Nieuwe targets en cfdna

Transcription

1 Nieuwe targets en cfdna dr. A.J. van der Wekken Universitair Medische Centrum Groningen Leek meeting 2017

2 Disclosure Advisory board: Lilly Boehringer-Ingelheim Pfizer AstraZeneca MSD Lectures: Lilly Boehringer-Ingelheim Pfizer AstraZeneca BMS

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4 Inhoud Nieuwe inzichten bekende targets Nieuwe targets cfdna

5 ALK / ROS1

6 y design Cohort flow chart Distribution of ALK variants (n = 129) ective study at Massachusetts Hospital (MGH) and University of -Irvine (UCI) d ALK+ NSCLC patients with a LK variant, treated with 1 ALK ALK+ NSCLC patients evaluated between 1/2008 1/2017 n = 380 EML4 E13 E20 A20 A20 ALK Kinase Kinase v1 v2 6.2% reviewed to extract data on thologic characteristics, t outcomes, and post-alk TKI notyping Known ALK fusion variant based on genotyping n = 137 E6 E2 A20 A20 Kinase Kinase v3a/b v5 2.3% Treated with at least one ALK TKI n = 129 E18 E14 A20 A20 Kinase Kinase v5' v7 0.8% 3.9% Final analysis set Coiled-coil region, EML4 TAPE domain, EML4 Non- EML4-ALK 4.7% 07: Clinical outcomes and ALK resistance mutations according to EML4-ALK variant et al.

7 Post-crizotinib biopsies Variant 1 (n = 14) Variant 3 (n = 12) Post-second generation ALK TKI biopsie Variant 1 (n = 19) Variant 3 (n = 32) L1196M 7% E1210K 7% F1174V 8% S1206Y 8% G1202del 5% E1210K+D12 03N E1210K+S12 6% 06C 6% G1202R+F11 74L 3% G1202R+L11 96M 3% I1171N+C115 6Y 3% V1180L+ G1202del+C1 156Y 3% I1171T 8% L1196M 11% WT 58% WT 34% WT 86% C1156Y 9% WT 67% F1174C 11% G1202R 37.5% I1171T 5% I1171N/S 9% T1 V1180L 3% v1 v3 P LK mutations R v1 v3 P % ALK mutations % G1202R : Clinical outcomes and ALK resistance mutations according to EML4-ALK variant et al.

8 Progression-free survival on ALK TKIs based on EML4-ALK variant 1 vs variant 3 otinib as first-line therapy (B) Second-generation TKI as post-crizotinib therapy (C) Lorlatinib as post-crizotinib and post-secon generation TKI therapy variant 1 variant variant 1 variant variant 1 variant Time (months) Time (months) Time (months) v1 v3 v1 v3 v1 v PFS 8.8 mos 5.6 mos 1.52 [95% CI ] p = n Median PFS 12.6 mos 8.1 mos HR 1.44 [95% CI ] p = n Median PFS 2.6 mos 7.1 m HR 0.18 [95% CI p = : Clinical outcomes and ALK resistance mutations according to EML4-ALK variant et al.

9 4 Design of TPX-0005: Systematically Overcoming Resistance Mutations ATP & Crizotinib solvent front mutations ATP & Alectinib ATP & Lorlatinib ATP & Ceritinib ATP & Brigatinib ATP & TPX-0005

10 TPX-0005: Potent Inhibitor against Wildtype and Mutant ALKs PX-0005 IC 50 (nm) at 10 µm ATP LK 1.04 PM-ALK 1.23 LK(T1151M) 0.49 LK(1151T Ins) 2.16 LK(L1152R) 1.23 LK(C1156Y) 0.93 LK (F1174L) 1.46 LK(F1174S) 1.02 LK (L1196M) 1.08 LK (G1202R) 1.21 LK(S1206R) 0.53 LK(G1269A) 5.5 LK(G1269S) 14.1 LK(R1275Q) 2.79 MW Ba/F3 EML4-ALK Cells IC 50 (nm Inhibitor WT G1202R TPX Crizotinib Ceritinib Alectinib Brigatinib Lorlatinib 0.7 NA Ba/F3 EML4-ALK G1202R xenograft model

11 Potently Inhibited Wildtype and Solvent Front Mutated ROS1 and TR Ba/F3 Cell Proliferation IC 50 (nm) Ba/F3 CD74-ROS1 G2032R xenograft CD74-ROS1 LMNA-TRKA ETV6-TRKB ETV6-TRKC Inhibitor WT G2032R WT G595R G639R G623R PX-0005 < < rizotinib orlatinib zantinib rigatinib Ceritinib trectinib trectinib NA NA NIH3T3 LMNA-TRKA G595R xenograft m

12 RET en partners

13 Vandetanibin 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 cases Yoh et al, Lancet RespMed,

14 NRG1-CD74 fusie

15 NRG1/NeuregulinFusion in Invasive Mucinous Adenocarcinoma Mean number of colonies ) NIH3T3 colonies Vector CD74-NRG1 (C8;N6) CD74-NRG1 (C6;N6) Lapatinib Afatinib Cancer stem cell marker CD74- NRG (Nakaoku et al., Clin Cancer Res, 2014; Murayama, Nakaoku et al., Cancer Res, 2015) 0,45 0,4 0,35 0,3 0,25 0,2 0,15 0,1 0,05 0 N.T. IGF-2 NAb Vector Sphere formation CD74-NRG1 (C6;N6) CD74-NRG1 (C8;N6)

16 cfdna Crowley et al., Nat Rev Cance

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18 Technical hemolysis: the effect on DNA content upon storage of blood tubes (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 Norton Clin Biochem 2013

19 d from Diaz, J Clin Oncol 2014

20 ample of plasma cfdna mutation levels of druggable (line) and ne resistant EGFR mutation (broken) Detection of new EGFR-T790M mutation upon progression might be reason for changing treatment Oxnard CCR

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22 Conclusie Mogelijk invloed van varianten op respons ALK RET cfdna wordt belangrijker voor analyse en behandelstrategie Plasma Urine (ucfdna)

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24 ??? VRAGEN???