Theranostics in Nuclear Medicine Patrick FLAMEN, MD, PhD Head Nuclear Medicine Institut Jules Bordet Université Libre de Bruxelles (U.L.B.)
n Theranostics in Nuclear Medicine n A form of (nuclear) diagnostic testing employed for selecting targeted therapy n Imaging Biomarkers è treatment personalization è precision medicine n Prognostic : likelihood of patient outcome regardless of a specific treatment n Eg. FDG uptake in neuro-endocrine tumors n Predictive : the likelihood of benefiting from a specific therapy n Eg. Oestrogen receptor expression in breast cancer Pied de page à compléter
+ Theranostics in Practice Today Cancer Type Target Diagnostic tool PET / SPECT Treatment modality Neuroendocrine SS receptor Ga68-octreotate Lu177-octreotate Thyroid NI Symporter I123,I131,I124, Tc99m I131 Bone mets Hydroxyapetite Tc99m-MDP Sm / Ra223 / Sr / Breast Ca HER2 Zr89-trastuzumab TDM-1 Lymphoma CD20 Zr89-rituximab Y90-rituximab Liver metastasis Arterial perfusion Tc99m-MAA Y90-microspheres Prostate cancer PSMA Ga68-antiPSMA Lu177-antiPSMA At- antipsma
+ Theranostics approaches n Verify drug target expression n High negative predictive value in terms of response n Heterogeneity of target expression n Radiolabeled drugs: simulation of drug distribution (pharmacokinetics) n Dosimetry n Explore methods for PK improvement n Defining «therapeutic window» SAFETY : Predictive dosimetry of critical organs (bone marrow / liver / lung / ) EFFICACY : Predictive dosimetry of tumor
+ Molecular Imaging of Biomarkers: Neuroendocrine tumors Octreotide Lanreotide Pasireotide (SOM230) SST1 SST2 SST3 SST4 SST5 Somatostatin
+ Molecular Imaging of NET è Molecular Radiotherapy of NET CHELATOR PEPTIDE SS receptor THERANOSTICS 68 Ga-DOTA-Tyr-OCTREOTATE IMAGING 177 Lu-DOTA-Tyr-OCTREOTATE PRRT + IMAGING
Peptid Receptor Radionuclide Therapy: Rationale 111 In 90 Y 177 Lu Octr Octr Octr internalization Residualizing Vs Non-residualizing
Molecular radiotherapy dosimetry u Time integrated activity map 4h PI 24h PI 178h PI ) A" #$ = & A t dt * TiA map 5
+ Theranostics for Predictive Dosimetry n Radiolabeled drug with long living isotopes for PK: n Zirconium 89 n Tracer dose of the therapeutical radiopharmaceutical n I131 or I124 for thyroid cancer n Lu177-octreotate n Dosimetry after first cycle and adapt the dosing of the following cycles
+ Ga68 Generator
111 In-octreotide SPECT/CT vs 68 Ga-DOTATATE PET/CT Weber J Clin Oncol 2006
MOLECULAR IMAGING NET PHENOTYPE Octreo PET-CT FDG PET-CT Octreo PET-CT FDG PET-CT Pattison DA et al: PET Clin 2015;10:461-76
+ Intrapatient Tumor Heterogeneity Octreo PET-CT FDG PET-CT
+ FDG PET/CT: prognostic value 38 pts NET (GEP & lung) prospective OS PFS FDG (+) : 42% at 2 yr FDG (-) : 95% at 2 yr FDG (+) : 7% at 1 yr FDG (-) : 87% at 1 yr 21% of G1 NET patients had FDG positivity (SUVmax >4.5) Garin et al, J Nucl Med 2009
+ Intrapatient Tumor Heterogeneity Molecular Image based Treatment individualization è eg. Locoregional ablation of FDG positive sites Octreo PET-CT FDG PET-CT
THERANOSTICS: PRRT Theranostics: the same pharmaceutical (e.g. a peptide), labeled with a γ emitter can be used for diagnosis, and labeled with a β emitter may be used for therapy. diagnostic: 68 Ga-DOTATATE PET/CT therapeutic 177 Lu-DOTATATE SPECT/CT
Metastatic mammary NET post 4 PRRT 68 Ga-DOTATATE PET/CT FDG PET/CT BASELINE 68 Ga-DOTATATE PET/CT FDG PET/CT 2 months after 4th cycle
Peptid Receptor Radionuclide Therapy Netter-1 trial Strosberg NEJM 2017
+ Theranostics and Mo-Antibodies Cancer cell Receptor Target Monoclonal Antibody Chelator or Molecular Imaging Radionuclide Therapy
Pharmacokinetics of Rituximab Zr89-rituximab Immuno-PET/CT 1 hour p.i. 1 day p.i. 3 days p.i. 6 days p.i. EANM 2009 ; K. Muylle, et al. Inst Bordet and VU Amsterdam
+ How to test a Imaging Biomarker 22 89 Zr-trastuzumab injection 89 Zr-trastuzumab PET/CT Screening D 0 D 4 Baseline FDG PET/CT Diagnostic CT T-DM1 D 1 5 T-DM1 T-DM1 D 1 D 22 J 43 D 57 D 6 4 FU until PD Early FDG PET/CT Late FDG PET/CT ZEPHIR TRIAL DESIGN Diagnostic CT G Gebhart, et al. Annals of Oncology 2015
Patterns of 89 Zr-trastuzumab PET/CT FDG HER2 G Gebhart, et al. Annals of Oncology 2015
Patterns of 89 Zr-trastuzumab PET/CT FDG HER2 G Gebhart, et al. Annals of Oncology 2015
Patterns of 89 Zr-trastuzumab PET/CT FDG HER2 G Gebhart, et al. Annals of Oncology 2015
Patterns of 89 Zr-trastuzumab PET/CT FDG HER2 G Gebhart, et al. Annals of Oncology 2015
PATTERNS OF HER2 EXPRESSION REVEALED BY HER2 PET/CT IMAGING A 37.5% C 12.5% B 34% D 16% All or most of the tumor load is seen on 89 Zr-Trastuzumab PET/CT Minority of tumor load or no lesions are seen on 89 Zr-Trastuzumab PET/CT G Gebhart, et al. Annals of Oncology 2015
+ TIME TO TREATMENT FAILURE TTF: Time from start of T-DM1 until its discontinuation 89 Zr-trastuzumab PET/CT Early FDG PET/CT 11.2 months 13.3 months 3.5 months 4.2 months 28
+ Biopsied lesion Biopsied lesion 3+ Baseline FDG HER2 Post 3 T-DM1 IHC
Immuno-PET imaging with 89 Zr-rituximab in patients with CD20+ B-cell lymphoma Accuracy: comparison with FDG-PET/CT FDG-PET/CT before treatment with 90 Y-rituximab Immuno-PET/CT 6 days p.i. of Zr89-rituximab FDG-PET/CT 6 months after treatment with 90 Y-rituximab (0,4 mci/kg) showing a complete remission MIP Coronal slice MIP Coronal slice MIP Coronal slice
Immuno-PET imaging with 89Zr-rituximab in patients with CD20+ B-cell lymphoma Example: preload??? FDG ImmunoPET - preload + preload FDG ImmunoPET - Preload + preload In this patient without B-cell depletion: Preload impairs uptake in involved lymph nodes < (partial) saturation with cold mabs. Preload enhances uptake in the 2 visceral lesions < reducing the uptake in the spleen > higher residence time of the radioconjugate in blood > binding in less accessible regions.
Conclusions u Nuclear Theranostics offers immense opportunities for u u Personalized medicine Early drug developpement u Technology and knowledge know is available u Awareness of power of Molecular Imaging for Theranostics lacks behind Pied de page à compléter
New Bordet Institute Opening: 2020 5 dedicated hospital rooms for radionuclide therapy GMP lab for Theranostic radiotracer