Michele Maio - Nadirex International | CongressiMichele Maio Medical Oncology and Immunotherapy, Department of Oncology University Hospital of Siena, Istituto Toscano Tumori SIENA,

Michele Maio Medical Oncology and Immunotherapy, Department of Oncology

University Hospital of Siena, Istituto Toscano Tumori

SIENA, ITALY

Immune checkpoint blockade for the

treatment of advanced cancer

6th Edition Innovative Therapy

Monoclonal antibodies and beyond 22 January, 2016 - Milan

Melanoma as a tool for cancer research

Tissue samples

readily

accessible

Adaptable to

tissue culture

Amenable to

testing of novel

therapies

D E C E M B E R 2 0 1 1 | VO L 4 8 0 | N AT U R E | 4 8 1

T-cell costimulatory receptors

T I M E

Cancer-cell directed vs immune-system directed cancer treatment: a matter of time

Chemotherapy/

target therapy

Tumour cell

destruction

Immunotherapy Immune system

activation

Tumour cell

destruction

Patterns of response to ipilimumab in advanced melanoma

150

125

100

75

50

25

0

-25

-50

-75

-100

-125

19,373

17,242

15,111

12,980

10,849

8,718

6,587

4,456

2,325

194

-1,937

SPD

(mm

2)

Relative week from first dose date

50

25

0

–25

–50

–75

–100

–125

Ch

ange

fro

m b

ase

line

SP

D (

%)


1,272

1,124

975

827

678

530

382

233

85

-64

-212

SPD

(mm

2)

Ch

ange

fro

m b

ase

line

SP

D (

%)

-9 -3 3 9 15 21 27 33 39 45 51


Ch

ange

fro

m b

ase

line

SP

D (

%)

SPD

(mm

2)

2,894

2,556

2,218

1,881

1,543

1,206

868

530

193

-145

-482

50

25

0

-25

-50

-75

-100

-125

Total tumor volume

Index lesions

New lesions

Ipilimumab dosing

SPD = Sum of the Product of the perpendicular Diameters (a measure of tumor volume)

-9 -3 3 9 15 21 27 33 39 45 51

-9 -3 3 9 15 21 27 33 39 45 51

'Stable disease' with slow, steady decline in total tumour volume

Response after initial increase in total tumour volume

Response in baseline lesions

Ch

ange

fro

m b

ase

line

SP

D (

%)

SPD

(mm

2)

2,810

2,482

2,154

1,826

1,498

1,171

843

515

187

-140

-468

50

25

0

-25

-50

-75

-100

-125

-9 -3 3 9 15 21 27 33 39 45 51

9 months


PD

PR

CR

5.2 months 6 months

9.4 months

Response in index and new lesions at or after the appearance of new lesions

Wolchok, et al. Clin Cancer Res 2009; Harmankaya, et al. ESMO 2008;#784P

Week 24 Baseline

CD8+ Granzyme+

Pre therapy

Post therapy

08-1999 03-2000 06-2000

11-2000 02-2001 08-2008

Maio M. et al, unpublished

Kaplan-Meier Plot of Overall Survival BMS CA184024

Maio M et al., J Clin Oncol, 2015

D E C E M B E R 2 0 1 1 | VO L 4 8 0 | N AT U R E | 4 8 1

T-cell costimulatory receptors

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)

Target Agent (Sponsor) Type of mAb

Phase

PD-1 Nivolumab (MDX 1106, BMS-936558,

BMS-ONO)

IgG4 fully human III

Pembrolizumab (MK-3475, Merck Sharp

& Dohme)

IgG4 humanized III

Pidilizumab (CureTech-Teva) IgG1 humanized II

AMP-514 (AZ/MedImmune) IgG I

PD-L1 Atezolizumab (Genetech/Roche) IgG1; fully human

engineered III

Durvalumab (MEDI4736;

AstraZeneca/MedImmune)

IgG; fully human

engineered III

Avelumab (Merck Serono) IgG1; fully human III

BMS-935559 (BMS-ONO) IgG4; fully human I

PD1/PD-L1 Inhibitors in clinical development for Lung Cancer

Patients with pretreated melanoma Died/Treated

n/N Median OS mo (95% CI)

All cohorts 67/107 17.3 (12.5, 37.8)

3.0 mg/kg 11/17 20.3 (7.2, NE)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69

Time Since Treatment Initiation (months)

Pa

tien

ts S

urv

ivin

g (

%)

100

90

80

70

60

0

50

40

30

20

10

1-year OS

65%

63% 2-year OS

47%

48%

3-year OS

41%

42%

4-year OS

35%

32% 3 mg/kg (N=17)

All cohorts (N=107)

CA209-003 Phase 1 Study: Overall Survival

Hodi FS, et al. Presented at: Society for Melanoma Research; November 13-16, 2014; Zurich, Switzerland.

KEYNOTE-001: Melanoma Cohorts

Resp

on

se

Time (months)

Chemotherapy/targeted agents and

immunotherapy differ in action and outcome

0 6 24

CT/target

CTLA-4

CTLA-4+PD-1/PD-L1

PD-1/PD-L1

Maio M, et al. Unpublished

CA209-067 Phase 3 Study: Efficacy

Co-primary Endpoint: PFS (Intent-to-Treat)

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 (95% CI) vs. IPI

0.42 (0.31–0.57)*

0.57 (0.43–0.76)*

--

HR (95% CI) vs. NIVO

0.74 (0.60–0.92)**

-- --

*Stratified log-rank P<0.00001 vs. IPI

**Exploratory endpoint

No. at Risk

314 NIVO + IPI 173 151 65 11 1 219 0

316 NIVO 147 124 50 9 1 177 0

315 IPI 77 54 24 4 0 137 0

0 6 9 12 15 18 3 21

NIVO

NIVO + IPI

IPI

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

po

rtio

n a

liv

e a

nd

pro

gre

ssio

n-f

ree

Wolchok J, et al. N Engl J Med. 2015

Treatment-Related Select AEs Reported in

≥10% of Patients

Patients Reporting Event, %* NIVO (N=313)

NIVO + IPI (N=313) IPI (N=311)

Any

Grade

Grade

3–4 Any

Grade Grade

3–4 Any

Grade Grade

3–4

Skin 41.9 1.6 59.1 5.8 54.0 2.9

Pruritus 18.8 0 33.2 1.9 35.4 0.3

Rash 21.7 0.3 28.4 2.9 20.9 1.6

Rash maculo-papular 4.2 0.3 11.8 1.9 11.9 0.3

Gastrointestinal 19.5 2.2 46.3 14.7 36.7 11.6

Diarrhea 19.2 2.2 44.1 9.3 33.1 6.1

Colitis 1.3 0.6 11.8 7.7 11.6 8.7

Hepatic 6.4 2.6 30.0 18.8 7.1 1.6

Increase in alanine

aminotransferase 3.8 1.3 17.6 8.3 3.9 1.6

Increase in aspartate

aminotransferase 3.8 1.0 15.3 6.1 3.5 0.6

Endocrine 14.4 0.6 30.0 4.8 10.9 2.3

Hypothyroidism 8.6 0 15.0 0.3 4.2 0 • With immune modulatory agents, resolution rates for the majority of grade 3–4 select AEs were:

85-100% for NIVO + IPI, 50-100% for NIVO, and 83-100% for IPI

• As observed in prior studies, most endocrine events did not resolve

Immunotherapy in solid tumours with

immunomodulating antibodies

www.ImmunOncologia.it

Survival improvement for advanced NSCLC in the last 25 years

5-years survival < 2-3%

CA209-017

NCT01642004

(Phase 3; N = 264)

Patients with stage

IIIb/IV squamous

cell NSCLC

CA209-057

NCT01673867

(Phase 3; N = 574)

Patients

with stage IIIb/IV

non-squamous cell

NSCLC

Docetaxel

Primary Objectives

• ORR and OS

Secondary Objectives

• PFS

• ORR and OS by PD-L1 status

• Duration of OR

• Time to OR

• Proportion of patients exhibiting

disease-related

symptom progression (Lung

Cancer Symptom Scale)

Primary Objective

• OS

Secondary Objectives

• ORR

• PFS

• ORR and OS by PD-L1 status

• Duration of OR

• Time to OR

• Proportion of patients exhibiting

disease-related symptom

progression (Lung Cancer

Symptom Scale)

Nivolumab

Docetaxel

Nivolumab

PFS = progression-free survival

Phase 3 trials of nivolumab in NSCLC

Time (mos)

OS

(%

)

Nivolumab

Docetaxel

292 232 194 169 146 123 62 32 0 9

290 244 194 150 111 88 34 10 0 5

100

9

0 80

70

60

50

40

30

10

0

20

27 21 18 15 12 9 6 3 0 24

Time (mos)

Nivolumab

Docetaxel

135 113 86 69 52 31 15 7 0

137 103 68 45 30 14 7 2 0

Number of Patients at Risk

Nivolumab

Docetaxel

24 21 18 15 12 9 6 3 0

100

90

80

70

60

50

40

30

10

0

20

OS

(%

)

Primary Endopoint: Overall Survival

CheckMate 017 SQ NSCLC1

CheckMate 057 Non-SQ NSCLC2

2 Horn L et al, ESMO 2015 1Reckamp K et al, WCLC 2015

Nivolumab

n = 292

Docetaxel

n = 290

mOS 12.2 9.4

P-valuea 0.0009

1-yr os rate, % 51 39

18-mo OS rate, % 39 23

Nivolumab

n = 292

Docetaxel

n = 290

mOS 9.2 6.0

P-valuea 0.00025

1-yr os rate, % 42 24

18-mo OS rate, % 28 13

Safety Summary

a No grade 5 events were reported with nivolumab. b 1% pts had increased ALT/AST,

increased lipase, myasthenic syndrome, or rash, and 2% pts had pneumonitis. c Peripheral

neuropathy (3%) and fatigue (2%). d Interstitial lung disease, pulmonary hemorrhage, and

sepsis (1 pt each).

Nivolumab

n = 131

Docetaxel

n = 129

Any

Grade

Grade

3–5a

Any

Grade

Grade

3–5

Treatment-related

AEs, % 59 8 87 58

Treatment-related

AEs leading to

discontinuation, %

5b 3 10c 7

Treatment-related

deaths, % 0 2d

Nivolumab

n = 287

Docetaxel

n = 268

Any

Grade

Grade

3–5a

Any

Grade

Grade

3–5

Treatment-related

AEs, % 69 10 88 54

Treatment-related

AEs leading to

discontinuation, %

5 4 15 7

Treatment-related

deaths, % 0b <1c

CheckMate 017 SQ NSCLC1

CheckMate 057 Non-SQ NSCLC2

a No grade 5 events were reported at DBL; 1 grade 5 event was reported for nivolumab post-DBL; b 1 death attributed to nivolumab (encephalitis); association to nivolumab changed after DBL; c 1 death attributed to docetaxel-related drug toxicity (grade 4 febrile neutropenia).

1Reckamp K et al, WCLC 2015 2Paz-Ares Parez L et al, ASCO 2015

Nivolumab approved for advanced NSCLC after a first-line CT

WCLC 2013 25 Mercury ID: ONCHQ13NP10127; Approved 5Nov2013; Expires 5 Nov2015

IMT Target PD-L1 selction criteria Comparators

Trials

Nivolumab PD-1 PD-L1+ CT (investigator choice) Checkmate-026

Pembrolizumab PD-1

PD-L1+

PD-L1 strong

Platinum doublet CT

Platinum doublet CT

Keynote-042

Keynote-024

Atezolizumab PD-L1

PD-L1+

PD-L1+

Platinum doublet CT

Platinum doublet CT

IMpower-110

IMpower-111

Durvalumab PD-L1 Stage 1b-IIIa

Resected NSCLC

Placebo

NCT02273375

Durvalumab PD-L1 Stage III unresectable

in disease control after

CT+RT, PD-L1 unselected

Placebo Pacific

(NCT02125461)

Phase III first-line or early stage trials with anti-PD-1/PD-L1 in NSCLC

Immunotherapy in solid tumors with



Slide 17

Presented By Dung Le at 2015 ASCO Annual Meeting

Effect in the CNS?

THE LANCET Oncology Volume 13, Issue 9; September 2012, Pages 879-886

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 NCT02460068

Science, 2013 Science 2013

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

• Hypomethylating agents

Tumor immunomodulatory activity of DNMTi in vitro

Coral S. et al, CII 2012

MAGE-A-specific CTL recognition of

5-AZA-CdR-treated melanoma clones

Sigalotti L. et al, Cancer Res 2004

CTRL

DHA

treate

d

gp100-specific CTL recognition of

SGI-110-treated melanoma cells

Fonsatti E. et al, CCR 2007

IIF analysis of

of SGI-110-treated melanoma cells

immune response (19 genes)

transport (16 genes)

signal transduction (12 genes)

spermatogenesis (8 genes)

G-protein coupled receptor protein

signaling pathway (6 genes)

antigen processing and presentation (5 genes)

response to virus (5 genes)

defense response to bacterium (5 genes)

innate immune response (5 genes)

Gene expression profiles modulated by DNMTi in syngeneic murine tumor TS/A

Significantly modulated pathways

Coral S. et al, BJC 2012

Maio M. et al., CCR 2015

Epigenetic Immunomodulation of Cancer cell

NEWS FEATURES Nature Medicine 2016

Epigenetic immuno-sequencing: the NIBIT-M4 Study

EUDRACT 2015-001329-17

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

Malignant Mesothelioma (MM) is a rapidly

progressive lethal tumor with a steadily

increasing incidence worldwide

No standard treatment significantly

improves prognosis of MM patients1

Median OS 12 months (ranged from 6 to 18

months) from diagnosis2

Survival in pretreated patients is even more

poor. The second-line therapy is undefined

and enrollment in clinical trial for fit patients

is encouraged3

1) Mak V et al, Thorax 2008; 63:160-166

2) AK G et al, J thorac Oncol 2009; 4:1425-30

3) Mott F, Ochsner J 2012

Tremelimumab treatment in

chemotherapy-resistant mesothelioma Best response and disease control

Calabrò L, et al. Lancet Respir Med 2015;3:301–309

n (%)

MESOT-TREM-2012:

tremelimumab Q4W x6 then Q12W (n=29)

irRC Modified RECIST

Complete response 0 0

Partial response 4 (13.8)* 1 (3.4)

Stable disease 11 (37.9) 10 (34.5)

Progressive disease 14 (48.2)† 18 (62.1)†

Disease control rate 15 (51.7) 11 (37.9)

*Three partial responses occurred after initial progressive disease (n=2) or stable disease (n=1) at the first assessment (Week 12) †Including one peritoneal mesothelioma

irRC, immune-related response criteria

Tremelimumab +

durvalumab

• Not eligible for 1st-line CT

• Relapsed/refractory to a

1st-line CT

• No autoimmune diseases

• ECOG PS 0/1

• Life expectancy >12 weeks

Patients (n=40)

A single-arm, Phase II clinical study of tremelimumab combined

with the anti-PD-L1 monoclonal antibody durvalumab in patients

with unresectable malignant mesothelioma:

NIBIT-MESO-1 study

FPFV: October 2015

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

Medical Oncology and Immunotherapy, University Hospital of Siena

Back-up slides

• 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

Lawrence et al, Nature 2013

Science, 2013 Science 2013

26-30 September 2014, Madrid, Spain

esmo.org

• 1st generation: Zebularine, 5-azacytidine,

5-aza-2’-deoxycytidine

• 2nd generation: SGI-110 (guadecitabine)

DNA hypomethylating agents (DHA)

COMBOS

TUMOR

Epigenetic drugs

Modulate Tumor immunogenicity

and immune recognition HOST

CTA-based vaccine

Immunomodulating mAb

Improved the activity of host immune system

Epigenetic immuno-sequencing

Lung cancer is a disease hard to treat

Most (often elderly) patients have comorbidities:

• Chronic obstructive pulmonary disease

• Hypertension

• Diabetes

• History of atrial fibrillation

• Clinical heart failure

Toxicity is a relevant aspect to consider

CLINICAL CASE

91-year-old male, comorbidities: atrial fibrillation, moderate heart failure

Stage IV Squamous NSCLC, 2nd line therapy with Nivolumab (EAP)

PR

Baseline Baseline

W12 W12

No relevant side

effects

Received 9 doses,

still being treated

Calabrò and Maio, unpublished

KEYNOTE-001

OS with pembrolizumab in NSCLC by PD-L1 expression

Garon et al, NEJM 2015

Oct 2, 2015 pembrolizumab approved by FDA in PD-L1+ advanced NSCLC (PD-L1 IHC 22C3 pharmDx test)

Lawrence et al, Nature 2013

KEYNOTE-021

Patnaik A, et al, J clin Oncol 2015,33. Abstract 8011

WCLC 2013 64 Mercury ID: ONCHQ13NP10127; Approved 5Nov2013; Expires 5 Nov2015

Trial N* ARMS Primary Endopoint

Checkmate-227

NCT02477826

1980 Nivolumab + Ipilimumab Nivolumab Platinum doublet CT OS

Mystic

NCT02453282

675 Durvalumab + Tremelimumab Durvalumab Platinum doublet CT PFS

Neptune

NCT02542293

800 Durvalumab + Tremelimumab

Platinum doublet CT -

OS

IMpower130

NCT02367781

550 Atezolizumab +

nab-paclitaxel/Carboplatin

nab-paclitaxel/Carboplatin - PFS

IMpower150

NCT02366143

1200 Atezolizumab+

paclitaxel/Carboplatin

+bevacizumab

Atezolizumab+



+bevacizumab

PFS

IMpower131

NCT02367794

1200 Atezolizumab +

nab-paclitaxel/Carboplatin

Atezolizumab+


nab-


PFS

Phase III first-line combination trials with anti-PD-1/PD-

L1 in advanced NSCLC (all PD-L1 unselected)

*Estimated enrollment

Immunotherapy in solid tumours with



• Randomised tremelimumab:placebo 2:1

• Stratification factors

– EORTC status (low-risk vs high-risk)

– Line of therapy (second vs third)

– Anatomical site (pleural vs peritoneal)

Tremelimumab

10 mg/kg Q12W (Non-dosing visits: V9, 11, 13) Relapsed / refractory malignant

mesothelioma (2nd/3rd line)

N=564

(Primary endpoint OS) Placebo

Q4W

x 6 doses

Placebo

Q12W (Non-dosing visits: V9, 11, 13)

Tremelimumab

10 mg/kg Q4W

x 6 doses

Phase II multicentre, international, randomised trial of

tremelimumab in patients with unresectable mesothelioma

(trial D4880C00003 sponsored by AstraZeneca/MedImmune)

2:1

February 2014: amendment to enrol 564 patients in ~180 centres worldwide

EORTC, European Organization for Research and Treatment of Cancer; Treme, tremelimumab

NCT01843374

Dosing as per Calabrò L, et al. Lancet Respir Med 2015;3:301–309

ECCO-ESMO 2015

CheckMate 025

• Patients were treated until progression or intolerable toxicity occurred

• Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted

67

Previously treated mRCC

Stratification factors

• Region

• MSKCC risk group

• Number of prior anti-angiogenic therapies

Nivolumab

3 mg/kg intravenously

every two weeks

Everolimus

10 mg orally

once daily R

an

do

miz

e 1

:1

MSKCC, Memorial Sloan-Kettering Cancer Center.

ECCO-ESMO 2015

Overall Survival

68

Median OS, months (95% CI)

Nivolumab 25.0 (21.8–NE)

Everolimus 19.6 (17.6–23.1)

HR (98.5% CI): 0.73 (0.57–0.93)

P = 0.0018

0 3 6 12 9 15

Months

18 21 24 27 30 33

No. of patients at risk

Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0

411 366 324 287 265 241 187 115 61 20 2 0 Everolimus

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Su

rviv

al

(Pro

ba

bilit

y)

Nivolumab

Everolimus

Minimum follow-up was 14 months.

NE = not estimable.

Atezolizumab (MPDL3280A): ORR in UBC by IC Status

Presented By Daniel Petrylak at 2015 ASCO Annual Meeting

Atezolizumab (MPDL3280A): Survival in UBC

Presented By Daniel Petrylak at 2015 ASCO Annual Meeting

24/02/2016

Medical Oncology and Immunotherapy, University Hospital of Siena

Patterns of response to ipilimumab in advanced melanoma

150

125

100

75

50

25

0

-25

-50

-75

-100

-125

19,373

17,242

15,111

12,980

10,849

8,718

6,587

4,456

2,325

194

-1,937

SPD

(mm

2)


50

25

0

–25

–50

–75

–100

–125

Ch

ange

fro

m b

ase

line

SP

D (

%)


1,272

1,124

975

827

678

530

382

233

85

-64

-212

SPD

(mm

2)

Ch

ange

fro

m b

ase

line

SP

D (

%)

-9 -3 3 9 15 21 27 33 39 45 51


Ch

ange

fro

m b

ase

line

SP

D (

%)

SPD

(mm

2)

2,894

2,556

2,218

1,881

1,543

1,206

868

530

193

-145

-482

50

25

0

-25

-50

-75

-100

-125

Total tumor volume

Index lesions

New lesions

Ipilimumab dosing

SPD = Sum of the Product of the perpendicular Diameters (a measure of tumor volume)

-9 -3 3 9 15 21 27 33 39 45 51

-9 -3 3 9 15 21 27 33 39 45 51

'Stable disease' with slow, steady decline in total tumour volume

Response after initial increase in total tumour volume

Response in baseline lesions

Ch

ange

fro

m b

ase

line

SP

D (

%)

SPD

(mm

2)

2,810

2,482

2,154

1,826

1,498

1,171

843

515

187

-140

-468

50

25

0

-25

-50

-75

-100

-125

-9 -3 3 9 15 21 27 33 39 45 51

9 months


PD

PR

CR

5.2 months 6 months

9.4 months

Response in index and new lesions at or after the appearance of new lesions

Wolchok, et al. Clin Cancer Res 2009; Harmankaya, et al. ESMO 2008;#784P

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 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


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



Documents

Michele Maio - Nadirex International | CongressiMichele Maio Medical Oncology and Immunotherapy, Department of Oncology University Hospital of Siena, Istituto Toscano Tumori SIENA,