Imunoterapia in

cancerul pulmonar
 Motivatia utilizarii imunoterapie in
cancerul pulmonar
• Sistemul imun joacă un rol important în patogenia
cancerului fiind alături de angiogeneză una din cele opt
caracteristici esențiale ale celulei neoplazice

• Celula canceroasă produce o multitudine de antigene care

stimulează producerea unui răspuns imun mai ales prin
activarea limfocitelor T CD8+ care migrează către
micromediul tumoral
Motivatia utilizarii imunoterapie in
cancerul pulmonar
• Cu toate că inițial sistemul imun pare să activeze un răspuns împotriva
tumorii, ulterior celula neoplazică poate să eludeze sistemul imun prin
diferite mecanisme, inclusiv imunosupresoare si prin interactiuni
patologice intre celulele canceroase și celulele sistemului imun din
micromediul tumoral

• Se creează o retea imunosupresiva care promoveaza cresterea

tumorală și o protejeaza de sistemul imun

• Fumatorii au incarcatura mutationala mai mare

Motivatia utilizarii imunoterapie in
cancerul pulmonar
• Folosirea sistemului imun ca armă împotriva cancerului a fost de mult timp
un deziderat al cercetătorilor, cele mai utilizate modalități de stimulare a
acestuia fiind, activarea celulelor dendritice, vaccinurile anti-tumorale și
folosirea imunostimulatoarelor, a interferonului și interlukinei 2.
• O limitare majoră a cestor modalități este reprezentată de faptul că
organismul posedă o serie de mecanisme pentru a contracara un răspuns
exagerat al sistemului imun care poate leza țesuturile sănătoase.
• Celulele canceroase se folosesc de aceste mecanisme de apărare pentru a
eluda sistemul imun. Printre aceste mecanismele cele mai importante sunt
reprezentate de inhibitorii punctelor de control (checkpoint-inhibitors)
care sunt induși de activarea limfocitelor T.
Imunologie tumorala
3
Cytokines
Activated T cell Resting T cell
TUMOR

LYMPH
2 NODE
T-cell
Tumor antigen clonal
expansion
1

Dendritic cell

Slide credit: clinicaloptions.com

Calea de semnalizare mediata de CTLA-4
• Limfocitele T recunosc antigenele
tumorale prezentate de complexul
major de histocompatibilitate
• Primul semnal nu este suficient
pentru a induce un raspuns din
partea limfocitului T asa ca e
nevoie de un al doilea semnal -
costimulato B7-CD28 ca LT sa se
activeze
• Imediat dupa activarea limfocitului
T, CTLA4 este up-regulat si
transmite semnale inhibitoare
limfocitului T cand se leaga de B7
• O cale de a creste raspunsul imun
MOAB ANTI CTLA4 impotriva tumorii este sa utilizam
IPILIMUMAB Ribas A. N Engl J Med. Ac monoclonali anti CTLA-4
TREMELIMUMAB 2012;366(26):2517-2519.
Calea de semnalizare PD-1/PD-L1
• Receptorul inhibitor PD-1 este exprimat
pe suprafata LT dupa expunerea lunga la
antigeni
• Atunci cand se leaga de liganzii sai PD-L1
si PD-L2 care sunt frecvent exprimati in
tesutul inflamator si in micromediul
tumoral, inhiba limfocitele T
• Blocarea PD-1 si PD-L1 conduce la
activarea preferențiala a celulor T cu
specificitate împotriva celulei canceroase.

MOAB ANTI PDL-1

MOAB ANTI PD-1 ATEZOLIZUMAB
NIVOLUMAB AVELUMAB Ribas A. N Engl J Med.
PEMBROLIZUMAB DURVALUMAB 2012;366(26):2517-2519.
Factori predictivi pentru raspunsul la
imunoterapie
• Expresia PD-L1 pe celula tumorală determinata prin
Imunohistochimie
• Incarcatura mutaționala
Incidenta

Freddie Bray, CA CANCER J CLIN 2018;0:1–31

Incarcatura mutationala in diferite tumori

Alexandrov LB,. Nature. 2013;500(7463):415-421.

Schumacher TN, et al. Science. 2015;348(6230)
Terapia personalizata în cancer pulmonar
Chemotherapy*† Targeted TKI Therapy Checkpoint Inhibitors
EGFR
Histologic ALK Anti–PD-1
subtype ROS1 Anti–PD-L1
BRAF V600E

1970s - 2000 - 2015 -

Inhibitori ai punctelor de control aprobati

• Nivolumab anti PD-1

• Second line therapy for Sq& Non-Sq

• Pembrolizumab anti PD-1

• 1stline therapy for PD-L1 > 50%
• 1stline therapy in combination with carboplatin and pemetrexedfor non-sq
• 2ndline therapy for PD-L1 > 1%

• Atezolizumab anti PD-L1

• 2ndline therapy for Sq& Non-Sq
Prima linie
• PEMBROLIZUMAB MONOTERAPIE CRESTE PFS vs CHT CAND PD-L1 ≥
50%
• 10.3 vs 6.0 LUNI

• PEMBROLIZUMAV + CHIMIOTERAPIE CRESTE RATA DE RASPUNS 55%

vs 29%, SI CRESTE PFS
 Pembrolizumab vs CT IN PRIMA LINIE
(KEYNOTE-024)
Stratified by ECOG PS (0 vs 1), histology
• Open-label phase III trial (squamous vs nonsquamous), and
enrollment region

Pts with stage IV NSCLC and ECOG Pembrolizumab 200 mg IV Q3W

PS 0/1, no previous systemic therapy, Until PD or unacceptable
for up to 35 cycles toxicity
no actionable EGFR/ALK mutations, (n = 154)
no untreated brain metastases, no
autoimmune disease requiring therapy, Platinum Doublet Until PD (crossover to
and PD-L1 TPS ≥ 50% (22C3 assay) Chemotherapy (histology pembrolizumab allowed) or
(N = 305) unacceptable toxicity
based) for 4 to 6 cycles
(n = 151)
• Primary endpoint: PFS (RECIST v1.1, blinded independent central review)
• Secondary and exploratory endpoints: ORR, OS, DoR, and safety

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

 KEYNOTE-024: PFS
100
Pembro CT
90 (n = 154) (n = 151)
80 62% Median PFS, 10.3 6.0
mos
70
HR (95% CI) 0.50 (0.37-0.68;
60 48% P < .001)
PFS (%)

50 50%
40 Pembrolizumab
30
20 15%

10 Chemotherapy
0
0 3 6 9 12 15 18
Mos
Pts at Risk, n 154 104 89 44 22 3 1
151 99 70 18 9 1 0
Reck M, et al. N Engl J Med. 2016;375:1823-1833.
 KEYNOTE-024: OS
100
90 80%
80 70%
70
Pembrolizumab
60 72%
OS (%)

50 Chemotherapy
54% Pembro CT
40 (n = 154) (n = 151)
30 Median OS, NR NR
mos
20
HR (95% CI) 0.60 (0.41-0.89;
10 P = .005)
0
0 3 6 9 12 15 18 21
Mos
Pts at Risk, n 154 136 121 82 39 11 2 0
151 123 106 64 34 7 1 0
Reck M, et al. N Engl J Med. 2016;375:1823-1833.
 Chemo ± Pembrolizumab as First-line
Therapy for Adv Nonsquamous NSCLC
(KEYNOTE-021)
• Randomized phase II cohort G of open-label multicohort trial Stratified by PD-L1 TPS
(< 1% vs ≥ 1%)

Pembrolizumab + Pembrolizumab
Pts with stage IIIB/IV
nonsquamous NSCLC and Carboplatin/Pemetrexed Q3W x 4 monotherapy
ECOG PS 0/1, no previous (n = 60) for up to 2 yrs*
systemic therapy, no actionable
PD Crossover to
EGFR/ALK mutations, no Carboplatin/Pemetrexed Q3W x 4*
untreated brain metastases, no
pembrolizumab
(n = 63)
need for steroids monotherapy allowed
(N = 123) *Followed by optional pemetrexed maintenance.
IV dosing: pembrolizumab 200 mg, carboplatin AUC 5 mg/mL/min, pemetrexed 500
• Primary endpoint: ORR (RECIST v1.1) mg/m2.

• Secondary endpoints: PFS, OS, DoR, activity by PD-L1 TPS, safety

Langer CJ, et al. Lancet Oncol. 2016;17:1497-1508.

 KEYNOTE-021 Cohort G: ORR by PD-L1
100
ORR in total population
80
ORR, % (95% CI)

60

40 80%
57% 54%
20 26% 38% 39%
13% 35%
0
< 1% ≥ 1% 1%-49% ≥ 50% < 1% ≥ 1% 1%-49% ≥ 50%
n = 21 n = 39 n = 19 n = 20 n = 23 n = 40 n = 23 n = 17
Pembrolizumab + Chemotherapy Chemotherapy Alone

Langer CJ, et al. Lancet Oncol. 2016;17:1497-1508.

LINIA a II de tratament
• Nivolumab:
• primul medicament aprobat, indiferent de histologie sau expresia PD-L1
• Creste OS vs second-line docetaxel
• Doza 240 mg IV Q2W 60 min
• Pembrolizumab:
• Al doilea medicament aprobat , orice histologie, PDL-1 ≥1%
• Creste OS
• Doza200 mg IV Q3W over 30 min
• Atezolizumab:
• Al treile primul medicament aprobat, indiferent de histologie sau expresia PD-
L1
• Creste OS
• Dosed at 1200 mg IV Q3W over 60 min
Immune Checkpoint Inhibitors linia II NSCLC:
Randomized Late-Stage Trials
CheckMate 017 CheckMate 057

Nivolumab Nivolumab
Squamous Nonsquamous
SIIIB/IV SIIIB/IV
(N = 272) (N = 582) Docetaxel
Docetaxel

KEYNOTE-010 OAK
Pembrolizumab
Adv NSCLC with (2 mg/kg) Atezolizumab
Adv NSCLC
≥ 1% PD-L1+
Pembrolizumab (2L/3L)
tumor cells (10 mg/kg) (N = 850)
(N = 1034) Docetaxel
Docetaxel
 Nivolumab vs Docetaxel in Previously
Treated Nonsquamous NSCLC
(CheckMate 057) Stratified by previous maintenance
therapy (yes vs no) and line of
therapy (second vs third line)

Pts with stage IIIB/IV Nivolumab 3 mg/kg IV Q2W

nonsquamous NSCLC and (n = 292)
Until disease
ECOG PS 0/1 who failed progression or
1 prior platinum doublet unacceptable toxicity
chemotherapy ± TKI therapy Docetaxel 75 mg/m2 IV Q3W
(N = 582) (n = 290)

• Primary endpoint: OS
• Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL
• Pretreatment (archival or recent) tumor samples required for measurement of PD-L1
expression by validated, automated IHC assay

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

VS 16
 Pembrolizumab vs Docetaxel in Adv NSCLC
After Progression on CT (KEYNOTE-010)
Stratified by ECOG PS (0 vs 1), region (east
Asia vs not east Asia), and PD-L1 expression
(≥ 50% vs 1% to 49%)

Pembrolizumab 2 mg/kg IV Q3W

Pts with advanced NSCLC who (n = 345)
progressed after platinum-based Treatment
chemotherapy (and TKI if EGFR+ continued for
Pembrolizumab 10 mg/kg IV Q3W
or ALK+); ≥ 1% PD-L1+ tumor 24 mos or until PD
(n = 346)
cells; ECOG PS 0/1; no active or unacceptable
brain mets toxicity
(N = 1034) Docetaxel 75 mg/m2 IV Q3W
(n = 343)

• Endpoints (in the TPS ≥ 50% stratum and TPS ≥ 1% population)

• Primary: PFS, OS
• Secondary: ORR, DoR, safety

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

 KEYNOTE-010: PD-L1 Expression
Correlates With Improved OS in Advanced
NSCLCPD-L1 TPS ≥ 1% PD-L1 TPS ≥ 50%
100 100
12 mos 12 mos
Pembrolizumab 2 mg/kg: 43% 80 Pembrolizumab 2 mg/kg: 53%
80 Pembrolizumab 10 mg/kg: 52% Pembrolizumab 10 mg/kg: 58%
Docetaxel: 35% Docetaxel: 38%

60 60

OS (%)
OS (%)

40 40

20 20
HR: 0.71 (95% CI: 0.58-0.88) HR: 0.54 (95% CI: 0.38-0.77)
HR: 0.61 (95% CI: 0.49-0.75) HR: 0.50 (95% CI: 0.36-0.70)
0 0
0 5 10 15 20 25 0 5 10 15 20 25
Mos Mos
Herbst RS, et al. Lancet. 2016;387:1540-1550. Slide credit: clinicaloptions.com
 Atezolizumab vs. Docetaxel for Advanced NSCLC After
Platinum Chemotherapy Failure (OAK)
Stratified by PD-L1 expression,
histology, prior chemotherapy regimens
PD or loss of
Metastatic or locally Atezolizumab clinical benefit NPT/Survival
advanced NSCLC 1200 mg IV Q3W Follow-up*
(2L/3L), PD on prior (n = 425) (n = 332)
platinum-based
treatment Docetaxel PD NPT/Survival
(N = 850) 75 mg/m2 IV Q3W Follow-up*
(n = 425) (n = 290)

*Pts in atezolizumab arm allowed to continue treatment beyond progression if they were deriving clinical benefit.
Crossover into the atezolizumab arm not permitted for pts assigned to docetaxel.

• Primary endpoint: OS in ITT population (first 850 enrolled pts)

• Secondary endpoints: PFS, ORR, DoR, safety
Gandara DR, et al. ASCO 2017. Abstract 9001. Rittmeyer A, et al. Lancet. 2017;389:255-265. Slide credit: clinicaloptions.com
 OAK: OS in ITT Population
100 Landmark OS, % 12 Mos 18 Mos
Atezolizumab (n = 425) 55 40
80 Docetaxel (n = 425) 41 27

60
OS (%)

HR: 0.73 (95% CI: 0.62-0.87; P = .0003)

40

20
Median: 9.6 mos Median: 13.8 mos
(95% CI: 8.6-11.2) (95% CI: 11.8-15.7)
0
0 3 6 9 12 15 18 21 24 27
Mos
Rittmeyer A, et al. Lancet. 2017;389:255-265.
S.J. Antonia, N Engl J Med 2017;377:1919-29.
PlanTreatment
• Chimioterapie neoadjuvanta 2-3 cicluri (sare de platina +
etoposide, vinblastine, vinorelbine, a taxane paclitaxel or docetaxel, or
pemetrexed) concomitent cu radioterapie definitiva 54 to 66 Gy),

Fara progresie dupa tratament

S.J. Antonia, N Engl J Med 2017;377:1919-29.

 Resultate
Durvalumab rata de raspuns 28% objective responce +
52% stable disease
Median PFS Durvalumab 16,8 vs 5,6 luni in placebo
OS 23 vs 14 luni in placebo

S.J. Antonia, N Engl J Med 2017;377:1919-29.

S.J. Antonia, N Engl J Med 2017;377:1919-29.
Safty

S.J. Antonia, N Engl J Med 2017;377:1919-29.

Efficacy update
• the median progression-free survival from randomization, was 17.2
months in the durvalumab group, vs 5.6 months HR, 0.51; 95% CI, 0.41
to 0.63)
• overall response rate was 30.0% (95% CI, 25.8 to 34.5) in the
durvalumab group, as compared with 17.8% (95% CI, 13.0 to 23.6) in the
placebo group (P<0.001)
• The time to death or distant metastasis was longer in the durvalumab
group than in the placebo group (median, 28.3 months vs. 16.2
months[95% CI, 12.5 to 21.1]; stratified hazard ratio, 0.53

S.J. Antonia, September 25, 2018, at NEJM.org

Latest overall survival assesment
The time to death or distant metastasis was
longer in the durvalumab group than in the
placebo group (median, 28.3 months [95% CI,
24.0 to 34.9] vs. 16.2 months[95% CI, 12.5 to
21.1]; stratified hazard ratio, 0.53;
95% CI, 0.41 to 0.68)

S.J. Antonia, September 25, 2018, at NEJM.org

Atezolizumab in SCLC
OS 12.3 months in the atezolizumab
group and 10.3 months in
the placebo group (hazard ratio for
death, 0.70; 95% confidence interval
[CI], 0.54to 0.91; P = 0.007).

The median progression-free survival

was 5.2 months and 4.3
months, respectively (hazard ratio for
disease progression or death, 0.77; 95%
CI,
0.62 to 0.96; P = 0.02).

Horn, N Engl J Med 2018;379:2220-9.

Combinatii ale inhibitorilor punctelor de
control (io)
• INHIBITORILOR PUNCTELOR DE CONTROL + CHIMIOTERAPIE

• INHIBITORILOR PUNCTELOR DE CONTROL + INHIBITORILOR

PUNCTELOR DE CONTROL (nivo+ipi)

• INHIBITORILOR PUNCTELOR DE CONTROL + ANTIANGIOGENIC

Efecte adverse imunologice
Eye
Skin  Uveitis Endocrine
 Dermatitis exfoliative  Iritis  Hypo- or hyperthyroidism
 Vitiligo  Adrenal insufficiency
 Alopecia  Hypophysitis

Hepatic Pulmonary
 Hepatitis,  Pneumonitis (< 5% incidence)
autoimmune

Cardiac
Gastrointestinal  Myocarditis
 Colitis
Neurologic
 Neuropathy
Renal  Guillain-Barre
 Nephritis  Myasthenia gravis–like
If not vigilant, may result in more serious syndrome
immune-related AEs