (0.67, 1.05) – –

Overall Survival

Months

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

Patients at risk:

0IPI 253285315 227 203 181 163 148 135 128 113 107 99 94 93 90 86 50 11

0265292314NIVO+IPI 247 226 221 209 200 198 192 186 180 178 171 166 160 154 96 13

NIVO 0266292316 245 231 214 201 191 181 175 171 164 158 150 144 140 135 85 18

64%58%

53%

59%

51%46%45%

34%30%

aDescriptive analysis

OS

(%

)

NIVO+IPI

NIVO

IPI

Hodi FS et al. Lancet Oncol 2018

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

Immunotherapy in melanoma brain metastases


Subject 6-202, PR in brain and PR in total tumor burden

Courtesy of Kim Margolin

Week 16Baseline

DOR 11+ mo

Baseline W4 W 20

DOR > 6 y


28% 28%

5/20 complete regressions of BM. Duration of brain CR was: 16, 28, 39,80+,94+ months

Screening/Baseline Randomization

Arm AInduction Phase

Fotemustine: 100mg/m2 ivq1 week for 3 doses

Manteinance PhaseFotemustine: 100mg/m2 q3 weeks

from week 9 for 6 doses

Arm BInduction Phase

Fotemustine: 100mg/m2 iv q1 week for 3 doses and then from week 9 for 6 doses

Ipilimumab: 10 mg/kg iv q3 weeks for 4 doses

Manteinance PhaseIpilimumab: 10 mg/kg iv q12 weeks from week 24

Arm CInduction Phase

Nivolumab 1mg/kg iv + ipilimumab3mg/kg iv q3 for 4 doses

Manteinance PhaseNivolumab 3mg/kg iv q2 weeks

Follow-up phaseTreatment until PD or excessive to toxicity or patient’s refusal

The NIBIT-M2 study design


CLINICAL CASE - Stage IV cutaneous melanoma

Baseline

W 24

W162 → ongoing brain CR

Di Giacomo and Maio, unpublished


IO Combination in melanoma brain metastases

Bringing I-O to earlier disease stage

20192013 2015 2016 2017

Anti-PD-1 for metastatic NSCLC

Anti-PD-1for metastatic melanoma

A historical view of immunotherapy in Italy

Anti-PD-1/PDL-1 in Hodgkin lymphoma, NSCLC, bladder, renal

2018

Anti-PD-1 forHNSCC, merkel

Anti-PDL-1 for NSCLC

Anti-CTLA-4 + anti-PD-1 for

melanoma and RCC

Adjuvant anti-PD-1 for melanoma

Anti-PD-1 forSCC

Anti-CTL-4 for advanced melanoma

5-Year Estimates of OS

M edian 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

BM S CA209-003: phase 1 dose finding study in NSCL C

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)

Overa

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

The evolving Cancer Immunotherapy Landscape>800 clinical combinations with PD-L1/PD-1 inhibitors

Hegde PS, AAADV, Washington DC, 2017

Atezo+chemo+/-bevacizumab

Durva+tremelimumab

Nivo+ipilimumab

Nivo+BMS-986016

Nivo+capmatinib

Nivo+dasatinib

Nivo+EGF816

Pembro+azacitidine

Pembro+acalabrutinib

Pembro+abemaciclib

Nivo+ipilimumab

Atezo +chemo

Durva+tremelimumab +/-chemo

Nivo+ ulocuplumab

Nivo+cabiralizumab

Nivo+ceritinib

Nivo+crizotinib

Nivo+epacadostat

Nivo+erlotinib

Nivo+galunisertib

Nivo+lirilumab

Nivo+urelumab

Nivo+varlilumab

Pembro+AM0010

Pembro+ipilimumab

Pembro+bevacizumab

Pembro+epacadostat

Pembro+entinostat

Pembro+crizotinib

Pembro+GSK-3174998

Pembro+gefitinib

Pembro+erlotinib

Pembro+PEGPH20

Pembro+necitumumab

Pembro+lenvatinib

Pembro+pexidartinib

Pembro+ramucirumab Atezo+cobimetinib

Atezo+epacadostat

Atezo+erlotinib

Atezo+GDC-0919

Atezo+ipilimumab

Atezo+varlilumab

Durva+AZD6738

Durva+epacadostat

Durva+gefinitib

Durva+ibrutinib

Durva+mocetinostat

Durva+ramucirumab

Ave+crizotinib

Ave+lorlatinib

Ave+PF-04518600

Ave+utomilumab

PDR001+LAG525

Nivo+ipilimumab

Pembro+epacadostat

Pembro+T-VEC

Nivo+BMS-986016

Nivo+cabiralizumab

Nivo+epacadostat

Nivo+lirilumab

Nivo+urelumab

Pembro+AM0010

Pembro+CAVATAK

Pembro+CMP-001

Pembro+darbafenib+trametinib

Pembro+entinostat

Pembro+GSK-3174998

Pembro+LV305

Pembro+IMP321

Pembro+lenvatinib

Pembro+pexidartinib

Pembro+SD-101

Pembro+X4P-001

Atezo+cobimetinib

Atezo+CPI-444

Atezo+GDC-0919

Atezo+IFNα-2b

Atezo+varlilumab

Durva+dabrafenib+trametinib

Durva+epacadostat

Ave+PF-04518600

Ave+utomilumab

PDR001+LAG525

NSCLC

SCLC

Melanoma

Nivo+ Rova-T

Atezo+bevacizumab

Ave+axitinib

Pembro+axitinib / lenvatinib

Nivo+BMS-986016

Nivo+lirilumab

Pembro+ipilimumab

Pembro+AM0010 Atezo+CPI-444

Pembro+GSK-3174998

Pembro+epacadostat Atezo+GDC-0919

Atezo+IFNα -2b

Atezo+varlilumab

RCC

Atezo+chemo

Pembro+chemo

Nivo+ipilimumab

Pembro+CAVATAK

Pembro+enadenotucirev

Pembro+epacadostat

Pembro+GSK-3174998

Pembro+lenvatinib

Pembro+pexidartinib

Pembro+ramucirumab

Atezo+CPI-444

Atezo+emactuzumab

Atezo+GDC-0919

Atezo+varlilumab

Durva+AZD4547 Durva+tremelimumab

Durva+tremelimumab

UC

Nivo+ipilimumab

Pembro+chemo / T-VEC

Nivo+BMS-986016

Nivo+cabiralizumab

Nivo+epacadostat

Nivo+urelumab

Nivo+varlilumab

Pembro+enadinotucirev

Pembro+epacadostat

Pembro+GSK-3174998

Pembro+lenvatinib

Pembro+pexidartinib

Atezo+CPI-444

Atezo+GDC-0919

Atezo+varlilumab Durva+AXAL

Durva+AZD5069

Durva+AZD6738

Durva+AZD9150

Durva+epacadostat

SCCHN

Nivo+BMS-986156 Nivo+BMS-986178 Nivo+mogamulizumab Pembro+MK-1248 Pembro+MK-4166

Pembro+MK-4280

Atezo+bevacizumab

Atezo+MOXR0916 Atezo+MTIG7192A Atezo+RG-7802

Atezo+RG-7813 Atezo+RG-7876 Atezo+vanicizumab

Durva+IMC-CS4 Durva+LY2510924

Durva+MEDI0562

Durva+MEDI0680

Durva+MEDI9447 Durva+monalizumab

Durva+mogamulizumab Durva+selumetinib

Pembro+demcizumab

Atezo+chemo

Pembro+chemo

Pembro+epacadostat

Pembro+GSK-3174998

Pembro+niraparib Nivo+ipilimumab

Atezo+CPI-444

Atezo+emactuzumab

Atezo+entinostat

Atezo+GDC-0919

Atezo+T-VEC

Atezo+varlilumab

Durva+tremelimumab

Ave+utomilumab

PDR001+BLZ945

TNBC

Ovarian

Ave+chemo

Atezo+chemo

Pembro+epacadostat

Pembro+niraparib

Nivo+lirilumab

Atezo+GDC-0919

Atezo+emactuzumab

Ave+entinostat

Nivo+epacadostat

Atezo+rucaparib

Nivo+varlilumab

Pembro+mirvetuximab soravtansine

Pembro+pexidartinib

Pembro+margetuximab

Atezo+GDC-0919

Atezo+emactuzumab

Pembro+PEGPH20

Pembro+pexidartinib

Pembro+ramucirumab

Pembro+trastuzumab

Nivo+BMS-986016

Atezo+bevacizumab

Durva+ramucirumab

PDR001+LAG525

Pembro+chemo

Nivo+ipilimumab

Gastric

Atezo+cobimetinib

Nivo+epacadostat

Pembro+enadenotucirev

Nivo+cabiralizumab

Atezo+bevacizumab

Nivo+ipilimumab

Pembro+GSK-3174998

Atezo+CPI-444

Atezo+GDC-0919

Atezo+T-VEC

Ave+PF-04518699

CRC


Pembro+BL-8040

Durva+tremelimumab

Nivo+cabiralizumab

Durva+AZD5069

Durva+epacadostat

Durva+galunisertib

Durva+ibrutinib

Pancreas

Nivo+ BMS-986016

Durva+ ramucirumab

PDR001+capmetinib

Durva+ tremelimumab

Nivo+CC-122

Nivo+galunisertib

Atezo+bevacizumab

Liver

Phase1or1/2

Phase2

Phase3

Marketed

Pembro+chemo

Atezo+CPI-444

Pembro+ipilimumab

Nivo+varlilumab

Nivo+ipilimumab

Pembro+INCB039110

Pembro+utomilumab PDR001+GWN323

PDR001+MBG453

Nivo+ipilimumab

Nivo+ulocuplumab

Pembro+pelareoprep

Pembro+pexidartinib

Nivo+lirilumab Nivo+varlilumab

Pembro+iMiD

Nivo+iMiD+/-elotuzumab

Durva+/-iMiD

Durva+azacitidine

Atezo+obinutuzumab+/-iMiD

Atezo+obinutuzumab+polatuzumab

Atezo+tazemetostat

Atezo+daratumumab+/-iMiD

Atezo+azacitidine

Durva+AZD9150

Durva+ibrutinib

Durva+rituximab+iMiD

Durva+rituximab+bendamustine

Durva+tremelimumab

Nivo+brentuximab vedotin

Nivo+epacadostat

Nivo+ibrutinib

Nivo+ipilimumab

Nivo+urelumab


Pembro+AFM13

Pembro+epacadostat

Pembro+dinaciclib

Pembro+G100

Pembro+dasatinib

Heme

Solid

PDR001 + BLZ945

PDR001+MCS110

Nivo+CB-1158

Atezo+codrituzumab

Atezo+BL-8040 Atezo+cobimetinib

+vemurafenib

Nivo+NKTR-214

Nivo+CV-301

Pembro+CAVATAK

PDR001+canakinumab

PDR001+CJM112

PDR001+EGF816

PDR001+trametinib Nivo+NKTR-214

PDR001+LAG525

PDR001+dabrafenib+trametinib


Nivo+NKTR-214

Pembro+B-701

Atezo+PEGPH20

Ave+defactinib

Nivo+JTX-2011

PDR001+CJM112

Pembro+pexidartinib

PDR001+canakinumab PDR001+EGF816

Adapted from Vanessa Lucey of CRI by Gergely Jarmy

Chen and Mellman, Nature 2017

Mechanisms of primary and secondary immuno-resistance

Syn et al, Lancet Oncol 2017

The future of Melanoma Immunotherapy

• Adapted from Hegde PS et al. Clin Cancer Res 2016;22(8):1865-1874.

Inflamed tumor Non-inflamed tumor

Immune desert tumorspre-existing immunity T-cell migration defect

angiogenesis, MDSC, immunosuppressive

reactive stroma

Low MHC I

TILsCD8 T cells/IFNγ

PD-L1 & checkpoints

Mutational Load

Epigenetic Immunomodulation of Cancer cell

• Maio M et al. CCR 2015

Epigenetic immuno-sequencing: the NIBIT-M4 Study NCT02608437

W1 W4 W7 W10

Ipilimumab4 x q21

W0 W3 W6 W9Guadecitabine5 days q21 WKTA

W12

Tumor biopsyPBMC

Tumor biopsyPBMC

Tumor biopsyPBMC

Methylome

DNA

Transcriptome

RNA

Exome

DNA

Epigenetic immuno-sequencing: the NIBIT-M4 Study NCT02608437

Phenotipic,functionalanalyses of

PBMC

IMMUNE-CONTEXTUREdensity, location, organization and

functional orientation of tumor-infiltrating

immune cellsFFPE

W1 W4 W7 W10

Ipilimumab4 x q21

W0 W3 W6 W9Guadecitabine5 days q21 WKTA

W12

Tumor biopsyPBMC

Tumor biopsyPBMC

Tumor biopsyPBMC

NGS analyses Peripheral and tumor immunophenotype

The future of Melanoma ImmunotherapyTargeting and modulating multiple compartments

TUMORMICROENVIRONMENT

Antigens

Active T cell

Cancer cell

Dendriticcell

Apoptoticcancer cell

Active T cell

IMMUNESYSTEM

TUMORMICRO-

ENVIRONMENT

TUMOR

IMMUNE SYSTEM

TUMOR

The future of Cancer ImmunotherapyPatient-tailored immunotherapeutic

approaches

TUMOR MICRO-ENVIRONMENT

Targeting and modulating multiple compartments

• Maresa Altomonte

• Luana Calabrò

• Maria Grazia Daffinà

• Riccardo Danielli

• Anna Maria Di Giacomo

• Elisabetta Gambale

• Santa Monterisi

• Ivan Parla

• Giulia Rossi

• Monica Valente

• Angela Iacovelli

• Sergio Speranza

• Marilena Piccinelli

• Marica Pierli

• Fatma Socrati

• Roberta Crispino

• Vincenzo Di Nuzzo

Medical Oncology and ImmunotherapyCenter for Immuno-Oncology

University Hospital of Siena - Italy

• Giovanni Amato

• Sara Cannito

• Carla Chiarucci

• Sandra Coral

• Alessia Covre

• Ornella Cutaia

• Carolina Fazio

• Simona Mastrandrea

• Gianluca Giacobini

• Elisa Ibba

• Andrea Lazzeri

• Fabrizio nardi

• Maria Lofiego

• Alessia Longo

• Tommaso Vittori

• Patrizia Tunici

• Filomena Cisternino

Michele Maio

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