Eventi Formativi...

Michele Maio Medical Oncology and Immunotherapy, Department of Oncology

University Hospital of Siena, Istituto Toscano Tumori

SIENA, ITALY

Eventi Formativi AIOM-SIAPEC-IAP

“VI Corso Nazionale”

Roma, 15 Giugno 2016

Strategie di immunoterapia nel melanoma

Surgery

Radiotherapy

Chemotherapy

Evolving Therapeutic Options for Cancer Treatment

Surgery

Radiotherapy

Chemotherapy

Immunotherapy

Evolving Therapeutic Options for Cancer Treatment

Tissue

samples

readily

accessible

Adaptable to

tissue culture

Amenable to

testing of

novel

therapies

Melanoma as a tool for cancer research

1970s 1980s 1990s 2000s 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)

2011 Ipilimumab approved

for advanced melanoma

2014–2015: Nivolumab,

pembrolizumab Approved in advanced melanoma and NSCLC.

Nivolumab + ipilimumab in

melanoma (US)

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…

6

Adapted from Pardoll DM 2012.

APC/

Tumor T cell

CD40 CD40L

CD137

OX40

CD137L

OX40L

Activation

Activation

Activation

PD-1

B7-1 (CD80)

PD-L1

PD-L2

LAG-3

MHC

CD28 Activation B7-2 (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

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)

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

8

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.

KEYNOTE-006

Topalian S, et al., NEJM 2012

PD-L1 tumor expression

PREDICTIVE MARKERS OF RESPONSE TO PD1/PD-L1 BLOCKADE

Robert C, NEJM, 2015

BMS CA209-066: Overall survival by treatment group

and PDL-1 status subgroup

[TITLE]

Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting

Unresectable or

Metatastic Melanoma

• Previously untreated

• 945 patients

CA209-067: Study Design CA209-067: Study Design

Treat until

progression**

or

unacceptable

toxicity

NIVO 3 mg/kg Q2W + IPI-matched placebo

NIVO 1 mg/kg +

IPI 3 mg/kg Q3W for 4

doses

IPI 3 mg/kg Q3W for 4 doses +

NIVO-matched placebo

Randomize

1:1:1

Stratify by:

• Tumor PD-L1 expression*

• BRAF mutation status

• AJCC M stage

*Verified PD-L1 assay with 5% expression level was used for the stratification

of patients; validated PD-L1 assay was used for efficacy analyses.

**Patients could have been treated beyond progression under protocol-defined circumstances.

N=314

N=316

N=315

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION

NIVO 3 mg/kg Q2W

Randomized, double-blind, phase III study

to compare NIVO+IPI or NIVO alone to IPI

alone

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION 13

Progression-Free Survival (Intent-to-Treat Population)

49%

42%

18%

46%

39%

14%

Pe

rce

nta

ge

of

PF

S

PFS per Investigator (months)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 27 24 21

314

316

315

174

148

78

133

114

46

103

94

25

8

8

3

219

177

137

156

127

58

126

104

40

48

46

15

0

0

0

Number of patients at risk:

Nivolumab + Ipilimumab

Nivolumab

Ipilimumab

NIVO+IPI

NIVO

IPI

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

Median PFS, months (95% CI)

11.5 (8.9–16.7)

6.9 (4.3–9.5) 2.9 (2.8–3.4)

HR (99.5% CI) vs. IPI 0.42 (0.31–

0.57)* 0.55 (0.43–

0.76)* --

HR (95% CI) vs. NIVO 0.76 (0.60–

0.92)** -- --


*Stratified log-rank P<0.00001 vs. IPI

**Exploratory endpoint


Database lock Sept 2015

14

Pro

gre

ssio

n-f

ree S

urv

ival (%

)

Progression-free Survival by Tumor PD-L1 Expression

Tumor PD-L1 Expression Level ≥5% Tumor PD-L1 Expression Level <5%

• Similar results were seen using 1% as the PD-L1 expression cut-off


NIVO + IPI

(N=68)

NIVO

(N=80)

IPI

(N=75)

Median PFS,

months (95%

CI)

NR

(9.7─NR)

22.0

(8.9─NR)

3.9

(2.8–4.2)

HR (95% CI) vs

NIVO

0.87

(0.54–

1.41)*

─ ─

NIVO + IPI

(N=210)

NIVO

(N=208)

IPI

(N=202)

Median PFS,

months (95%

CI)

11.1

(8.0–

22.2)

5.3

(2.8–7.1)

2.8

(2.8–3.1)

HR (95% CI) vs

NIVO

0.74

(0.58–

0.96)*

─ ─ *Exploratory endpoint *Exploratory endpoint


Database lock Sept 2015

15

Pro

gre

ssio

n-f

ree S

urv

ival (%

)

Pro

gre

ssio

n-f

ree S

urv

ival (%

)

Response

Time (months)

Chemotherapy/Targeted Agents and

Immuno-therapy Differ in Action and Outcome

0 6 24

CT/target

CTLA-4

CTLA-4+PD-1

PD-1

Maio M. et al, unpublished

New Clinical Settings

Mechanism(s) of resistance

New Targets

New combos/sequences

Effect in the CNS?

26-30 September 2014, Madrid, Spain

esmo.org

IPILIMUMAB Margolin K, Lancet Oncol 2012

N

DCR

OS (m)

PSF (m)

Asymptomatic 51 24% 7.0 1.5

Symptomatic 21 10% 4.0 1.2

IPILIMUMAB + FTM

NIBIT M1

Di Giacomo AM, ESMO 2013

N

DCR

OS (m)

PSF (m)

Asymptomatic 20 50% 12.7 3.4

CTLA-4 blockade in MBM

NIBIT - M1

3-years survival update

Di Giacomo AM et al., Annals Oncol 2015

Secondary Endpoints Study population

(N=86)

Patients with

MBM (N=20)

Median OS, months (95% CI)

12.9 (7.1-18.7) 12.7 (2.7-22.7)

3-year survival rate, % (95% CI)

28.5 (20.1-41.3) 27.8 (17.2-60.6)

Median ir-PFS, months (95% CI)

4.5 (3.1-5.9) 3.4 (2.3-4.5)

Screening/ Baseline Randomization

Arm A Induction Phase

Fotemustine: 100mg/m2 iv q1 week for 3 doses

Manteinance Phase Fotemustine: 100mg/m2 q3 weeks

from week 9 for 6 doses

Arm B Induction 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 Phase Ipilimumab: 10 mg/kg iv q12 weeks from week 24

Arm C Induction Phase

Nivolumab 1mg/kg iv + ipilimumab 3mg/kg iv q3 for 4 doses

Manteinance Phase Nivolumab 3mg/kg iv q2 weeks

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

The NIBIT-M2 study design

Siena - Azienda Ospedaliera Universitaria Senese

PI - Coordinatore nazionale Dr. ssa Anna Maria Di Giacomo

Milano - I.E.O. Istituto Europeo di Oncologia

PI Dr. Pier Francesco Ferrucci

Milano - Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori

PI Dr. Michele Del Vecchio

Torino –AOU Città della salute e della Scienza

PI Dr. Pietro Quaglino

Padova- Istituto Oncologico Veneto

PI Dr. ssa Vanna Chiarion-Sileni

Genova - Istituto Nazionale per la Ricerca sul Cancro

PI Dr. ssa Paola Queirolo

Bergamo - Azienda Ospedaliera Papa Giovanni XXIII

PI Dr. Mario Mandalà

Bari - IRCCS Giovanni Paolo II

PI Dr. Michele Guida

Roma - Istituto Dermatopatico dell’Immacolata -IDI

PI Prof. Paolo Marchetti

Candiolo –Istituto Candiolo I.R.C.C.S.

PI Prof. Massimo Aglietta

NIBIT – M2



New Targets


Tumors develop multiple mechanisms

to evade the immune system

HLA class I downregulation in different tumor lesions

Courtesy of S. Ferrone

It takes two to tango



New Targets


Multiple immune inhibitory and co-stimulatory pathways in the tumor microenvironment are

targets of therapeutic manipulation by antibodies or drugs.

Drew Pardoll, and Charles Drake J Exp Med 2012;209:201-

209

© 2012 Pardoll and Drake

IDO-mediated immunesuppression

(MK-3475-022) - Studio di Fase I/II per valutare la sicurezza e l’efficacia di MK-3475 in combinazione con trametinib e dabrafenib in soggetti con melanoma avanzato

(MK-3475 Protocol 252) - A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Pembrolizumab (MK-3475) in Combination With Epacadostat or Placebo in Subjects with Unresectable or Metastatic Melanoma (Keynote-252/INCB 24360-

301)

SNDX-275-0601 NSCLC and Melanoma, immuno-oncology study (pembro+entinostat)

Ongoing combos



New Targets


Immune check-point(s) blockade-based

combinations/sequences holding the most promise

for future development

• Vaccines

• Cytokines

• Tumor microenvironment modulating agents

• Selected chemotherapeutic agents

• Targeted therapies

• Epigenetic therapies

Heritable changes in gene expression

not based

on modifications of the DNA sequence

EPIGENETICS

EPIGENETICS AND CANCER D

NA

me

thyla

tio

n

Cancer development and progression

GLOBAL genomic DNA

HYPOMETHYLATION

GENE-SPECIFIC promoter

HYPERMETHYLATION

DNA

methylation

Histone

modifications

MicroRNA

gene silencing

EPIGENETIC MODIFICATIONS

PHARMACOLOGICALLY

REVERSIBLE

DNMTs inhibitors

(DNMTi)

HDAC inhibitors

(HDACi)

Maio et al, unpublished

Immunomodulatory activities of DNMTi and HDACi

Effect target DNMTi HDACi ref

CTA expression X Sigalotti L, Blood, CCR, CR, 2003-2005

MHC class I expression X X Sigalotti L Pharmacology & Therapeutics 2014

MHC class II expression X X Gialitakis M, Nucleic Acids Res. 2006

co-stimulatory molecules expression X X Magner WJ, J Immunology 2000

NKG2D ligands expression X Armeanu S, Cancer Res. 2005

FOXP3 expression X X Licciardi PV, ISRN Hematology 2012

function of DC X Licciardi PV, ISRN Hematology 2012

TRAIL and FAS expression X Sigalotti L Pharmacology & Therapeutics 2014

pro-apoptotic genes expression X Sigalotti L Pharmacology & Therapeutics 2014

CD4 proliferation X Kroesen M, Oncotarget 2014

function of CD8 X X Kroesen M, Oncotarget 2014

Can epigenetic modulation of

neoplastic cells be used to design

novel immunotherapeutic

approaches in cancer?

Maio M. et al., CCR 2015

Epigenetic Immunomodulation of Cancer cell

COMBOS

TUMOR

Epigenetic drugs

Modulate

tumor immunogenicity

and immune recognition HOST

Check-point mAb

Improve host’s immune

system activity

Epigenetic immuno-sequencing

Antitumor activity of SGI-110 + α-CTLA-4 mAb in TS/A (breast) tumors

A. Covre et al., Semin Oncol 2015

84%

63%

Epigenetic immuno-sequencing: the NIBIT-M4 Study

(NCT02608437)

W1 W4 W7 W10 Ipilimumab 4 x q21

W0 W3 W6 W9

SGI-110

5 days q21

WK

TA W 12

A.M. Di Giacomo et al. Semin Oncol, 2015

FPFV October 12, 2015

NEWS FEATURES Nature Medicine 2016

CTLA-4 PD1-PDL1 CTLA-4/PD1

Combos

Melanoma Lung cancer

Other tumors

Mesothelioma Urothelial

Colorectal

Glioblastoma

Head-Neck

Ovarian

Breast

Renal

Novel targets

4-1BB

OX-40 ICOS KIR

TIM-3

LAG-3 CD40

IDO

Cancer Bio- Immunotherapy in Siena XIV NIBIT Meeting

• Maresa Altomonte • Erika Bertocci • Luana Calabrò • Ornella Cutaia • Riccardo Danielli • Anna Maria Di Giacomo • Carolina Fazio • Ester Fonsatti • Cristina Maccalli • Lorenzo Pilla

MEDICAL ONCOLOGY AND IMMUNOTHERAPY DEPT. OF MEDICAL ONCOLOGY UNIVERSITY HOSPITAL OF SIENA

• Francesca Colizzi • Sandra Coral • Alessia Covre • Elisabetta Fratta • Hugues Nicolay • Giulia Parisi • Aurora Rizzo • Luca Sigalotti

Michele Maio and

Medical Oncology and Immunotherapy, University Hospital of Siena

© 2015 Amgen Inc. All rights reserved

1

T-VEC – an HSV-1-derived oncolytic

immunotherapy designed to produce local

and systemic effects

Proposed mechanism of action for T-VEC.

Local effect:

virus-induced tumour-cell lysis

Systemic effect:

tumour-specific immune response

Selective viral

replication in

tumour tissue1,2

Tumour cells rupture for

an oncolytic effect1–3

Systemic

tumour-specific

immune response4,5

Death of distant

cancer cells4–6

Oncology

© 2015 Amgen Inc. All rights reserved

Response to T-VEC + ipilimumab

The waterfall plot shows best reductions in tumour burden at a single time point. For the immune-related response criteria (irRC)

response table, CR, PR and PD needed to be confirmed by consecutive assessments no less than 4 weeks apart to be considered

confirmed with the following exception: if PD was the last evaluable tumour assessment, it was considered as confirmed.

*The actual number of overall responders by irRC at time of data analysis was 10, but subsequently one was found to be incorrectly

reported as a confirmed PR instead of the correct assessment of SD. The table has been updated to reflect the corrected data; †Last response was PD followed by unevaluable response. ‡This subject was incorrectly reported to have best overall response

(BOR) of −100% at time of data analysis, but the corrected BOR is −46%; §Unconfirmed CR.

Best irRC confirmed

response

Per irRC

n (%)

ORR* 9 (50)

CR 4 (22.2)

PR 5 (27.8)

SD 4 (22.2)

PD 4 (22.2)

Unevaluable† 1 (5.6)

Disease control rate

(CR + PR + SD) 13 (72.2)

d

N = 18

d

Stage IIIC (n = 3)

Stage IV M1c (n = 4)

Stage IV M1b (n = 5)

Stage IV M1a (n = 4)

Stage IIIB (n = 1)

-100

-50

0 25 50

100

200

300

400

500

600

Ch

an

ge

fro

m b

ase

line

(%

)

‡ §

Puzanov I, et al. ASCO 2015: Abstract 9063.

Phase 1b: Study design

Treatment until whichever occurs first: • Progressive disease (PD) per irRC • Intolerance • 2 Years • All injectable tumors disappeared (T-VEC only)

S

A

F

E

T

Y

F

O

L

L

O

W

-

U

P

30 (+7)

days after

end of

treatment

• Unresectable stage

III or IV melanoma

• Treatment naive

• Injectable lesions

• No clinically active

brain mets

• No active herpetic

skin lesions or prior

complications from

herpetic infection

N=21

Wk 6 DLT

Window

Pembrolizumab 200mg IV Q2W

Wk 0

T-VEC intralesional

Up to 4 mL per treatment

1st dose 106 PFU/mL

Then 108 PFU/mL Q2W

T-VEC Intralesional

Wk -5 Wk -2

Next steps

Phase 2

Monotherapy T-VEC to evaluate correlation between

ORR and baseline intratumoral CD8+ cell density

Phase 3 (MASTERKEY-265)

T-VEC + pembrolizumab vs pembrolizumab

T I M E

Cancer-Cell Directed vs Immune-System Directed

Cancer Treatment: a Matter of Time

Chemotherapy/

Target Therapy

Tumor Cell

Destruction

Immunotherapy Tumor Cell

Destruction

Immune System

Activation

“Unconventional” clinical responses with I-O agents

Vaccines

(i.e., PD followed by OR)

08-1999 03-2000 06-2000

11-2000 02-2001 08-2008

Maio M. et al, unpublished

Metastatic melanoma



Vaccines

CTLA-4

Survival 52 months, received 8 cycles (last one in Aug 2012)

Baseline PD after 2nd dose PR after 4th dose PR after 7th dose

Calabrò et al, OncoImmunology 2014

Pleural mesotelioma


PD1/PDL1


Vaccines

CTLA-4

Early responses



PD1/PDL1

Vaccines

CTLA-4

PD1/PDL1 +

CTLA-4

On treatment

Off treatment

First response

Ongoing response

0 8 16 24 32 40 48 64 72 80 56

Time (weeks)

NIV

O+

IPI

Timing of OR induced by anti-CTLA4 + anti-PD1

Earlier

responses

True tumor progressions

Pseudoprogressions

Tumor flares

IPILIMUMAB PATTERN OF RESPONSE

W 24 Baseline

Baseline

W 12 PD

W 12

Induction Phase IPI 10mg/Kg ev d1, Q3ws x 4 Maintenance Phase IPI 10mg/Kg ev d1, Q12ws

Di Giacomo AM., Cancer Immunol Immunother., 2011

W 24

SD

Histopathology of cutaneous biopsy at week 56

Haematoxylin and eosin staining depicting strong regressive changes both in

flat and nodular areas of the tumor biopsy; neoplastic melanocytes were

virtually absent throughout the whole lesion.


Histopathology of liver biopsy at week 102

Histological examination of a liver melanoma mts showed massive necrosis of melanocytes.

On left, well-preserved fibroblats with rare lymphocytes inside a fibrotic septum, and

melanophages are recognizable (original magnification 200x)



Baseline W 12 PD W 120 SD W 24 SD

Baseline W 12 W 120 W 24

Induction Phase Maintenance Phase IPI 10mg/Kg ev d1, Q3ws x 4 IPI 10mg/Kg ev d1, Q12ws



W1R (W152)

Follow-up Reinduction Phase IPI 3mg/Kg iv d1, Q3 ws x4

PD

CR

W60 R

CR

CR

W12 R

CR

PR

w24 Baseline

CD8+ Granzyme+

Pre-therapy

W12

W20 CLINICAL CASE 60-year-old Female Affected by Stage III Melanoma

“Inflammatory flares -Pseudo-progression”

W24 W36 W48 W60 W72 W80

W18

MAINTENANCE

TA

INDUCTION

W24 W18


•Early appearance following adjuvant ipi treatment (Protocol. BMS CA 184029)

–early induction phase, up to week 12

–enlarged lymph nodes

*FNA left palatine tonsil: normal

Adjuvant melanoma trial BMS029/EORTC 18071

W60

W66

W60

At W60 evidence of a Single pulmonary lesion (37x34mm), with the morphologic feature of an inflammatory lesion.

According with the current recommendations we have skipped the scheduled dose (W60)

and we have obtained a F/U scan after 6 weeks.

CLINICAL CASE 60-year-old Female Affected by Stage III Melanoma


W60

W66

CLINICAL CASE 60-year-old Female Affected by Stage III Melanoma


INDUCTION MAINTENANCE

W24 W36 W48 W60 TA W72 W80

W72 Current Recommendations

•If F/U scan stable or resolved or biopsy negative for tumor:

–scan as scheduled at next time point

–maintain treatment per

protocol schedule

irAE management

What patients don’t say!

03 Feb 2015 diagnosis of epithelioid pleural mesothelioma, stage IV

19 Feb 2015 start 1st line CT w Cisplatin/Pemetrexed x 4 cyclesPR

--> CT w Carboplatin/Pemetrexed x 4 cycle (until 07 July 2015)-->SD

Jan 2016 PD-->enrollement in NIBIT-MESO-1 study

Clinical Case 3

M, 48-year-old, PS=0

NIBIT-Meso-1: Study Design

Cycle

Week

Re-treatment in case of PD after induction phase or follow-up

13 12 11 10 9 8 7 6 5 4 3 2 1

48 44 40 36 32 28 24 20 16 12 8 4 0

Treatment FU Screening

MEDI4736 Dose Q4W (9 doses)

Tremelimumab +

MEDI4736 Dose

Q4W (4 doses)

TA TA TA TA TA

FU= follow-up; TA= tumor assessment

08 Mar 2016 lab tests showed increase levels of Bilirubin total and direct,

transaminases (G3 CTC)

• No deterioration of clinical condition (PS=0)

• No significant abnormalities showed at liver ultrasound and liver MRI

• Viral test negatives

• Autoimmunity test negatives

21 Mar 2016 Liver biopsy

23 Feb 2016 1st dose with treme+MEDI4736

25 Mar 2016 we knew that the patient had taken homeopathy compound

(Ganoderma/Coriulus, chinese mushroom) -->hospitalization for

worsening of lab tests

Bilirubin

0

5

10

15

20

25

8 9 11 14 15 16 17 25 28 30 1 3

mg

/dl

Low doses of steroids

High doses of steroids*

Beware of “non-conventional” concurrent medications

Take home message (Case 1)

Case study liver toxicity

0

200

400

600

800

1000

1200

1400

1600

1800

W1 W12 W24 W48 W70 W71 W72 W73 W84

ALT

AST

Clincalbenefit

SD

PR

* Dexamethasone 8 mg i.v. BID x 7 daysslow tapering

*

Take home message (Case 2)

Don’t drink and drive

Don’t drink and get treated with I-O

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