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Nicht-kleinzelliges Lungenkarzinom
Frank Griesinger
Klinik für Hämatologie und Onkologie
Universitätsklinik Innere Medizin-Onkologie
Pius-Hospital Oldenburg
Medizinischer Campus
Universität Oldenburg
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Fortschritt in 22 Jahren
Supportive Therapie plus Chemotherapie
Supportive Therapie
6 Monate
1995: BMJ
37 Monate
2012: Lancet Oncol 2015
1995
EGFR mt+ ALK +
2016: NEJM
89,8 Monate
2017: Oncotarget
Medizinischer Campus
Universität Oldenburg
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Themen
Medizinischer Campus
Universität Oldenburg
• Frühe Stadien
• Immun-Checkpoint-Inhibitoren
• Molekulare Therapie
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J Thorac Oncol. 11:39 (2016)
UICC/IASLC Stadieneinteilung: 8. Auflage Medizinischer Campus
Universität Oldenburg
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5 Villegas A | LBA1
Antonia et al. N Engl J Med. 2017, doi: 10.1056/NEJMoa1709937; https://www.ncbi.nlm.nih.gov/pubmed/28885881
1US National Institutes of Health. https://www.clinicaltrials.gov/ct2/show/NCT02125461 2Paz-Arez A et al. Poster presented at: ESMO Annual Meeting, September 8-12, 2017; Madrid, Spain.
BICR: blinded independent central review; DoR: duration of response, Ansprechdauer; NSCLC: non-small cell lung cancer, nicht klein-zelliges Lungenkarzinom; ORR: objetive response
rate; OS: overall survival; OS24: number (%) of patients who are alive at 24 months; PFS: progression-free survival; PK: pharmacokinetics; QoL: quality of life; q2w: every 2 weeks, alle 2
Wochen; SoC: standard of care; TTDM: time to death or distant metastasis
R 2:1
1-42 days after
cCRT
• Patients with non-resectable
NSCLC Stage III withouth
Progression after Platinum-
basied concurrent
Radiochemo-therapy (≥2
cycles)
• ≥18 years
• WHO PS Score 0 or 1
• Life expectancy ≥12 Weeks
• Archived tissue collected
All-comers Population
Co-primary endpoints
•PFS (BICR) by RECIST
v1.1*
•OS
Important secondary
Endpoints
•ORR (per BICR)
•DoR (per BICR)
•Safety and tolerability
•PROs
Durvalumab iv 10 mg/kg
q2w for up to 12 Montjhs
N=476
Placebo 10mg/kg q2w
für bis zu 12 Monate
N=237
RECISTv1.1: Response Evaluation Criteria In Solid Tumors v1.1
*Definiert als Zeit seit Randomisierung (bis zu 6 Wochen nach cCRT) bis zum ersten dokumentierten Ereignis von Progression oder Tod ohne Progression
Stratified: age, gender, smoking
status
N=713
PACIFIC Studie: Phase III, doppel blind
Medizinischer Campus
Universität Oldenburg
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Congress Update | Oncology | ESMO 2017
Baseline characteristics
6 Villegas A | LBA1
Antonia et al. N Engl J Med. 2017, doi: 10.1056/NEJMoa1709937; https://www.ncbi.nlm.nih.gov/pubmed/28885881
cCRT: concurrent chemoradiation therapy, simultane Radiochemotherapie, TC: Tumorzelle; TC ≥25%, ≥25% PD-L1 Expression auf TC; TC <25%,
<25% PD-L1 Expression auf TC
Characteristic Durvalumab
N=476
Placebo
N=237
Age
Median (CI), years
≥65 years %
64 (31-84)
45,2
64 (23-90)
45,1
Gender, %
Male
70,2
70,0
WHO Performance Status Score, %*
0 / 1
49,2 / 50,4
48,1 / 51,5
Smoking status, %
Smoker / Ex-Smoker / Never Smoker
16,6 / 74,4 / 9,0
16,0 / 75,1 / 8,9
Stage, %†
IIIA
IIIB
52,9
44,5
52,7
45,1
Histology, %
SQU/non-SQU
47,1 / 52,9
43,0 / 57,0
PD-L1 Status, %
TC <25% / TC ≥25% / Unknown‡
39,3 / 24,2 / 36,6
44,3 / 18,6 / 37,1
Prior chemotherapy, %
Induction / Definitive cCRT
25,8 / 99,8
28,7 / 99,6
Prior RTx, %*
<54 Gy / 54 to ≤66 Gy / >66 to ≤74 Gy
0,6 / 92,9 / 6,3
0 /
91,6 / 8,0
Best Response on prior cCRT, %
CR/ PR/ SD / PD¶
1,9 / 48,7 / 46,6 / 0,4
3,0 / 46,8 / 48,1 / 0
*Nic
ht
berichte
t oder
fehle
nd (
Durv
alu
mab, P
lacebo, G
esam
t): W
HO
Perf
orm
ance S
tatu
s (
je 0
,4%
), v
orh
erige
Bestr
ahlu
ng (
0,2
%, 0,4
%, 0,3
%).
†A
ndere
: D
urv
alu
mab 2
,5%
; P
lacebo 2
,1%
; gesam
t 2,4
%.
‡K
ein
e P
robe g
esam
melt
oder
kein
e v
alid
en T
este
rgebnis
se ¶
Nic
ht
evalu
ierb
ar/
nic
ht
anw
endbar:
Durv
alu
mab 2
,3%
; P
lacebo 2
,1%
; gesam
t
2,2
%
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PFS according to BICR (Primary Endpoint; ITT)
7 Villegas A | LBA1
Antonia et al. N Engl J Med. 2017, doi: 10.1056/NEJMoa1709937; https://www.ncbi.nlm.nih.gov/pubmed/28885881
BICR = blinded independent central review ; ITT = intent-to-treat; PFS = progression-free survival.
PF
S P
rob
ab
ilit
y
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
0 3 6 9 12 15 18 21 24 27
Time since Randomisation (Months)
Placebo
Durvalumab
Stratified HR 0,52 (95%KI 0,42; 0,65)
double sided P<0,0001
476 377 301 264 159 86 44 21 4 237 163 106 87 52 28 15 4 3
1 0
Number of Pts
Durvalumab Placebo
Durvalumab N=476
Placebo N=237
Median PFS, Months (95%KI) 16,8 (13,0; 18,1) 5,6 (4,6; 7,8)
12-Month PFS Rate, % (95%KI) 55,9 (51,0; 60,4) 35,3 (29,0; 41,7) 18-Month PFS Rate, % (95%KI) 44,2 (37,7; 50,5) 27,0 (19,9; 34,5)
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Time to occurrence of distant mets or death (BICR; ITT)
8 Villegas A | LBA1
Antonia et al. N Engl J Med. 2017, doi: 10.1056/NEJMoa1709937; https://www.ncbi.nlm.nih.gov/pubmed/28885881
BICR: blinded independent central review; ITT: intent-to-treat; NR: not reached
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
1 3 6 9 12 15 18 21 24 27 30
Pro
ba
biliy
of
de
ath
or
dis
tan
t m
ets
Stratified HR 0,52 (95%KI 0,39; 0,69) Double sided P<0,0001
Time since Randomisation (Months
Placebo
Durvalumab
N Patients Durvalumab
Placebo 476 407 336 288 173 91 46 22 4 1 0 237 184 129 106 63 32 16 5 4 0 0
Months (95%KI) Durvalumab Placebo
Median time 23,2 (23,2, NR) 14,6 (10,6, 18,6)
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Subgruppenanalyse (I): präspezifiziert Medizinischer Campus
Universität Oldenburg
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Subgruppenanalyse II: exploratorisch
Villegas A | LBA1
Antonia et al. N Engl J Med. 2017, doi: 10.1056/NEJMoa1709937;
https://www.ncbi.nlm.nih.gov/pubmed/28885881
Medizinischer Campus
Universität Oldenburg
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Pneumonitis und Strahlenpneumonitis
11
Villegas A | LBA1
Antonia et al. N Engl J Med. 2017, doi: 10.1056/NEJMoa1709937;
https://www.ncbi.nlm.nih.gov/pubmed/28885881
Pneumonitis (group
denomination/radiation-pneumonitis, N
(%)*
Durvalumab
N=475
Placebo
N=234
All Grades 161 (33,9) 58 (24,8)
Grade 3/4 16 (3,4) 6 (2,6)
Grad 5 5 (1,1) 4 (1,7)
Leading to discontinuation of therapy 30 (6,3) 10 (4,3)
Sicherheitsanalyse-Set (alle Ursachen). *Pneumonitis/Strahlenpneumonitis durch Studienarzt mit anschließendem Review und Entscheidung
durch den Studien-Sponsor.
Außerdem ist Pneumonitis, wie es oben dargestellt ist, eine Gruppenbezeichnung, die auch akute interstitielle Pneumonitis, interstitielle
Lungenerkrankung, Pneumonitis und pulmonale Fibrose enthält
Medizinischer Campus
Universität Oldenburg
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Zusammenfassung
12 Villegas A | LBA1
Antonia et al. N Engl J Med. 2017, doi: 10.1056/NEJMoa1709937; https://www.ncbi.nlm.nih.gov/pubmed/28885881
• Durvalumab zeigt ein statistisch signifikante Verbesserung des PFS (HR 0,52; P<0,0001;) und
des medianen PFS (>11 Monate) in einer geplanten Interims-Analyse
• PFS Verbesserung in allen präspezifizierten Subgruppen
• Verbesserung der ORR (28,4 vs. 16%, p<0,001) und der DoR (nicht erreicht vs. 13,8 Monate)
• Reduktion der Inzidenz von Metastasen inklusive ZNS Metastasen
• Keine neue Toxizitätssignale
• Studie verbleibt verblindet bis zur OS-Analyse
• Kritik:
• Staging nicht nach S3 Leitlinie inklusive EBUS/EUS oder PET-CT oder MRT
• Unklar, wieviele Pat. nach RTx-CTx in die Studie randomisiert werden konnten (von 963
eingeschlossenen Patienten konnten nur 713 randomisiert werden)
DoR: duration of response, Ansprechdauer; NSCLC: nicht-kleinzelliges Lungenkarzinom; ORR: objektive Ansprechrate; PD-L1: programmed cell death
ligand-1; PFS: Progressionsfreies Überleben
1Antonia SJ et al. Poster presented at: European Society for Medical Oncology (ESMO) Annual Meeting; October 7-11, 2016; Copenhagen, Denmark.
Ann Oncol. 2016;27(suppl 6):1216PD.
Medizinischer Campus
Universität Oldenburg
Durvalumab CUP ist gestartet in Deutschland
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1st L
Algorithmus Erstlinie
Nicht-Platte
16.000
Platte
4.000
20-25%
3.200
EGFR+,
ALK+, ROS+
C met, BRAF
54%
8640
PDL-1
<50%
26%
4160
PDL-1
>50%
30%
1200
PDL-1
>50%
70%
2800
PDL-1 <50%
EGFR IHC+
TKI
3.200
CTx +/-Bev
8640 Pembrolizumab
5360
Platin-Ctx
2800
Testung NGS, PDL-1-IHC
Testung PDL-1-IHC
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14
Immuntherapie (ICI): 2nd L Blockade der CTLA-4- und PD-1- Signalwege
Wolchock et al, J Clin Oncol 2013 ASCO Annual Meeting Abstracts 31:15_suppl
Aktivierung (Zytokine, Lyse, Proliferation,
Migration zum Tumor)
T-Zelle Dendritische Zelle
MHC TCR
CD28
B7 CTLA-4 - - -
B7 + + +
+ + +
CTLA-4 Signalweg
Anti-CTLA-4
Lymphknoten
T-Zelle Tumorzelle
MHC TCR
PD-L1 PD-1
PD-1 Signalweg
Anti-PD-1/PD-L1
Mikroumgebung des Tumors
+ + +
PD-L2 PD-1 Anti-PD-1
- - -
- - -
PD-1 begrenzt die T-Zell-Aktivierung in der
Peripherie während einer Entzündungsreaktion.
CTLA-4 reguliert die Amplitude der frühen
Aktivierung von naiven und Memory T-Zellen.
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Dauerhaftes klinisches Ansprechen
Potential von Immuncheckpoint-Inhibitoren
Chemotherapie/TKI Kontrollen
Ü b
e r
l e
b e
n
Z e i t
Immuntherapie
Langfristiges Überleben
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Langfristiges Überleben durch Immuntherapie
bei metastasiertem Melanom
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Konsistenter OS Vorteil
Medizinischer Campus
Universität Oldenburg
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CM 057: OS abhängig von PD-L1
Borghaei et al., NEJM 2015
53% PD-L1
positiv
47% PD-L1 negativ
Cross-over: 2% zu Immuncheckpoint-Inhibition
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Patienten mit aggressivem Krankheitsverlauf profitierten von Nintedanib+ Docetaxel1
Pro
gre
ss
fr
üh
er
1. Reck M et al. Lancet Oncol. 2014;15(2):143–155.│ 2. Borghaei H et al. N Engl J Med. 2015;373(17):1627–
39
Patienten mit Adenokarzinom-Histologie
LUME-Lung 1: Effekt der Therapie auf das Gesamtüberleben1
Pro
gre
ss
fr
üh
er
Patienten mit nicht-plattenepithelialem NSCLC
CheckMate 057: Effekt der Therapie auf das Gesamtüberleben2
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Medianes follow-up: 11,2 Mo.
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Kaplan-Meier Estimate of OS: <br />Updated Analysis
Presented By Julie Brahmer at 2017 ASCO Annual Meeting
64% Cross over von CTx
44% post study treatment Pembro
UPDATE: ASCO 2017
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• primärer Endpunkt:
signifikant überlegenes PFS vs. Chemo (HR 0,50)
• signifikant überlegenes OS vs. Chemo (HR 0,63) (reif)
- signifikant trotz hohen Cross Overs (64%)
• überlegene Ansprechraten (ORR) vs. Chemo: 45% vs. 28%
• gute Verträglichkeit, weniger Grad 3-5 Toxizitäten als Chemotherapie
• Zulassung seit 31.1.2017
• CRISP: Testrate derzeit unter 50% (auch in 2017)
• PDL-1 >50% erhalten zu etwa 75 % Pembrolizumab
KEYNOTE-024: Zusammenfassung
Medizinischer Campus
Universität Oldenburg
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PD-L1 ≥1% (n = 38)
38 10 8 7 7 7 2 0 1
Years
100
0 1 2 3 4 5 6 7 8
5 y OS,
23%
20
40
60
80
0
5-Year Estimates of OS by PD-L1 Statusa CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC
24
PD-L1 <1% (n = 30)
No. at Risk
OS
(%
)
0 1 2 3 4 5 6 7 8
Years
20
40
60
80
100
0
5 y OS,
20%
30 13 7 5 4 3 0 0 0
PD-L1 ≥50% (n = 13)
13 5 5 5 5 5 2 0 1
Years
100
0 1 2 3 4 5 6 7 8
0
5 y OS,
43%
20
40
60
80
aPD-L1 status was not evaluable in 61 (47%) of 129 patients; the estimated 5-y OS rate in patients with unknown PD-L1 status was 10%
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Biomarker für Immuntherapie
In den Gewebsproben von Therapie-naiven Patienten im Stadium IV, welche keine
therapierbaren Mutationen (z.B. EGFR, EML4-ALK, ROS1) aufweisen, sollte eine
immunhistochemische Untersuchung auf PD-L1-Expression durchgeführt werden.
Das Ergebnis ist als Prozentsatz membranös positiver Tumorzellen (sog. Proportion
Score) anzugeben. Eine externe Qualitätssicherung im Rahmen von Ringversuchen soll
nachgewiesen werden. (Empfehlungsgrad B).
Bei Therapie-naiven Patienten im Stadium IV, welche keine therapierbaren Mutationen
(z.B. EGFR, EML4-ALK, ROS1) aufweisen, und welche in Gewebsproben eine PD-L1-
Expression von >50 % der Tumorzellen aufweisen, sollte als Erstlinientherapie
Pembrolizumab (200 mg i.v. alle 3 Wochen) als Erstlinientherapie angeboten werden
[Empfehlungsgrad B).
Anmerkung: natürlich nach entspr. Zulassung
Weitere Biomarker sind derzeit nur in explorativen retrospektien Analysen
untersucht, eine prospektive Validierung ist notwendig (auch TMB).
Medizinischer Campus
Universität Oldenburg
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PFS by TMB Subgroup and PD-L1 Expression CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC
32 24 13 12 7 5 2 1
28 18 9 3 2 2 2 0
53 35 23 13 10 8 3 0
41 30 14 10 5 4 2 0
No. at Risk
High TMB, PD-L1 ≥50%
High TMB, PD-L1 1–49%
Low/medium TMB, PD-L1 1–49%
Low/medium TMB, PD-L1 ≥50%
16 13 10 8 8 6 2 0 0
31 17 16 13 8 6 2 1 0
70 33 18 9 7 5 1 1 1
41 21 12 6 2 2 1 0 0
26
Months
100
75
50
25
0
6 18 9 3 0 12 15 21
Months
100
75
50
25
0
6 18 9 3
PF
S (
%)
0 12 15 24 21
High TMB, PD-L1 ≥50%
High TMB, PD-L1 1–49%
Low/medium TMB, PD-L1 1–49%
Low/medium TMB, PD-L1 ≥50%
Low/medium TMB, PD-L1 ≥50%
High TMB, PD-L1 1–49%
Low/medium TMB,
PD-L1 1–49%
High TMB, PD-L1 ≥50%
Nivolumab Arm Chemotherapy Arm
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Wie bekommt man kalte Tumore heiß?
Medizinischer Campus
Universität Oldenburg
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Neue Studiengeneration: IO/IO Kombi und
IO/Chemotherapie Kombi
Medizinischer Campus
Universität Oldenburg
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Impower 150: dreiarmige Studie: Carbo-Pacli-Bev-
Atezo vs. Carbo-Pacli-Bev (vs. Carbo-Pacli-Atezo)
Medizinischer Campus
Universität Oldenburg
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Untersucher-bestimmtes PFS: B: AB-CP vs. B-CP
Medizinischer Campus
Universität Oldenburg
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Subgruppenanalyse: PFS
Medizinischer Campus
Universität Oldenburg
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OS: AB-CP vs. B-CP: Präliminär
Medizinischer Campus
Universität Oldenburg
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Zusammenfassung IMPOWER
• Erste Phase III Studie mit PFS Vorteil in „all comers“ Nicht-Platte
• Vorteil auch bei Patienten mit EGFR und ALK Alterationen
• Keine neuen Sicherheits-Signale
• OS Daten noch unreich
• Signifikantes Signal trotz Einsatz von Pacli mit hoch-dosiertem kurzfristigen Dexa
Medizinischer Campus
Universität Oldenburg
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KEYNOTE-189 Phase III Study of Platinum+ Pemetrexed Chemotherapy with or without Pembrolizumab in First Line Metastatic Non-squamous NSCLC
34
Carboplatin/Cisplatin + Pemetrexed + Saline (placebo) (Q3W, 4 cycles)
R 2:1
Carboplatin/Cisplatin + Pemetrexed + Pembrolizumab 200 mg (Q3W, 4 cycles)
PD
Off Study
PD
Patients: (n = 570) Metastatic Non-squamous NSCLC First line metastatic treatment Measurable disease ECOG PS 0-1 Any PD-L1 status EML4/ALK fusion negative EGFR wild type Stable CNS metastases
Primary Endpoint: PFS & OS Secondary Endpoints: Safety, ORR
Stratification factors considered: • PD-L1 expression: (PS ≥1 vs 0) • Platinum chemotherapy:
• cisplatin vs carboplatin • Smoking status:
• never vs former/current
Pemetrexed Pembrolizumab
Pemetrexed Saline (placebo)
Pembrolizumab
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Molekular definierte Subgruppen NSCLC
Reck M et al., Lancet 2013
Medizinischer Campus
Universität Oldenburg
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Incidence of driver mutations in metastatic NSCLC
Barlesi, et al. Lancet 2016
12%
EGFR
Adenocarcinoma
Never smoker
15%WT
32%KRAS
32%Unbekannt
2% BRAF1% HER2
2% PIK3CA
5% ALK
32%
Unknown
13%
Unknown
15%WT
29%KRAS
2% BRAF1% HER2
2% PIK3CA5% ALK
35%
Unknown
All n=18,679
11%
EGFR
21%
EGFR
Female
28%
Unknown
12%
EGFR
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Nicht squamöses NSCLC
Sequentielle Testung mit NGS: Multiplex PCR NGS: EGFR, KRAS, BRAF IHC: ALK FISH: ROS, RET NGS :c-met
Plattenepithel-Karzinom
EGFR IHC
Testalgorithmus Lungenkarzinom Stadium IIIb, IV bei Diagnose
Hybrid capture NGS inkl. Mutationen: EGFR, KRAS, BRAF Fusionen: ALK, RET, ROS, c-met
oder
Nie- oder wenig Raucher: (< 100 Zigaretten oder <10 pack years und vor >10 Jahren gestoppt )
PD-L1 % positiver Tumorzellen Validiertes Assay
ggf.
Fast track &
umfassenden
Bericht in
10 Arbeitstagen
Nicht
ausreichend
Gewebe in
30% der Fälle
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a
38
2. Linie Chemotherapie
1. Linie
ECOG 0-2
EGFR aktiv. Mutation
NSCLC IV – Nicht-Plattenepithelkarzinom
Ja
Mutation/
Translokation
uncommon
Mutation
ECOG 3-4
ECOG 0-2
ECOG 3-4 Gr.2 Gr.3
T790M-spez.
Substanzen
Osimertinib bei BRAF, MET, RET, PKICA
individuelle Entscheidung
Gr.1
E21
EGFR-TKI
(Afatinib, Erlotinib,
Gefitinib) bevorzugt
Afatinib
Rebiopsie und
Molekulare Testung
sonstige
behandelbare
Mutation
T790M-Mutation SCLC
oder
nicht behandelbare Mutation
E19
EGFR-TKI
Molekulare Testung
Testrate in CRISP:
72%
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Molekularer Mechanimsus von akquirierter Resistenz
Universitätsklinik Innere Medizin-Onkologie
Klinik für Hämatologie und Onkologie
Medizinischer Campus Universität Oldenburg
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Gatekeeper Resistenzmutation, wie bei CML (BCR-ABL), GIST (KIT)
Medizinischer Campus
Universität Oldenburg
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AURA 3: Osimertinib vs. CTx nach TKI Versagen
Mok et al., NEJM 2016
Medizinischer Campus
Universität Oldenburg
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Tissue-based paradigm for use of plasma genotyping
• These data support consideration of a paradigm where plasma genotyping is used
as a screening test for T790M, prior to performing an EGFR resistance biopsy
A. Current paradigm
Acquired resistance to EGFR-TKI
All patients undergo biopsy,
FDA-approved FFPE assay for
T790M
Third gen. EGFR-TKI T790M
positive
T790M
negative Chemotherapy
B. Proposed paradigm for use of plasma diagnostics
Acquired resistance to EGFR-TKI
FDA-approved plasma assay
for T790M and sensitising
mutations T790M
negative
T790M
positive Skip biopsy, start third gen. EGFR-TKI
Biopsy, FDA approved
FFPE assay for T790M
T790M
positive
T790M
negative
Third gen. EGFR-TKI
Chemotherapy
Oxnard G, et al. ELCC 2016; Abstract 1350_PR
> 80 % Sensitivität
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Slide 43
NEOliquid Nachweis genomischer Veränderungen an Blut
cfDNA
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Slide 44
Konkordanzanalytik Vergleich funktioneller EGFR Mutationen in Gewebe und Blut
0 20 40 60 80 100
Konkordanz
Sensitivität
PPV
in%
MutationeninEGFR
Lakis S., Heuckmann J, Heukamp L, Griesinger F et al. JTO submitted 2017
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Liquid biopsy erspart etwa 50% der Patienten eine Rebiopsie
60% EGFR p.T790M
5% cMET
5% ERBB2
Liquid Biopsy (Sensitivität 80%)
56% positiv
TKI Resistenz
Keine Rebiopsie
44% negativ
Rebiopsie
PPV für EGFR: 100% bei 80 Proben
Müller, Griesinger, Heukamp, Heuckmann et al. JTO 2017, I.V. Vertrag NOWEL.ORG
Medizinischer Campus
Universität Oldenburg
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© AstraZeneca 2017 Proprietary and Confidential ©AstraZeneca 2017 – any content used externally must be approved locally by local Nominated Signatory prior to use
FLAURA double-blind study design
FLAURA data cut-off: 12 June 2017; NCT02296125
*≥20 years in Japan; #With central laboratory assessment performed for sensitivity; ‡cobas EGFR Mutation Test (Roche Molecular Systems); §Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation; ¶Every 12 weeks after 18 months
CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; p.o., orally; RECIST 1.1, Response Evaluation Criteria In Solid Tumors version 1.1; qd, once daily; SoC, standard-of-care; TKI, tyrosine kinase inhibitor; WHO,
World Health Organization
Stratification by
mutation status
(Exon 19 deletion
/ L858R)
and race
(Asian /
non-Asian)
Crossover was allowed for patients
in the SoC arm, who could receive
open-label osimertinib upon central
confirmation of progression and
T790M positivity
Patients with locally advanced or
metastatic NSCLC
Key inclusion criteria
• ≥18 years*
• WHO performance status 0 / 1
• Exon 19 deletion / L858R (enrolment
by local# or central‡ EGFR testing)
• No prior systemic anti-cancer /
EGFR-TKI therapy
• Stable CNS metastases allowed
Endpoints
• Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1)
• The study had a 90% power to detect a hazard ratio of 0.71 (representing an improvement in median PFS from 10 months to 14.1 months) at a two-sided alpha-level of 5%
• Secondary endpoints: objective response rate, duration of response, disease control rate, depth of response, overall survival, patient
reported outcomes, safety
Randomised 1:1
RECIST 1.1 assessment every
6 weeks¶ until objective
progressive disease
EGFR-TKI SoC§;
Gefitinib (250 mg p.o. qd) or
Erlotinib (150 mg p.o. qd)
(n=277)
Osimertinib
(80 mg p.o. qd)
(n=279)
Ramalingam SS, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care EGFR-TKI as first-line therapy in patients with EGFRm advanced NSCLC: FLAURA.[
Oral presentation]. European Society for Medical Oncology Conference, Madrid, Spain, September 8-12, 2017.
46
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© AstraZeneca 2017 Proprietary and Confidential ©AstraZeneca 2017 – any content used externally must be approved locally by local Nominated Signatory prior to use
Median PFS, months (95% CI)
18.9 (15.2, 21.4)
10.2 (9.6, 11.1)
1.0 P
rob
ab
ilit
y o
f p
rog
res
sio
n-f
ree
su
rviv
al
0.2
0.4
0.6
0.8
0.0
0 3 6 9 12 15 18 21 24 27
Time from randomisation (months)
279
277
262
239
233
197
210
152
178
107
139
78
71
37
26
10
4
2
0
0
No. at risk
Osimertinib
SoC
Osimertinib
SoC
Primary endpoint: PFS by investigator assessment
FLAURA data cut-off: 12 June 2017
Tick marks indicate censored data;
CI, confidence interval; DCO, data cut-off; HR, hazard ratio; SoC, standard-of-care; PFS, progression-free survival. Ramalingam et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain.
342 events in 556 patients at DCO: 62% maturity; osimertinib: 136 events (49%), SoC: 206 events (74%)
HR 0.46
(95% CI 0.37, 0.57)
p<0.0001
47
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© AstraZeneca 2017 Proprietary and Confidential ©AstraZeneca 2017 – any content used externally must be approved locally by local Nominated Signatory prior to use
Overall survival interim analysis
FLAURA data cut-off: 12 June 2017; Tick marks indicate censored data
CI, confidence interval; DCO, data cut-off; HR, hazard ratio; SoC, standard-of-care. . Ramalingam et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain.
Pro
ba
bil
ity o
f o
ve
rall
su
rviv
al
0.2
0.4
0.6
0.8
1.0
0.0
0 3 6 9 12 15 18 21 27
Time from randomisation (months)
279
277
276
263
269
252
253
237
243
218
232
200
154
126
87
64
4
1
No. at risk
Osimertinib
SoC
30 24
0
0
29
24
Osimertinib
SoC
HR 0.63
(95% CI 0.45, 0.88)
p=0.0068ǂ
Median overall survival
Not reached
Not reached
141 deaths in 556 patients at DCO: 25% maturity; osimertinib: 58 deaths (21%), SoC: 83 deaths (30%)
ǂA p-value of <0.0015 was required for
statistical significance at current maturity
48
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ALK + NSCLC: Erstlinientherapie: TKI ist
Standard, Testrate in CRISP: 66%
Solomon NEJM 2014
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Impact of sequential ALKi on OS
Duruisseaux et al. Oncotarget 2017
mOS 89,8 Mo
mOS 28,2 Mo
mOS 19,6 Mo
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Secondary endpoint: PFS, IRC-assessed
Presented By Alice Shaw at 2017 ASCO Annual Meeting
ALEX: Crizotinib vs. Alectinib
Highlights Onkologie 2016, Thorakale Tumore
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PFS by baseline CNS metastases status*
Presented By Alice Shaw at 2017 ASCO Annual Meeting
ALEX: Crizotinib vs. Alectinib
Highlights Onkologie 2016, Thorakale Tumore
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• Ergebnisse
LUNGENKARZINOME | Ergebnisse
ESMO 2017, T. S. Mok et al,, LBA50: Overall Survival (OS) for First-Line Crizotinib Versus
Chemotherapy in ALK+ Lung Cancer: Updated Results from PROFILE 1014
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ALK Varianten und Resistenzentstehung
Highlights Onkologie 2016, Thorakale Tumore
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ROS 1: Crizotinib: Testrate: 50% in CRISP
Highlights Onkologie 2016, (Kurztitel)
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Background
Presented By Mark Awad at 2017 ASCO Annual Meeting
C-met Exon 14 Skipping Mutationen: neues Target: Testrate in CRISP: 25%
Highlights Onkologie 2016, Thorakale Tumore
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Overall survival from date of stage IV diagnosis
Presented By Mark Awad at 2017 ASCO Annual Meeting
C-met Exon 14 Skipping Mutationen: neues Target
Highlights Onkologie 2016, Thorakale Tumore
Tepotinib Studie in Oldenburg
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a
BRAF Mutationen: V600 E (etwa 1%), Testrate in CRISP: 30%
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59
BRAF mt+ NSCLC: PFS in 1st line
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60
BRAF mt+: OS in 1st line
Dabrafenib und Trametinib: Zulassung seit 2017
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Executive Steering Committee:
Prof. Dr. F. Griesinger (Speaker)
Prof. Dr. M. Thomas (Deputy Speaker)
Dr. M. Sebastian
Dr. W. Eberhardt
Clinical Research platform Into molecular testing, treatment and outcome of non-Small cell lung carcinoma Patients
AIO-TRK-0315
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CR
IS
P
Studien gGmbH
Deutsche Gesellschaft für Hämatologie und Onkologie
Deutsche Gesellschaft für Pathologie
Deutsche Gesellschaft für Thoraxchirurgie
Arbeitsgemeinschaft Radiologische Onkologie
Deutsche Krebsgesellschaft/POA, AIO
Deutsche Gesellschaft für Radioonkologie
NHO Niedergelassene Hämatologen und Onkologen
Deutsche Gesellschaft für Pneumologie
AstraZeneca
Boehringer-Ingelheim
Bristol Meyer Squibbs
Celgene
Lilly
Merck Sharp Dome
Novartis
Pfizer
Roche
Sponsor CRO
Medizinischer Campus Universität Oldenburg
Supporting Societies
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CR
IS
P
CRISP
NSCLC Register
10.000 Patienten
PRO
Virtual Biobank
IT Platform
CRISP
63
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CR
IS
P
Rekrutierungsstand
kumuliert
64 Stand 14.11.2017
0
200
400
600
800
1000
1200
1400
An
zah
l P
ati
en
ten
1347
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Medizinischer Campus
Universität Oldenburg
Vielen Dank für die
Aufmerksamkeit!