Strategie di immunoterapia nel melanoma

(1)

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

(2)

Surgery

Radiotherapy

Chemotherapy

Evolving Therapeutic Options for

Cancer Treatment

(3)

Surgery

Radiotherapy

Chemotherapy

Immunotherapy

Evolving Therapeutic Options for

Cancer Treatment

(4)

 Tissue samples readily

accessible

 Adaptable to tissue culture

 Amenable to testing of

novel

therapies

Melanoma as a tool for cancer research

(5)

1970s 1980s 1990s 2000s 2010s

Spontaneous regressions in melanoma: immune

component?

1^st 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)

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

(7)

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)

(8)

0 1 2 3 4 5 6 7 8 9 10 100

90 80 70 60

0 50 40 30 20 10

Overa ll Su rviva l (%)

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.

(9)

KEYNOTE-006

(10)

Topalian S, et al., NEJM 2012

PD-L1 tumor expression

PREDICTIVE MARKERS OF RESPONSE TO PD1/PD-L1 BLOCKADE

(11)

Robert C, NEJM, 2015

BMS CA209-066: Overall survival by treatment group

and PDL-1 status subgroup

(12)

[TITLE]

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

(13)

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

(14)

Progression-Free Survival

(Intent-to-Treat Population)

49%

42%

18%

46%

39%

14%

Percentage of PFS

PFS per Investigator (months) 0

10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27

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)** -- --

CONFIDENTIAL – NOT FOR FURTHER DISTRIBUTION

*Stratified log-rank P<0.00001 vs. IPI

**Exploratory endpoint

Database lock Sept 2015

14

Progression-free Survival (%)

(15)

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

Database lock Sept 2015

15

Progression-free Survival (%) Progression-free Survival (%)

(16)

R es p onse

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

(17)

 New Clinical Settings

 Mechanism(s) of resistance

 New Targets

 New combos/sequences

(18)

Effect in the CNS?

(19)

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

(20)

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)

(21)

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

(22)

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

(23)

 New Clinical Settings

 Mechanism(s) of resistance

 New Targets

 New combos/sequences

(24)

Tumors develop multiple mechanisms

to evade the immune system

(25)

HLA class I downregulation in different tumor lesions

Courtesy of S. Ferrone

(26)

(27)

It takes two to tango

(28)

 New Clinical Settings

 Mechanism(s) of resistance

 New Targets

 New combos/sequences

(29)

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

(30)

IDO-mediated immunesuppression

(31)

(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

(32)

 New Clinical Settings

 Mechanism(s) of resistance

 New Targets

 New combos/sequences

(33)

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

(34)

Heritable changes in gene expression not based

on modifications of the DNA sequence

EPIGENETICS

(35)

EPIGENETICS AND CANCER

D N A met hy lat ion

Cancer development and progression

GLOBAL genomic DNA

HYPOMETHYLATION

GENE-SPECIFIC promoter

HYPERMETHYLATION

(36)

DNA methylation

Histone modifications

MicroRNA gene silencing

EPIGENETIC MODIFICATIONS

PHARMACOLOGICALLY REVERSIBLE

DNMTs inhibitors (DNMTi)

HDAC inhibitors (HDACi)

Maio et al, unpublished

(37)

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

& Therapeutics 2014

pro-apoptotic genes expression X

& Therapeutics 2014

CD4 proliferation X

Kroesen M,

Oncotarget 2014

function of CD8 X X

Kroesen M,

Oncotarget 2014

(38)

Can epigenetic modulation of

neoplastic cells be used to design novel immunotherapeutic

approaches in cancer?

(39)

Maio M. et al., CCR 2015

Epigenetic Immunomodulation of Cancer cell

(40)

COMBOS

TUMOR

Epigenetic drugs

Modulate

tumor immunogenicity and immune recognition HOST

Check-point mAb

Improve host’s immune system activity

Epigenetic immuno-sequencing

(41)

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

A. Covre et al., Semin Oncol 2015

84%

63%

(42)

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

(43)

NEWS FEATURES

Nature Medicine 2016

(44)

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

(45)

(46)

(47)

Cancer Bio- Immunotherapy in Siena

XIV NIBIT Meeting

(48)

• 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

(49)

Medical Oncology and Immunotherapy, University Hospital of Siena

(50)

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 tissue

^1,2

Tumour cells rupture for an oncolytic effect

^1–3

Systemic tumour-specific immune response

^4,5

Death of distant cancer cells

^4–6

Oncology

(51)

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 25 0 50 100 200 300 400 500 600

C hange from bas eline (%)

‡ §

Puzanov I, et al. ASCO 2015: Abstract 9063

.

(52)

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 1

^st

dose 10

⁶

PFU/mL

Then 10

⁸

PFU/mL Q2W

T-VEC Intralesional

Wk -5 Wk -2

(53)

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

(54)

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

(55)

“Unconventional” clinical responses with I-O agents

Vaccines

(i.e., PD followed by OR)

(56)

08-1999 03-2000 06-2000

11-2000 02-2001 08-2008

Maio M. et al, unpublished

Metastatic melanoma

(57)

“Unconventional” clinical responses with I-O agents

(i.e., PD followed by OR)

Vaccines

CTLA-4

(58)

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

Baseline PD after 2

^nd

dose PR after 4

^th

dose PR after 7

^th

dose

Calabrò et al, OncoImmunology 2014

Pleural mesotelioma

(59)

“Unconventional” clinical responses with I-O agents

PD1/PDL1

(i.e., PD followed by OR)

Vaccines

CTLA-4

(60)

Early responses

(61)

“Unconventional” clinical responses with I-O agents

(i.e., PD followed by OR)

PD1/PDL1 Vaccines

CTLA-4

PD1/PDL1

+

CTLA-4

(62)

On treatment Off treatment First response Ongoing response

0 8 16 24 32 40 48 56 64 72 80

Time (weeks)

NIVO+IPI

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

Earlier

responses

(63)

 True tumor progressions

 Pseudoprogressions

 Tumor flares

(64)

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

(65)

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.

Di Giacomo AM., Cancer Immunol Immunother., 2011

(66)

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)

Di Giacomo AM., Cancer Immunol Immunother., 2011

(67)

IPILIMUMAB PATTERN OF RESPONSE

Baseline W 12 PD W 24 SD W 120 SD

Baseline W 12 W 24 W 120

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

(68)

IPILIMUMAB PATTERN OF RESPONSE

W1R (W152)

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

PD

CR

W60 R

CR CR W12 R

CR

PR

(69)

w24

Baseline

(70)

CD8+ Granzyme+

Pre-therapy

(71)

W12

CLINICAL CASE W20

60-year-old Female Affected by Stage III Melanoma

“Inflammatory flares -Pseudo-progression”

W24 W36 W48 W60 W72 W80

W18

MAINTENANCE

TA

INDUCTION

W18 W24

•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

(72)

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

(73)

CLINICAL CASE

60-year-old Female Affected by Stage III Melanoma

INDUCTION MAINTENANCE

W24 W36 W48 W60 TA W72 W80 Current Recommendations W72

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

–scan as scheduled at next time point

–maintain treatment per

protocol schedule

(74)

irAE management

What patients don’t say!

(75)

03 Feb 2015 diagnosis of epithelioid pleural mesothelioma, stage IV 19 Feb 2015 start 1st line CT w Cisplatin/Pemetrexed x 4 cyclesPR

--> 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

(76)

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

(77)

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

(78)

(79)

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

m g /d l

Low doses of steroids

High doses of steroids*

(80)

Beware of “non-conventional” concurrent medications

Take home message (Case 1)

(81)

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 Clincal benefit

SD

PR

* Dexamethasone 8 mg i.v. BID x 7 daysslow tapering

*

(82)