PSMA Targeted Therapies Professor Michael Hofman , MBBS, FRACP, - PowerPoint PPT Presentation

#APCCC2019 PSMA Targeted Therapies Professor Michael Hofman , MBBS, FRACP, FAANMS Molecular Imaging & Therapeutic Nuclear Medicine, Centre for Cancer Imaging Peter MacCallum Cancer Centre / The University of Melbourne @DrMHofman michael.hofman@petermac.org

Disclosures Research Support Endocyte (a Novartis company) Consulting none Honoraria/travel support Janssen, Sanofi Genzyme, Ipsen Stock ownership None Study Chair TheraP 2

Prostate Specific Membrane Antigen (PSMA) O’Driscott C et al, Br J Pharm 2016 #PSMA 3 doi:10.1111/bph.13576

THERANOSTICS TARGETED THERAPEUTIC + DIAGNOSTIC COMPANION 177 Lu-PSMA-617 68 Ga-PSMA-11 radioactive small molecule targeting prostate specific membrane antigen (PSMA) SPECT PET highly over-expressed in prostate cancer Post-therapy Pre-therapy SPECT/CT PET/CT O’Driscott C et al, Br J Pharm 2016 doi:10.1111/bph.13576

Lutetium-177 ( 177 Lu): short path-length beta emitter mean path length 1mm, average penetration 0.3mm, 6.7 day half-life targeted drug: “too smart” 1mm path-length: cross-fire effect all cells in 1mm radius targeted ne arby cells not expressing target develop resistance

2014: high activity of small molecule (not Ab) targeting PSMA Serial 124 I-MIP-1095 PET 131 I-MIP-1095 Best PSA response in 25 pt PSA ≥ 50% in 61% Zechmann CM et al , Eur J Nucl Med Mol Imaging 2014, 14:1280-1929

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 2015

2015: 1 st published report of 177 Lu-PSMA617 2 cycles 177 Lu-PSMA617 Kratochwil et al, Eur J Nucl Med Mol Imaging 2015 . May;42(6):987-8 DOI 10.1007/s00259-014-2978-1

Theranostics @ Peter Mac 600 177 Lu-PSMA No of therapies per year 1 st PSMA therapy in Australia 400 200 177 Lu-DOTATATE 0 Gastro-entero-pancreatic Neuroendocrine Tumours Prostate 9

2015-8: 1 st prospective phase II study @ Peter Mac Remarkable responses in patients who progressed after conventional therapies 10

Peter Mac Phase II Baseline characteristics & schema Median or N (%) Characteristic 75 pt screened for eligibility Age (years) 71 Alkaline phosphatase (U/L) 131 PSA (ng/mL) 189.8 PSA doubling time (ng/mL/month) 2.6 50 enrolled ECOG performance status 0 20 (40%) 1 22 (44%) 2 8 (16%) Up to 4 cycles 177 Lu-PSMA Prior treatments Abiraterone or enzalutamide or both 45 (90%) Docetaxel 42 (84%) Cabazitaxel 24 (48%) 50 included in analysis Docetaxel + abi / enza ± Cabazitaxel 39 (78%) median follow-up: 31.4 months

Best PSA Response (N=50) 100 PSA Response N (%) 95% CI ≥ 30% 37 (74%) 60 - 84 ≥ 50% 32 (64%) 50 - 77 50 ≥ 80% 22 (44%) 30 - 59 PSA Response % <30% ≥30% ≥50% 0 -50 -100 Patients Hofman MS et al, ASCO GU 2019.

#PSMA IMAGE OF THE YEAR 2018 EANM'18 13

Treatment-emergent adverse events attributable to Lu-PSMA 1 2 3 4 Dry mouth 29 (58%) 4 (8%) 0 (0%) 0 (0%) Lymphocytopenia 7 (14%) 13 (26%) 16 (32%) 0 (0%) Thrombocytopenia 11 (22%) 3 (6%) 4 (8%) 1 (2%) Fatigue 15 (30%) 3 (6%) 1 (2%) 0 (0%) Nausea 20 (40%) 4 (8%) 0 (0%) 0 (0%) Anaemia 3 (6%) 6 (12%) 5 (10%) 0 (0%) Neutropenia 6 (12%) 6 (12%) 3 (6%) 0 (0%) Bone Pain 5 (10%) 4 (8%) 0 (0%) 0 (0%) Vomiting 11 (22%) 2 (4%) 0 (0%) 0 (0%) Anorexia 8 (16%) 0 (0%) 0 (0%) 0 (0%) Dry eyes 4 (8%) 1 (2%) 0 (0%) 0 (0%) Renal injury * 4 (8%) 1 (2%) 0 (0%) 0 (0%) Weight loss 3 (6%) 1 (2%) 0 (0%) 0 (0%) * 51 Cr-EDTA GFR measured 3 months after completion of 177 Lu-PSMA-617 in 28 pt demonstrated mean decline of -11.7 mL/min (95% CI -19 to -4)

Lu-PSMA re-treatment 75 pt screened for eligibility Up to 4 cycles 177 Lu-PSMA #APCCC2019 50 included in analysis 15 (30%) received further LuPSMA PSA ≥50% response: 73% Hofman MS et al (unpublished)

69yo progressed after docetaxel, enzalutamide, abiraterone & cabazitaxel baseline FDG 175 Gy after LuPSMA #1 PSMA PSMA PET baseline 16

100 * LuPSMA 90 80 70 PSA (ug/L) 60 50 40 30 * 20 10 * * * * * 0 -10 0 10 20 30 40 months from Lu-PSMA 17

100 * LuPSMA 90 80 70 PSA (ug/L) 60 50 40 30 * 20 10 * * * * * 0 -10 0 10 20 30 40 months from Lu-PSMA 18

Brief pain inventory Pain Severity  QoL ● Cycle 2 ● Cycle 3 Cycle 4 ● ● 3 month FU Pain Interference ● Cycle 2 ● Cycle 3 ● Cycle 4 ● 3 month FU −2.0 −1.5 −1.0 −0.5 0.0 0.5 19 Mean difference from cycle 1

How do our results compare to others? N=50 N=145 PSA response PSA ≥50% in 64% PSA ≥50% in 45% ** Hofman MS et al Rahbar K et al 46 pt had PSA follow-up less than 8 wk

50 N=145 N=100 N=50 0 -50 -100 PSA ≥50% in 64% PSA ≥50% in 45% PSA ≥50% in 32% Hofman MS et al Rahbar K et al Heck et al

Is this patient suitable? 20 SUV SUVmax 70 PSMA

FDG PET: see something different 20 SUV 10 SUV (B) PSMA FDG

#APCCC2019 FDG+ PSMA- disease in liver (& bone) 20 SUV 10 SUV (B) (C) Can target with 177 Lu- PSMA Cannot target (most aggressive sites) PSMA FDG PSMA/FDG Thang SP et al Eur Urology Oncology 2018

Disease heterogeneity: what does it mean? (C) (D) (E) PSMA FDG (F) (G) PSMA FDG Thang SP et al Eur Urology Oncology 2018

PSMA/FDG phenotypes PSMA+ PSMA+ PSMA- PSMA+ FDG- FDG+ concordant FDG+ FDG+ discordant SUV 20 SUV 10 SUV 10 SUVmax 7 35 15 60 26 72 n/a 15 Unsuitable Suitable #APCCC2019

What happened to the patients we didn’t treat ? 16 patients excluded PSMA- (or low expression) PSMA+ low PSMA-expression (50%) FDG+ FDG+ discordant discordant FDG+ disease (50%) Median OS 2.5 months (95% CI 1.7 – 5.0 months) SUVmax 7 35 15 15 Unsuitable Thang SP et al Eur Urology Oncology 2018

Overall survival (n=50) A. OS 100% 100% Best PSA response > 50% OS=13.3 months ≥50% 75% (95% CI 10.5 - 18.7) 75% % survival % survival 50% 50% + 25% p = 0.00017 + + 25% 0% 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 months months 0% # at risk (censored) 50 (0) 50 (0) 44 (0) 36 (0) 13 (0) 9 (1) 5 (3) 5 (3) 29 (0) 20 (0) 19 (0) PSA ≥50% : 18.4 months (95% CI 13.8 – 23.8) - PSA< 50% : 8.7 months (95% CI 6.5 to 13.4) Hofman MS et al ASCO GU 2019 (updated May 2019)

PSA≥50%: significantly longer overall survival 100% Best PSA response > 50% ≥50% 75% % survival 50% + 25% p = 0.00017 0% 0 3 6 9 12 15 18 21 months PSA ≥50% : 18.4 months (95% CI 13.8 – 23.8) PSA< 50% : 8.7 months (95% CI 6.5 to 13.4) Hofman MS et al ASCO GU 2019 (updated May 2019)

Prognostic 100% 100% 100% FDG PSMA LDH FDGvol PSMAmean LDH markers with volume + intensity + + >= 207 ml >= 10.55 >= 240.5 U/L + + + < 207 ml < 10.55 < 240.5 U/L 75% 75% 75% Lu-PSMA survival survival survival + + ++ + 50% 50% 50% + + + + + + 25% ++ + 25% 25% ++ + + 1 + 2 3 + 0% 0% 0% 0 10 months 20 30 0 10 months 20 30 0 10 months 20 30 1: Whole-body FDG volume 100% 100% Cut-off : 207 ml ALP Bone scan Median OS: 6.1 vs 9.6 months (p < 0.001) alkaline phosphatase BSI + + >= 126.5 U/L index >= 5.37 % 2: Whole-body PSMA SUVmean + + < 126.5 U/L < 5.37 % Cut-off : 10.3 75% 75% Median OS: 9.8 vs 6.3 months (p = 0.002) survival survival 3: Lactate dehydrogenase Cut-off : 240.5 U/L + 50% 50% Median OS: 6.9 vs 10.2 months (p = 0.03) + 4: Alkaline phosphatase + + Cut-off : 126.5 U/L + Median OS: 6.0 vs 9.7 months (p < 0.001) 25% 25% + ++ + FerdinandusJ, ++ + 5: EXINI Bone Scan Index (%) Cut-off : 5.37 % Hofman MS et al, 4 5 + Median OS: 5.4 vs 8.3 months (p = 0.002) 0% 0% (unpublished) 0 10 months 20 30 0 10 months 20 30

Theranostics: we can quantify radiation dose (“dosimetry”) 3 x qSPECT/CT 4hrs 24hrs 96hrs Violet J … Hofman MS, JNM 2019

50 Gy 2 x 10 6 Bq/mL Dose in Gy (tumour and normal tissue) 3 x qSPECT/CT 4hrs 24hrs 96hrs CT-CT deformable image registration mean voxel activity (Bq/mL) 4 24 96 time (hours) voxelised kinetics

“Whole body” tumour dose correlates with PSA response @ 12 weeks <10 Gy: 10 non-responders 1 responder ≥50% <50% 33 PSA Response

TheraP Trial: 177 Lu-PSMA-617 vs. cabazitaxel Metastatic castration-resistant 177 Lu-PSMA-617 SPECT/CT @ 24 hours prostate cancer post docetaxel ▪ Suspend Rx if exceptional ▪ 8.5GBq  0.5GBq/cycle suitable for cabazitaxel response ▪ Up to 6 cycles ▪ Recommence upon progression N = 200; 11 sites (Australia) PSMA + FDG PET/CT 1:1 randomisation stratified by: Endpoints ▪ SUVmax > 20 at a site of disease • disease burden (>20 sites vs ≤ 20 sites) ▪ Measurable sites SUVmax > 10 • prior enzalutamide or abiraterone ▪ No discordant FDG+ PSMA-disease 1. PSA response • site ▪ Centrally reviewed 2. OS cabazitaxel 3. rPFS / PSA PFS ▪ 20mg/m2 IV q3 weekly 4. QoL ▪ Up to 10 cycles 5. AEs