I° CONVEGNO REGIONALE SIFO “MEETING DI PRIMAVERA”– “IL FARMACISTA CLINICO E I NUOVI MODELLI DI CURA”

Taormina, 11/12/13 maggio 2017

Stato dell’arte dell’immunoterapia.

Il Paziente con NSCLC

Francesco Ferraù

Oncologia Medica

Ospedale “S.Vincenzo”, Taormina

Possibilità terpeutiche per personalizzare

la terapia nel Paziente con NSCLC

Qual’è il setting ottimale per il “giusto”trattamento nel “giusto” Paziente (prima linea, seconda linea, linee successive) ?

Chemotherapy Checkpoint InhibitorsTargeted Therapy

Genomics-

driven TKIs:

EGFR

ALK

ROS1

Histologic

subtyping for

chemotherapy

Anti–PD-1

Anti–PD-L1

Anti–CTLA-4

Ribas A. N Engl J Med. 2012;366:2517-2519.

CTLA-4 and PD-1/PD-L1 Checkpoint

Blockade for Cancer Treatment

CTLA-4 mAbs:

Ipilimumab

Tremelimumab

PD-1 mAbs:

Nivolumab

Pembrolizumab

PD-L1 mAbs:

Atezolizumab

Avelumab

Durvalumab

Priming phase

(lymph node)

Effector phase

(peripheral tissue)

T-cell

migration

Dendriti

c cellT-cell

MH

CTC

R

B7

CD

28

CTLA

-4

T-cellCancer

cell

MH

CTC

R

PD

-1PD-L1

T-cellCancer

cell

Dendriti

c cellT-cell

Check point inhibitors augments T-Cell

activation

Ledezma B, Cancer Manag Res 2014

Cancer Management and Research 2014:6submit your manuscript | www.dovepress.com

Dovepress

Dovepress

6

Ledezma and Heng

Nurses are often the first and most frequent point of con-

tact for patients undergoing cancer treatment. It is therefore

crucial that the full clinical management team, particularly

nurses, is armed with all necessary information regarding

management of patients, side effects, methods of infusion,

and other critical aspects related to treatment. Since ipili-

mumab is a relatively novel treatment with a clinical profile

that differs in some respects from those of traditional mela-

noma therapies, such as cytotoxics, education of this nature

related to ipilimumab is particularly important and timely to

provide to nurses. Therefore, the purpose of this review is to

convey collective learning from ipilimumab clinical trials,

case studies, and our own clinical experience to address com-

monly asked questions related to ipilimumab therapy. These

questions include understanding the mechanism of action,

efficacy, patient evaluation and follow-up, toxicity manage-

ment, and patterns of response. We often hear questions on

these topics from fellow nurses, but they may also originate

from patients and caregivers.

Frequently asked questions: mechanism of actionThe mechanism of action of ipilimumab differs from those

of traditional chemotherapy or small-molecule inhibitors,

which means that response kinetics may differ as well.10,11

Activation of the immune system begins when a T-cell recep-

tor recognizes and binds a foreign compound, or antigen,

that is presented on the surface of an antigen-presenting

cell. This recognition generates an activation signal to the

T-cell. To reinforce this initial activation signal, a costimu-

latory signal is then provided from the antigen-presenting

cell (via the B7 family of molecules) to the T-cell (via the

CD28 receptor). Conversely, to keep the activation signal

in check and prevent overstimulation, the T-cell expresses a

second receptor, CTLA-4, which also binds B7, but results

in inhibition of the T-cell. The balance of these stimulatory

and inhibitory signals determines whether the T-cell. is acti-

vated in response to the antigen or fails to respond (anergy)

(Figure 1A). Preclinical and clinical research have revealed

that in many types of cancers, tumors evade elimination by

the immune system by tipping the balance toward anergy

using a variety of mechanisms, some of which directly

involve CTLA-4.12 Thus, monoclonal antibodies that bind

CTLA-4 were developed as anticancer therapies under the

theory that through blockade of the CTLA-4-mediated

inhibitory signal, the activity of T-cells may be activated

against tumor antigens and their activity harnessed for

treatment of cancer.3,13

A T-cell activation T-cell inhibition T-cell remains activated

CTLA-4

ActivationTCR

CD28 ActivationTCR

CD28CTLA-4 Inhibition Activation

TCRCD28

CTLA-4

Activation

MHCB7

APC

MHCB7

APC

MHC

B7

APC

Ipilimumab

blocks

CTLA-4

B TCR: MHC antigen

T-cell activation CTLA-4 blockade/T-cell

proliferationT-cell inhibition

lpilimumabCTLA-4: B7CD28: B7

Figure 1 (A and B) Role of CTLA-4 in T-cell responses and the impact of CTLA-4 blockade with ipilimumab. Ipilimumab mechanism of action (A) and “brake and pedal”

analogy (B) as used to explain the mechanism to patients and caregivers.

Abbreviations: CTLA, cytotoxic T-lymphocyte antigen; APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor.

KEYNOTE-024: Pembrolizumab vs CT as

First-line Therapy for Advanced NSCLC

Open-label phase III trial

Primary endpoint: PFS

Secondary and exploratory endpoints: ORR, OS, DoR, and safety

Pts with stage IV NSCLC and

ECOG PS 0/1, no previous

systemic therapy, no actionable

EGFR/ALK mutations, and PD-

L1 TPS ≥ 50%*

(N = 305)

Pembrolizumab 200 mg IV Q3W

for up to 35 cycles

(n = 154)

Chemotherapy (histology

based) for up to 6 cycles

(n = 151)

Stratified by ECOG PS (0 vs 1), histology (squamous vs

nonsquamous), and enrollment region

Until PD (crossover to

pembrolizumaballowed)

Until PD or unacceptable

toxicity

Reck M, et al. N Engl J Med. 2016;375:1823-1833.

KEYNOTE-024: Survival Outcomes

Reck M, et al. N Engl J Med. 2016;375:1823-1833.

PFS OS

PF

S (

%)

1

0

08

0

6

0

4

0

2

0

0

Mos

180 3 6 9 12 15

Mos

OS

(%

)

10

0

80

60

40

20

0210 3 6 9 12 15 18

Pembro

(n = 154)

CT

(n = 151)

Median PFS,

mos

10.3 6.0

HR (95% CI) 0.50 (0.37-0.68); P <

.001

Pembro

(n = 154)

CT

(n = 151)

Median OS, mos NR NR

HR (95% CI) 0.60 (0.41-0.89); P =

.005

Slide credit: clinicaloptions.com

CheckMate-026: Nivolumab vs CT in

First-line Therapy for Advanced NSCLC

Primary endpoint: PFS (≥ 5% PD-L1 positive)

Secondary endpoints: PFS (≥ 1% PD-L1 positive), ORR, OS

Pts with stage IV/recurrent

NSCLC, no previous systemic

therapy, no actionable

EGFR/ALK mutations,

PD-L1 expression ≥ 1%*

(N = 541)

Nivolumab 3 mg/kg IV Q2W

(n = 271)

Chemotherapy (histology

based) for up to 6 cycles

(n = 270)

Until PD or unacceptable

toxicity

Stratified by PD-L1 expression (< 5% vs ≥ 5%) and histology (squamous vs

nonsquamous)

Until PD (crossover to

nivolumab allowed)

Socinski M, et al. ESMO 2016. Abstract LBA7_PR.

*≥ 1% tumor cell staining using

28-8 complementary diagnostic

IHC assay.

Slide credit: clinicaloptions.com

IMMUNOTERAPIA DI PRIMA LINEA NEL NSCLC

NEL TUMORE POLMONARE NON MICROCITOMA

LE EVIDENZE DI LETTERATURA INDICANO CHE

• PEMBROLIZUMAB E’ SUPERIORE ALLA CHEMIOTERAPIA

• NIVOLUMAB NON E’ SUPERIORE ALLA CHEMIOTERAPIA

• PEMBROLIZUMAB E NIVOLUMAB SONO MEGLIO TOLLERATI

DELLA CHEMIOTERAPIA

• MAGGIO 2017: PEMBROLIZUMAB HA INDICAZIONE MA NON

RIMBORSABILITA’ PER NSCLC IN PRIMA LINEA

Impact of Tumor Mutation Burden on the Efficacy of First-

Line Nivolumab in Stage IV or Recurrent Non-Small Cell

Lung Cancer:

An Exploratory Analysis of CheckMate 026

Solange Peters,1 Benjamin Creelan,2 Matthew D. Hellmann,3 Mark A. Socinski,4 Martin Reck,5

Prabhu Bhagavatheeswaran,6 Han Chang,6 William J. Geese,6 Luis Paz-Ares,7 David P. Carbone8

1Oncology Department, Lausanne University Hospital, Lausanne, Switzerland; 2H. Lee Moffitt Cancer Center, Tampa, FL, USA; 3Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4Florida Hospital Cancer Institute, Orlando, FL, USA; 5LungenClinic Grosshansdorf,

Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 6Bristol-Myers Squibb, Princeton, NJ, USA; 7Hospital Universitario Doce de Octubre, CNIO and Universidad Complutense, Madrid, Spain; 8Ohio State University

Comprehensive Cancer Center, Columbus, OH, USA

PFS by Tumor Mutation Burden TertileCheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12

Months

15 18 21 24

PF

S (

%)

High

Low

Medium

Medium

n = 49 n = 47

3.6

(2.7, 6.9)

Low

n = 62

4.2

(1.5, 5.6)

9.7

(5.1, NR)

Median PFS, months

(95% CI)

High

Nivolumab Arm Chemotherapy Arm

Medium

n = 53 n = 60

6.5

(4.3, 8.6)

Low

n = 41

6.9

(5.4, NR)

5.8

(4.2, 8.5)

Median PFS, months

(95% CI)

High100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12

Months

15 18

High

Low

Medium

21

Data for patients with low and medium TMB were pooled in subsequent

analyses

Kinetics of Appearance of irAEs

1. Weber JS, et al. J Clin Oncol 2012;30:2691–7

Time course (weeks)

Gra

de o

f to

xic

ity

Rash, pruritus

2 4 6 8

Liver toxicity

10 12

Diarrhea, colitis

14

Hypophysitis

20% 80%

LA CHEMIOTERAPIA NEL NSCLC : “ALIVE AND WELL”

LA CHEMIOTERAPIA NELLO SCENARIO TERAPEUTICO ATTUALE DEL NSCLC

Open-label, randomized phase III trials

Primary endpoint: OS

Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL

CheckMate 017 and 057: Nivolumab vs

Docetaxel in Previously Treated Advanced

NSCLC

Pts with stage

IIIB/IV

squamous

NSCLC and

ECOG PS 0-1

with failure of 1

previous

platinum doublet

chemotherapy

(N = 272)

Nivolumab

3 mg/kg IV Q2W

(n = 135)

Docetaxel

75 mg/m2 IV Q3W

(n = 137)

Pts with stage

IIIB/IV

nonsquamous

NSCLC and

ECOG PS 0-1

who failed

1 prior platinum

doublet

chemotherapy

± TKI therapy

(N = 582)

Nivolumab

3 mg/kg IV Q2W

(n = 292)

Docetaxel

75 mg/m2 IV Q3W

(n = 290)

Until disease progression

or unacceptabl

e toxicity

Until disease progression

or unacceptabl

e toxicity

CheckMate 017: Squamous NSCLC CheckMate 057: Nonsquamous NSCLC

Brahmer J, et al. N Engl J Med. 2015;373:123-135.

Borghaei H, et al. N Engl J Med. 2015;373:1627-1639. Slide credit: clinicaloptions.com

CheckMate 017 and 057: OS With a Minimum

2-Yr Follow-up

22

CheckMate 017: Squamous CheckMate 057: Nonsquamous

Borghaei H, et al. ASCO 2016. Abstract 9025. Slide credit: clinicaloptions.com

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27

Mos

OS

(%

)

Nivo

(n = 135)

Docetaxe

l

(n = 137)

Median OS, mos 9.2 6.0

1-yr OS, % 42 24

2-yr OS, % 23 8

HR (95% CI) 0.62 (0.47-0.80)

Nivolumab

Docetaxel

30 33 36 39

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27

Mos

OS

(%

)

Nivo

(n = 292)

Docetaxe

l

(n = 290)

Median OS, mos 12.2 9.5

1-yr OS, % 51 39

2-yr OS, % 29 16

HR (95% CI) 0.75 (0.63-0.91)

Nivoluma

b

Docetaxel

30 33 36 39

KEYNOTE-010: Pembrolizumab vs Docetaxel

in Advanced PD-L1–Positive NSCLC

Multicenter, randomized, open-label phase II/III trial

Primary endpoints: OS, PFS

Secondary endpoints: DoR, ORR, safety

Pembrolizumab 2 mg/kg IV Q3W (n = 345)

Docetaxel 75 mg/m2 IV Q3W (n = 343)

Treatment

continued for 24

mos or until PD

or unacceptable

toxicity

Pts with advanced

NSCLC who

progressed after

platinum-based

chemotherapy

(and TKI if EGFR+ or

ALK+);

≥ 1% PD-L1+ tumor

cells; ECOG PS 0/1

(N = 1034)

Pembrolizumab 10 mg/kg IV Q3W (n = 346)

Herbst RS, et al. Lancet. 2016;387:1540-1550. Slide credit: clinicaloptions.com

KEYNOTE-010: OS in Pts With PD-L1 TPS ≥ 1%

and TPS ≥ 50%

Pts With PD-L1 TPS ≥ 1% Pts With PD-L1 TPS

≥ 50%

OS

(%

)

Mos Mo

sHerbst RS, et al. Lancet. 2016;387:1540-1550.

mOS,

MosHR (95% CI)

Pembrolizumab 2 mg/kg

(n = 139)14.9

0.54 (0.38-

0.77)

Pembrolizumab 10

mg/kg

(n = 151)

17.30.50 (0.36-

0.70)

Docetaxel (n = 152) 8.2

mOS,

Mos

1-Yr OS,

%HR (95% CI)

Pembrolizumab

2 mg/kg (n = 344)10.4 43.2

0.71 (0.58-

0.88)

Pembrolizumab

10 mg/kg (n = 346)12.7 52.3

0.50 (0.49-

0.75)

Docetaxel (n = 343) 8.5 34.6

Slide credit: clinicaloptions.com

10

08

06

04

02

00

0 5 1

0

1

5

2

0

2

5

OS

(%

)

10

08

06

04

02

00

0 5 1

0

1

5

2

0

2

5

OAK: Atezolizumab vs Docetaxel in

Progressive Advanced NSCLC

Multicenter, randomized, open-label phase III trial

Primary endpoints (first 850 pts enrolled): OS in ITT population; OS in pts with ≥ 1% PD-L1 expression

Secondary endpoints: ORR, PFS, DoR, safety

Atezolizumab 1200 mg IV Q3W

(n = 425)

Docetaxel 75 mg/m2 IV Q3W

(n = 425)

Metastatic or locally

advanced NSCLC

(2L/3L), PD on prior

platinum-based treatment

(N = 1225)

Stratified by PD-L1

expression, histology, prior

chemotherapy regimens

No crossover allowed

Until loss of

clinical benefit

Until PD

Rittmeyer A, et al. Lancet. 2016;389:255-265. Slide credit: clinicaloptions.com

OAK: OS in ITT Population

Rittmeyer A, et al. Lancet. 2017;389:255-265. Slide credit: clinicaloptions.com

OS

(%

)

Mo

s

10

0

8

0

6

0

4

0

2

0

00 3 6 9 12 15 18 21 24 27

Median: 9.6 mos

(95% CI: 8.6-

11.2)

Median: 13.8

mos

(95% CI: 11.8-

15.7)

Landmark OS, % 12 Mos 18 Mos

Atezolizumab 55 40

Docetaxel 41 27

HR: 0.73 (95% CI 0.62-0.87;

P = .0003)

IMMUNOTERAPIA DI LINEE SUCCESSIVE ALLA PRIMA NEL NSCLC

NEL TUMORE POLMONARE NON MICROCITOMA

LE EVIDENZE DI LETTERATURA INDICANO CHE

•NIVOLUMAB E’ SUPERIORE ALLA CHEMIOTERAPIA

•PEMBROLIZUMAB E’ SUPERIORE ALLA CHEMIOTERAPIA

•ATEZOLIZUMAB E’ SUPERIORE ALLA CHEMIOTERAPIA

•TUTTI GLI ANTICORPI SONO MEGLIO TOLLERATI DELLA

CHEMIOTERAPIA

•MAGGIO 2017: NIVOLUMAB HA INDICAZIONE E

RIMBORSABILITA’ PER NSCLC PRETRATTATO (qualunque

istologia)

Select Ongoing Randomized Phase III Trials of

PD-1/PD-L1 Therapy in Advanced NSCLC

Trial* Disease Setting Treatment

CheckMate 227 (NCT02477826) First line Nivolumab or nivolumab + ipilimumab or nivolumab + Plt

doublet CT vs Plt doublet CT

KEYNOTE-042 (NCT02220894) First line/PD-L1+ Pembrolizumab vs Plt doublet CT

KEYNOTE-189 (NCT02578680) First line (nonsq) Plt/pemetrexed ± pembrolizumab

KEYNOTE-407 (NCT02775435) First line (sq) Cb/pac or nab-pac ± pembrolizumab

IMpower 110 (NCT02409342) First line/PD-L1+ Atezolizumab vs Plt doublet CT

IMpower 130 (NCT02367781) First line (nonsq) Cb/nab-pac vs Cb/nab-pac ± atezolizumab

IMpower 131 (NCT02367794) First line (sq) Cb/pac or nab-pac + atezolizumab vs Cb/nab-pac

IMpower 132 (NCT02657434) First line (nonsq) Plt/pemetrexed ± atezolizumab

IMpower 150 (NCT02366143) First line (nonsq) Atezolizumab + Cb/pac ± bev vs Cb/pac/bev

JAVELIN Lung 100 (NCT02576574) First line/PD-L1+ Avelumab vs Plt doublet CT

JAVELIN Lung 200 (NCT02395172) Post-CT/PD-L1+ Avelumab vs docetaxel

NEPTUNE (NCT02542293) First line Durvalumab + tremelimumab vs Plt doublet CT

*All trials enrolling pts as of February 2017. Slide credit: clinicaloptions.com

Prevenzione primaria?

?

Grazie per l’attenzione