Onkologische Aspekte - Tumorzentrum Berlin-Buch

Aktuelle Therapieoptionen im Stadium
IIIB/IV des Lungenkarzinom
Tumorzentrum Berlin - Buch
13.1. 2016
Ansatzpunkte zur Aktivierung des
Immunsystems
Stimulierende und inhibierende Faktoren des Tumor-Immunitäts-Zyklus
3
Priming und
Aktivierung
Trafficking von T-Zellen
zu Tumoren
CD28/B7.1, CD137/CD137L
OX40/OX40L, CD27/CD70
HVEM, GITR, IL-2, IL-12
CX3CL1, CXCL9, CXCL10,
CCL5
CTLA4/B7.1, PDL1/PD-1
PD-L1/B7.1
2
Tumor
Erkennung von Tumorzellen durch T-Zellen
Chen and Mellman, Immunity. 2013 Jul 25; 39(1): 1
6
T-Zell Rezeptor
Verringerte pMHC auf
Tumorzellen
Freisetzung von
Tumorzell-Antigenen
Immunogener Zelltod
Tolerogener Zelltod
5
LFA1/ICAM1, Selectins
VEGF,
Endothelin-B Rezeptor
Tumor-Antigen
Präsentation
TNF-, IL-1
IFN-, CD40L/CD40
CDN, ATP
HMGB1, TLR
IL-10, IL-4, IL-13
1
Infiltration von T-Zellen
in Tumore
Blood
vessel
Lymphknoten
4
Zerstörung von Tumorzellen
IFN- , T-Zell-Granulat Inhalt
PD-L1/PD-1
PD-L1/B7.1
IDO
TGF-
BTLA
VISTA
7
LAG-3
Arginase
MICA/MICB
B7-H4
TIM3/Phospholipide
3
Blockade der CTLA-4- und PD-1- Signalwege
Mikroumgebung des Tumors
Lymphknoten
Aktivierung
(Zytokine, Lyse, Proliferation,
Migration zum Tumor)
MHC
TCR
TCR
Dendritische B7 CD28
Zelle
B7 CTLA-4
Anti-CTLA-4
+++
+++
+++ T-Zelle
---
MHC
T-Zelle
---
PD-1
PD-L1
Tumorzelle
Anti-PD-1/PD-L1
---
PD-1
PD-L2
Anti-PD-1
CTLA-4 Signalweg
CTLA-4 reguliert die Amplitude der frühen
Aktivierung von naiven und Memory T-Zellen.
PD-1 Signalweg
PD-1 begrenzt die T-Zell-Aktivierung in der
Peripherie während einer Entzündungsreaktion.
Wolchock et al, J Clin Oncol 2013 ASCO Abstracts 31:15
4
CA184-041: Phase II trial to evaluate Ipilimumab in combination with chemotherapy
(carboplatin/paclitaxel) in lung cancer (NSCLC and SCLC):
Immunrelated progression free survival of concurrent and phased regimen
0.8
Control
Concurrent
Ipilimumab
0.6
Events/
patients
56/66
55/70
0.4
0.2
0
0
No. at risk
Control
Ipilimumab
2
4
6
8
10
12
Time (months)
66 59 55 41 38 28 17 13 11 5
70 62 48 44 40 34 29 20 18 9
4
8
3
6
3
2
14
3
1
1
1
1
0
1
0
irPFS (probability)
0.6
0.4
0.2
0
0
2
4
6
8
10 12 14 16
Time (months)
0.6
0.4
0.2
0
2
4
18
20
22
No. at risk
Control
45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0 0
Ipilimumab 43 38 36 31 29 26 16 12 11 10 9 9 8 5 4 3 3 2 2 2 2 2 1 0
6
8
10
12
Time (months)
No. at risk
Control
66 59 55 41 38 28 17 13 11 5
Ipilimumab 66 59 55 41 38 28 17 13 11 5
ED-SCLC (Phased)
Median
Events/ OS,
P
patients months 95% CI HR value
4,67–
Control
40/45
5,26
5,72
Concurrent
5,19– 0,7
37/43
5,68
0,11
Ipilimumab
6,87
5
0.8
0.8
0
0
0
Median
Events/ OS,
P
patients months 95% CI HR value
4,14–
Control
56/66
4,63
5,52
Phased
4,76– 0,7
54/68
5,68
0,05
Ipilimumab
7,79
2
1.0
16
ED-SCLC (Concurrent)
1.0
NSCLC (Phased)
irPFS (probability)
1.0
Median
OS,
P
months 95% CI HR value
4,63
4,14–5,52
0,8
5,52
4,17–6,74
0,13
1
irPFS (probability)
irPFS (probability)
NSCLC (Concurrent)
1.0
0.8
0.6
4
4
3
3
3
3
14
3
3
1
1
16
1
1
1
1
0
0
Median
Events/ OS,
P
patients months 95% CI HR value
4,67–
Control
40/45
5,26
5,72
Phased
5,29– 0,6
38/42
6,44
0,03
Ipilimumab
7,75
4
0.4
0.2
0
0
2
4
6
8 10 12 14
Time (months)
16
18
20
22
No. at risk
Control
45 44 42 38 36 26 11 10 7 5 4 3 2 2 2 2 1 0 0 0 0 0 0
Ipilimumab 42 42 40 37 35 31 22 18 10 7 7 6 6 6 5 5 5 3 2 1 1 1 0
Data from trial CA184-041.; a Statistically significant per protocol-stipulated one-sided α=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; Lynch et al, J Clin Oncol. 2012; 30: 2046; Reck et al, Ann Oncol. 2013; 24: 75
5
Remission unter Therapie
Ausgewählte Biomarker-Ansätze für
Immunonkologische Therapien
1. Expression von Markern bezogen auf das Ziel-Molekül
oder den Ziel-Signalweg
z. B. PD-L1 für PD-1-Signalweg gerichete Therapien1
2. Therapiebedingte Veränderungen des Immunsystems
oder der Tumorumgebung („Microenvironment”)
z. B. absolute Lymphozytenzahl (ALC)2, Antikörperantwort auf Tumorantigene3
oder Veränderung der Tumor-infiltrierenden Lymphozyten (TIL)4
3. Genexpressionsprofil des Patienten oder des Tumors
z. B. differenzielle Expression des Tumors von immunologischen Genen5
1. Callahan et al, J Clin Oncol 2013; 31(15 Suppl): abstract 3003; 2. Ku et al, Cancer 2010; 116: 1767; 3. Postow et al, N Engl J Med 2012; 366(10):
925; 4. Hamid et al, J Transl Med 2011; 9: 204; 5. Ulloa-Montoya et al, J Clin Oncol 2013; 31: 2388
8
KEYNOTE-001: Response Rate by Level of
PD-L1 Expression (RECIST v1.1, Central
Review)
• Clinical trial assay
– Strong PD-L1 expression: defined as ≥50% membranous staining in tumor cells
– Weak PD-L1 expression: defined as 1–49% membranous staining in tumor cells
Garon et al, Oral presentation at ESMO 2014
10
CA209-003 NSCLC cohort: Change in tumour burden according to EGFR and
KRAS mutation status: example with Nivolumab (anti-PD-1) in NSCLC
Change in tumour size (%)
100
80
60
120
EGFR mutation status
Mutant
100
Unknown
WT
40
20
0
–20
–40
–60
Change in tumour size (%)
120
80
60
KRAS mutation status
Mutant
Unknown
WT
40
20
0
–20
–40
–60
–80
–80
–100
–100
Patients
Patients
Dashed horizontal lines denote 30% decrease for PR (in the absence of new lesions) and 20% increase for PD per
RECIST v1.0
Nivolumab demonstrates responses across a broad array of NSCLC patient populations
regardless of the KRAS or EGFR mutational status
Adapted from Gettinger et al, Poster presentation at WCLC 2013. J Thorac Oncol. 2013; 8(suppl 2): abstract:
P2.11-038
11
Pembrolizumab versus docetaxel for
previously treated,
PD-L1-positive, advanced non-small-cell
lung cancer (KEYNOTE-010): a randomised
controlled trial.
Lancet. 2015 Dec 18. pii: S0140-6736(15)01281-7. doi: 10.1016/S0140-6736(15)01281-7. [Epub ahead of print]
KEYNOTE-001: Summary of Exposure and
Treatment-Related-AEs
• Infusion-related reactions occurred in 4 patients
(1,5%)
• Other potentially immune-mediated AEs that occurred
in <1% of patients were colitis and hyponatremia
Garon et al, Oral presentation at ESMO 2014
18
CA209-003: Response by smoking exposure according to RECIST
response in NSCLC patients treated with nivolumab
50
0
-50
-100
Patients
100
50
0
-50
-100
Patients
Nivolumab (NSCLC-Cohort)
100
>5 pack-yrs smokers
Change From Baseline (%)
Change From Baseline (%)
≤5 pack-yrs smokers
PD = progressive disease
PR = partial response
SD = stable disease
Hellmann et al, Poster presentation at ESMO 2014
19
CA209-003: Response by smoking
exposure in NSCLC patients treated with
nivolumab
Variable
ORR, % (n/N) [95% CI]
P-value
Smoking exposure
≤5 pack-yrs
0 (0/14) [0, 23]
>5 pack-yrs
30 (20/66) [20, 43]
0,018
Time since quitting
0/never smoker
0 (0/10) [0, 31]
Current smoker
27 (6/22) [11, 50]
1–5 yrs prior
46 (6/13) [19, 75]
6–15 yrs prior
17 (2/12) [2, 48]
>15 yrs prior
26 (6/23) [10, 48]
0,12
• Among smokers, there was no
association between ORR and
time since quitting
• The impact of smoking in
squamous lung cancers could not
be assessed, as there was only
one non-smoker among patients
with squamous lung cancers
Subgroup
Nivolumab 3 or 10 mg/kga
≤5 pack-yrs
• ORR was significantly higher in >5
pack-yrs smokers compared with
≤5 pack-yrs smokers; this
differential response rate was
numerically more pronounced in
the subgroup receiving 3 mg/kg or
higher and remained true in the
adenocarcinoma-only cohort
0 (0/10) [0, 31]
0,023
>5 pack-yrs
37 (19/52) [24, 51]
Adenocarcinoma
≤5 pack-yrs
0 (0/13) [0, 25]
0,049
>5 pack-yrs
25 (8/32) [11, 43]
20
CA209-003: Conclusion NSCLC cohort
NSCLC cohort (n=129)
Nivolumab demonstrates responses across a broad array of NSCLC patient populations
regardless of histology, including populations of more heavily pretreated patients (≥3 prior
approximately), older patients (age ≥70 years old) and patients with and without tumors
driven by KRAS or EGFR mutations
Nivolumab activity was numerically higher in the PD-L1 positive patients, but PD-L1
negative patients also exhibited overall responses
A history of smoking was significantly associated with improved response and
PFS to nivolumab
Hodi et al, Poster presentation at ECC 2013: abstract 880
21
Unterschiedliches Nebenwirkungsprofil
onkologischer Therapien
Chemotherapie
I-O Therapien
Zielgerichtete Therapien
Ziel
Sich schnell teilende
Tumorzellen und normale Zellen
Ziel
Immunsystem
Ziel
Spezifische Moleküle, die in
Tumorwachstum involviert sind
Nebenwirkungen
Divers aufgrund unspezifischer
Therapie
Nebenwirkungen
Einzigartige NW aufgrund der
Aktivierung des Immunsystems
Nebenwirkungen
Spiegeln die Rolle des Targets
wider
Unterschiedliches Spektrum an Nebenwirkungen
Manche NW unter I-O Therapien ähneln den NW der anderen Therapien
ABER – NW können unterschiedliche Ursachen haben
Beispiele: Diarrhö/Kolitis, Fatigue, Rash/Juckreiz, Endokrinopathien
Andere Strategien zum NW-Management notwendig
Topalian et al, N Eng J Med 2012; 366(26): 2443 oral presentation at ASCO 2013: J Clin Oncol 2013; 31(15 suppl): abstract
3002; Hamid et al, N Eng J Med 2013; 369: 134;
22
Management of acquired resistance to epidermal growth
factor receptor kinase inhibitors in patients with advanced
non-small cell lung cancer
Cancer
Volume 120, Issue 15, pages 2289-2298, 17 APR 2014
Distribution of the 60 rare EGFR mutations
The Oncologist 2015;20:1–8
Time to treatment failure of common
and uncommon EGFR mutations
The Oncologist 2015;20:1–8
Management of acquired resistance to
epidermal growth factor receptor kinase
inhibitors in patients with advanced non-small
cell lung cancer
Cancer
Volume 120, Issue 15, pages 2289-2298,
AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
Best Percentage Change in Target-Lesion Size.
Jänne PA et al. N Engl J Med 2015;372:1689-1699.
Best Response to Rociletinib.
Sequist LV et al. N Engl J Med 2015;372:1700-1709.
Management of acquired resistance to
epidermal growth factor receptor kinase
inhibitors in patients with advanced non-small
cell lung cancer
Cancer
Volume 120, Issue 15, pages 2289-2298,
Die Biopsie ist Grundlage einer erfolgreichen Bestimmung
des EGFR-Mutationsstatus
• Vorab zu klären:
Wie kann das tumorhaltige Material am
besten gewonnen werden?
(endoskopisch, perkutan etc.)
• Falls erforderlich:
Rücksprache, wie das Material zum
Pathologen versendet werden soll
• Zu beachten/Empfehlung:
Immer 4 bis 5 Biopsien pro Läsion
• Wenn möglich:
Unterschiedliche Areale der Läsion
biopsieren
• Neben dem Primärtumor ggf. auch
Metastasen biopsieren
Mechanismen zur Freisetzung von Tumorzell-DNA in den Blutkreislauf –
Absterben von Tumorzellen durch Nekrose oder Apoptose
1. Pathak, AK et al. Clinical Chemistry 2006; 52: 1833–1842.
2. Gormally, E et al. Mutation Research 2007; 635: 105–117.
3. Aung, KL et al. The HUGO Journal 2010; 4: 11–21.
Mechanismen zur Freisetzung von Tumorzell-DNA in den Blutkreislauf –
Spontane und aktive Sekretion von DNA aus den Tumorzellen in die Zirkulation
1. Pathak, AK et al. Clinical Chemistry 2006; 52: 1833–1842.
2. Gormally, E et al. Mutation Research 2007; 635: 105–117.
3. Aung, KL et al. The HUGO Journal 2010; 4: 11–21.
ctDNA-Testung – von der Probe zur Analyse
• Plasma eignet sich am besten für die ctDNA-Isolation
• Aus 10ml Vollblut können etwa 5ml Plasma gewonnen werden
• Zur Maximierung des Testerfolgs sollte das größtmögliche Volumen gewählt werden.
Abnahme des peripheren
Blutes im Plasmaröhrchen
(mind. 10 ml)
Abpipettieren des Plasmas
bis 0,5 cm oberhalb der
festen Blutbestandteile
Aufteilen des gewonnenen
Plasmas (2–5 ml) auf
Kryoröhrchen
Zentrifugation des
Plasmaröhrchens
für 10 min bei 4°C und 2000 g
Tieffrieren des Plasmas nach
Möglichkeit auf Trockeneis
Versand des Plasmas auf
Trockeneis an das molekularpathologische Labor
Durchführung der
DNA-Extraktion und
anschließende
EGFR-Mutationsanalyse
Assess Study design
Objectives
Primary
Patients
• Patients with newly diagnosed,
locally advanced/metastatic
chemotherapy-naïve NSCLC not
suitable
for curative treatmenta
or
• Recurrent disease and surgical
resection with / without
adjuvant chemotherapy
• Concordance between EGFR
mutation status obtained via
tissue / cytology and blood
(plasma) based testing
Secondary
• EGFR mutation frequency
Samples
• Provision of tumour and
plasma samples for EGFR
mutation testing
Assessments
Tissue / cytologyb
• Correlations between EGFR
mutation status and demographic
data / disease status
• EGFR mutation testing
according to local practices
following histopathological
review (WHO classification)
• EGFR mutation testing practices
Blood (plasma)b
• 1st-line therapy (all patients)
• Samples processed to plasma
and transported to designated
laboratories for EGFR mutation
testing
• 2nd-line therapy (patients with
EGFR mutation-positive NSCLC)
EGFR mutation frequency
ADC
non-ADC
n/N (%)
n/N (%)
Japan
78/195 (40.0)
6/77 (7.8)
Europe
99/712 (13.9)
6/180 (3.3)
Japan
40 (51.3)
-
Europe
54 (54.5)
-
Japan
37 (47.4)
-
Europe
28 (28.3)
-
Japan
0 (0)
-
Europe
1 (1.0)
-
Japan
0 (0)
-
Europe
4 (4)
-
Japan
1 (1.3)
-
Tissue / cytology
Overall EGFR mutationpositive % (n=189)
•
Female gender, ADC histology,
never-smoking status, and Japanese
ethnicity significantly correlated with
EGFR mutation-positive
tissue/cytology and plasma sample
(all p<0.1)
•
There was a trend between
increasing number of metastases and
EGFR mutation-positive plasma
sample (p=0.054)
•
Immunohistochemistry analyses
showed that 4.3% (10 / 231) of TTF-1negative tissue / cytology samples
were EGFR mutation-positive
– Exon 19 del (n=4), L858R (n=4),
G719X (n=1), S768I & V769L
(n=1)
Subtype (% of overall positive)a
Exon 19 deletion
L858R only
T790M + other
Exon 20 insertion
-
Serial measurement of plasma genotype for disease monitoring.
Geoffrey R. Oxnard et al. Clin Cancer Res 2014;20:16981705
ADAURA Trial Design
•Phase III, double-blind, randomized, placebo-controlled study
•Assess the efficacy and safety of AZD9291 vs placebo in patients with stage IB-IIIA NSCLC with centrally confirmed, common
sensitising EGRF mutations (Ex19Del of L858R) who have had complete tumour resection, with or without postoperative adjuvant
chemotherapy
Stage IB–
IIIA
EGFRm+
NSCLC
(Ex19del or
L858R)
No
adjuvant
chemo
Physician choice
(N~700)
1:1 Randomization
Complete
Adjuvant
surgical
•Estimated
of 700 patients
resectionEnrolment chemo
37
DFS: disease free survival; OS: overall survival;
* Initial dose of 80mg QD can be reduced to 40mg QD
NCT02511106 Accessed 22 September 2015
Stratification:
(stage, race, mutation type)
AZD9291
80mg*
QD
3 years of
treatment
Placebo
Endpoints:
1ry: DFS
2ry: OS
Vielen Dank
1744204/12