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Nieuwe targets en cfDNAdr. A.J. van der Wekken
Universitair Medische Centrum Groningen
Leek meeting 2017
Disclosure
• Advisory board: • Lilly• Boehringer-Ingelheim• Pfizer• AstraZeneca• MSD
• Lectures:• Lilly• Boehringer-Ingelheim• Pfizer• AstraZeneca• BMS
InhoudNieuwe inzichten bekende targets
Nieuwe targets
cfDNA
ALK / ROS1
Study design
Retrospective study at Massachusetts General Hospital (MGH) and University of California-Irvine (UCI)
Advanced ALK+ NSCLC patients with a ALK variant, treated with ≥1 ALK
Records reviewed to extract data on clinicopathologic characteristics, treatment outcomes, and post-ALK TKI biopsy genotyping
ALK+ NSCLC patients evaluated between
1/2008 – 1/2017n = 380
Known ALK fusion variant based on genotyping
n = 137
Treated with at least one ALK TKI
n = 129
Cohort flow chart
4.7%
0.8%
3.9%
2.3%
6.2%
Non-EML4-ALK
v7
v5'
v5
v3a/b
v2
v1
Distribution of ALK variants (n = 129)
Final analysis set
Kinase
Kinase
Kinase
Kinase
Kinase
Kinase
EML4 ALK
E20
E2
E18
E14
A20
A20
A20
A20
A20
A20
E13
E6
Coiled-coil region, EML4
TAPE domain, EML4
MA 07.07: Clinical outcomes and ALK resistance mutations according to EML4-ALK variantLin JJ et al.
WT34%
T1151KI1171N/S9%
V1180L3%
G1202R37.5%
G1202R+L1196M3%
G1202R+F1174L3%
I1171N+C1156Y3%
V1180L+G1202del+C1
156Y3%
Variant 1 (n = 14) Variant 3 (n = 12)
WT86%
L1196M7%
E1210K7%
WT67%
C1156Y9%
I1171T8%
F1174V8%
S1206Y8%
Variant 1 (n = 19) Variant 3 (n = 32)
WT58%
I1171T5%
F1174C11%
L1196M11%
G1202del5%
E1210K+S1206C6%
E1210K+D1203N6%
Post-crizotinib biopsies Post- second generation ALK TKI biopsies
v1 v3 P
ALK mutations 14 33 0.365
G1202R 0 0 1
v1 v3 P
% ALK mutations 42 66 0.145
% G1202R 0 44 0.001
MA 07.07: Clinical outcomes and ALK resistance mutations according to EML4-ALK variantLin JJ et al.
Progression-free survival on ALK TKIs based on EML4-ALK variant 1 vs variant 3(A) Crizotinib as first -line therapy (B) Second-generation TKI as post-crizo tinib
therapy(C) Lorlatinib as post-crizotinib and post- secondgeneration TKI therapy
v1 v3
27 28
Median PFS 8.8 mos 5.6 mos
1.52 [95% CI 0.85-2.72]p = 0.153
v1 v3
n 37 40
Median PFS 12.6 mos 8.1 mos
HR 1.44 [95% CI 0.86-2.40]p = 0.164
v1 v3
n 11 17
Median PFS 2.6 mos 7.1 mos
HR 0.18 [95% CI 0.05-0.67]p = 0.004
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60Time (months)
variant 1variant 3
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60Time (months)
variant 1variant 3
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60Time (months)
variant 1variant 3
MA 07.07: Clinical outcomes and ALK resistance mutations according to EML4-ALK variantLin JJ et al.
Design of TPX- 0005: Systematically Overcoming Resistance Mutation s ATP & Crizotinib
solvent front mutations
ATP & Ceritinib
ATP & Alectinib
ATP & TPX-0005
ATP & Lorlatinib
ATP & Brigatinib
4
TPX-0005 IC50 (nM) at 10 µM ATP
ALK 1.04NPM-ALK 1.23ALK(T1151M) 0.49ALK(1151T Ins) 2.16ALK(L1152R) 1.23ALK(C1156Y) 0.93ALK (F1174L) 1.46ALK(F1174S) 1.02ALK (L1196M) 1.08ALK (G1202R) 1.21ALK(S1206R) 0.53ALK(G1269A) 5.5ALK(G1269S) 14.1ALK(R1275Q) 2.79
TPX-0005: Potent Inhibitor against Wildtype and Mutant ALKs
MW 355.3
Ba/F3 EML4-ALK Cells IC50 (nM)
Inhibitor WT G1202R
TPX-0005 17.8 20.5
Crizotinib 74.8 359.4
Ceritinib 2.1 388
Alectinib 18.9 607
Brigatinib 11.8 399
Lorlatinib 0.7 NA
Ba/F3 EML4-ALK G1202R xenograft model
11
Ba/F3 Cell Proliferation IC 50 (nM)
CD74-ROS1 LMNA-TRKA ETV6-TRKB ETV6-TRKC
Inhibitor WT G2032R WT G595R G639R G623R
TPX-0005 <0.2 8.4 <0.2 0.4 0.6 3.0
Crizotinib 18.4 1402
Lorlatinib 0.2 262.4
Cabozantinib 0.5 60.7
Brigatinib 34.5 1385
Ceritinib 70.9 2000
Entrectinib 11.3 2404 0.3 705 1384 1000
Larotrectinib NA NA 3.5 1024 3000 1500
Ba/F3 CD74-ROS1 G2032R xenograft model
TPX-0005 Potently Inhibited Wildtype and Solvent Front Mutated ROS1 and TRKs
NIH3T3 LMNA-TRKA G595R xenograft model
RET en partners
Yoh et al, Lancet Resp Med, 2017
Vandetanib in patients with previously treated RET-rearranged advanced
non-small-cell lung cancer (LURET): an open-label, multicenter phase 2 trial
9 PR and ORR 53% (90% CI, 31 to 74)
in 17 eligible cases13
NRG1-CD74 fusie
NRG1/Neuregulin Fusion in Invasive Mucinous Adenocarcinoma
Lapatinib Afatinib
0
10
20
30
40
50
60
70
80Vector
CD74-NRG1 (C8;N6)
CD74-NRG1 (C6;N6)
Me
an
nu
mb
er
of
colo
nie
s
M)
(Nakaoku et al., Clin Cancer Res, 2014; Murayama, Nakaoku et al., Cancer Res, 2015)
CD74-NRG1 - + +
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
Vector CD74-NRG1
(C6;N6)
CD74-NRG1
(C8;N6)
N.T. IGF-2 NAb
Sphere formationCancer stem cell markerNIH3T3 colonies
cfDNA
Crowley et al., Nat Rev Cancer 2013
Norton Clin Biochem 2013
“Technical” hemolysis: the effect on DNA content upon storage of bloodtubes (EDTA vs BCT/Streck) before processing plasma.
DNA content upon storage in time in EDTA tubes DNA content upon storage in time in BCT tubes
Adapted from Diaz, J Clin Oncol 2014
Example of plasma cfDNA mutation levels of druggable (line) and new resistant EGFR mutation (broken)
Oxnard CCR 2014
Detection of new EGFR-T790M mutation upon progressionmight be reason for changing treatment
Conclusie
• Mogelijk invloed van varianten op respons
• ALK
• RET
• cfDNA wordt belangrijker voor analyse en behandelstrategie
• Plasma
• Urine (ucfDNA)
??? VRAGEN ???