PEPTIDE RECEPTOR RADIONUCLIDE THERAPY HOW, WHY AND WHEN

PEPTIDE RECEPTOR RADIONUCLIDE THERAPY HOW, WHY AND WHEN Richard P. Baum, MD, PhD THERANOSTICS Center for Molecular Radiotherapy & Molecular Imaging ENETS Center of Excellence, Zentralklinik Bad Berka, Germany

Lecture Outline Personalized Medicine, Precision Oncology, THERANOSTICS Molecular imaging - the importance of PET/CT for selection of patients and in F/U Peptide Receptor Radiotherapy (PRRT) of NETs Results Zentralklinik Bad Berka in 1048 patients Results RCT NETTER-1 Future prospects - new peptides - new treatment combinations

Proteomics Metabolomics Serum Biomarker CTC Detection Multimodal Imaging PET/CT, PET/MR Structure Function Molecular Biology Patient History Familiy hx / Demographics Environmental Risk Factors / Treatments Precision Oncology Personalized Medicine Early Diagnosis, Risk Assessment Therapy Selection and Monitoring Epidemiology / Prevention Gen Expr Profile Tissue arrays Tumor Cell Genetics Genetics SNPs NGSequencing Adpted from Markus Schwaiger

Personalized Medicine The right treatment, for the right patient, at the right time, at the right dose»not anymore targeting the disease but the specific tumor of a patient The concept of PM has now been extended to Personalized Health Care that includes all steps relevant for the cure of the patient at an individual level from the first sign of disease up to full recovery, including the physicians, the technologies, the drugs and of course all economic aspects, but also extended to the environment, relatives, nurses Theranostics Theranostics is the combination of a Diagnostic Tool that helps to define the right Therapeutic Tool for a specific disease we see what we treat. The first Theranostics World Congress (TWC) in NM was organized in 2011 at Zentralklinik Bad Berka (>400 participants from 56 countries). Term coined first by PharmaNetics CEO John Funkhouser in 1998 at the same time the concept of Personalized Medicine appeared. Concerning radioisotopes, the term THERAGNOSTICS was created by Suresh Srivastava (Brookhaven National Laboratory). The most prominent and oldest application is radioiodine (switch of the radionuclide from diagnosis to radionuclide therapy). Molecular Nuclear Medicine and THERANOSTICS within MNM are definitely part of Personalized Health Care.

PubMed-derived number of publications including the term theranostic or theragnostic during each year from 2001 to 2017 (search performed July 16, 2017). Ken Herrmann et al. J Nucl Med 2017;58:1S-2S (c) Copyright 2014 SNMMI; all rights reserved

From Trial and Error Medicine to Personalized Medicine New paradigm: personalized medicine Observation Test Action Predictable Response Breaking the cycle of trial and error medicine PRECISION ONCOLOGY Targeted radionuclide therapy has unique promise for personalized treatment of cancer, because both the targeting vehicle and the radionuclide can be tailored to the individual patient. Courtesy Damian Wild

Creativity Paul Ehrlich Side Chain Theory Amboceptors and formation of antitoxins Corpora non agunt nisi fixata Zauberkugeln (Magic Bullits) Frankfurt/Main (1899) Nobel Prize in Physiology or Medicine 1908 The goundbreaking idea and basic principle of how molecules are talking to each other

Somatostatin Receptors Ala-Gly-Cys-Lys-Asp-Phe-Phe -Trp-Lys-Thr-Phe-Thr-Ser-Cys SST-14 (1973) 5 subtype receptors (SSTR1-5) predominant expression of SSTR2 in most NET tumours SSTR1 (4): Prostate, Sarcoma some: Pheochromocytma, GEP SSTR3: Inactive Pituitary Adenoma SSTR5: Gastric Carcinomas, GH Pituitary A. Reubi EJNM 2001

THERANOSTIC PAIRS Targeted Molecular Imaging and Therapy WE TREAT WHAT WE SEE Schematic Representation of a Drug for Imaging and Targeted Therapy pharmacokinetics/biodistribution modifier Target Ligand Linker Chelator Lock Key 68 Ga, 90 Y, 177 Lu Targets Antigens e.g. CD20, HER2) GPCR e.g. SSTR Enzymes & inhibitors e.g. PSMA Transporters Molecular Address Antibodies, minibodies, Affibodies, SHALs, aptamers Regulatory peptides (agonists & antagonists) Amino Acids Reporting Unit 99m Tc, 111 In 68 Ga, 44 Sc, 152 Tb, 64 Cu Cytotoxic Unit 90 Y, 177 Lu 225 Ac, 213 Bi Courtesy Helmut Mäcke (modified)

Somatostatin Analogs: Improvement of SST Receptor Affinity D-Phe Cys Tyr D-Trp D-Phe Cys *I-Tyr D-Trp Thr-ol Cys Thr Lys Thr-ol Cys Thr Lys D-Phe Cys Phe D-Trp TOC I*-TOC Thr-ol Cys Thr Lys HA-DOTATATE OCTREOTIDE DOTA D-Phe Cys Tyr D-Trp DOTA D-Phe Cys *I-Tyr D-Trp Thr-ol Cys Thr Lys Thr Cys Thr Lys DOTA-TOC DOTA-TATE Wester HJ, Schottelius M et al. 2013

From..Tide to..tate Affinity profiles of DOTA-octapeptides (IC 50 ) for hsst1 5 receptors subtypes hssr1 hssr2 hssr3 hssr4 hssr5 Ga DOTA NOC >10000 1.9 ± 0,4 40 ± 5.8 260 ± 64 7.2 ± 1,6 Ga DOTA TOC >10000 2.5 ± 0,5 613 ± 140 <1000 73 ± 21 Ga DOTA TATE >10000 0.2 ± 0.04 >1000 300 ± 140 377 ± 18 IC 50 values are in nmol/l (mean±sem)

90 Yttrium versus 177 Lutetium Y-90 Lu-177 ß - max. 2280 kev high energy pure beta emitter max. tissue penetration 12 mm tumour lesions > 1 g inhomogenous tumours (no micrometastases) 90 Y 177 Lu ß - γ max. 498 kev 208 kev low energy max. tissue penetration 2 mm small tumour lesions micrometastases < 1 g

Radioparmaceuticals SST analogue 90 Y D-Phe Cys Tyr D-Trp Lys Thr(ol) Cys Thr Chelator = DOTA 90 Y-DOTA-TOC D-Phe Cys Tyr 177 Lu D-Trp Lys 177 Lu-DOTA-TATE Thr Cys Thr

Ga-68 Generator System TiO 2 based Simultaneous use of several generators Developed in close collaboration between Radiopharmacy PET/CT Center, Zentralklinik Bad Berka and Institute of Nuclear Chemistry Johannes Gutenberg-Universität, Mainz, Germany Zhernosekov K, Filosofov DV, Baum RP. Rösch F J Nucl Med 2007 (Oct); 48:1741-48 68 Ga β + 1.9 67.7 m 68 Ga-elution, purificaton and synthesis module First clinical use in 2004, up to now over 12,000 studies done at ZKL Bad Berka

CARDIAC metastasis also a suitable target for PRRT! Ga-68 DOTATATE PET MIP CT transverse Ga-68 DOTATATE PET/CT - coronal MRI - transverse Ga-68 DOTATATE PET/CT transverse Metastatic functional highly differentiated NEN of terminal ileum Theranostics Research Center, Zentralklinik Bad Berka, ENETS Center of Excellence, Germany

Announcement of approval of There a

PRRT of SSTR positive tumors NET family and beyond medullary thyroid Thyroid C cells Adrenal medulla & paraganglia phaeochromocytoma paraganglioma neuroblastoma Pancreatic endocrine cells dispersed NET cells with somatostatin receptors islet cell tumors, insulinoma gastrinoma, glucagonoma VIPoma and others GI endocrine cells midgut NEN undifferentiated NET Bronchopulmonary carcinoids small cell lung ca Leptomeninx & glial meningiomas glioma Miscellaneous ovary, cervix, endometrium, breast, kidney, larynx, sinus, salivary glands Adapted from Michael Hofman

1972 1987 somatostatin first isolated (Roger Guillemin) octreotide synthesis scintigraphy with 123 I-octreotide 40 years ago!! Autoradiography 1984 1991 111 In-octreotide first employed 1992 five G-protein coupled somatostatin receptors (sst1 5), identified and cloned 1993 111 In-octreotide registered Scintigraphy 1987 1994 First PRRT with high-dose 111 In-octreotide 1996 First 90 Y-octreotide PRRT - Basel PRRT 1994 2000 2012 First 177 Lu-octreotate PRRT - Rotterdam Phase III registration trial of 177 Lu-octreotate 2016 Completion of NETTER-1 Trial

First Y-90 DOTATOC* Peptide Receptor Radionuclide Therapy in Germany July 1997 * provided by Helmut Mäcke

Patient Selection for Personalized PRRT The Bad Berka Score (BBS) SUV on receptor PET/CT (referrals: OctreoScan K.S.) Renal function (GFR and TER / creatinine & BUN) Hematological status (blood counts) Liver involvement Extrahepatic tumor burden Ki-67 index / tumor grade FDG status (glucose hypermetabolism of tumors/mets) Tumor dynamics (doubling time, new lesions) Karnofsky performance index Weight loss Time since first diagnosis Functional activity of tumor Previous therapies

PATIENT EVALUATION BEFORE PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT) Treatment decisons based on Ga-68 SMS receptor PET/CT: Bad Berka scoring system is based on SUVs not on visual analogue scales as previously derived from OctreoScans

SSTRI FDG The NETPET Grade

PRRT THE BAD BERKA CONCEPT Dedicated multidisciplinary team of experienced NET specialists Selection of patients for PRRT based on Bad Berka Score (BBS) i.e. clinical aspects / molecular features: progressive tumors, uncontrolled symptoms despite maximum conventional therapy / high SMS-receptor expression (as determined by receptor PET/CT) Individualized therapy plan for each patient by tumor board consensus Frequent cycles (4-6, up to 12) applying low/intermediate doses of radioactivity: long term low dose, not short term high dose concept Combined use of Lu-177 and Y-90 (in sequence, in few concurrent) Intra-arterial PRRT (for liver metastases & inoperable primary tumors) Standardized evaluation before therapy and systematic restaging All clinical data entered into a prospective clinical database (since 2004)

BAD BERKA PROTOCOL FOR PRRT Studies before therapy Renal scintigraphy [ 99m Tc- MAG 3 ] GFR measurement [ 99 Tc- DTPA] 90 Y / 177 Lu-DOTA-TATE Peptide Receptor Radiotherapy Receptor PET/CT* [ 68 Ga-DOTA-NOC] Infusion of aminoacid solution (- 0.5 until 4 hrs) plus Gelofusine - 2 days 0 Infusion (15 min.) of 90 Y / 177 Lu- DOTA-TATE 1 2 3 days Studies under /after therapy, dosimetry 177 Lu- DOTA-TATE WB scan [planar scans for dosimetry] 177 Lu- DOTA-TATE- SPECT of the tumor region Blood sampling Urine sampling * Since July 2004. Previously, Tc-99m EDDA Hynic TOC (planar & SPECT) was performed. In selected patients, also F-18 FDG and / or F-18 fluoride PET/CT is performed as well as MRI of the liver / bones

RADIOPEPTIDE THERAPY (ZKL BAD BERKA) As of September 30, 2017 Patients treated n = 1494 Therapy cycles n = 5384 Lu-177 n = 3710 Y-90 n = 1712 Bi-213 n = 1 Somatostatin receptor positive neuroendocrine tumors Y-90 Lu-177 Mean 3,35 GBq 6.5 GBq Max. 9,50 GBq 12.0 6 GBq Age: 4 85 years Median: 59.9 years

Center for Molecular Radiotherapy, Zentralklinik Bad Berka Primary tumors of patients with metastatic NETs treated by PRRT n=1494 patients THERANOSTICS Center for Molecular Radiotherapy and Molecular Radiotherapy, Zentralklinik Bad Berka

PATIENT SELECTION Patients screened for eligibility since 2004 N=2294 Not eligible N= 570 Eligible but PRRT not performed N= 676 Treated with PRRT between 2004 and 2015 N=1048 Included in the intention to treat analysis N=1048 Progression-free survival as determined by RECIST as well as by 68 Ga somatostatin receptor (SSTR) PET/CT using the EORTC response criteria was analyzed in all patients.

OVERALL SURVIVAL ACCORDING TO PRIMARY TUMORS Patients with NENs of small intestinal origin (69 months 53.7-84.2 95% CI) had a better survival than those with other primary tumors Proportion event free (%) 100 80 60 40 20 0 Lung Pancreas Small bowel CUP other Time (months) Number at risk: Total 1048 561 262 103 28 5 Bronchial 75 37 15 4 1 0 Pancreas 384 202 95 32 9 2 Small bowel 315 185 91 45 12 2 CUP 151 72 32 11 2 0 Other 123 65 29 11 4 1 Kaplan-Meier plot

Presented at ENETS 2017 After surgery of the primary tumor, pts. have a better survival after PRRT. These effects may result from selection bias, however, there are strong indicators for clinical practice that primaries should be removed when feasible.

THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka Neuroendocrine neoplasm of the right kidney with extensive bilateral liver metastases (size 3.7 cm in S7) and retroperitoneal lymph node (size up to 6.5 cm) and bone metastases MOLECULAR RESPONSE BY 68 GA DOTA-TOC PET/CT IMPROVEMENT OF KIDNEY FUNCTION IN A PATIENT WITH A SINGLE KIDNEY May 2009 before PRRT Sept. 2009 - after 1st PRRT Jan. 2010-4mo after 2nd PRRT TER 97 ml/min (35 %) TER 147 ml/min (54 %) TER 202 ml/min (74 %)

Serial renal function assessment in a patient treated with 10 PRRT cycles over 9 years by measurement of the tubular extraction rate (TER) using Tc-99m MAG3.

Bodei L et al. Eur J Nucl Med Mol Imaging 2015; 42:5-19 Hematological toxicity of PRRT MDS/AML in <3% of patients

despite the lack of homogeneity among studies EFFICACY Tumor shrinkage Symptom relief and QoL improvement Biomarker reduction Impact on survival TOLERABILITY Generally well tolerated Generally mild acute side effects: AA-related: nausea, vomiting PRRT-related: fatigue, mild hair loss (Lu-tate), rare exacerbation of syndromes Chronic and permanent effect on kidney, BM, (testes) Generally mild if necessary precautions are taken

A landmark publication in Theranostics TRC N Engl J Med 2017;376:125-35.

Presented by Richard P. Baum Participating Sites in 51 Centers - 11 Countries

177 Lu-DOTATATE: Compare PFS Octreotide LAR: Courtesy Lisa Bodei

NETTER-1 RCT Results in SI-NET N = 229 (ITT) Number of events: 90 Long Progression-Free Survival 177 Lu-Dotatate Median PFS: Not reached 177 Lu-Dotatate: 23 Oct 60 mg LAR: 67 Hazard ratio: 0.21 [0.129 0.338] p < 0.0001 79% reduction in the risk of disease progression/death Octreotide LAR 60 mg Median PFS: 8.4 months Estimated Median PFS Lu-DOTATATE arm 40 month All progressions centrally confirmed and independently reviewed for eligibility (SAP) Presentation Presidential Session II of the 18th ECCO 40th ESMO European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna

Overall Survival (interim analysis) N = 229 (ITT) Number of deaths: 35 177 Lu-Dotatate: 13 Octreotide 60 mg LAR: 22 P = 0.0186 Presented by Richard P. Baum

Safety and Tolerability (Safety Set; n=221) 177 Lu-Dotatate (n=111) Octreotide LAR 60mg (n=110) Any adverse event 106 (96%) 95 (86%) Related to treatment 95 (86%) 34 (31%) Serious adverse events 29 (26%) 26 (24%) Withdrawals due to adverse events Related to treatment 10 (9%) 1 (1%) 7 (6%) 10 (9%) Related to treatment 5 (5%) 0 (0%) Presented by Richard P. Baum

Creatinine Clearance Renal function remains stable over the 2-year observation period 177 Lu-Dotatate (N = 111) Octreotide LAR (N = 110) Grade 3/4 Grade 3/4 Creatinine increased 0% 0% Presented by Richard P. Baum

Summary and Conclusions Final analysis : In this first prospective randomized study in patients with progressive metastatic midgut NETs, 177 Lu-Dotatate was superior to Octreotide 60 mg in terms of: PFS (Not reached vs 8.4 months, p<0.0001) ORR (18% vs 3%, p=0.0008) Interim analysis suggests increased OS (13 vs 22 deaths) 177 Lu-Dotatate demonstrates a favorable safety profile 177 Lu-Dotatate has a major therapeutic benefit for patients progressing under SSAs Presented by Richard P. Baum

The COMPETE study Controlled, Open-label, Multicentre study of PRRT with 177 Lu-Edotreotide compared to targeted molecular Therapy with Everolimus in neuroendocrine tumours of the pancreas (P-NET) and midgut Trial started in 2017

J Nucl Med 2011; 52:1361-1368

J Nucl Med 2011; 52:1361-1368 Conclusion: GHS/QOL, KPS, and symptoms improved significantly after Lu-177 octreotate therapy, and there was no significant decrease in QOL in patients who had no symptoms before therapy. In patients who had suboptimal scores for GSH/QOL or symptoms before therapy, a clinically significant improvement was demonstrated. Our results indicate that Lu-177 octreotate therapy not only reduces tumors and prolongs overall survival, but also improves the patients self-assessed QOL.

Quality of life findings in the NETTER-1 Study Jonathan Strosberg Associate Professor H. Lee Moffitt Cancer Center Tampa, FL

Methods: QOL analysis QOL surveys obtained every 12 weeks (EORTC QLQ C-30 and GI-NET 21 questionnaires). Answers are scored on a 0-100 point scale. A 10-point change in score over time is considered clinically significant. Percentage of patients on each arm of the study with QOL changes 10 points from baseline were recorded at each 12-week timepoint from week 12-72. Due to higher rates of progression/death on the octreotide arm, relative number of patients on this arm is increasingly lower at each timepoint. Aaronson et al. JNCI 1993; 85:365-76

Global Health Status How would you rate your overall health during the past week How would you rate your overall quality of life during the past week * * In mean, during the study, global health status was* : improved in 28% of the patients in 177 Lu-DOTA-TATE (177-Lu) vs. 15% in the Octreotide LAR arm (Oct)* worsened in 18% of the patients in 177 Lu-DOTA-TATE (177-Lu) vs. 26% in the Octreotide LAR arm (Oct) 48 * Statistically significant difference between the arms (p 0.05) weeks 24 and 48

Physical functioning Do you have any trouble doing strenuous activities like carrying a heavy shopping bag or suitcase Do you have any trouble taking a long walk Do you have any trouble taking a short walk outside of the house Do you need to stay in bed or a chair during the day Do you need help with eating, drinking, washing yourself or using the toilet In mean, during the study, global physical functioning was : improved in 18% of the patients in 177- Lu vs. 5% in the Octreotide LAR arm (Oct) worsened in 15% of the patients in 177- Lu vs. 21% in the Octreotide LAR arm (Oct) 49

Role functioning Were you limited in doing either your work or other daily activities Were you limited in pursuing your hobbies or other leisure time activities In mean, during the study, global role functioning was : improved in 29% of the patients in 177-Lu vs. 18% in the Octreotide LAR arm (Oct) worsened in 20% of the patients in 177-Lu vs. 29% in the Octreotide LAR arm (Oct) 50

Pain Have you had pain Did pain interfere with your daily activities In mean, during the study, global pain was : improved in 41% of the patients in 177-Lu vs. 28% in the Octreotide LAR arm (Oct) worsened in 17% of the patients in 177-Lu vs. 25% in the Octreotide LAR arm (Oct) 51

Diarrhea Have you had diarrhea * In mean, during the study, diarrhea: improved in 39% of the patients in 177-Lu vs. 23% in the Octreotide LAR arm (Oct) worsened in 19% of the patients in 177-Lu vs. 23% in the Octreotide LAR arm (Oct) 52 * Statistically significant difference between the arms (p=0.05) at week 48.

Conclusions Treatment with 177 Lu-Dotatate is associated with improvement in quality of life in several key domains including global health and diarrhea. Non-statistically-significant improvement in QOL seen (more improvement/less worsening) observed with 177 Lu- Dotatate in most domains. No evidence of significantly decreased quality of life with 177 Lu-Dotatate observed in any domain. Limitation of study includes lack of blinding. Patients were aware of treatment assignment.

ENETS Guidelines 2016 Intestinal NET Pavel et al Neuroendocrinology 2016

ENETS Guidelines 2016 Pancreatic NET Pavel et al Neuroendocrinology 2016

Peptide Receptor Radiotherapy what does the future hold? Combination therapies PRRT+ o PRCRT (PRRT + chemotherapy) o PRIT (PRRT + immunotherapy) o Surgery (neoadjuvant / adjuvant PRRT, use of intraoperative probes) o TACE (transarterial chemoembolization) o SIRT (selected internal radiation therapy) o RFA (radiofrequency ablation) o Kinase inhibitors o Radiosensitizers Targeted alpha radiation therapy (ART, e.g. Bismuth-213, Actinium-225) Novel radioisotopes for imaging and therapy (theranostic pairs - Sc-44/Sc-47, Cu-64/Cu-67, Tb-152/Tb-149, Tb-155/Tb-161) Novel targets (e.g. SSR antagonists, CXCR4) Liquid biopsy (pcr and gene analysis for better selection of patients for PRRT, prognostication of efficacy of therapy and of possible side effects) Radiomics (selection of patients for PRRT, prognostication of therapy effects) DUO-PRRT i.e., using Y-90 and Lu-177 labeled SSA in sequence TANDEM-PRRT i.e., using Y-90 and Lu-177 labeled SSA simultaneously Intra-arterial PRRT Improvements in dosimetry (personalized and predictive dosimetry)

PeptideReceptorChemoRadioTherapy Australia Leading the Way: RCT of PRCRT Cohort A: pancreatic NETs: Lu-177 DOTATATE+CAPTEM vs. CAPTEM (control) Cohort B: small bowel NETs: Lu-177 DOTATATE+CAPTEM vs. Lu-DOTATATE (control)

online August 2017

Cancer-immunity cycle: Immunotherapeutic points of attack Adaptive immune system long-term remission Chen and Mellman, Immunity 2013

Phase 0 PRIT Trial Immune Modulation to enhance PRRT Efficacy - Treatment Scheme 3-4 Cycles NET Typer Check Point Typer Immune Function dx NET Typer Check Point Typer Immune Function dx NET Typer Check Point Typer Immune Function dx Biopsy CPI Tox check 5 7 d PRRT 177 Lu DOTATATE 7 d CPI 14 d CPI NETest NETest NETest NETest Liquid Biopsy Tests Liquid Biopsy Tests Liquid Biopsy Tests Liquid Biopsy Tests Primary Endpoint: Toxicity / Safety Secondary Endpoint: Biomarker Change associated with Respnse by RECIST & PERCIST

Jean-Claude Reubi, Bern, Switzerland Antagonist labels more sst 2 sites than agonist in human cancer tissues Agonist Lu DOTA-TATE Antagonist Lu DOTA-BASS Total ns Total ns Renal Cell Ca Br4 Expo 40h P-329 II Expo 40h NHL 26171-90 Expo 40h Breast-Tu Ha 7 Expo 17h 60

Extensive NET of pancreas with liver metastasis SMS-Agonist Ga-68 DOTATOC SMS-Antagonist Ga-68 NODAGA JR11 Antagonist labels more sst 2 sites than agonist in cancer patients leading to higher diagnostic sensitivity (first in human study at Zentralklinik Bad Berka)

Comparison of 177 Lu-DOTATATE and 177 Lu-DOTA-JR11 dosimetry (G3) Patient with NEC (G3) of the bladder with lymphnode and uterus metastases, shows progression after surgery and treatment with Somatostatin analogues 68 Ga-DOTA-TATE PET 177 Lu-DOTA-TATE (Agonist) Isodose curves based on 3D voxel dosimetry analysis 177 Lu-DOTA-JR11 (Antagonist) Isodose curves based on 3D voxel dosimetry analysis Limited kidney function Creatinine clearence: 54 ml/min (norm 90 179 ml/min) mean dose: 1.4 Gy/GBq Tumor-to-kidney dose ratio: 1.1 sst 2 affinity profile (IC 50 ) 0.7 ± 0.15 nm mean dose: 5.7 Gy/GBq Tumor-to-kidney dose ratio: 2.5 sst 2 affinity profile (IC 50 ) 1.5 ± 0.4 nm D. Wild et al. J Nucl Med 2014;55:1248-52

Dosimetry Perspectives - New Isotopes Pre-therapeutic organ and tumor dosimetry using receptor PET/CT and longer lived positron emitters, e.g. Sc-44,Cu-64 Tb-152 and comparison with Ga-68 results. Selection of the optimal peptide and radionuclide for individual therapy of each patient ( personalized dosimetry ) by pretherapeutic measurement of organ and tumor doses. Y-86 DOTA-NOC Receptor PET/CT

Ga-68 DOTATOC --- PET/CT --- Sc-44 DOTATOC 4h p.i. Personalized dosimetry

SUMMARY TAKE HOME MESSAGES PRRT is effective and well tolerated even in very advanced NET cases Median overall survival from start of treatment: > 46-59 (up to >90) months PRRT leads to significant improvement of clinical symptoms Cure is rarely possible - but excellent palliation can be achieved PRRT: part of the clinical algorithms of major scientific & clinical societies Standardized treatments are usually applied - guidelines are available Significant kidney damage can be avoided (or reduced) PRRT should be performed at specialized centres: NET patients need highly individualized interdisciplinary treatment and long term care. Future perspectives: personalized treatment based on Genetic characteristic & clinical features Dosimetry Biological information regarding the tumor cell and its microenvironment New interface between molecular imaging and circulating biomarkers