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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
Gautschi, Aebi, Heukamp, JTO 2015
Serielle Messung von T790M im Plasma unter AZD9291
5
Was ist häufig, was selten?
www.mycancergenome.org
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
Gautschi, DGHO 2015 9
0 10 20 30 40 50 60 70 80 90 100
HER2 ins20
MET ampl
RET
BRAF V600E
EGFR T790M
EGFR all
ROS1
ALK
Shaw, NEJM 2014 10
Crizotinib ROS1 Studie
Mazieres, Gautschi, JCO 2015 11
EUROS1 Kohorte
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
26-30 September 2014, Madrid, Spain
esmo.org
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
26-30 September 2014, Madrid, Spain
esmo.org
Presented by David. Planchard et al 18
SD
PD
NE
PR Best Confirmed Response
380
360
340
100
80
60
40
20
0
-20
-40
-60
-80
-100
Maxim
um
Perc
en
t R
ed
ucti
on
fro
m B
aselin
e M
easu
rem
en
t
Maximum Reduction of Sum of Lesion Diameters By Best Confirmed Response in ≥ 2nd Line (N = 78)
ORR=32% in pretreated pts
26-30 September 2014, Madrid, Spain
esmo.org
Presented by David. Planchard et al 19
Responders in ≥ 2nd Line N = 25
Progressed, n (%) Ongoing, n (%)
12 (48) 13 (52)
Duration of Response
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)
5.5 (2.8 – 7.3)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Number of Prior Systemic
Anti-Cancer Therapy
Regimens for Metastatic
Disease:
1
> 2
Duration of treatment (months)
Duration of Investigator Assessed Response in ≥ 2nd Line (n = 25)
a 62% of patients progressed or died.
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, France; 2Groningen, Netherlands; 3Seoul, Korea; 4Hanover, New Hampshire, USA; 5Pierre-Bénite, France; 6Seattle, 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)
21
• The median duration of response was not reached
Maxim
um
Perc
ent
Reductio
n a
t T
ime o
f B
est D
isease A
ssessm
ent
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
Best Confirmed Response PR
SD
PD
a1 patient discontinued at day 23 and did not have any post-baseline scans for efficacy.
ORR=63% by investigator
Duration of Treatment for All Enrolled Patients
in the Interim Analysis (n = 33)
22
*
0 1 2 3 4 5 6 7 8 9
*1st-line patient (protocol deviation) Treatment Duration (Months)
Complete Response
Partial Response
Stable Disease
Progressive Disease
Not Evaluable
Not Available
First complete or partial response
Disease progressed
Still on study treatment
Best Unconfirmed Response
• Median time on study treatment (dabrafenib and trametinib) = 108 days (range,1 to 244 days)
Dacomitinib Phase II Studie
Kris, Ann Oncol 2015 23
ORR=12% (all ins20)
Mazieres, Gautschi JCO 2013 25
EUHER2 Kohorte
OR=50%, PFS=5 months
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
Best
Respons
e
% (n)
PR 44%
(7/16)
confirmed
unconfirme
d
38%
(6/16)
6%
(1/16)
SD 56%
(9/16)
ORR 38% (95% CI
15%-65%)
ORR12wks 36% (95% CI
13%-65%) (5 PRs of 14 evaluable at 12
wks)
PR - partial response, SD - stable disease
ORR – overall response rate, CI - confidence interval
Response to Cabozantinib in Patients with
RET-Rearranged Lung Adenocarcinomas
imaging performed at baseline, 4 weeks, and every 8 weeks thereafter
response evaluable patients received ≥ 1 cycle of therapy
confirmed PR
SD
-90%
-60%
-30%
0%
30%
0 3 6 9 12 15 18 21 24 27 30
Duration of Cabozantinib Therapy
months
confirmed partial response
x
x
x
x
x
x
x
x
x
stable disease
x disease progression (RECIST)
Median duration of response
8 months (range 5.5-26 months)
treatment allowed post-radiologic
progression if with continued clinical benefit
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
Gautschi ELCC 2014; Michels JTO 2015 30
EURET Kohorte
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
Therapie-Algorithmus in Luzern
(modifiziert nach: www.uptodate.com) 34
Unbekanntes oder schwieriges Ziel (KRAS, PIK3CA, TP53…)
Etabliertes Ziel (EGFR, ALK, ROS1)
Etablierte gezielte Therapie
Nicht-squamöses NSCLC M1
Platin-haltige Chemotherapie
«Neues» Ziel (BRAF V600, HER2ins20, RET, MET)
Immuntherapie
Supportive Therapie
Squamöses NSCLC M1
«Neue» gezielte Therapie(n)
Platin-haltige Chemotherapie
Test-Algorithmus in Luzern
Diebold/Gautschi 2015
Sequenzierung:
EGFR/KRAS
IHC/FISH:
ALK/ROS1
BRAF
HER2
MET
RET
KIF5B
MET
„Next generation sequencing“
«Tripel-negatives NSCLC»
Stufe 1:
Indikation am
Tumorboard
Stufe 2: auf
ärztliche
Anordnung
Stufe 3: Im
Rahmen einer
Registerstudie
«Pan-negatives NSCLC»
Material asservieren
für klinische Studien
(auch squamöse)
Fortgeschrittene nicht-squamöse NSCLC:
PDL1
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.
