Preliminary efficacy and safety results from the TATCIST trial: A PSMA-directed targeted alpha therapy with FPI-2265 (225Ac-PSMA-I&T) for the treatment of metastatic castration-resistant prostate cancer

Preliminary efficacy and safety results from the TATCIST trial: A PSMA-directed targeted alpha therapy with FPI-2265 (225Ac-PSMA-I&T) for the treatment of metastatic castration-resistant prostate cancer Ebrahim S. Delpassand,1 Mohammad Jawed Hashmi,1 Julia Kazakin,2 A. Omer Nawaz,2 Gabriella Garufi,2 Joanne Schindler,2 Luke Nordquist3 1Excel Diagnostics and Nuclear Oncology Center, Houston, TX; 2Fusion Pharmaceuticals Inc., Hamilton, ON, Canada; 3Urology Cancer Center & XCancer, Omaha, NE Introduction Targeted radiopharmaceuticals are designed to deliver radiation specifically to cancer cells by combining a radionuclide with a ligand that binds with high affinity to a membrane antigen (e.g., prostate-specific membrane antigen [PSMA], somatostatin receptor).1,2 β-emitting radioligand therapies (RLTs), such as lutetium-177 (177Lu)-PSMA-therapy, have been shown to prolong radiographic progression-free (PFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC); however, almost 50% of patients do not respond to this treatment, therefore identifying a further unmet medical need.2,3 Targeted α-therapies have the potential to overcome limitations of β-therapies in that α-emitting radioisotopes have i) a higher probability of causing catastrophic double-strand DNA breaks and ii) a shorter radiation path length that may lessen unwanted exposure of surrounding healthy cells (Table 1).2,4 Table 1. Comparison of radiotherapy approaches Composition Primary Mechanism of Cell Death Penetrating Power in the Body (Emission Travel Distance) Alpha particles 2 protons and 2 neutrons Double-strand DNA breaks 50–100 µm (~ few cells) Beta particles 1 electron Single-strand DNA breaks Up to 12 mm External beam X-rays: High-energy electromagnetic radiation Gamma rays: High-energy photons Single-strand DNA breaks Several cm FPI-2265 (225Ac-PSMA-I&T) • FPI-2265 is a small molecule containing a PSMA-targeting ligand coupled with an 225Ac radionuclide that is currently being evaluated in the phase 2 TATCIST study (Figure 1 and Figure 2) Figure 1. Chemical structure of 225Ac-PSMA-I&T Figure 3. TATCIST open-label trial in participants with mCRPC aThe TATCIST PSMA ligand study included both diagnostic gallium-68 (68Ga) and 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)- amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL) PET/CT. bRevised per a protocol amendment. cTreatment was continued until radiographic or clinical progression; serious or intolerable adverse events; completion of 4 RLT cycles; subject withdrawal o r noncompliance; required use of prohibited treatment; sponsor/investigator decision; or death. dSuperscan is a bone scan that demonstrates markedly increased skeletal radioisotope uptake relative to soft tissues in association with absent or faint ren al activity (absent kidney sign). ARPI, androgen receptor pathway inhibitor; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; IV, intravenously; Lu, lutetium; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PET/CT, positron emission tomography/computed tomography; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors . Exploratory Analysis: Mean Standardized Uptake Value (SUVmean) • Quantifying 68Ga-labeled PSMA PET uptake may predict response in patients with prostate cancer who receive RLT • Some studies have shown that SUVmean may predict improved outcomes in patients with mCRPC6 – SUVmean, a measure of PSMA PET uptake, is the average SUV within a region of interest7 – Lower SUVmean has been associated with worse radiographic PFS and OS in patients treated with 177Lu-PSMA-6178 • In this exploratory analysis, PSA50 was evaluated by PSMA SUVmean >6 or ≤6 References 1. Sathekge MM, et al. Lancet Oncol. 2024;25(2):175-183. 2. Jang A, et al. Ther Adv Med Oncol. 2023;15:17588359231157632. 3. Sartor O, et al. N Engl J Med. 2021;385:1091-1103. 4. De Vincentis G, et al. Ann Oncol. 2019;30:1728-1739. 5. Zacherl MJ, et al. J Nucl Med. 2021;62:669-674. 6. Parihar AS, et al. Presented at the American Society of Clinical Oncology Annual Meeting; June 2 -6, 2023; Chicago, IL. 7. Kinahan PE, et al. Semin Ultrasound CT MR. 2010;31:496-505. 8. Kuo P. Presented at the 36th Annual Congress of the European Association of Nuclear Medicine; September 9 -13, 2023; Vienna, Austria. Acknowledgments The authors thank the participants, their families, and the clinical and research teams for their participation in this study. Disclosures ESD: Chairman and Medical Director (Excel Diagnostics and Nuclear Oncology Center) and CEO ( RadioMedix, licensing drug to Fusion); MJH: Employment (Excel Diagnostics and Nuclear Oncology Center); JK: Employment (Fusion); ON: Employment (Fusion); GG: Employment (Fusion); JS: Employment (Fusion); LN: Nothing to disclose Methods Conclusions Results Participant Disposition • As of the data cutoff of March 1, 2024, 35 participants received ≥1 dose of FPI-2265 (Table 2), with 25 participants having ≥12 weeks follow-up – 4 participants were identified as superscan o Superscan participants are excluded from the efficacy analyses and reported separately in the safety analysis – 1 participant was excluded from the PSA endpoint analysis due to uninterpretable PSA response Participant Disposition N Participants received ≥1 dose of FPI-2265 35a Participants with ≥12 weeks of follow-up assessments after first administration 25 Safety population 25 Non-superscan participants 21 Superscan participants 4 Participants included in efficacy analysis 20b aAs of the March 1, 2024, data cut, 5 additional participants received the first treatment dose after January 30, 2024. b4 participants with skeletal metastases presenting as superscan were excluded from efficacy analyses following a protocol amendment; 1 participant with uninterpretable PSA data was excluded from all analyses. • Baseline participant demographics and disease characteristics are presented in Table 3 Clinical Characteristics Total Number of Participants N=25 Age, y, median (range) 70 (52–84) PSA, ng/mL, median (range)​ 37.9 (0.14–4729) ECOG performance status, n (%)​ 0–1 24 (96) 2a 1 (4) Gleason score, median (range)​ 8 (7–10)b SUV​mean Median (range) 6.3 (3.7–12.6) ≤6 10 (40) >6 15 (60) Site of metastases, n (%)​ Bone 24 (96) Superscanc,d 4 (16) Lymph node 5 (20) Visceral 8 (32) Lines of prior anticancer therapy, n (%)​ Median (range) 4 (1–6) ARPI 25 (100) ≥2 18 (72) 1 7 (28) Chemotherapy 20 (80) Taxane 19 (76) ≥2 10 (40) 1 9 (36) Docetaxel 14 (56) Cabazitaxel 10 (40) Carboplatine 11 (44) 177Lu-PSMA RLT ​9 (36) 6 cycles 5 (20) 1–3 cycles 4 (16) Radium-223 4 (16) Other (sipuleucel-T, olaparib) 6 (24) aParticipants enrolled based on an earlier protocol version. Following a protocol amendment, only participants with ECOG performance status 0–1 are eligible for enrollment; bData are missing for 3 participants; cParticipants enrolled based on an earlier protocol version. Following an amendment, superscan participants are excluded. dSuperscan status was determined via Technetium -99m bone scan. eCarboplatin was given as part of a taxane regimen. Primary Endpoint: PSA50 Response • PSA50 was achieved in 10/20 participants (50%), regardless of prior Lu treatment (Figure 4) – PSA50 was achieved by 7/13 (54%) of Lu-naïve participants and by 3/7 (43%) of Lu-treated participants Figure 4. Maximum percent PSA change from baseline during the treatment period (weeks 0–28) by prior Lu treatment a% maximum PSA increase shown to 100%. Exploratory Analysis: SUVmean • In participants with baseline PSMA SUVmean >6 (n=13, overall; post-Lu, n=6), PSA50 was achieved in 9 participants (69%; Figure 5A) • Durable PSA response by week 24 was observed in participants with PSMA SUVmean >6 (Figure 5B) Figure 5A. Percent change in PSA from baseline by baseline SUVmean Figure 5B. PSA changes over 24 weeks by SUVmean status PET (Apr 11, 2022) PET (Aug 24, 2022) Total Tumor Burden Statistics PET (Apr 11, 2022) PET (Aug 24, 2022) % Change Volume (mL) 2775.9 3 -99.9 SUVmean 6.5 3.6 -44.8 Case Study A 72-year-old male with an 8-year history of prostate cancer (Gleason score 9) with extensive skeletal disease was enrolled into the TATCIST study and received 4 cycles of treatment with FPI-2265. The participant had bone-only mCRPC. Initial treatment for mCRPC included prostatectomy and external-beam radiation therapy. Subsequently, the participant received bicalutamide, enzalutamide, apalutamide, abiraterone, Radium-223, olaparib, and cabazitaxel + carboplatin. The participant continued treatment with leuprolide during the study. Disease response to treatment: • Biochemical response: reduction of PSA by 99.8% (from 1119 to 2.43 ng/mL) • PSMA-PET/CT: PSMA-tumor volume decrease by 99.9% • PCWG3: prolonged non-progressive disease PD, progressive disease; SD, stable disease. Table 4. Independent reviewer response by RECIST v1.1 criteria Best Response by RECIST v1.1 Participants​ Evaluable by RECIST 1.1 (n=9) PR, n (%) 3 (33) SD, n (%) 4 (44) PD, n (%) 2 (22) Secondary Endpoint: PCWG3 and RECIST v1.1 Criteria • 14/20 (70%) of participants had non-progressive disease per PCWG3 criteria • Per RECIST v1.1 criteria – Objective response rate was 3/9 (33%); all 3 participants had a partial response (PR; Table 4) Figure 6. TRAEs occurring in >10% of participants (safety population) aParticipants were counted once in a preferred term category for the worst severity if >1 event occurred in that category. Safety: FPI-2265 Exposure • As of the March 1, 2024, data cut, participants received a total of 71 cycles of treatment, with a median of 3 cycles • 7/10 participants had dose de-escalation due to a biochemical response of ≥PSA50 Safety: Treatment-Related Adverse Events • In non-superscan participants, most hematologic and non-hematologic treatment-related adverse events (TRAEs) were grade 1 or 2 (Figure 6) • 1 treatment-related death due to cerebral hemorrhage secondary to thrombocytopenia was reported in a superscan participant • 2 (8%) participants discontinued treatment due to TRAEs, including 1 participant in the superscan group • All incidences of xerostomia were grade 1–2 in severity (Figure 6) • There were no discontinuations due to xerostomia Presented at the American Association for Cancer Research (AACR) Annual Meeting; April 5-10, 2024; San Diego, CA SUVmean >6 SUVmean ≤6 -100 -50 0 50 100 0 4 8 12 16 20 24 % PSA change Weeks FPI-2265 100 kBq/kg (± 10%) IV every 8 weeks for up to 4 cyclesc Participant population: Progressive mCRPC based on serum PSA, soft tissue, and/or bone progression; positive PSMA PET/CTa scans to confirm PSMA expression; ECOG PS 0–2/0–1b Key Inclusion Criteria • Progressive mCRPC • Positive PSMA PET/CT • Must have received ≥1 ARPI • Prior Lu-PSMA RLT permitted • Prior taxanes were allowed Key Exclusion Criteria • <6 weeks from prior myelosuppressive therapy • Skeletal metastases presenting as superscanb,d • Known CNS or liver metastasesb • >4 prior therapiesb Enrolling in the US Dose could be de-escalated based on PSA response: ‒ PSA ≥50% decline: dose should be de-escalated to 87 kBq/kg ‒ PSA >85% decline: additional de-escalation to 75 kBq/kg, then 50 kBq/kg Primary endpoint: • PSA50 (≥50% decline in PSA by 12 weeks after first treatment) Secondary endpoints include: • Safety and tolerability • Maximum % PSA decline • Response based on RECIST v1.1 criteria • Non-progression by PCWG3 Figure 2. Mechanism of action of 225Ac-PSMA-I&T Results Table 2. Participant disposition Table 3. Baseline demographics and disease characteristics • Data from this prospective study support prior clinical reports on the safety and efficacy of 225Ac-PSMA-I&T (FPI-2265) despite enrolling a more heavily pretreated patient population • Preliminary efficacy data suggest that FPI-2265 has activity in heavily pretreated participants with progressive mCRPC, including those participants who had received prior 177Lu-PSMA therapy – PSA50 was achieved by 50% of participants overall, including 54% in the 177Lu-naïve population and 43% in the 177Lu-treated population • Safety and tolerability were consistent with other published studies of 225Ac-PSMA RLTs – The majority of TRAEs were grade 1 or 2 – Xerostomia was the most common TRAE, and the majority of occurrences were grade 1 o Incidences of grade 1 and 2 xerostomia were 61.9% and 23.8%, respectively o No participants discontinued because of this particular AE – Hematologic toxicity was observed at an expected rate; the extent of bone marrow involvement (i.e., superscan or multiple sites of bone disease) appears to correlate with a higher rate of myelotoxicity • In an exploratory analysis, PSA50 was achieved by 69% of participants with a baseline PSMA PET SUVmean >6 • These initial results support further investigation of FPI-2265 – An upcoming registration-enabling phase 2/3 trial will further examine the efficacy and tolerability of FPI-2265 NCT05219500: Trial Currently Enrolling Participants • The efficacy and safety profile of FPI-2265 is consistent with data from the published literature, which includes almost 500 patients treated with PSMA-targeted Ac radiopharmaceuticals • In this heavily pretreated population, PSA50 was 50%, and was 69% when a PSMA PET SUVmean cutoff of 6 was used • Durable PSA response by week 24 was observed in participants with PSMA SUVmean >6 • No discontinuations occurred owing to xerostomia • Safety signals were consistent with the literature, where higher grades of hematologic toxicity were observed mainly in participants with superscan or who had received multiple lines of chemotherapy • A registration-enabling phase 2/3 trial will further evaluate the efficacy/safety of FPI-2265 Highlights 75.0% 25.0% 25.0% 50.0% 25.0% 50.0% 50.0% 25.0%25.0% 0102030405060708090100 4.8% 14.3% 23.8% 23.8% 61.9% 4.8% 9.5% 4.8% 4.8% 4.8% 23.8% 23.8% 4.8% 4.8% 9.5% 4.8% 23.8% 14.3% 0 10 20 30 40 50 60 70 80 90 100 % of participantsa Anemia Decreased white blood cell count Thrombocytopenia Decreased neutrophil count Non-superscan participants (n=21)Superscan participants (n=4) Fatigue Dry eye Nausea Dysgeusia Xerostomia Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Hematologic TRAEs Non-hematologic TRAEs 0.0% 0.0% 0.0% 0.0% Treatment with actinium-225 (225Ac)-PSMA-RLT including 225Ac-PSMA-I&T , a small molecule comprising PSMA-targeting ligand coupled with the multi-alpha emitter 225Ac radionuclide, has shown strong clinical activity in mCRPC across multiple studies.4,5 Decreased prostate-specific antigen (PSA) levels have been observed in 79% of treated patients, as well as a ≥50% decline in PSA (PSA50) in 50% of patients, including those previously treated with 177Lu-PSMA-617.5 This herein described TATCIST study was designed to confirm the safety and efficacy results of 225Ac-PSMA-I&T (renamed FPI-2265) to results published to date. -100 -50 0 50 100 % PSA change Lu-treated Lu-naïve a SUVmean >6 -100 -50 0 50 100 % PSA change Lu-treated Lu-naïve a SUVmean ≤6 -100 -50 0 50 100% PSA change Lu-treated Lu-naïve a% maximum PSA increase shown to 100%. a

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