Charakterisierung neuer therapeutischer Targets beim Lungenkarzinom

Transkript

1 Charakterisierung neuer therapeutischer Targets beim Lungenkarzinom Jürgen Wolf Lung Cancer Group Cologne & Netzwerk Genomisches Medizin Centrum für Integrierte Onkologie, Uniklinik Köln

2 Interessenkonflikte Advisory Boards und Vortragshonorare: AstraZeneca, BMS, Boehringer-Ingelheim, Celgene, Chugai, Lilly MSD, Novartis, Pfizer, Roche Forschungsunterstützung: BMS, MSD, Novartis, Pfizer, Roche,

3 Systemische Therapie des fortgeschrittenen NSCLC 2017 NSCLC Stadium IIIB, IV Nicht-Plattenepithel-Karzinom Plattenepithelkarzinom EGFR ca. 12 % ALK ca. 4 % ROS1 ca. 2 % BRAF V600 ca. 1.5 % Erlotinib Gefitinib Afatinib Crizotinib Dabrafenib + Trametinib PDL1 > 50% Pembrolizumab PDL1 / < 50% Chemotherapie T790M MET, RET, HER2, TRK... Zielgerichtete Therapie Osimertinib Ceritinib Alectinib Lorlatinib Brigatinib... Chemotherapie Nivolumab: PD-L1 unabängig Atezolizumab: PD-L1 unabhängig Pembrolizumab: nur PD-L1 +

4 Neue therapeutische Targets Etablierte Targets: Rezidiv und Sequenztherapie Neue Targets Konsequenzen für die klinische Versorgung

5 Neue therapeutische Targets Etablierte Targets: Rezidiv und Sequenztherapie Neue Targets Konsequenzen für die klinische Versorgung

6 EGFRmut

7 Aquired EGFR-TKI resistance: T790M allows efficient treatment with 3 rd gen. inhibitors Initial biopsy PD: rebiopsy EGFR del 19 L858R Erlotinib, Gefitinib, Afatinib (8-12m) T790M also: liquid biopsy Osimertinib (8-10m) EU approval Jan Tagrisso R Yu et al., Clin Cancer Res 2013; Kobayashi et al., NEJM 2005; Jänne et al, NEJM 2015

8 PFS 3 rd gen. EGFR-TKI shows high efficacy in 1 st line treatment Initial biopsy PD: rebiopsy EGFR del 19 L858R Erlotinib, Gefitinib, Afatinib (8-12m) T790M Osimertinib (8-10m) also: liquid biopsy Osimertinib (19) 1,0 0,8 Osimertinib SoC Median PFS, months (95%KI) 18,9 (15,2; 21,4) 10,2 (9,6; 11,1) 0,6 0,4 HR 0,46 (95%KI 0,37; 0,57) p<0,0001 0,2 0, time since randomisation (months) Ramalingam et al. ESMO 2017

9 Challenge: T790M neg. acquired resistance Initial biopsy PD: rebiopsy EGFR del 19 L858R Erlotinib, Gefitinib, Afatinib T790M hl MET ampl. Osimertinib (10m) EGFR-TKI + METinh. HER2 ampl. SCLC??? EGFR-TKI + HER2inh. Chemo, I-O, anti-dll3 Chemo clinical trials > wenn möglich, NGS-basierte Diagnostik im Rezidiv Yu et al., Clin Cancer Res 2013; Kobayashi et al., NEJM 2005; Jänne et al, NEJM 2015

10 Challenge: resistance to 3 rd gen. inhibitor Initial biopsy PD: rebiopsy PD: rebiopsy EGFR del 19 L858R Erlotinib, Gefitinib, Afatinib (10m) T790M Osimertinib (10m) EGFR C797S also: liquid biopsy EGFR G724S Osimertinib (20m) hl MET amp. HER2 amp. KRAS mut Thress et al, NEJM 2015, Ortiz-Cuaran et al, CCR 2016, Fassunke, Michels et al, in prep.

11 Challenge: resistance to 3 rd gen. inhibitor Initial biopsy PD: rebiopsy PD: rebiopsy EGFR del 19 L858R Erlotinib, Gefitinib, Afatinib (10m) T790M Osimertinib (10m) EGFR C797S Osimertinib (20m) also: liquid biopsy EGFR G724S hl MET amp. HER2 amp. KRAS mut clinical trials > wenn möglich, NGS-basierte Diagnostik im Rezidiv Thress et al, NEJM 2015, Ortiz-Cuaran et al, CCR 2016, Fassunke, Michels et al, in prep.

12 Molecular profiles of baseline biopsies: High-level MET abolishes efficacy of 3rd gen inhibitors (A) Diagnostics flow chart Baseline FFPE biopsy Central massively parallel sequencing (MPS) Fluorescence in-situ hybridization (FISH) Amongst others EGFR, exons KRAS TP53 PIK3CA PTEN CTNNB1 HER2 GCN and ratio MET GCN and ratio N=30 N=28 N=30 (B) Response and molecular characteristics Pat. ID *Response PR, 56%; SD, 28%; PD, 13% **EGFR del19, 72%; L858R, 2%5; L861Q, 3% ***MET hl, 13%; ll, 20% **** HER2 ampl, 10% TP53 mut, 40% CTNNB1 mut, 7% PTEN mut, 7% PIK3CA mut, 3% * according to RECIST V1.1; green: PR, orange: SD, red: PD; ** violet: del19, light blue: L858R, beige: L861Q; *** green: WT; blue: low-level amplification; red: high-level amplification; **** hl: high-level amplification, ll: low-level amplification Michels and Heydt et al., in preparation

13 ALKfus

14 Sequential therapy with ALK-inhibitors: Next-gen. inhibitors move to 1 st line Crizotinib (11m) Alectinib (9m) Alectinib (26 m) Ceritinib (17 m) Solomon et al, NEJM 2014; Soria et al, Lancet 2017; Peters et al, NEJM 2017

15 Sequential therapy with ALK-inhibitors: 3 rd gen. inhibitors in clinical development Crizotinib (11m) Alectinib (9m) 3 rd gen. ALK-i. Alectinib (26 m) 3 rd gen. ALK-i. Lorlatinib Brigatinib Entrectinib Ensartinib others

16 Resistance mutation status determines ALK-inhibitor efficacy Gainor et al, Cancer Disc 2016

17 Clonal evolution during therapy leads to different patterns of ALK-mutations in rebiopsies from resistant patients Figure 1 A) Crizotinib-Resistant Specimens B) Ceritinib-Resistant Specimens C) N=55 N=24 Alectinib-Resistant Specimens N=17 L1196M G1269A C1156Y I1171T/N/S ALK WT G1202R G1202del F1174C/L V1180L S1206Y E1210K 2 ALKmutations a ALK amplification b Downloaded from cancerdiscovery.aacrjournals.org on November 2, American Association for Cancer Research. Gainor et al, Cancer Disc 2016

18 Clonal evolution during therapy leads to different patterns of ALK-mutations in rebiopsies from resistant patients Figure 1 A) Crizotinib-Resistant Specimens B) Ceritinib-Resistant Specimens C) N=55 N=24 Alectinib-Resistant Specimens N=17 L1196M G1269A C1156Y I1171T/N/S ALK WT G1202R G1202del F1174C/L V1180L S1206Y E1210K 2 ALKmutations a ALK amplification b Downloaded from cancerdiscovery.aacrjournals.org on November 2, American Association for Cancer Research. Gainor et al, Cancer Disc 2016

19 Activity of different ALK-inhibitors depends on given resistance mutations > about 50% of alectinib resistant patients have resistance mutations responding to lorlatinib Gainor et al, Cancer Disc 2016

20 The future: molecularly guided sequential therapy Rebiopsy Rebiopsy Alectinib (26 m) G1202 L1196M I1171T Lorlatinib? other mutations other next.gen.inh.? L1198F Crizotinib? METamp Crizotinib? SCLC Chemo- / Immuntherapy? ? Chemotherapy Exp. Combinations? Shaw. et al, NEJM 2016, Gainor et al, Cancer Disc. 2016, Lin, Rieley, Shaw Cancer Disc. 2017

21 ROS1fus

22 ROS1 + NSCLC Crizotinib in ROS1-rearranged NSCLC Phase I extension (ALK-trial): 50 patients with ROS1+ NSCLC ORR: 72% / mpfs: 19.2 months EMA approval: Aug Shaw et al., NEJM 2014

23 ROS1-positivity: a prognostic factor (?) ROS1+ stage IV pts (n=14/20) ROS1+ stage IV pts chemotherapy only (n = 9/14): mos 36m RET Scheffler ONCOTARGET 2015

24 Tot. n enroled EUCROSS trial finished European phase II trial of crizotinib in ROS1+ NSCLC Statistical assumptions and For ORR: safety α = 0.05, of power crizotinib 92%, 95% CI treatment in H0: ORR 20% vs. H1: ORR>45% - N=30 arbouring ROS1 rearrangements > Screening of 6000 adenocarcinoma patients ttonet C. 1, Grohé C. 5, Sebastian M. 6, Thomas M. 7, Reck M. 8, Thomas R. 9, Büttner R. 3, Massuti B. 10, Rosell R. 2, Wolf J. 1 g Cancer Group 35 für Pathologie, Köln, Germany, 4 Uniklinik Köln, Zentrum für klinische Studien, Köln, Germany, 5 Evangelische Lungenklinik, Berlin, Germany ment of Translational Genomics, Köln, Germany, 10 Universidad Miguel Hernandez de Elche, Valencia, Spain Genetic characterization of the ROS1 fusion 15 IIIB or IV), independent from the number of 10 5 ROS1 FISH positive (N=34) CAGE sequencing 23 samples 11 samples ROS1 rearranged (N=21) Not ROS1 rearranged (N=2) Not sufficient tissue for sequencing 0 ptomatic for 14 days before starting (A) (B) or QTcF > 470ms sis or interstitial lung disease of any grade Reatreat Sebastian Michels CD74-ROS1 SLC34A2-ROS1 15% 45%

25 EUCROSS High overall response rate Sequencing superior to FISH (A) Best response of the FISH population (N=29) (B) Best response in the sequencing population (N=20/18) 60 Partial response (PR) 40 Stable disease (SD) Progressive disease (PD) Partial response (PR) Stable disease (SD) Progressive disease (PD) FISH positive Seq. positive (N=30) % (N; 95% CI) % (N; 95% CI) % (N; 95% CI) ORR 66.7 (20; ) DCR 83.3 (25; ) PD 13.3 (4; ) NE 3.3 (1; ) ORR 75.0 (15; ) 83.3 (15; ) DCR 80.0 (16; ) 88.9 (16; ) PD 15.0 (3; ) 5.6 (1; ) NE 5.0 (1; ) 5.6 (1; ) Fisher exact: p = 0.6 Reatreat 2017 Sebastian Michels

26 Meeting of German and Dutch ROS1+ lung cancer patients in Cologne Summer 2015

27 Molecular mechanisms underlying resistance: mutations in the ROS1 kinase domain ROS1 as a Therapeutic Target Jürgen Wolf 1 st resistance mutation described: G2032R Arwad et al., NEJM 2013

28 Lorlatinib (PF ) phase I: efficacy in crizotinib-resistant ROS1+ NSCLC Shaw et al., WCLC 2015 Solomon et al, ASCO 2016 ROS1 as a Therapeutic Target Jürgen Wolf > Compassionate use Programm auch in Deutschland aktiv

29 Mutations in the ROS1 kinase domain conferring crizotinib resistance Mutation Location ROS1 fusion Active next generation inhibitor G2032R 1 solvent front CD74-ROS1 cabozantinib, lorlatinib, foretinib, brigatinib (in vitro) 4 cabozantinib, lorlatinib (patient) D2033N 2 solvent front CD74-ROS1 cabozantinib (in vitro, patient) 2 L2155S (cell line)3 n.r. SLC34A2- ROS1 L2026M 4 gate-keeper CD74-ROS1 cabozantinib, brigatinib, certinib, foretinib, lorlatinib 4 S1986Y/F 5 double mutation EZR-ROS1 lorlatinib (patient) 5 L solvent front cabozantinib (in vitro, pat.-derived cells) 6 n.r. ROS1 as a Therapeutic Target Jürgen Wolf 1 Awad et al, NEJM 2013; 2 Drilon et al, 2015; 3 Song et al, 2015; 4 Chong et al, CCR 2016; 5 Facinetti et al., CCR 2016, 6 Katayama et al, CCR 2015

30 Future scenario: molecularly-guided sequential treatment of ROS1 + NSCLC Rebiopsy Rebiopsy ROS1+ Crizotinib PD G2032R D2033N L2155S L2026M S1986Y/F L1951 C-KIT... Lorlatinib Cabozantinib Brigatinib Alectinib Foretinib Ponatinib... PD G2032R D2033N L2155S L2026M S1986Y/F L1951 C-KIT... Lorlatinib Cabozantinib Brigatinib Alectinib Foretinib Ponatinib... > wenn möglich, Rebiopsie und NGS-basierte Diagnostik im Rezidiv ROS1 as a Therapeutic Target Jürgen Wolf

31 Neue therapeutische Targets Etablierte Targets: Rezidiv und Sequenztherapie Neue Targets Konsequenzen für die klinische Versorgung

32 mut BRAFV600

33 BRAF-Mutationen im Adenokarzinom Molekulare Testung von ca Patienten mit NSCLC (nicht-plattenepithel-histologie) im Netzwerk Genomische Medizin BRAF: 3% BRAF V600E: ca. 1,3% ALK transl; 4% KEAP1; 2% ERBB2; 1% MET ampl; 4% Other; 1% ROS1 transl; 1% CTNNB1; 1% DDR2; 1% EGFR; 10% TP53; 32% KRAS; 37% PTEN; 1% PIK3CA; 1% MET mut; 3% CLCGP & NGM, Sci Transl Med 2013; Kron et al, in prep.

34 Zulassungsstudie Dabrafenib + Trametinib (BRF113928) Nicht randomisierte, open-label multi-kohorten Phase II Studie Cohort A (dabrafenib monotherapy) planned n = 60 Interim futility analysis Stage IV NSCLC BRAF V600E ECOG PS platinum-based chemotherapy Dabrafenib 150 mg b.i.d. Stage 1 n = 20 Stage 2 n = 20 Expansion n = 20 n = 78 ( 2nd line) Cohort B (combination dabrafenib + trametinib) planned n = 40 Stage IV NSCLC BRAF V600E ECOG PS prior treatments 1 platinum-based chemotherapy Dabrafenib 150 mg b.i.d. Trametinib 2 mg q.d. Stage 1 n = 20 Stage 2 n = 20 n = 57 (2nd 4th line) Cohort C (combination dabrafenib + trametinib in 1st line) planned n = 25 Stage IV NSCLC BRAF V600E ECOG PS 0 2 No prior treatment Dabrafenib 150 mg b.i.d. Trametinib 2 mg q.d. n = 34 ENROLLMENT COMPLETED Primärer Endpunkt: Ansprechen (ORR) Sek. Endpunkte: Progressions-freies Überleben (PFS), Dauer des Ansprechens (DOR) Gesamtüberleben (OS) b.i.d., twice daily; ECOG, Eastern Cooperative Oncology Group; PS, performance status; q.d., once daily. Planchard D, et al. Lancet Oncol. 2016;17: Planchard D, et al. Lancet Oncol. 2016;17:

35 Kohorte B: Ansprechen (ORR) Ansprechrate (ORR): 63.2% (primärer Endpunkt) Disease control rate (CR + PR + SD): 79% Planchard D, et al. Lancet Oncol Jul;17(7):984-93

36 Kohorte B: Progressions-freies Überleben (PFS) Median PFS: 9.7 months 65% of patients achieved 6-month PFS 40% achieved 12-month PFS Planchard D, et al. Lancet Oncol Jul;17(7):984-93

37 Kohorte B: Häufige Nebenwirkungen Kategorie AEs, n (%) Alle Grade Grad 3 allgemein Fieber 26 (46) 1 (2) Schwäche 18 (32) 2 (4) Appetitverlust 17 (30) 0 Schüttelfrost 13 (23) 1 (2) Ödeme 13 (23) 0 Husten 12 (21) 0 Haut Trockene Haut 15 (26) 1 (2) Hautausschlag 12 (21) 1 (2) GI-Trakt Übelkeit 23 (40) 0 Erbrechen 20 (35) 0 Durchfall 19 (33) 1 (2) Most common AEs 20% Verteilung und Häufigkeit ähnlich Melanom Planchard D, et al. Lancet Oncol Jul;17(7):984-93

38 Zulassung der Kombination Dabrafenib (Tafinlar R ) und Trametinib (Mekinist R ) jetzt auch zur Behandlung des fortgeschrittenen NSCLC mit BRAF-V600 Mutation Melanom Dabrafenib ist angezeigt als Monotherapie oder in Kombination mit Trametinib zur Behandlung von erwachsenen Patienten mit nicht-resezierbarem oder metastasiertem Melanom mit einer BRAF-V600-Mutation Nicht-kleinzelliges Lungenkarzinom (NSCLC) Dabrafenib in Kombination mit Trametinib ist angezeigt zur Behandlung von erwachsenen Patienten mit fortgeschrittenem nicht-kleinzelligen Lungenkarzinom mit einer BRAF-V600-Mutation.

39 Indikationen für zielgerichtete Therapien beim NSCLC 2017 Gene Alteration Häufigkeit EMA - Approved Drugs EGFR Mutation 10 15% Erlotinib, Gefitinib, Afatinib, Osimertinib ALK Rearrangement 3 4% Crizotinib, Ceritinib, Alectinib ROS Rearrangement 1% Crizotinib BRAFV600 Mutation 2-4% Dabrafenib + Trametinib MET HER2 Amplifikation, Mutation Amplifikation Mutation 2-4% Crizotinib 4% Trastuzumab, Pertuzumab, Afatinib RET Rearrangement 1% Cabozantinib, Vandetanib u.a. MEK1 Mutation 1% Trametinib FGFR1 Amplifikation 10% in label S3 Leitlinie: 1 st line Testen & Behandeln Zulassung 04/17 off label S3 Leitlinie: 2 nd line Testen und Behandlung erwägen KRAS Mutation 15-25% NRAS Mutation 1% Clinical trials PIK3CA Mutation 1-3% NTRK Fusion 4% drugs approved in NSCLC drugs approved in NSCLC, but for other molecular subtype drugs approved in other cancer drugs in clinical development

40 Indikationen für zielgerichtete Therapien beim NSCLC 2017 Gene Alteration Häufigkeit EMA - Approved Drugs EGFR Mutation 10 15% Erlotinib, Gefitinib, Afatinib, Osimertinib ALK Rearrangement 3 4% Crizotinib, Ceritinib, Alectinib ROS Rearrangement 1% Crizotinib BRAFV600 Mutation 2-4% Dabrafenib + Trametinib MET HER2 Amplifikation, Mutation Amplifikation Mutation 2-4% Crizotinib 4% Trastuzumab, Pertuzumab, Afatinib RET Rearrangement 1% Cabozantinib, Vandetanib u.a. MEK1 Mutation 1% Trametinib FGFR1 Amplifikation 10% in label S3 Leitlinie: 1 st line Testen & Behandeln Zulassung 04/17 off label S3 Leitlinie: 2 nd line Testen und Behandlung erwägen KRAS Mutation 15-25% NRAS Mutation 1% Clinical trials PIK3CA Mutation 1-3% NTRK Fusion 4% drugs approved in NSCLC drugs approved in NSCLC, but for other molecular subtype drugs approved in other cancer drugs in clinical development

41 MET-high level Amplifikation MET-exon14 Mutation

42 MET amplification in NSCLC 2 nd NGM evaluation (currently ongoing) N = 6210 lung cancer pts. MET: Schildhaus et al, CCR 2014 PIK3CA: Scheffler et al, ONCOTARGET 2014 ROS1: Scheffler et al, ONCOTARGET 2015 RET: Michels et al,, JTO 2016 RAS: Scheffler et al, in preparation

43 MET Exon 14 skipping Mutation im Stadium IV NSCLC Retrospektive OS Analyse (n=61) Awad et al., #8511

44 treatment of a variety of cancers, including prostate, breast, and ovarian cancer [35,38,39]. However, the development of HAIs cmet in cancer treatment inhibitors: is still in mode the early of stages. action Further work is required to determine the true clinical value of HAIs as cancer therapeutic agents or as prognostic biomarkers. Figure 1. Representative examples of different mechanism classes of HGF and MET Zhang et al, Biomedicines 3, 149, 2015

45 Best % change from baseline Best % change from baseline Best % change from baseline Capmatinib phase I trials showed tumour shrinkage in intermediate and high level amplified MET cohorts Best response n (%) GCN < 4 (n = 17) GCN 4 and < 6 (n = 12) GCN 6 (n = 15) CR PR 0 2 (17) 7 (47) SD 8 (47) 3 (25) 5 (33) PD 5 (29) 3 (25) 2 (13) Unknown 4 (24) 4 (33) 1 (7) ORR 0 2 (17) 7 (47) 95% CI DCR 95% CI 8 (47) (42) (80) cmet GCN < 4 n/n (%) = 11/17 (64.7%) cmet GCN 4 and < 6 n/n (%) = 7/12 (58.3%) cmet GCN 6 n/n (%) = 12/15 (80.0%) GCN, gene copy number. Schuler M, et al. ASCO J Clin Oncol. 2016;34 Suppl:abstract 9067.

46 Cohort 5: Treatmentnaïve for advanced disease Cohorts 1-4: Pre-treated patients (1-2 prior systemic therapies) GEOMETRY mono-1: global phase II trial for evaluating capmatinib in MET + NSCLC Sub-cohort 1a (n=69): cmet GCN 10 (no cmet mut) Am 3 Stage IIIB/IV NSCLC EGFR wt (for L858R and dele19) and ALK-negative rearrangement Different levels of cmet amplification by FISH and/or cmet mut by RT-qPCR PS 0 1 N=399 Sub-cohort 1b (n=69): cmet GCN 6 and <10 (no cmet mut) Cohort 2 (n=69): cmet GCN 4 and < 6 (no cmet mut) ~40% of pts with GCN 5 and < 6 Cohort 3 (n=69): cmet GCN < 4 (no cmet mut) Cohort 4 (n=69): cmet mutation regardless of GCN Cohorts/Sub-cohorts 1b, 2 and 3 are closed for futility Am 4 Sub-cohort 5a (n=27): cmet GCN 10 (no cmet mut) Sub-cohort 5b (n=27): cmet mutation regardless of GCN > Germany top recruiting country: Köln, Heidelberg, Frankfurt, Berlin, Göttingen...

47 RETfus

48 Overview of RET case series and studies Treatment Vandetanib (Seto 2016) Vandetanib (Lee 2016) Vandetanib (Gautschi 2016) Vandetanib (Horiike 2016) Cabozantinib (Drilon 2015) Cabozantinib (Gautschi 2016) Sunitinib (Gautschi 2016) Lenvatinib (Velcheti 2016) n Response rate (%) PFS (months) OS (months) % 1yr OS NR Drilon AE, et al. ASCO J Clin Oncol. 2015;33 Suppl:abstract Gautshi O, et al. ASCO J Clin Oncol. 2016;34 Suppl:abstract Lee SH, et al. ASCO J Clin Oncol. 2016;34 Suppl:abstract Seto T, et al. ASCO J Clin Oncol. 2016;34 Suppl:abstract Horiike A, et al. ESMO Abstract 1203PD. Velcheti V, et al. ESMO Abstract 1204PD.

49 Best response (%) Response to cabozantinib in patients with RET-rearranged lung adenocarcinomas 30 0 Stage 1 (N = 16) Confirmed PR SD 90 Best response Stage 1 (N = 16) PR, % (n/n) 44 (7/16) Confirmed 38 (6/16) Unconfirmed 6 (1/16) SD, % (n/n) 56 (9/16) ORR, % (95% CI) 38 (95% CI 15 65) ORR 12wks 36 (95% CI 13 65) DOR, median (range), mo 8 ( months) PFS (95% CI), mo 7 (95% CI 5 NA) Baseline 4 weeks Drilon AE, et al. ASCO J Clin Oncol. 2015;33 Suppl:abstract 8007.

50 Maximum tumour shrinkage from baseline (%) Phase 2 study to evaluate efficacy and safety of vandetanib in RET-rearranged NSCLC KIF5B-RET CCDC6-RET Unknown-RET n = 19, ITT population Efficacy according to RET fusion All (n = 19) KIF5B-RET (n = 10) CCDC6-RET (n = 6) Unknown (n = 3) ORR, % (95% CI) 47 (24 71) 20 (3 56) 83 ( ) 67 (9 99) DCR, % (95% CI) 90 (67 99) 90 ( ) 100 (54 100) 67 (9 99) Median PFS, mo (95% CI) 4.7 ( ) 2.9 ( ) 8.3 ( ) 4.7 ( ) 1-year OS, % (95% CI) 47 (21 69) 42(11 71) 67 (5 95) 33 (1 77) ITT, intention-to-treat. Seto T, et al. ASCO J Clin Oncol. 2016;34 Suppl:abstract 9012.

51 TRK

52 TRK-fusions: new pan-tumor targets tropomyosin receptor kinases, activated by gene fusions Neurotrophin-receptor family: pain, temperature, weight Drugs: Entrectinib, Larotectinib Hyman et al, # LBA2501 ASCO2017

53 STARTRK-2 Study Design Studies of Tumor Alterations Responsive to Targeting Receptor Kinases STARTRK-2: Open-Label, Multicenter, Global Basket Study of Entrectinib Patients with Solid Tumors (any line of therapy) MOLECULAR TESTING CONSENT Local Testing [NGS, Sanger, RT-PCR, NanoString, EdgeSeq] Submit tissue for independent central testing OR Submit tissue for Central Testing at Ignyta s CLIA Lab Testing Results for NTRK1/2/3, ROS1, or ALK Gene Fusions Possible Chemother apy per MD POSITIVE CLINICAL TRIAL CONSENT Patient is enrolled Patient does NOT enroll Assignment by Gene Fusion and Tumor Type NEGATIVE NO FURTHER FOLLOW-UP NATURAL HISTORY FOLLOW-UP COHORT: Patients will be followed to collect data regarding their alternate anticancer treatment(s), including best response, and survival status every 3 months until death, loss of follow-up, or withdrawal of consent, whichever comes first TRK ROS1 ALK Non Evaluable 53

54 Sustained Clinical Response to Entrectinib in a 46M Patient With NTRK1-Rearranged NSCLC Baseline Day 26: -47% response Day 317: -79% response Images courtesy of A. Shaw, MD, PhD and A. Farago, MD, PhD (MGH).

55 Rapid Clinical Response to Entrectinib With CNS CR in a Patient With NTRK1-Rearranged NSCLC Baseline Day 26: CR Day 317: CR Patient clinically progression-free >12 months

56 Where to Check for TRK fusions? NSCLC ( pan-negatives ) Gastrointestinal (ChAMP) Cholangiocarcinoma Appendicial carcinoma Metastatic colorectal (MSIhigh, right-sided) Pancreatic Head and Neck (SAAS) Salivary Advanced thyroid Acinic cell carcinoma Squamous head and neck Sarcoma (all types) GIST (KIT & PDGFRA negative) Gynecologic (advanced tumors) Melanoma (BRAF & NRAS negative, pt in need of targeted therapy) > Prescreening by IHC > Confirmation by - FISH - RNA-, DNA-sequencing

57 Driver mutations in lung sqamous cell cancer Analysis of 1498 patients with SQ in the Network Genomic Medicine Kostenko et al., WCLC 2015

58 The FGFR-TKI BGJ398 in FGFR-aberrant solid tumors: Final results of the global personalized FIM phase I trial ORR: 11% DCR: 50% Weiss,...Büttner, Wolf,...Thomas, Sci Transl Med 2010 Malchers...Büttner, Wolf...Thomas, Cancer Dis 2014 Nogova... Büttner, Wolf, JCO 2017

59 Neue therapeutische Targets Etablierte Targets: Rezidiv und Sequenztherapie Neue Targets Konsequenzen für die klinische Versorgung

60 Systemische Therapie des fortgeschrittenen NSCLC 2017 NSCLC Stadium IIIB, IV Nicht-Plattenepithel-Karzinom Plattenepithelkarzinom EGFR ca. 12 % ALK ca. 4 % ROS1 ca. 2 % BRAF V600 ca. 1.5 % Erlotinib Gefitinib Afatinib Crizotinib Dabrafenib + Trametinib PDL1 > 50% Pembrolizumab PDL1 / < 50% Chemotherapie T790M MET, RET, HER2, TRK... Zielgerichtete Therapie Osimertinib Ceritinib Alectinib Lorlatinib Brigatinib... Chemotherapie Nivolumab: PD-L1 unabängig Atezolizumab: PD-L1 unabhängig Pembrolizumab: nur PD-L1 +

61 Systemische Therapie des fortgeschrittenen NSCLC 2017 NSCLC Stadium IIIB, IV EGFR ca. 12 % Erlotinib Gefitinib Afatinib ALK ca. 4 % Nicht-Plattenepithel-Karzinom ROS1 ca. 2 % BRAF V600 Upfront molekulare ca. 1.5 Multiplex- % Testung incl. PD-L1 (min.: EGFR, ALK, ROS1, BRAF) Crizotinib Dabrafenib PDL1 > 50% + Pembrolizumab Trametinib Plattenepithelkarzinom PDL1 / < 50% Chemotherapie T790M Osimertinib Ceritinib Alectinib MET, RET, HER2, TRK... Zielgerichtete Therapie Lorlatinib Brigatinib... Chemotherapie Nivolumab: PD-L1 unabängig Atezolizumab: PD-L1 unabhängig Pembrolizumab: nur PD-L1 +

62 Systemische Therapie des fortgeschrittenen NSCLC 2017 NSCLC Stadium IIIB, IV EGFR ca. 12 % Erlotinib Gefitinib Afatinib ALK ca. 4 % Nicht-Plattenepithel-Karzinom ROS1 ca. 2 % BRAF V600 Upfront molekulare ca. 1.5 Multiplex- % Testung incl. PD-L1 (min.: EGFR, ALK, ROS1, BRAF) Crizotinib Dabrafenib PDL1 > 50% + Pembrolizumab Trametinib Plattenepithelkarzinom PDL1 / < 50% Chemotherapie T790M Osimertinib Rebiopsie und Testung auf Ceritinib Alectinib alle bekannten Resistenmutationen Lorlatinib Brigatinib... Chemotherapie MET, RET, HER2, TRK... Zielgerichtete Therapie Nivolumab: PD-L1 unabängig Atezolizumab: PD-L1 unabhängig Pembrolizumab: nur PD-L1 +

63 Systemische Therapie des fortgeschrittenen NSCLC 2017 NSCLC Stadium IIIB, IV EGFR ca. 12 % Erlotinib Gefitinib Afatinib ALK ca. 4 % Nicht-Plattenepithel-Karzinom ROS1 ca. 2 % BRAF V600 Upfront molekulare ca. 1.5 Multiplex- % Testung incl. PD-L1 (min.: EGFR, ALK, ROS1, BRAF) Crizotinib Dabrafenib PDL1 > 50% + Pembrolizumab Trametinib Plattenepithelkarzinom PDL1 / < 50% Chemotherapie T790M Osimertinib Rebiopsie und Testung auf Ceritinib Alectinib Alle bekannten Resistenmutationen Lorlatinib Brigatinib... Chemotherapie Ggf. Testung auf noch nicht MET, RET, HER2, getestete Mutationen TRK... Zielgerichtete Therapie Nivolumab: PD-L1 unabängig Atezolizumab: PD-L1 unabhängig Pembrolizumab: nur PD-L1 +

64 Broad implementation of molecular multiplex testing: Network Genomic Medicine First flatrate model for NGS genotyping in Germany

65 nngm Beirat berät nngm Steering Board Abstimmung Koordination Repräsentation nngm initiative: National Network Genomic Medicine Berichte und Empfehlungen der Task Forces (zu 1 6) Koordination der Task Forces Nationwide implementation of NGM-like networks in Oncology Centers of Excellence funded by German Cancer Aid (DKH) Zu 1a: Molekulare Diagnostik Koordination und Entwicklung der Zentrenplattformen Zu 1b: SOPs und Kriterien der Qualitätssicherung Zu 2: Forschungsanbindung Dokumentation und Evaluation Aufbau der verknüpften Datenbankstruktur nngm Task Forces Zu 3: Beratung Netzwerkweite Beratungs- Leitfäden Zu 4: Klinische Studien Abstimmung des Studienangebots im Netzwerk Zu 5: Zusammenarbeit mit Kostenträgern Netzwerkweite Verhandlungen mit den Kostenträgern Zu 6: Qualitätssicherung Weitergehende Analyse ausgewählter Fälle Speakers: J Wolf, R Büttner (Köln) C v Kalle (Heidelberg Durchführung der Diagnostik CCCs / Universitäre Zentren Dokumentation der Ergebnisse Interaktion mit Task Forces Beratung der klinischen Partner und Patienten Einsendung von Tumormaterial Regionale Netzwerke Primärkontakt Probengewinnung Behandlung

66 Netzwerkbildung notwendig zur optimalen Nutzung aller neuen Möglichkeiten für die Patienten heimatnah behandeln zentral diagnostieren + beraten MolekulareDiagnostik (NGS, WGS, RNA) Molekulares Tumorboard Therapieempfehlung Studie + transl. Forschung Dokumentation (Register)

67 Thanks! to all the patients and their families Clinical Trials & NGM Study Center Sebastian Michels Rieke Fischer Diana Abdulla Richard Riedel Matthias Scheffler Elisabeth Bitter Juliane Süptitz Anna Kron Lucia Nogova Jürgen Wolf Molecular Pathology Carina Heydt Sabine Merkelbach-Bruse Andreas Scheel Reinhard Büttner Translational Genomics Florian Malchers Dennis Plenker Roland Ulrich Christian Reinhard Martin Sos Roman Thomas Molecular Imaging Carsten Kobe Markus Dietlein Alexander Drzezga Thorsten Persigehl David Maintz Network Genomic Medicine all 280 NGM partners Spanish Lung Cancer Group Niki Karachaliou Bartomeu Massuti Rafael Rosell DKG AIO ETOP Rolf Stahel Solange Peters Egbert Smit / /

68 SAVE THE DATE: 2 nd Cologne Conference on Lung Cancer June