Precision guided munitions using PSMA theranostics to target prostate cancer

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Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne Sir Peter MacCallum

1 Precision guided munitions using PSMA theranostics to target prostate cancer Professor Michael Hofman, MBBS, FRACP, FAANMS Nuclear Medicine Physician Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne Sir Peter MacCallum Dept of Oncology, University of Melbourne

No of therapies per year Theranostics @ Peter Mac 600 Lu-177 NET 400 PSMA

2 No of therapies per year Peter Mac 600 Lu-177 NET 400 PSMA ABX 200 ANSTO 0 2 Imaging@Brisbane 2018 Neuroendocrine Tumours ANZUP Prostate

3 Prostate Specific Membrane Antigen (PSMA) 3 O Driscott C et al, Br J Pharm 2016 doi: /bph.13576

Lu-PSMA-617 111 In-capromab Prostascint submandibular +++ liver+ kidney++ + parotid +++ spleen+ small bowel+

4 Image from Maurer T et al. Nat Rev Urol, 2016 Apr;13(4): Prostate Specific Membrane Antigen (PSMA) lacrimal +++ suv 68 Ga-PSMA Lu-PSMA In-capromab Prostascint submandibular +++ liver+ kidney++ + parotid +++ spleen+ small bowel+ (duodenum++ ) radioactive urine PSMA PET normal biodistribution Type II transmembrane glycoprotein (FOLH1) Highly over-expressed in prostate cancer castrate-resistant metastatic disease 4 Imaging@Brisbane 2018

5 2014: high activity of small molecule targeting PSMA Serial 124 I-MIP-1095 PET 131 I-MIP-1095 Best PSA response in 25 pt PSA 50% in 61% SNMMI Zechmann CM et al, Eur J Nucl Med Mol Imaging 2014, 14:

6 2015: retrospective data suggests high activity of 177 Lu Best PSA Response in 37 patients mcrpc. 177 Lu-PSMA-I&T Baum R et al, 3 rd World Congress in Theranostics, John Hopkins Medical Centre, USA, March SNMMI 2018

7 First published report of 177 Lu-PSMA617 2 cycles 177 Lu-PSMA617 7 Imaging@Brisbane 2018 Cratochwil et al, Eur J Nucl Med Mol Imaging May;42(6):987-8 DOI /s

8 2015-8: 1 st prospective phase II Peter Mac 8 ANZUP 2018

9 HOFMAN THERANOSTICS TARGETED THERAPEUTIC + DIAGNOSTIC COMPANION 177 Lu-PSMA Ga-PSMA-11 PET/CT Post-therapy SPECT/CT Pre-therapy PET/CT LuPSMA Theranostic

10 HOFMAN PATIENT ELIGIBILITY (N=30) Inclusion Castration-resistant Documented progression after Docetaxel Enzalutamide or abiraterone ECOG 2 High uptake on PSMA PET unless contraindicated or patient refused Exclusion GFR < 40 ml/min Platelet < 75,000 Neutrophil < 1.5 Hb < 9.0 Albumin < 25 FDG PET/CT demonstrating discordant disease LuPSMA Theranostic

11 13 Patient characteristics (N=50) Characteristic Median or N (%) Range Age (years) Gleason score Alkaline phosphatase (U/L) Haemoglobin (g/l) Lactate dehydrogenase (U/L) PSA (ng/ml) PSA doubling time (ng/ml/month) to ECOG performance status Prior treatments Abiraterone or enzalutamide or both Docetaxel Cabazitaxel Docetaxel + abi / enza ± Cabazitaxel 177 Lu-PSMA-617 Number of cycles Admin. radioactivity per cycle (GBq) 20 (40%) 22 (44%) 8 (16%) 45 (90%) 42 (84%) 24 (48%) 39 (78%)

12 14 Patient characteristics (N=50) Characteristic Median or N (%) Range Age (years) Gleason score Alkaline phosphatase (U/L) Haemoglobin (g/l) Lactate dehydrogenase (U/L) PSA (ng/ml) PSA doubling time (ng/ml/month) to ECOG performance status Prior treatments Abiraterone or enzalutamide or both Docetaxel Cabazitaxel Docetaxel + abi / enza ± Cabazitaxel 177 Lu-PSMA-617 Number of cycles Admin. radioactivity per cycle (GBq) 20 (40%) 22 (44%) 8 (16%) 45 (90%) 42 (84%) 24 (48%) 39 (78%) heavily pre-treated patients

13 Trial Profile 75 pt assessed for eligibility 50 pt enrolled 177 Lu-PSMA + SPECT/CT Up to 4 cycles, 6 weekly 3 months follow-up Restaging CT Bone scan FDG PET PSMA PET 51 Cr-EDTA GFR 1-30: 10/ / : 03/ /2017 QoL: EORTC QLC-30, BPI-SF Prior to each cycle : bloods (PSA, FBE / UE / LFTs), clinical Ax Repeated +2 and +4 weeks CT Bone scan FDG PET PSMA PET 51 Cr-EDTA GFR 25 patients not eligible Imaging (16): low PSMA (8), FDG discordance (8) ECOG>2 (4), Hb<90 (3), other exclusion (2) 21 patients received <4 cycles 10 disease progression 8 exceptional responses 2 prolonged cytopenia 1 non-prostate cancer death 15 Cut-off date for analyses. N=30-9/11/2017 (Lancet Oncology). N=50 - Interim analysis 19/01/18 (ASCO, SNMMI)

14 Trial Profile 75 pt assessed for eligibility 50 pt enrolled 177 Lu-PSMA + SPECT/CT Up to 4 cycles, 6 weekly 3 months follow-up Restaging CT Bone scan FDG PET PSMA PET 51 Cr-EDTA GFR 1-30: 10/ / : 03/ /2017 QoL: EORTC QLC-30, BPI-SF Prior to each cycle : bloods (PSA, FBE / UE / LFTs), clinical Ax Repeated +2 and +4 weeks CT Bone scan FDG PET PSMA PET 51 Cr-EDTA GFR patients not eligible Imaging (16): low PSMA (8), FDG discordance (8) ECOG>2 (4), Hb<90 (3), other exclusion (2) 20% excluded on PSMA/FDG imaging phenotype 21 patients received <4 cycles 10 disease progression 8 exceptional responses 2 prolonged cytopenia 1 non-prostate cancer death

15 Trial Profile 75 pt assessed for eligibility 50 pt enrolled 177 Lu-PSMA + SPECT/CT Up to 4 cycles, 6 weekly 3 months follow-up Restaging CT Bone scan FDG PET PSMA PET 51 Cr-EDTA GFR 1-30: 10/ / : 03/ /2017 QoL: EORTC QLC-30, BPI-SF Prior to each cycle : bloods (PSA, FBE / UE / LFTs), clinical Ax Repeated +2 and +4 weeks CT Bone scan FDG PET PSMA PET 51 Cr-EDTA GFR 25 patients not eligible Imaging (16): low PSMA (8), FDG discordance (8) ECOG>2 (4), Hb<90 (3), other exclusion (2) 21 patients received <4 cycles 10 disease progression 8 exceptional responses 2 prolonged cytopenia 1 non-prostate cancer death 17 15% exceptional responders 20% progressed during Rx

16 1 Endpoint: Safety (N=50) Dry mouth 33 (66%) 1 (2%) 0 (0%) 0 (0%) Lymphocytopenia 7 (14%) 13 (26%) 16 (32%) 0 (0%) Thrombocytopenia 11 (22%) 3 (6%) 4 (8%) 1 (2%) Fatigue 16 (32%) 2 (4%) 1 (2%) 0 (0%) Nausea 21 (42%) 3 (6%) 0 (0%) 0 (0%) Anaemia 3 (6%) 6 (12%) 5 (10%) 0 (0%) Neutropenia 6 (12%) 6 (12%) 3 (6%) 0 (0%) Pain 4 (8%) 1 (2%) 1 (2%) 0 (0%) Vomiting 11 (22%) 2 (4%) 0 (0%) 0 (0%) Anorexia 7 (14%) 0 (0%) 0 (0%) 0 (0%) Dry eyes 4 (8%) 1 (2%) 0 (0%) 0 (0%) Weight loss 2 (4%) 1 (2%) 0 (0%) 0 (0%) Treatment-emergent adverse events (AEs) possibly, probably or definitely according to CTCAE 18 No episodes of febrile neutropenia No measures to minimise xerostomia performed

17 1 Endpoint: Safety (N=50) Dry mouth 33 (66%) 1 (2%) 0 (0%) 0 (0%) Lymphocytopenia 7 (14%) 13 (26%) 16 (32%) 0 (0%) Thrombocytopenia 11 (22%) 3 (6%) 4 (8%) 1 (2%) Fatigue 16 (32%) 2 (4%) 1 (2%) 0 (0%) Nausea 21 (42%) 3 (6%) 0 (0%) 0 (0%) Anaemia 3 (6%) 6 (12%) 5 (10%) 0 (0%) Neutropenia 6 (12%) 6 (12%) 3 (6%) 0 (0%) Pain 4 (8%) 1 (2%) 1 (2%) 0 (0%) Vomiting 11 (22%) 2 (4%) 0 (0%) 0 (0%) Anorexia 7 (14%) 0 (0%) 0 (0%) 0 (0%) Dry eyes 4 (8%) 1 (2%) 0 (0%) 0 (0%) Weight loss 2 (4%) 1 (2%) 0 (0%) 0 (0%) Treatment-emergent adverse events (AEs) possibly, probably or definitely according to CTCAE 19 No episodes of febrile neutropenia No measures to minimise xerostomia performed

18 Best PSA Response (N=50) PSA response PSA 50% in 62% (95% CI 47-75) PSA 30% in 74% (60-84%)

19 21 SNMMI 2018 IMAGE OF THE YEAR 2018

20 Baseline PSMA PET 136 post 177 Lu-PSMA 617 < progressed after docetaxel and enzalutamide lymph node confined disease complete & durable response A/Prof Michael Hofman

21 PSA progressed after docetaxel, enzalutamide, abiraterone & cabazitaxel back pain with rapidly progressing retroperitoneal lymphadenopathy FDG baseline 175 Gy after LuPSMA # PSMA 40 PSMA PET baseline Days 23 Imaging@Brisbane 2018

PSA FDG PSMA 120 100 80 60 40 20 PSMA PET

200 300 400 500 Days from first cycle of

22 PSA FDG PSMA PSMA PET baseline PSMA PET post LuPSMA Days from first cycle of treatment 24 Treatment ceased after 3 cycles owing to an exceptional response Complete response, durable for >450 days with no further Rx

PSA 2531 PSA nadir 7 baseline +4 months Before: on

he was up and cleaning the garage, without

24 PSA 2531 PSA nadir 7 baseline +4 months Before: on heavy medications to cope with bone pain, he spent most of the day asleep. He felt weak and without hope After: Within a week he was up and cleaning the garage, without painkillers. As a former oncology nurse she d never seen anything work like this before

25 Exceptional Response Post therapy SPECT/CT cycle #1 cycle #2 PSA 880 PSA 93 (-90%) Days from 1 st dose LuPSMA 27

26 PSA PSA death on trial 28 Imaging@Brisbane 2018 Days from cycle #1 LuPSMA

27 Survival Probability Overall Survival: 18 vs 10 months if PSA 50% (N=30) Total: Median 13.4 months PSA < 50%: Median 9.9 months PSA 50%: Median 17.8 months p = Months *immature data on the additional 20 patient extension cohort to provide reliable updated estimates of OS

28 Quality of Life (baseline to 2 nd cycle) Better; 11; 37% Unchanged; 7; 26% Better; 10; 37% Unchanged; 16; 53% EORTC Global Health Score n=30 Worse; 3; 10% BPI Mean Severity Score n=27 with pain Worse; 10; 37% EORTC QLQ-C30 / BPI-SF better: +10 points worse: -10 points or not completed owing to progression/death 30

29 Significant improvement in pain Unchanged; 7; 26% Better; 10; 37% BPI Mean Severity Score n=27 with pain Worse; 10; 37%

30 Quality of Life (each time point compared to baseline) 32 EORTC QLQ-C30 change from baseline scores with 95% confidence intervals of functional scales and global health status

31 Theranostics: see what you treat 1. LOW PSMA EXPRESSION 2. DISCORDANT FDG+ PSMA- SUV 20 PSMA FDG + PSMA PET PSMA PET FDG PET 34 ANZUP 2018

32 Is this patient suitable? SUVmax SUV PSMA 35 ANZUP 2018

33 Is this patient suitable? 20 SUV (B) 10 SUV 36 ANZUP 2018 PSMA FDG

34 Is this patient suitable? 20 SUV (B) 10 SUV (C) 37 ANZUP 2018 PSMA FDG PSMA/FDG

35 Disease heterogeneity: what does it mean? (C) (D) (E) PSMA (F) FDG (G) PSMA FDG 38 ANZUP 2018

36 Can baseline imaging provide prognostic info? PSMA-PET FDG-PET Bone scan* SUVmax : 41 SUVmean : 7,98 Volume : 1290 ml SUVmax : 7,1 SUVmean : 5,9 Volume: 50,8 ml *with EXINI BSI BSI : 7.75 % Hostpots :64 39 Imaging@Brisbane 2018

Survival probability Survival probability FDG metabolic tumour volume

75 FDG : OS + +++ >500mL 1.00 0.75 FDG : PFS 0.50 0.25 ++ <500mL p < 0.

37 Survival probability Survival probability FDG metabolic tumour volume (MTV): only progostic imaging parameter for OS / PFS FDG : OS >500mL FDG : PFS <500mL p < p = months months N=50 extension cohort [interim analysis only] Group + high FDG (16) + low risk (34) Group + + Imaging@Brisbane 2018 high FDG (16) low risk (34)

38 3 x qspect/ct Discussion: voxel-based Dosimetry 4hrs 24hrs 96hrs 41 SNMMI 2018

39 (Bq/mL) mean voxel activity 3 x qspect/ct 2 x 10 6 Bq/mL 50 Gy 42 SNMMI hrs 24hrs CT-CT deformable image registration time (hours) voxelised kinetics 96hrs Dose in Gy (tumour and normal tissues)

40 Dosimetry from cycle #1 (30 patients treated with 177 Lu-PSMA617) >50 Dose in Gy (tumour and normal tissues)

41 Whole body tumour dose correlates with PSA 12 weeks 44 SNMMI 2018 <10 Gy: 10 non-responders 1 responder <50% 50% PSA Response

42 TheraP Study Theranostic PSMA A randomised phase 2 trial of 177 Lu-PSMA 617 theranostic versus cabazitaxel in progressive metastatic castration resistant prostate cancer Australian Sponsor: ANZUP Study Chair: Prof Michael Hofman Co-ordinating Centre: NHMRC Clinical Trials Centre Collaborative Group Chair: Prof Ian Davis Senior Statistician: Dr Andrew Martin CTC Clinical In Lead: collaboration Prof with Martin Stockler

TheraP Study A randomised phase 2 trial of 177 Lu-PSMA 617 theranostic versus cabazitaxel in progressive metastatic castration resistant prostate cancer 1:1 10 sites around Australia Australian

43 TheraP Study A randomised phase 2 trial of 177 Lu-PSMA 617 theranostic versus cabazitaxel in progressive metastatic castration resistant prostate cancer 1:1 10 sites around Australia Australian Sponsor: ANZUP Study Chair: Prof Michael Hofman Co-ordinating Centre: NHMRC Clinical Trials Centre Collaborative Group Chair: Prof Ian Davis Senior Statistician: Dr Andrew Martin CTC Clinical In Lead: collaboration Prof with Martin Stockler

$resistant prostate cancer \ Australian Sponsor: ANZUP Study Chair:$ Centre Collaborative Group Chair: Prof Ian Davis Senior

44 TheraP Study A randomised phase 2 trial of 177 Lu-PSMA 617 theranostic versus cabazitaxel in progressive metastatic castration resistant prostate cancer \ Australian Sponsor: ANZUP Study Chair: Prof Michael Hofman Co-ordinating Centre: NHMRC Clinical Trials Centre Collaborative Group Chair: Prof Ian Davis Senior Statistician: Dr Andrew Martin CTC Clinical In Lead: collaboration Prof with Martin Stockler

45 TheraP: Robust QC for multi-centre trial 3x 68 Ga-PSMA-11 validation runs propsma trial 3x 177 Lu-PSMA-617 validation runs PET camera validation propsma trial

46 TheraP Study A randomised phase 2 trial of 177 Lu-PSMA 617 theranostic versus cabazitaxel in progressive metastatic castration resistant prostate cancer Australian Sponsor: ANZUP Study Chair: Prof Michael Hofman Co-ordinating Centre: NHMRC Clinical Trials Centre Collaborative Group Chair: Prof Ian Davis Senior Statistician: Dr Andrew Martin CTC Clinical In Lead: collaboration Prof with Martin Stockler

47 177 Lu-PSMA shows promise: can it be used earlier? Chemotherapy 50??curative LuPSMA palliative life prolongation

48 177 Lu-PSMA shows promise: can it be used earlier? +/- combined with other therapies? Chemotherapy 51 LuPSMA + immunotherapy radiosensitiser

49 Thank-you! Molecular Imaging Peter Eu (Radiopharmacist) Rod Hicks, Amir Iravani, Aravind Ravi Kumar, Grace Kong, Tim Akhurst (Nuc Med Doctors) Mark Scalzo (Lead Technologist) Price Jackson (Medical Physicist) Uro-oncology Multi-Discplinary Team John Violet (Radiation Oncology) Shahneen Sandhu (Medical Oncology) Declan Murphy (Surgical Oncology) Funding partners ANSTO ABX Endocyte Prostate Cancer Foundation of Australia (PCFA) Movember Prostate Cancer Foundation (PCF) Victorian Cancer Agency Collaborative partners ANZUP NHMRC CTC ARTnet 52

50 Uro-oncology team Nuclear Medicine team esmo.org Peter MacCallum Cancer Centre, Melbourne, Australia

Lutetium-177 PSMA (LuPSMA) Theranostic Phase II trial: Efficacy, safety and QoL in patients

Lutetium-177 PSMA (LuPSMA) Theranostic Phase II trial: Efficacy, safety and QoL in patients with castrate-resistant prostate cancer treated with LuPSMA M. S. Hofman, S. Sandhu, P. Eu, P. Jackson, T. Akhurst,