NSCLC: seltene molekular definierte Subgruppen. oliver.gautschi@luks.ch

NSCLC: seltene molekular definierte Subgruppen oliver.gautschi@luks.ch

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 60 70 80 90 100 Gautschi, DGHO 2015 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. Planchard 1, T.M. Kim 2, J. Mazieres 3, E. Quoix 4, G.J. Riely 5, F. Barlesi 6, P.-J. Souquet 7, E.F. Smit 8, H.J.M. Groen 9, R. J. Kelly 10, B.-C. Cho 11, M.A. Socinski 12, C. Tucker 13, B. Ma 13, B. Mookerjee 13, C.M. Curtis, Jr. 13, B.E. Johnson 14 1 Department of Medical Oncology, Gustave Roussy, Villejuif, France; 2 Seoul National University Hospital, Seoul, Korea; 3 Hôpital Larrey CHU Toulouse, Toulouse, France; 4 Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 5 Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 6 Aix Marseille University Assistance Publique Hôpitaux de Marseille, Hôpital Nord, Marseille, France; 7 Centre Hospitalier Lyon-Sud, Pierre-Bénite, France; 8 Vrije Universiteit VU Medical Centre, Amsterdam, Netherlands; 9 University of Groningen and University Medical Center Groningen, Groningen, Netherlands; 10 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA; 11 Yonsei Cancer Center, Seoul, Korea; 12 University of Pittsburgh, Pittsburgh, PA, USA; 13 GlaxoSmithKline, Collegeville, PA, and Research Triangle Park, NC, USA; 14 Dana-Farber Cancer Institute, Boston, MA, USA 26-30 September 2014, Madrid, Spain esmo.org

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 80 60 ORR=32% in pretreated pts 40 20 0-20 -40-60 -80-100 Best Confirmed Response PR SD PD NE 26-30 September 2014, Madrid, Spain esmo.org 18 Presented by David. Planchard et al

Duration of Investigator Assessed Response in 2nd Line (n = 25) Number of Prior Systemic Anti-Cancer Therapy Regimens for Metastatic Disease: 1 > 2 Responders in 2nd Line N = 25 Progressed, n (%) Ongoing, n (%) Duration of Response Median, months (95% CI) < 6 months, n (%) > 6 months, n (%) > 9 months, n (%) > 12 months, n (%) Median PFS a, months (95% CI) 12 (48) 13 (52) 11.8 (5.4 NR) 11 (44), 4 ongoing 14 (56), 9 ongoing 10 (40), 8 ongoing 6 (24), 4 ongoing 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 Duration of treatment (months) a 62% of patients progressed or died. 26-30 September 2014, Madrid, Spain esmo.org 19 Presented by David. Planchard et al

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. Planchard 1, H.J.M. Groen 2, T.M. Kim 3, J.Rigas 4, P-J. Souquet 5, C. Baik 6, F. Barlesi 7, J. Mazieres 8, E. Quoix 9, C.M. Curtis, Jr., 10 B. Mookerjee 10, L. Pandite 10, C. Tucker 10, A. D Amelio 10, B.E. Johnson 11 1 Villejuif, France; 2 Groningen, Netherlands; 3 Seoul, Korea; 4 Hanover, New Hampshire, USA; 5 Pierre-Bénite, France; 6 Seattle, Washington, USA; 7 Marseille, France; 8 Toulouse, France; 9 Strasbourg, France; 10 Collegeville, Pennsylvania and Research Triangle Park, North Carolina, USA; 11 Boston, Massachusetts, USA

Maximum Percent Reduction at Time of Best Disease Assessment Maximum Reduction of Sum of Lesion Diameters By Best Confirmed Response in 2nd Line (N = 24 a ) 20 10 0-10 -20-30 -40-50 -60 ORR=63% by investigator -70-80 -90 Best Confirmed Response PR SD PD -100 a 1 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 2 3 4 5 6 7 8 9 *1 st -line patient (protocol deviation) Treatment Duration (Months) Median time on study treatment (dabrafenib and trametinib) = 108 days (range,1 to 244 days) 22

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 % (n) PR 44% (7/16) -60% confirmed unconfirme d SD 38% (6/16) 6% (1/16) 56% (9/16) confirmed PR SD -90% 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 ORR 12wks 36% (95% CI PR - partial response, SD - stable disease ORR overall response rate, CI - confidence interval

Duration of Cabozantinib Therapy x Median duration of response 8 months (range 5.5-26 months) x x x x confirmed partial response stable disease x disease progression (RECIST) 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

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Therapie-Algorithmus in Luzern Nicht-squamöses NSCLC M1 Squamöses NSCLC M1 Etabliertes Ziel (EGFR, ALK, ROS1) «Neues» Ziel (BRAF V600, HER2ins20, RET, MET) Unbekanntes oder schwieriges Ziel (KRAS, PIK3CA, TP53 ) Etablierte gezielte Therapie Platin-haltige Chemotherapie Platin-haltige Chemotherapie «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.