combining immunotherapeutic agents - cddf

Combining immunotherapeutic agents

Paolo A. Ascierto, MDUnit Melanoma, Cancer Immunotherapy and Innovative Therapies

Istituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, Italy

Disclosure

• Employment or Leadership Position: None

• Consultant/Advisory Role: Bristol-Meyers Squibb,

Roche-Genentech, Merck Sharp & Dohme, Novartis,

Amgen, Array, Merck Serono

• Stock Ownership: None

• Research Funding: Bristol-Meyers Squibb, Roche-

Genentech, Array

• Expert Testimony: None

• Other Remuneration: None

The goals for treatments ……

early and fast

responses

Long-term

benefit

cure the patients

Ascierto ESMO 2016

Two different drugs... Two different concepts

Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy

Oct-2010 Jun-2011

immunotherapy

slow acting, but possibility to

reach long-term benefit

target therapy

fast acting, rapid metabolic shutdown,

unfortunately resistance

Day 15Day 0

Ascierto ESMO 2016

Figure modified from Ribas et al., Clin Cancer Res. 2012.

Combination?

Pe

rce

nt a

live

Years

1 2 30

Immunotherapy

Pe

rce

nt a

live

Years

1 2 30

Targeted therapy

Pe

rce

nt a

live

Years

1 2 30

Raising the bar ……

Chemotherapy

Immunotherapy

Radiotherapy

Targeted therapy

Combinationapproaches


Ascierto ESMO 2016

Chemotherapy

Immunotherapy

Radiotherapy

Targeted therapy



Immunotherapy+

Ascierto ESMO 2016

Components of eliciting a clinically relevant immune response

Abrogate immuno-suppressive networks

T-regs B-regs

IDO

MDSC

adenosine

arginine

TGF-β exosomes

M2 MO

IL-10

PGE2VEGF

Turn on NK cell

a-KIR

sMICAFc/CD16

IL-2

CD137

IL-15

NKG2D

sMICB

Turn on T-cellactivate inhibit

CD137

CD40

OX40

GITR CD27 BTLA

PD-1

CTLA4

TIM-3

LAG-3

Prime system• chemotherapy• radiation therapy• vaccine• intratumoral

– oncolytic virus– cytokines– TLR agonists

T & NK cell

trafficking

and

infiltration

into the

tumor

SMR 2014 BMS scientific symposium

Targeting CTLA-4 and PD-1 pathways

Wolchock J, et al. JCO 2013 Volume 31, Issue 15_suppl ; abstr 9012^

T cell Tumour cell

MHCTCR

PD-L1PD-1T cellDendritic

cell

MHCTCR

CD28

B7 CTLA-4- - -

Activation(cytokines, lysis, proliferation,

migration to tumour)

B7+++

+++

CTLA-4 pathway PD-1 pathway

Anti-CTLA-4

Anti-PD-1/PD-L1

Periphery Tumour microenvironment

+++

PD-L2PD-1

Anti-PD-1

- - -

- - -

CA209-067 study: ORR and PFS

Larkin et al. NEJM 2015Wholchok et al ASCO 2016

CA209-069 study: PFS and OS

Postow et al AACR 2016Hodi et al. Lancet Oncol. 2016 Sep 9

KEYNOTE-029: Study Design

Dose Run-In

(Part 1A)

Tolerable

based on

DLT rate?

Patients

• Advanced MEL,

≥0 prior therapies

OR

• Advanced RCC,

≥1 prior therapy

Pembro

2 mg/kg Q3W

up to 24 months

+

Ipi 1 mg/kg Q3W

x 4 doses

Primary end point:

Safety

Secondary end points:

ORR, DOR, PFS, OS

Stop

development

No

Dose Expansion

(Part 1B)

Patients

• Advanced MEL

• ≥0 prior therapies

• No prior anti–CTLA-4,

PD-1, or PD-L1

• ECOG PS 0 or 1

Yes

Combination tolerable based on DLT rate and AE profile1,2

ClinicalTrials.gov, NCT02089685.

Long G et al ASCO 2016

Keynote 029: Best Change From Baseline in Tumor Size (RECIST v1.1, investigator review)

-100

-80

-60

-40

-20

0

20

40

60

80

100C

han

ge F

rom

Baseli

ne,

% 81%

Data cutoff date: Mar 17, 2016.

ORR = 57%

Median change:

–54.5%

PD-L1 positive

PD-L1 negative

PD-L1 unknown

Long et al. ASCO 2016

Keynote 029: AE Summary

Category

Treatment

Related

N = 153

Immune

Mediateda

N = 153

Any grade 145 (95%) 89 (58%)

Grade 3-4 64 (42%) 38 (25%)

Led to death 0 0

Led to ipilimumab discontinuation

only

16 (10%) 12 (8%)

Led to pembrolizumab

discontinuationb

11 (7%) 6 (4%)

Led to ipilimumab and

pembrolizumab discontinuationc

16 (10%) 11 (7%)

Long et al. ASCO 2016

Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination with Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination with Ipilimumab 3 mg/kg in Subjects with Previously Untreated, Unresectable or Metastatic Melanoma

PreviouslyUntreatedUnresectableStage III-IVMelanoma

Randomize(N = 346)

1:1

Stratify by• PD-L1

expression• M stage

Arm A (n = 173)

nivolumab 3 mg/kg IV+ ipilimumab 1 mg/kg IV

Every 3 weeks for 4 doses

Arm B (n = 173)

nivolumab 1 mg/kg IV+ ipilimumab 3 mg/kg IV

Every 3 weeks for 4 doses

Nivolumab Flat Dose 480 mg

Every 4 weeks

Nivolumab Flat Dose 480 mg

Every 4 weeks

*6 weeks from last dose in part 1 to Part 2 monotherapy flat dose **Treatment beyond initial investigator-assessed RECIST 1.1-defined progression will beconsidered in subjects experiencing investigator assessed clinical benefit and tolerating study therapy. Such subjects must discontinue therapy when further progression is documented.*** The treatment arm assigned in Part 1 will no be revealed until the end of the study

Double BlindedPart 1

Treat until progression** or unacceptable toxicity

Open-labelPart 2***

6 weeks*

CA209-511: Study Design

Changes in Target Lesions: Nivo/Ipi and Pembro/Epacadostat

Wolchok JD, et al. J Clin Oncol 2013;31(suppl): abstract 9012^;

Sznol M, et al. J Clin Oncol 2013;31(suppl): abstract CRA9006^

Hamid et al. SMR November 21, 2015

1 mg/kg nivolumab

+ 3 mg/kg ipilimumab

First occurrence

of new lesion

Weeks since treatment initiation

Cha

ng

e in

ta

rge

t le

sio

ns fro

m b

ase

line

(%

)

–100

–80

–60

–40

–20

0

20

40

60

80

300

100

200

0 10 20 30 40 50 60 70 80 90 100 110

nivolumab + ipilimumab pembrolizumab + epacadostat

T-VEC + ipilimumab

Puzanov et al JCO 2016; 34:2619-2626

T-VEC + pembrolizumab

Long et al SMR 2015

MASTERKEY-265 Phase 3 Study Design

N = 660

1:1

N = 330

N = 330

Pembrolizumab 200mg IV Q3W

T-VEC Intralesional

Pembrolizumab 200mg IV Q3W

T-VEC placebo Intralesional

Primary Endpoints: PFS and OS

R

NCT02263508

• Unresectable stage III or

IV melanoma

• Treatment naive

– Prior BRAFi allowed

• Injectable lesions

Long et al SMR 2015

Mozzillo N, Simeone E, et al.Oncoimmunology 2015 in press

Survival results

All cohort 6 months-OS was 93,3 % and1 y-OS was 86,2%

9/9 (100%) responder patients were alive at a medianfollow up of 16,2 months.

Mozzillo N, Simeone E, et al.Oncoimmunology 2015

Heppt et al. Cancer Immunol Immunother. 2016 Aug;65(8):951-9

Rationale for investigating opportunities to combine immunotherapy with other therapeutic modalities

Multiple mechanisms of potential synergy between the different treatment modalities

CD8 T cellAdhesion molecules

(CAM-1) and death

receptors (FAS)

Peptide pools

Vascular normalisation

T cell initiation

Cytokine release

CD8 T cells

T cell functionMDSC

Tregs

Activation of apoptosis

Blockage of cell cycle

TAA

Upregulates MHCI

Adhesion molecules/

death receptors

APM

CD8 T cells

(homeostatic peripheral

expansion)

MDSC

Tregs

M2 macrophages

TAA cross-

presentation

CD8 T cells

Effector immune infiltrate

Release of tumour

antigens (cascade)

Translocation of

calreticulin

Radiation

Chemotherapy Targeted therapies

Dendritic cell

Upregulation of MHCI

Uploading

of antigen

processing

machinery

1. Adapted from Hodge JW. Semin Oncol 2012;39:323–39; 2. Drake CG Ann Oncol 2012;23 Suppl 8:viii41–6; 3. Ménard C, et al. Cancer Immunol Immunother2008;57:1579-87; 4. Hannani D, et al. Cancer J 2011;17:351–58; 5. Ribas A at al. Curr Opin Immunol 2013:25:291–96.

Chemotherapy

Immunotherapy

Radiotherapy

Targeted therapy



Radiotherapy modifies the immune system

interaction with cancer

Demaria & Formenti, Front Oncol 2012

Lymphocyte-poor

Lymphocyte-rich

Radiation + ipilimumab

• A patient with melanoma received ipilimumab and radiotherapy

• The target and other lesions regressed

• Regression of distant lesions may be due to an enhanced systemic response

Figure adapted from Postow M, et al. N Engl J Med 2012; 366(10): 925–931.

Abscopal Effects of Radiotherapy in Melanoma Patients

Progressing After Ipilimumab (cont’d)

• Patient survival according to abscopal responses

• Abscopal response was present in 11 patients and absent in 10 patients

• Groups were compared using the log-rank test; p=0.002

Grimaldi AM, et al. Oncoimmunology 2014;3:e28780

100

80

60

40

20

0

OS

(%

)

0 6 12 18 24 30 36

Months

No abscopal response

Median OS, months

(95% CI): 8.3 (7.6–9.0)

Abscopal response

Median OS, months

(95% CI): 22.4 (2.5–50.3)

Abscopal Effects of Radiotherapy in Melanoma Patients Progressing After Ipilimumab

• 54-year old patient

• Received 4 cycles of

ipilimumab 3 mg/kg

• Followed by palliative

whole brain radiotherapy

• Post RT follow-up CT

scans indicative of

abscopal response

Grimaldi AM, et al. Oncoimmunology 2014;3:e28780

Baseline

Post

ipilimumab

Post

radiotherapy

799 patients randomized

Site: bone mets

Dose : 8 Gy, single fraction

Time: RT within 2 days from

IPI, then anytime during IPIStudy powered to detect a 4 month

difference in median overall survival (15.8

versus 12 months)

RT

Chemotherapy

Immunotherapy

Radiotherapy

Targeted therapy



Combining Ipilimumab with Chemotherapy

Summary of Efficacy Results in Melanoma

Robert C, et al. N Engl J Med 2011;364(26):2517–26

Di Giacomo AM, Lancet Oncol 2012;13(9):879–86

Patel SP, et al. Presented at ESMO 2012. P1126

Randomised

phase 2 trial of

ipilimumab 3 mg/kg +

DTIC vs ipilimumab

alone

Randomised

phase 3 trial of

ipilimumab 10 mg/kg +

DTIC vs DTIC alone

Single arm

phase 2 trial of

ipilimumab

10 mg/kg +

fotemustine

Single arm

phase 2 trial of

ipilimumab

10 mg/kg +

temozolomide

Treatment-naïve Treatment-naïve

Patient population Ipi + DTIC Ipi Ipi + DTIC DTICPretreated and

Treatment-naïve Treatment-naïve

Patients, n 35 37 250 252 86 64

Median OS, months 14.3 11.4 11.2 9.1 13.3 Not reached

1-year OS, % 62 45 47.3 36.3 52.6 68

Median PFS,

monthsNot reported

24% reduction in the risk

of progression with ipi +

DTIC

5.3 5.1

Best overall

response rate, %14.3 5.4 15.2 10.3 29.1 30

Median duration of

response, months

Not reported

(durable CRs and

PRs of 20+ months)

19.3 8.1 Not reached 12+

Caution is warranted when comparing across trials

Langer et al ESMO 2016

Phase 2 trial to evaluate CTLA-4 T cell checkpoint inhibition with ipilimumab in combination

with chemotherapy (carboplatin/paclitaxel) in lung cancer

Data from trial CA184-041. aStatistically significant per protocol-stipulated one-sided =0.1; P values not adjusted for multiple comparisons.

HR = hazard ratio; Ipi = ipilimumab; irPFS = PFS by immune-related response criteria (irRC);

mWHO-PFS = PFS by modified WHO criteria (mWHO); Pbo = placebo; PFS = progression-free survival.

1. Lynch TJ, et al. J Clin Oncol. 2012;30:2046–2054; 2. Reck M, et al. Ann Oncol. 2013;24:75–83.

NSCLC (Concurrent) NSCLC (Phased)

1.0

0.8

0.6

0.4

0.2

0

0 2 4 6 8 10 12 14 16

Time (months)

irP

FS

(pro

babili

ty) Events/

patientsMedian OS,

months 95% CI HR P value

Control 56/66 4.63 4.14–5.52

PhasedIpilimumab

54/68 5.68 4.76–7.79 0.72 0.05

66 59 55 41 38 28 17 13 11 5 4 3 3 3 1 1 1 0

66 59 55 41 38 28 17 13 11 5 4 3 3 3 1 1 1 0

Control

Ipilimumab

No. at risk

1.0

0.8

0.6

0.4

0.2

0

0 2 4 6 8 10 12 14 16 18 20 22

Time (months)

irP

FS

(pro

babili

ty) Events/

patientsMedian OS,


Control 40/45 5.26 4.67–5.72

PhasedIpilimumab

38/42 6.44 5.29–7.75 0.64 0.03

Control

Ipilimumab

No. at risk

45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0

42 42 40 37 35 31 22 18 10 7 7 6 6 6 5 5 5 3 2 1 1 1 0

1.0

0.8

0.6

0.4

0.2

0

Time (months)

irP

FS

(pro

babili

ty)

Events/patients

Median OS,months 95% CI HR P value

Control 40/45 5.26 4.67–5.72

ConcurrantIpilimumab

37/43 5.68 5.19–6.87 0.75 0.11

Control

Ipilimumab

No. at risk

0 2 4 6 8 10 12 14 16 18 20 22

45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0 0

1.0

0.8

0.6

0.4

0.2

0

0 2 4 6 8 10 12 14 16

Time (months)

irP

FS

(pro

babili

ty) Events/

patientsMedian OS,


Control 56/66 4.63 4.14–5.52

ConcurrantIpilimumab

55/70 5.52 4.17–6.74 0.81 0.13

66 59 55 41 38 28 17 13 11 5 4 3 3 3 1 1 1 0

70 62 48 44 40 34 29 20 18 9 8 6 2 1 1 0 0 0

Control

Ipilimumab

No. at risk

ED-SCLC (Concurrent) ED-SCLC (Phased)

43 38 36 31 29 26 16 12 11 10 9 9 8 5 4 3 3 2 2 2 2 2 1 0

Chemotherapy

Immunotherapy

Radiotherapy

Targeted therapy



Summary of Published Data of Immunotherapy in Combination with Targeted Agents

Jang, S, Atkins M. Lancet Oncol 2013;14:e60–9

Ribas A, et al. N Engl J Med 2013;368:1365–6

• The combination of ipilimumab with targeted agents could in theoryresult in synergistic effects

Effect of BRAF inhibitors on the immune system

CD4+ and CD8+ increase in

responder lesion and

decrease in lesions which

progressed

Wilmott JS, et al. Clin Cancer Res 2011;18:1386–94, Reprinted from Clinical Cancer Research 2012, with permission from AACR

Frederick DT, et al. Clin Cancer Res 2013;19:1225–31, Reprinted from Clinical Cancer Research 2013, with permission from AACR

3. From Hu-Lieskovan S et al. Sci Transl Med 2015;7:279ra41., Reprinted with permission from AAAS

BRAF inhibition is

associated with increased

melanoma antigen

expression in tumours of

patients with metastatic

melanoma

↑ MHC and melanoma

antigen expression3

Antitumour activity of

combined BRAFi+MEKi

plus anti-PD-13

BRAF inhibition is associated with

increased CD8+ T-cell infiltrate in

tumours of patients with metastatic

melanoma


• Concurrent administration of vemurafenib and ipilimumab may notbe feasible

– Increased incidence of hepatotoxicity observed in a phase 1 safety study

– Toxicity may preclude adequate dosing






Puzanov I, et al. J Clin Oncol 2014;32(suppl 5s): abstract 2511





• Phase 1 data show that combinations of dabrafenib + ipilimumabwith or without trametinib are not associated with hepatotoxicity







• The triplo combo ipilimumab/dabrafenib/trametinib is not feasibledue to the increase of gastro-intestinal toxicity (bowel perforation)





Ackerman A, et al. J Clin Oncol 2012; 30 (suppl): abstract 8569

Ascierto PA, et al. J Transl Med 2012;10: Epub ahead of print









• The triplet combo ipilimumab/dabrafenib/trametinib is not feasibledue to the increase of gastro-intestinal toxicity (bowel perforation)

• Sequential treatment with ipilimumab and targeted therapies maybe a more appropriate therapeutic approach


• What about the combo anti-PD-1/PD-L1 with Target Therapy ?



• We know that anti-PD-L1can be combined with BRAFi


Sullivan R et al SMR 2015



• What about the triplet ?





• It’s feasible !


Ribas et al. ASCO 2015




• It’s feasible !


Hwu P et al. ESMO 2016

• Primary endpoint: PFS

• Interim Analysis for early efficacy signal

KEYNOTE-022 Phase 2 Trial Design

Advanced melanoma

• BRAFi/MEKi , anti-

PD-1/L1, IPI naïve

• N=120 Placebo +

Dabrafenib + Trametinib

Pembrolizumab +

Dabrafenib + Trametinib

1:1

Clinicaltrials.gov NCT02130466

50

100

1 2

PFS curves may predict long-term benefit …

% P

rogr

essi

on

-Fre

e

Years

Anti-PD-1

Combo target

Ascierto & Long. Lancer Oncol. 2016

50

100

1 2

PFS curves may predict long-term benefit …

% P

rogr

essi

on

-Fre

e

Years

Anti-PD-1

Combo Target

Ascierto & Long. Lancer Oncol. 2016

Via Mariano Semmola, 80131, Napoli, Italy

Tel. +39 081 5903 431; Fax +39 081 5903 841

Email: [email protected]

combining immunotherapeutic agents - cddf

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