ANNA SUNDLÖV, BITR ÖVERLÄKARE ONKOLOGI, SKÅNES UNIVERSITETSSJUKHUS & LUNDS UNIVERSITET

Radionuklidterapi vid prostatacancer ANNA SUNDLÖV, BITR ÖVERLÄKARE ONKOLOGI, SKÅNES UNIVERSITETSSJUKHUS & LUNDS UNIVERSITET

Disclosures Föreläsningar, möten, mm på uppdrag av Novartis, Ipsen och Bayer Medprövare i fas I- program med Th227 (Bayer) Nationell huvudprövare fas III studie med Lu177- PSMA (Endocyte/Novartis)

RNT i prostatacancer Dåtid, nutid, framtid 1997 2013 2021????? Indikation: Multipla, smärtsamma, osteoblastiska skelettmetastaser. Primär Effekt: smärtlindring Indikation: Skelettmetastaserad, kastrationsresistent prostatacancer Primär Effekt: tumörhämning

Omvärldsbevakning

AAA/Novartis RNT pipeline

Endocyte/Novartis RNT pipeline

Bayer pipeline in oncology

EANM 2018 - the buzz words PSMA-baserad theranostics 68 Ga- & 177 Lu-PSMA Alfa-terapier 225 Ac 227 Th 213 Bi Olika indikationer = olika målsökande bärarmolekyler

223 Ra-klorid (Xofigo)

Ra223 en kalcium look-alike Calcium mimetic Incorporates into bone mineral like calcium Primarily emits α-particles Has a half-life of 11.4 days 20 Ca 38 Sr 56 Ba 88 Ra 1. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

α vs β

Ra223 Kort räckvidd ger låg benmärgstoxicitet α β Marrow Range of β-particle (long range: 10-1000 cell diameters 2 ) Range of α-particle (short range: 2-10 cell diameters 2 ) β-emitter Bone Radium Ra 223 dichloride 1. Henriksen G, et al. Cancer Res. 2002;62:3120-3125. 2. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

Ra223 fas III studien ALSYMPCA

Ra223 Förlänger överlevnaden! Parker C, et al, NEJM 2013

ERA 223: Concomitant Treatment of Asymptomatic or Mildly Symptomatic CRPC with Bone Metastases with Radium-223 in Combination with Abiraterone and Prednisone 1,2 N=806 Radium-223 dichloride 55 kbq/kg IV every 4 weeks for 6 cycles Study Population Patients ( 18 years old) with bone-predominant mcrpc Asymptomatic or mildly symptomatic 2 bone metastases ECOG PS of 0 or 1 No known brain or visceral metastases 1:1 Randomization In combination with abiraterone (1000 mg qd) + prednisone/prednisolone (5 mg bid) Stratification factors Geographical region Use of bone health agents ALP level at baseline (ALP <90 vs 90 U/L) Matching placebo In combination with abiraterone (1000 mg/qd) + prednisone/prednisolone (5 mg/bid) Endpoints Primary endpoint SSE-FS Secondary endpoints Overall survival Time to opiate use for cancer pain Time to chemotherapy Radiologic PFS Safety ERA 223 was unblinded early on November 17, 2017, based on the recommendation of the IDMC Results are based on the primary analysis with data cutoff date on February 15, 2018 ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group performance status; IDMC, independent data monitoring committee; IV, intravenous; mcrpc, metastatic castration-resistant prostate cancer; PFS, progression-free survival; SSE-FS, symptomatic skeletal event-free survival. 1. ClinicalTrials.gov. NCT02043678. Available at: https://www.clinicaltrials.gov/ct2/show/nct02043678. Accessed March 2018. 2. Smith M et al. Lancet Oncol 2018. In press. S Nilsson 2019-01 Courtesy of prof Sten Nilsson

Shorter Median Time to Fracture Was Observed in the Combination Arm Placebo + AAP Radium-223 + AAP Fracture Radium-223 + AAP N=392 Placebo + AAP N=394 Events, n (%) 112 (29%) 45 (11%) Median (95% CI), months HR (95% CI) 31.7 (27.6 NE) 3.135 (2.206 4.455) NE Number at risk Months Since Randomisation 392 394 368 378 314 338 243 296 176 234 135 189 90 137 52 95 28 56 16 33 7 14 4 8 3 2 3 2 1 0 0 0 Data cutoff February 15, 2018. AAP, abiraterone/prednisone; NE, not estimable. Smith M et al. Lancet Oncol 2018. In press.. S Nilsson 2019-01 Courtesy of prof Sten Nilsson

177 Lu-PSMA

177 Lu-PSMA Tillgängliga kliniska resultat: Data från compassionate use program i Tyskland En prospektiv fas II studie En randomiserad fas III studie pågår VISION 68 Ga-PSMA-11 177 Lu-PSMA-617 Sverige är med!» Stockholm, Lund, Göteborg, Uppsala, Umeå

177 Lu-PSMA Retrospektiva data Retrospektiv studie av 145 tyska patienter (Rahbar et al, JNM 2017) 12 centra 145 patienter progressiv mcrpc 68 Ga-PSMA PET ++ 248 cykler 177 Lu-PSMA-617 á 2-8 GBq (mean 5.9 GBq) 1-4 cykler/pat med 8-12 veckors intervall

177 Lu-PSMA Retrospektiva data Median F-U 16 veckor 8% Muntorrhet (g1-2) 12% Hematologisk tox (g3-4) 12% GFR (g1-2) Ju fler cykler desto bättre respons Best PSA-response from baseline 45% PSA-decline 50% 60% any PSA-decline Rahbar et al, JNM 2017

177 Lu-PSMA Prospektiva data Fas II studie (Hofman et al, Lancet Oncology 2018) 30 patienter med progressiv, kemorefraktär mcrpc 18 F-FDG-PET och 68 Ga-PSMA-PET i screening Pat med mismatch exkluderades (7/43 pat) Pat med SUV max tumor > 1.5x SUV max lever på PSMA- PET inkluderades Inj aktivitet anpassades till pat tumörbörda, vikt och njurfunktion 6 +/- 2 GBq (mean 7.5 GBq) Post-terapeutisk SPECT/CT för dosimetri och behandlingsuppföljning

177 Lu-PSMA Prospektiva data Median F-U 25 månader Muntorrhet Hematologisk tox 100% förbättrades i smärta Median PSA-PFS 7.6 m Median OS 13.5 m Best PSA-response from baseline 57% PSA-decline 50% 97% any PSA-decline Hofman et al, Lancet Oncology 2018

VISION-studien Hur bra är 177 Lu-PSMA egentligen? Randomiserad fas III-studie för män med mcrpc Tidigare taxanbeh och NAAD 2:1 randomisering mellan 177Lu-PSMA-617 och BSC

Alfa-terapierna då?

α-terapi kliniska studier 225Ac-PSMA-617 Resultat publicerade» Kratochwil, JNM 2017» Sathekge EJNMMI 2019 227Th-PSMA-MoAb Pågående Fas I

225 Ac-PSMA-617 mcrpc Kratochwil, JNM 2017

225 Ac-PSMA-617 mcrpc PSA-response Kratochwil, JNM 2017

225 Ac-PSMA-617 mcrpc Kratochwil, JNM 2017

Targeted Thorium Conjugates: Development Overview Targeted thorium conjugates are being investigated in several tumor types 1 5 MSLN-TTC (anetumab-ttc): mesothelioma, ovarian cancer, pancreatic cancer PSMA-TTC (Progenics Pharma, Inc. antibody): metastatic castration-resistant prostate cancer HER2-TTC (trastuzumab-ttc): HER2+ breast cancer Thorium-227 Pre-clinical Phase I HER2-TTC (breast cancer) MSLN-TTC (various solid tumors) PSMA-TTC (prostate cancer) HER2, human epidermal growth factor receptor 2; MSLN, mesothelin; PSMA, prostate-specific membrane antigen; TTC, targeted thorium-227 conjugate. 1. Hammer S et al. Presented at: AACR; April 1 5, 2017; Washington, DC. Abstract 5200. 2. Karlsson J et al. Presented at: AACR; April 1 5, 2017; Washington, DC. Abstract 5859. 3. Hagemann UB et al. Presented at AACR; April 1 5, 2017; Washington, DC. Abstract 5199. 4. Hagemann UB et al. Presented at: AACR; April 16 20, 2016; New Orleans, LA. Abstract 591. 5. ClinicalTrials.gov. NCT02581878. Available at: https://www.clinicaltrials.gov/ct2/show/nct02581878. Accessed March 2018. 29

3 Key Components of Targeted Thorium Conjugates Monoclonal antibody with tumor target specificity Chelator moiety covalently linked to the antibody + Thorium-227 Alpha-particle-emitting radionuclide 227 Th Lys Lys RT, 5 10 min 227 Th Conjugate TTC Lys, lysine; RT, room temperature; 227 Th, thorium-227; TTC, targeted thorium-227 conjugate. Bayer. Data on file. 30

Sammanfattning Sm153-lexidronam används allt mindre Ra223 har haft lite svårt att få fotfäste på ett bestående vis Lu177-PSMA har väckt stor uppmärksamhet och entusiasm både från kollegor och patientgrupper Alfa-strålarna är på stark frammarsch!

Tack för er uppmärksamhet!

Back-up slides

177 Lu-PSMA Prospektiva data Fas II studie (Hofman et al, Lancet Oncology 2018) Inj aktivitet anpassades till pat tumörbörda, vikt och njurfunktion 6 +/- 2 GBq (mean 7.5 GBq)» +1 GBq if >20 sites of disease (93%)» -1 GBq if <10 sites of disease» + 0.5 GBq if weight >90 kg» + 0.5 GBq if GFR >90 ml/min» - 0.5 GBq if weight <70 kg» - 0.5 GBq if GFR <60 ml/min

Hofman et al, Lancet Oncology 2018

Hofman et al, Lancet Oncology 2018

Hofman et al, Lancet Oncology 2018

Hofman et al, Lancet Oncology 2018

Targeted Thorium Conjugates: Development Overview Targeted thorium conjugates are being investigated in several tumor types 1 5 MSLN-TTC (anetumab-ttc): mesothelioma, ovarian cancer, pancreatic cancer PSMA-TTC (Progenics Pharma, Inc. antibody): metastatic castration-resistant prostate cancer HER2-TTC (trastuzumab-ttc): HER2+ breast cancer Thorium-227 Pre-clinical Phase I HER2-TTC (breast cancer) MSLN-TTC (various solid tumors) PSMA-TTC (prostate cancer) HER2, human epidermal growth factor receptor 2; MSLN, mesothelin; PSMA, prostate-specific membrane antigen; TTC, targeted thorium-227 conjugate. 1. Hammer S et al. Presented at: AACR; April 1 5, 2017; Washington, DC. Abstract 5200. 2. Karlsson J et al. Presented at: AACR; April 1 5, 2017; Washington, DC. Abstract 5859. 3. Hagemann UB et al. Presented at AACR; April 1 5, 2017; Washington, DC. Abstract 5199. 4. Hagemann UB et al. Presented at: AACR; April 16 20, 2016; New Orleans, LA. Abstract 591. 5. ClinicalTrials.gov. NCT02581878. Available at: https://www.clinicaltrials.gov/ct2/show/nct02581878. Accessed March 2018. 40

41 Increased Cytotoxicity of the Combination of MSLN-TTC and ATRi A MSLN-TTC combined with ATRi increased the level of DNA damage, decreased cell viability, and enhanced apoptosis in OVCAR-3 cells beyond either treatment alone B C D ATR, ataxia telangiectasia and Rad3-related; MSLN, mesothelin; OVCAR-3, ovarian carcinoma cell line; TTC, targeted thorium conjugate. Wickstroem K et al. Presented at: the American Association for Cancer Research Annual Meeting; April 14 18, 2018. Chicago, IL, USA. P849.

42 Observed for Low MSLN-TTC Doses When Combined with Non-Efficacious Doses of ATR or PARP Inhibitors The observed increase was more pronounced in the ATRi combination than in the PARPi combination Enhanced in vivo antitumor activity was observed when MSLN-TTC was combined with ATRi BAY 1895344 or PARPi olaparib in the OVCAR-3 ovarian cancer xenograft model in mice **P<0.01, ***P<0.001, ****P<0.0001. MSLN, mesothelin; OVCAR-3, ovarian carcinoma cell line; PARP, poly (ADP-ribose) polymerase; TTC, targeted thorium conjugate. Wickstroem K et al. Presented at: the American Association for Cancer Research Annual Meeting; April 14 18, 2018. Chicago, IL, USA. P849.