convegno regionale sifo meeting di primavera –“il ...€¦ · tremelimumab pd-1 mabs: nivolumab...
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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