Neuroendokrine Tumoren: Neue medikamentöse Therapie B. Wiedenmann Charite Universitätsmedizin Berlin Campus Virchow-Klinikum

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1 Neuroendokrine Tumoren: Neue medikamentöse Therapie B. Wiedenmann Charite Universitätsmedizin Berlin Campus Virchow-Klinikum

2 Behandlungsprinzipien neuroendokriner Tumore Dr. A. Pascher Prof. Dr. B. Wiedenmann Dr. H. Amthauer Dr. A. Pascher

3 Behandlungsprinzipien neuroendokriner Tumore

4 LDCV= large dense core vesicles 100 nm - Chromogranin A - Cytochrom b561 SSV analogues = small synaptic vesicle analogues nm Synaptophysin MW SST-R Nucleus IF-α-R

5 IFN-R GPCR α GTP GDP TGFß TGFß-R VEGF VEGF-R VEGF CgA VMAT p16 Smad4 COX-2 PDGF-R Menin IGF-R Ca ++ channel RET IGF-1 IGF-1

6 Ligand PDK-1 PI3K L R R Growth Factor Receptor SOS Shc Grb Ras raf AKT MEK1/2 p70s6 ERK1/2 Growth Glucose Metabolism Growth Survival Growth Mitogenesis

7 Medikamentöse Therapieoptionen bei GEP-NET Biotherapie IF-a SMS Neu ØEGF-R.-Inhib. ØVEGF-R.-Inhib. ØSOM 230 Chemotherapie STZ/5 FU od. Doxo. Cisplatin/VP/16 Neu: FOLFOX/ CapOx

8 Neue Therapieansätze Orale Chemotherapeutika Biologika (Biologicals) Antikörper Synthetische Peptide kleine Moleküle ( Small molecules)

9 Wirkung neuer Therapeutika Wirkungsmechanismus Wirkform Wirkungsort Wirkungsdauer Alleinige vs. Kombinierte Wirkung

10 Neue Medikamente Bevacicumab (Avastin) James Yao, MD Anderson CC, Houston, USA SU (Sutent) M. Kulke et al., Harvard Medical School, Boston, USA RAD 001 (Everolimus) James Yao, MD Anderson CC, Houston, USA SOM230 (Pasireotid) Kvols, Tampa, USA

11 In-situ-Tumor Tumor-Angiogenese angiogenic switch Tumorwachstum Anti-Angiogene Therapie Tumorregression Anti-Angiogene Faktoren Tumorprogression Angiostatin, Endostatin, IL-10,-12 Thrombospondin-1 Pro-Angiogene Faktoren VEGF FGF, PDGF, EGF, TNF-a, TGF-a

12 Neue Medikamente Wirkung Bevacizumab (BVZ)/ PEG Interferon (PEG) Behandlungsschema Patienten (44) BVZ (22) PEG (22) 18 Wochen Patienten (35) BVZ + PEG 18 Wochen

13 Neue Medikamente Wirkung Bevacizumab (BVC)/ PEG Interferon (PEG) Bluthochdruck Gi- Blutungen Durchfall Bauchschmerzen Übelkeit Appetitlosigkeit Stomatitis Atemnot

14 Neue Medikamente Nebenwirkungen Bevacizumab (PVC)/ PEG Interferon (PEG) Partielle Remission 3 Patienten (3 BVZ 0 PEG) Stabile Erkrankung 31 Patienten (16 BVZ 15 PEG) Fortschreitende Erkrankung 6 Patienten (1 BVZ 5 PEG)

15 Neue Medikamente Bevacicumab (Avastin) James Yao, MD Anderson CC, Houston, USA SU (Sutent) M. Kulke et al., Harvard Medical School, Boston, USA RAD 001 (Everolimus) James Yao, MD Anderson CC, Houston, USA SOM230 (Pasireotid) Kvols, Tampa, USA

16 Neue Medikamente Wirkung SU11248 Oral verfügbare Substanz Tyrosinkinase-Inhibitor Inhibition von VEGF-R., PDGF-R. und c-kit Phase II-Studie

17 Neue Medikamente Wirkung SU Dosiseskalation: 50, 62,5 und 75 mg pro Tag Patienten, n= 126, bisher behandelt: 102 NET (gastrointestinal): 63 NET (pankreatisch): 63 Primärer Endpunkt: Objektives Ansprechen nach sog. RECIST-Kriterien SeKundärer Endpunkt: Zeitpunkt bis zum Tumorfortschreiten, Lebensqualität, etc. Rekrutierung: 3/03 3/05

18 Neue Medikamente Wirkung SU NET (GI) F: 34, M: 46, H: 17 NET (Pankreas) Gastrinom 8; Insulinom 5, VIPom 3, Glucagonom 7 Mediane Dosierung 50 mg, medianer Zyklus 5

19 Neue Medikamente Wirkung SU Schwerwiegende Nebenwirkungen bei 25% der Patienten mit Abgeschlagenheit Durchfall Haut- und Haarveränderungen Geschmacksveränderungen Übelkeit Erbrechen Flush Periorbitalödem

20 Neue Medikamente Ergebnisse SU Fälle mit partieller Remission entspr. 9% aller Patienten (NET/ Pankreas: 8, NET (GI): Medianes Überleben noch nicht bestimmt Mittlere Zeit bis Tumorprogression: 40 Wo. 82 Patienten mit stabilen Erkrankungen

21 Neue Medikamente Bevacicumab (Avastin) James Yao, MD Anderson CC, Houston, USA SU (Sutent) M. Kulke et al., Harvard Medical School, Boston, USA RAD 001 (Everolimus) James Yao, MD Anderson CC, Houston, USA SOM230 (Pasireotid) Kvols, Tampa, USA

22 Phase II Studie mit RAD001 und Depot Octreotide bei fortgeschrittenen NET Dosage RAD 5mg/d or 10 mg plus octreotide 30mg LAR PR SD PR Carc. (12%) Carc. (82%) Carc (6%) EPT (15%) EPT (62%) EPT (23%) Overall response Specifics SAE Overall PFS at 24 wks. 64% Skin rash (2/34), fatigue (3/34) None Yao et al., ASCO abstr. 4042

23 Neue Medikamente Bevacicumab (Avastin) James Yao, MD Anderson CC, Houston, USA SU (Sutent) M. Kulke et al., Harvard Medical School, Boston, USA RAD 001 (Everolimus) James Yao, MD Anderson CC, Houston, USA SOM230 (Pasireotid) Kvols, Tampa, USA

24 Ergebnisse zur Wirkung von SOM Patienten auswertbar 7 Patienten hatten ein PR., 1 weiterer Patient, der zunächst eine PR hatte entwickelte anschließend sogar eine CR 3 Patienten mit PR erhielten SOM230 mit 600 µg bid, 2 Patienten SOM230 mit 750 µg bid and 2 Patienten SOM230 mit 900 µg bid. Der Patient mit CR erhielt SOM230 in einer Dosierung von 900 µg bid Kvols et al Proc.ASCO 2005

25 Neue Medikamente Temozolamid Harvard, Charite Oxaliplatin Uppsala, Charite Gefitinib Harvard Thalidomid Harvard

26 Temozolomide and Bevacizumab Radiologic Response Rate (RECIST) Partial Response Stable Disease Progressive Disease Pancreatic NET (n=17) 4 (24%) 12 (71%) 1 (6%) Carcinoid Tumor (n=12) 0 (0%) 11 (92%) 1 (8%) Overall 4 (14%) 23 (79%) 2 (7%) (n=29 evaluable)

27 A phase II study of temozolomide and bevacizumab in patients with advancedneuroendocrine tumors Patients (n) Primary Pretreatment Functionality Differentiation Centricity Drug(s) tested Follow-up Primary endpoint 19 m 16 carcinoid CE (7), CTX (12), biotx (17) Not given 27 wd Mono TMZ, bevacizumab 22 wk Safety and response rates 15 f 18 EPT 7 m/pd Comparator None Side effects Myelosupression SAEs Grade 3 ande 4: 62% Kulke et al., 2006, ASCO abstr > nausea, vomiting, fatigue, hypertension

28 Temozolamid Harvard, Charite Oxaliplatin Uppsala, Charite Gefitinib Harvard Neue Medikamente

29 Temozolamid Harvard, Charite Oxaliplatin Uppsala, Charite Gefitinib Harvard Neue Medikamente

30 A phase II trial of gefitinib in patients with progressive neuroendocrine tumors: A phase II consortium study PR Carcinoid (55) 1/40 EPT (41) 2/31 SD (PFS at 6/12) PD Specifics Dosage 51% 32% 28% 17% Documented PD, biotx allowed 250 mg/d Hobday et al., 2006, ASCO, abstr. 4043

31 Neue Medikamente Bevacicumab (Avastin) James Yao, MD Anderson CC, Houston, USA SU (Sutent) M. Kulke et al., Harvard Medical School, Boston, USA RAD 001 (Everolimus) James Yao, MD Anderson CC, Houston, USA SOM230 (Pasireotid) Kvols, Tampa, USA

32 Temozolamid Harvard, Charite Oxaliplatin Uppsala, Charite Gefitinib Harvard Neue Medikamente

33 NET mit Carcinoid-Syndrom: Neue Entwicklungen SOM 230 Depot Chemoembolisation im Kombination mit Sutent Peptide Receptor Radiotherapy +/- Xeloda Sandostatin LAR plus IFN vs. Sando plus Avastin Avastin plus Sutent

34 Zukünftige Entwicklungen Neue Biologika und oral verfügbare Chemotherapeutika Neue Kombinationstherapien (medikamentös und multimodal) Individuell angepaßte Therapien Biomathematisch berechnete Kombinationstherapien

35 Vielen Dank

36

37 Phase II study of RAD001 and depot octreotide in patients with advanced NET Patients (n) Primary Pretreatment Functionality Differentiation Centricity Drug(s) tested Follow-up Primary endpoint Comparator Side effects SAEs Female 16, Male 14 foregut (18), midgut (8), hindgut (1), unknown (2) CTX (13), IF (6), Bev (6), CE (1) Not given Low grade NET Mono RAD 001und Octreotide 12 and 24 wks. Objective response: RECIST criteria None Fatigue, nausea, anemia etc. (3-9%) None Bello et al., 2006, ASCO abstr. 4045

38 Neue Medikamente Bevacicumab (Avastin) James Yao, MD Anderson CC, Houston, USA SU (Sutent) M. Kulke et al., Harvard Medical School, Boston, USA RAD 001 (Everolimus) James Yao, MD Anderson CC, Houston, USA SOM230 (Pasireotid) Kvols, Tampa, USA

39 Neue Medikamente Wirkung SOM 230 Ziel: Nachweis einer Überlegenheit von SOM230 mit Octreotid Gezielte Behandlung nur von Patienten mit Carcinoid-Syndrom Ergebnis: ca % der behandelten Patienten profitierten von SOM230 Einschränkung: Phase II- Studie Ergebnisse bisher nur vorläufig

40 Neue Medikamente Wirkung SOM 230 Bauchschmerzen (35%) Gewichtsverlust Übelkeit Diabetes mellitus Abgeschlagenheit (13%) Dosierung: 2x 300 bis max. 1200mg/Tag

41 Neue Medikamente Wirkung Gefitinib Dosierung 250 mg, 1x pro Tag, alle 28 Tage (Zyklus 1) Patienten N = 37, 22 NET (GI), 15 NET (Pankreas)

42 Medikamentöse Therapieoptionen bei GEP-NET Biotherapie IF-a SMS Neu ØEGF-R.-Inhib. ØVEGF-R.-Inhib. ØSOM 230 Chemotherapie STZ/5 FU od. Doxo. Cisplatin/VP/16 Neu: FOLFOX

43 A phase II study of temozolomide and bevacizumab in atients with advanced neuroendocrine tumors Dosage PR SD PR TMZ: 150mg/m2//7d EPT (24%) EPT (70%) EPT (6%) Bev.: 5 mg/kg every 2.wk carc. (0%) carc. (92%) carc. (8%) specifics specifics Octreotide maintained Prophylaxis c TMX/ acyclovir SAE Lymphopenia (62%) Thrombocytopenia (21%) Kulke et al., 2006, ASCO abstr. 4044

44 Sunitinib Malate (Sutent) Oral multi-targeted tyrosine kinase inhibitor Blocks VEGFR 1, 2 and 3 as well as PDGF and c-kit

45 Hypothesis Blockade von VEGF Rezeptoren nach Chemoembolisation verhindert die Neoangiogneses und die Gefäßneubildung in embolisierten Tumoren.

46 Geplantes Behandlungsregime: HAE SUTENT HAE SUTENT SUTENT SUTENT SUTENT >7 Tage >7 Tage *No fewer than seven days will separate treatment with sutent and scheduling of hepatic artery embolization.

47 Patients with Regression (%) 80% 70% 60% 50% 40% 30% 20% 10% 0% 8. Berliner Informationstag für Patienten Chemotherapy for Pancreatic Endocrine Tumors RR= 69% RR= 30% Chlorozotocin (n=33) RR= 45% Fluorouracil + Streptozocin (n=33) Doxorubicin + Streptozocin (n=36) (Moertel et al, 1992) Any Regression

48 Temozolomide (Temodar) Spontane chemische Degradation in Monomethyl Triazenoimidazole Carboxamide (MTIC) Cytotoxic Alkylatans wurde als orale Alternative für das infusionale DTIC entwickelt Verbessertes Nebenwirkungsprofil im Vergleich zu DTIC

49 Temozolomide and Thalidomide Efficacy Radiologic Response Radiologic Response Complete Response (CR) Partial Response (PR) Carcinoid (n = 14) Pancreatic NET (n= 11) Pheochromocytoma (n = 3) CR+PR Stable Disease Progressive Disease Number of Evaluable Patients n = 28 (%) 1 (4%) 6 (21%) 1 (7%) 5 (45%) 1 (33%) 7 (25%) 19 (68%) 2 (7%)

50 Temozolomide and Thalidomide Toxicity Toxicity Maximum Toxicity Grade N =? (%) Hemoglobin 9 (31%) 6(21%) 2(7%) * Leukocytes (total WBC) 11(38%) 8(28%) 3(10%) 1(3%) Neutrophils/Granulocytes 7(24%) 4(14%) 1(3%) 1(3%) Lymphocytes 1(3%) 7(24%) 12(41%) 8(28%) Platelets 6(21%) 3(10%) 1(3%) * Neuropathy 3(10%) 8 (28%) * * Infection 3(10%) 3(10%) 5 (17%) * Thrombosis/Embolism (3%) *

51 Neuroendocrine Tumors Express VEGF and VEGFR Positive staining for VEGF (carcinoid) Extent of marker expression by tumor type 1 VEGF VEGFR Carcinoid (N=67) 70% 70% Positive staining for VEGFR (carcinoid) Pancreatic endocrine tumor (N=16) 100% 85% 1 Courtesy J. Glickman, MD, PhD, Department of Pathology, Brigham and Women s Hospital, Boston, MA

52 Targeting the VEGF Receptor in Neuroendocrine Tumors Bevacizumab (Avastin) VEGF VEGF Receptor Sunitinib (Sutent) Angiogenesis and Tumor Growth

53 Best Tumor Response to Sunitinib (RECIST) N (%) Partial Response Stable Disease Progressive Disease Not Evaluable Carcinoid 1 (2%) 38 (93%) 0 2 (5%) N= Islet Cell 9 (15%) 45 (75%) 4 (7%) 3 (5%) N= All Patients N= (10%) (81%) 4 (4%) 5 (5%) Response based on baseline and at least one subsequent imaging assessment using RECIST (ITT population)

54 Maximum % Reduction of Target Lesions by Patient: Sunitinib Carcinoid Percentage (%) Partial responders by RECIST Islet Cell

55 Temozolomide and Bevacizumab Schema Patients treated until progression, unacceptable toxicity, or withdrawal of consent Wk: B T - Bevacizumab 5 mg/kg IV every other week - Temozolomide, 150 mg/m2/d po for 7 days every other week - Trimethoprim-sulfamethoxazole (1 double-strength tablet tiw) and acyclovir (400 mg po tid) prophylaxis for anticipated lymphopenia R E S T A G E Q 8 W K S

56 Temozolomide and Bevacizumab Major (Grade 3-4) Toxicities Lymphopenia Leukopenia Neutropenia Hyponatremia Vomiting Nausea Dehydration Fatigue Hypertension Constipation Toxicity Thrombocytopenia Number of Patients (%) with Grade 3-4 Toxicity (N=34) 21 (62%) 2 (6%) 7 (21%) 2 (6%) 1 (3%) 3 (9%) 2 (6%) 1 (3%) 2 (6%) 1 (3%) 1 (3%)

57 Conclusions Temozolomide-based therapy is active in pancreatic NET; efficacy in carcinoid is less clear VEGF pathway inhibitors are active in both pancreatic NET and carcinoid Temozolomide + Bevacizumab in safe and effective in NET Future studies needed to assess relative benefit of cytotoxic chemotherapy + VEGF inhibitor combinations

58 Neue Medikamente Wirkung Bevacizumab (BVZ)/ PEG Interferon (PEG) Patientencharakteristika BVZ. (22) vs. PEG (22) Vorderdarm Mitteldarm Hinterdarm unbekannt

59 Vascular Endothelial Growth Factor (VEGF) in Tumor Biology cellular transformation endothelial cells tumor cells induction of angiogenesis blood vessel VEGF Y VEGF receptor 1 proliferation 2 survival of endothelial cells 3 4 migration vascular permeability expansion of tumor mass hematogenous metastatic spread

60 Neue Aspekte zur Diagnostik Koopmans et al., Groningen, Abstr Patienten untersucht 18-F-DOPA PET SRS/ Octreoscan Computertomographie PET/CT

61 Therapeutische Strategien zur Blockade von Ang-2 Tie-2 stie-2 Tie-2 P stie-2 Ang-2 Tumorzelle (Lymph-) Endothelzelle Tumorzelle

62 Retrospective Studies of Chemotherapy for Pancreatic Neuroendocrine Tumors Regimen # of Patients Response Rate STZ/Dox % STZ/Dox % STZ/Dox/5FU % 1.Cheng et al, Cancer 1999; 86: McCollum et al, Am J Clin Oncol 2004; 27: Kouvaraki et al, J Clin Oncol 2004; 22:

63 Neue Medikamente Wirkung Bevacizumab (BVZ)/ PEG Interferon (PEG) Dosierung Bevacizumab 15 mg/ kg KG und PEG Interferon (PEG) 0,5 mcg/ kg KG/ Woche Patienten n=44, 18 Wochen, danach Kombinationstherapie

64 Neue Medikamente Wirkung Gefitinib Behandlungsschema Patienten (37) GI (22) Pankreas (17) 6 Monate Patienten (16) Gefitinib 6 Monate

65 Neue Medikamente Ergebnisse Gefitinib Ergebnis der Behandlung Laborchemische Besserung: Keine Aussage Progressionsfreie Überlebenszeit nach 6 Monaten 64% NET (GI), 13% NET (Pankreas) Keine OR, 8 Pat verstorben, 5 Patienten weiter in Behandlung

66 Neue Medikamente Nebenwirkungen Gefitinib Übelkeit Durchfall Abgeschlagenheit Hautausschlag Unterzuckerung Schwindel

67 Neue Aspekte zur Diagnostik Koopmans et al., Groningen, Abstr Ergebnisse: F-18-DOPA PET pos. in 53/54 Patienten (98%) CT pos. in 45/54 Patienten (83%) SRS pos. in 44/ 54 Patienten (83%) SRS plus CT pos. in 49/54 Patienten (91%) >>>> CT plus DOPA-PET beste Auflösung

68 Sunitinib Inhibits Phosphorylation of VEGFR, PDGFR and c-kit Of ~40 kinases tested, sunitinib inhibited the following receptor tyrosine kinases: Ligand-binding domain Kinase domains Cell surface *Receptor phosphorylation Mendel DB, et al. Clin Cancer Res 2003;9: ; Pfizer data on file Receptor tyrosine kinase (RTK) VEGFR2 VEGFR1 VEGFR3 PDGFRa/b KIT FLT3 ITD FLT3 RET Cellular IC50* (μm)

69 Multicenter Phase 2 Study of Sunitinib in Neuroendocrine Tumors 43 Carcinoid* 66 Pancreatic Islet Two stage design H 0 RR 5%; H a RR 15% 85% power, alpha patients enrolled initially per cohort; if RR 1 then patient enrollment terminated SU mg po qd X 4 wks First patient enrolled: March 2003 Last patient enrolled: March wks off Dose escalation was permitted to 62.5 mg and then 75 mg after discussion with sponsor RESTAGE END OF CYCLE 1 THEN Q 2 CYCLES *Accrual to carcinoid arm suspended (1 response) Kulke MH, Lenz HJ, Meropol NK, Posey J, Ryan DP, Picus J, Bergland E, Stuart K, Baum CM, Fuchs CS. Proc ASCO, 2005, A4008

70 Phase III Study in Metastatic Carcinoid: E Randomized Patients 5-FU/Doxorubicin Response Rate = 15.9% Median Survival = 15.7 months 5-FU/STZ Response Rate = 16% Median Survival = 24.3 months Renal Toxicity = 35% Disease Progression Dacarbazine Response Rate = 8.2% Sun et al, J Clin Oncol 2005; 23:

71 Dimethyltriazenoimidazole Carboxamide (DTIC) in Neuroendocrine Tumors Study Tumor Type Regimen Response Toxicity SWOG, 1993 ECOG, 2001 Carcinoid DTIC mg/m2 q 4wks Pancreatic Islet Cell DTIC 850 mg/m2 q 4 wks 9/56 (16%) 17/52 (33%) Nausea and Vomiting (88%) 2 lethal

72 Phase II Trial of Temozolomide and Thalidomide in Neuroendocrine Tumors Week Thalidomide mg po qd R E S T A G E Kulke MH, Stuart K, Enzinger PC, et al. J Clin Oncol 24: Temozolomide 150 mg/m2 po qd X 7d

73 Liver Metastasenbildung Local Primary regional tumor spread und -ausbreitung Spread of neuroendocrine tumors Oesophagus Stomach Foregut Pancreas Midgut Large intestine Hindgut Small intestine Rectum

74 Temodar und Thalidomide in pankreatischen NET 5/25/02 8/10/02

75 Therapie Thermoablation: RFA

76 Therapie Thermoablation: RFA Celon Prosurge Rinderleber 125 W 25 min 3 x 4 cm 3 cm Abstand Läsion: 6 x 7.5 cm