2015 DGHO Gautschi - Luzerner Kantonsspital

NSCLC: seltene molekular
definierte Subgruppen
[email protected]
Potenzielle Interessenkonflikte
• Beraterfunktion für AstraZeneca, BMS,
Novartis, Pfizer und Roche
• Zusammenarbeit mit NEO New Oncology
• Alle Honorare gehen an das Luzerner
Kantonsspital
2
Umfassende Tumordiagnostik
ist heute möglich
Bilck in die (nahe) Zukunft:
Molekulare Diagnostik im Blut
Serielle Messung von T790M im Plasma unter AZD9291
Gautschi, Aebi, Heukamp, JTO 2015
Was ist häufig, was selten?
www.mycancergenome.org
5
www.uptodate.com
First line:
• ROS1 fusion: crizotinib
Second line:
• HER2 ins20: TKI or trastuzumab+chemo
• BRAF V600E: BRAFi (+MEKi)
• RET fusion: cabozantinib or vandetanib
• MET ex14: crizotinib
Other targets: may become preferred option…
Sequist 2015
7
«Echte» gezielte Therapie
Tumor-spezifisch
Hohe Ansprechrate (≥50%)
Gut verträglich
→ Fokus auf Treibermutationen mit verfügbaren
gezielten Therapien («off label use»)
Mok, Clin Lung Cancer 2010
8
Ansprechraten in prospektiv
kontrollierten Studien
ALK
ROS1
EGFR all
EGFR T790M
BRAF V600E
RET
MET ampl
HER2 ins20
0
10
20
30
40
50
Gautschi, DGHO 2015
60
70
80
90
100
9
Crizotinib ROS1 Studie
Shaw, NEJM 2014
10
EUROS1 Kohorte
Mazieres, Gautschi, JCO 2015
11
ROS1: Resistenz
Awad, NEJM 2013
12
MET ampl: Crizotinib Studie
Camidge, ASCO 2014
13
MET ampl: Crizotinib Studie
Camidge, ASCO 2014
14
BASKET Studie
• n=19 NSCLC (lokaler BRAF Test)
• ORR=42%, PFS: 7.3 Monate
Hyman, NEJM 2015
15
EURAF Kohorte
Gautschi, JTO 2015
16
Dabrafenib in patients with BRAF V600E-mutant
Advanced Non-Small Cell Lung Cancer (NSCLC): a
multicenter, open-label, phase 2 trial (BRF113928)
D. Planchard1, T.M. Kim2, J. Mazieres3, E. Quoix4, G.J. Riely5, F.
Barlesi6, P.-J. Souquet7, E.F. Smit8, H.J.M. Groen9, R. J. Kelly10, B.-C.
Cho11, M.A. Socinski12, C. Tucker13, B. Ma13, B. Mookerjee13, C.M.
Curtis, Jr. 13, B.E. Johnson14
1Department
of Medical Oncology, Gustave Roussy, Villejuif, France; 2Seoul National University Hospital, Seoul, Korea; 3Hôpital
Larrey CHU Toulouse, Toulouse, France; 4Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 5Memorial Sloan-Kettering
Cancer Center, New York, NY, USA; 6Aix Marseille University – Assistance Publique Hôpitaux de Marseille, Hôpital Nord, Marseille,
France; 7Centre Hospitalier Lyon-Sud, Pierre-Bénite, France; 8Vrije Universiteit VU Medical Centre, Amsterdam, Netherlands;
9University of Groningen and University Medical Center Groningen, Groningen, Netherlands; 10The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins University, Baltimore, MD, USA; 11Yonsei Cancer Center, Seoul, Korea; 12University of Pittsburgh,
Pittsburgh, PA, USA; 13GlaxoSmithKline, Collegeville, PA, and Research Triangle Park, NC, USA; 14Dana-Farber Cancer Institute,
Boston, MA, USA
esmo.org
26-30 September 2014, Madrid, Spain
Maximum Percent Reduction from Baseline Measurement
Maximum Reduction of Sum of Lesion Diameters By Best
Confirmed Response in ≥ 2nd Line (N = 78)
380
360
340
100
ORR=32% in pretreated pts
80
60
40
20
0
-20
-40
Best Confirmed Response
-60
-80
PR
SD
PD
NE
-100
26-30 September 2014, Madrid, Spain
18 Presented by David. Planchard et al
esmo.org
Duration of Investigator Assessed
Response in ≥ 2nd Line (n = 25)
Responders in ≥ 2nd Line
N = 25
Progressed, n (%)
Ongoing, n (%)
12 (48)
13 (52)
Duration of Response
Number of Prior Systemic
Anti-Cancer Therapy
Regimens for Metastatic
Disease:
1
>2
0
1
a
2
3
4
5
6
7
8
Median, months (95% CI)
< 6 months, n (%)
> 6 months, n (%)
> 9 months , n (%)
> 12 months, n (%)
11.8 (5.4 – NR)
11 (44), 4 ongoing
14 (56), 9 ongoing
10 (40), 8 ongoing
6 (24), 4 ongoing
Median PFSa,
months (95% CI)
9
10 11
12 13 14
Duration of treatment (months)
15
16
17
5.5
(2.8 – 7.3)
18
19
20
21
22
23
62% of patients progressed or died.
26-30 September 2014, Madrid, Spain
19 Presented by David. Planchard et al
esmo.org
24
Dabrafenib Plus Trametinib in Patients With
BRAF V600E-mutant Advanced Non-Small Cell
Lung Cancer (NSCLC): A Multicenter, Open-label,
Phase 2 Trial (BRF113928)
D. Planchard1, H.J.M. Groen2, T.M. Kim3, J .Rigas4,
P-J. Souquet5, C. Baik6, F. Barlesi7, J. Mazieres8,
E. Quoix9, C.M. Curtis, Jr.,10 B. Mookerjee10,
L. Pandite10, C. Tucker10, A. D’Amelio10, B.E.
Johnson11
1Villejuif,
6Seattle,
France; 2Groningen, Netherlands; 3Seoul, Korea; 4Hanover, New Hampshire, USA; 5Pierre-Bénite, France;
Washington, USA; 7Marseille, France; 8Toulouse, France; 9Strasbourg, France;10Collegeville, Pennsylvania and
Research Triangle Park, North Carolina, USA; 11Boston, Massachusetts, USA
Maximum Reduction of Sum of Lesion Diameters By Best
Confirmed Response in  2nd Line (N = 24a)
Maximum Percent Reduction at Time of Best Disease Assessment
20
10
0
-10
-20
-30
-40
-50
ORR=63% by investigator
-60
-70
Best Confirmed Response
-80
-90
-100
a1
PR
SD
PD
patient discontinued at day 23 and did not have any post-baseline scans for efficacy.
• The median duration of response was not reached
21
Duration of Treatment for All Enrolled Patients
in the Interim Analysis (n = 33)
Best Unconfirmed Response
Complete Response
Partial Response
Stable Disease
Progressive Disease
Not Evaluable
Not Available
*
First complete or partial response
Disease progressed
Still on study treatment

0
1
*1st-line patient (protocol deviation)
2
3
4
5
6
7
Treatment Duration (Months)
• Median time on study treatment (dabrafenib and trametinib) = 108 days (range,1 to 244 days)
22
8
9
Dacomitinib Phase II Studie
ORR=12% (all ins20)
Kris, Ann Oncol 2015
23
EUHER2 Kohorte
OR=50%, PFS=5 months
Mazieres, Gautschi JCO 2013
25
Trastuzumab emtansin (T-DM1)
Weiler, Gautschi, JTO 2015
26
Phase II study of cabozantinib
for patients with advanced
RET-rearranged lung cancers
A Drilon, CS Sima, R Somwar, R Smith, MS Ginsberg,
GJ Riely, CM Rudin, M Ladanyi, MG Kris, NA Rizvi
Memorial Sloan Kettering Cancer Center, New York, NY
30%
Response to Cabozantinib in Patients with
RET-Rearranged Lung Adenocarcinomas
0%
-30%
Best
Respons
e
PR
confirmed
-60%
unconfirme
d
SD
-90%
% (n)
44%
(7/16)
38%
(6/16)
6%
(1/16)
56%
(9/16)
ORR 38% (95% CI
15%-65%)
imaging performed at baseline, 4 weeks, and every 8 weeks thereafter
response evaluable patients received ≥ 1 cycle of therapy
ORR12wks 36% (95% CI
confirmed PR
SD
PR - partial response, SD - stable disease
ORR – overall response rate, CI - confidence interval
Duration of Cabozantinib Therapy
Median duration of response
8 months (range 5.5-26 months)
x
confirmed partial response
x
stable disease
x
x
x disease progression (RECIST)
x
treatment allowed post-radiologic
progression if with continued clinical benefit
x
x
x
x
0
3
6
9
12
15
18
21
24
27
30
months
median duration of response in 6 confirmed partial responders calculated from date of cabozantinib initiation to radiologic progression, cutoff for data analysis 5/11/15
EURET Kohorte
Gautschi ELCC 2014; Michels JTO 2015
30
Rein prädiktiv oder auch prognostisch?
Daten aus einer Gefitinib Langzeitstudie
Gautschi, Oncology Research and Treatment 2015
31
Beispiele externer Befunde
1. «Das vorliegende Material erlaubt keine
weitergehende Diagnostik»
2. «Wir haben die Mutation XYZ gefunden, die
klinische Relevanz ist unklar»
3. «Lung cancer with elevated TYMS expression:
possible resistance to capecitabine and 5FU»
32
33
Therapie-Algorithmus in Luzern
Nicht-squamöses NSCLC M1
Etabliertes Ziel
(EGFR, ALK, ROS1)
Squamöses NSCLC M1
(BRAF V600, HER2ins20, RET, MET)
Unbekanntes oder schwieriges
Ziel (KRAS, PIK3CA, TP53…)
Platin-haltige Chemotherapie
Platin-haltige Chemotherapie
«Neues» Ziel
Etablierte gezielte Therapie
«Neue» gezielte Therapie(n)
Immuntherapie
Supportive Therapie
(modifiziert nach: www.uptodate.com)
34
Test-Algorithmus in Luzern
Stufe 1:
Indikation am
Tumorboard
Fortgeschrittene nicht-squamöse NSCLC:
Sequenzierung:
EGFR/KRAS
IHC/FISH:
ALK/ROS1
Material asservieren
für klinische Studien
«Tripel-negatives NSCLC»
Stufe 2: auf
ärztliche
Anordnung
BRAF
HER2
MET
RET
KIF5B
MET
PDL1 (auch squamöse)
«Pan-negatives NSCLC»
Stufe 3: Im
Rahmen einer
Registerstudie
„Next generation sequencing“
Diebold/Gautschi 2015
Zusammenfassung
• Mutationen werden immer häufiger
«unaufgefordert» diagnostiziert: setzen sie im Team
ihre lokalen Standards für Tests und Therapien fest
• Interpretation kann nicht alleine dem Kliniker
überlassen werden: schliessen sie sich einem
Kompetenzzentrum ihres Vertrauens an
• Neue Zulassungen sind wichtig: behandeln sie
Patienten wenn immer möglich im Rahmen von
Studien (oder schliessen sie sie in Kohorten ein)
Dank
•
•
•
•
B. Besse, D. Planchard, A. Drilon für Slides
J. Diebold (Luzern)
J. Mazieres, J. Milia (Toulouse)
R. Thomas, J. Wolf, L. Heukamp, R. Büttner
(Köln), sowie allen anderen Kollegen, die an
den Kohorten beteiligt sind.