Preliminary Dosimetry Results from a First-in-Human Phase 1 Study Evaluating the Efficacy and Safety of [225Ac]-FPI-1434 in Patients with IGF-1R Expressing Solid Tumors (Poster)

SNMMI 2021 Publication #74 Preliminary Dosimetry Results from a First-in-Human Phase 1 Study Evaluating the Efficacy and Safety of [225Ac]-FPI-1434 in Patients with IGF-1R Expressing Solid Tumors Background Dosimetric Methodology Radiation Absorbed Doses Imaging Procedure Safety Conclusions Daniel Juneau1, Fred Saad1, Alejandro Berlin2, Ur Metser2, Igor Puzanov3, Dominick Lamonica3, Richard Sparks4, Eric S. Burak5, Ryan Simms5, John Rhoden5, James O’Leary5, Julia Kazakin5, Courtney Watson5, Lauren Creeden5, Thomas Armor5, Jean-Mathieu Beauregard6, Maxime Chénard-Poirier6 1Centre Hospitalier de l’Université de Montréal, Montreal, QC; 2Princess Margaret Hospital, Toronto, ON; 3Roswell Park Comprehensive Cancer Center, Buffalo, NY; 4CDE Dosimetry Services, Inc. Knoxville, TN; 5Fusion Pharmaceuticals, Hamilton, ON; 6CHU de Québec - Université Laval, Quebec City, QC Target Organ Mean* (mGy-Eq/MBq) Minimum* (mGy-Eq/MBq) Maximum* (mGy-Eq/MBq) Standard Deviation* (mGy-Eq/MBq) Adrenals 78 56 102 14 Brain 94 56 169 34 Esophagus 75 54 99 14 Eyes 74 53 98 14 Gallbladder Wall 77 55 100 14 Left colon 81 59 104 14 Small Intestine, 75 54 99 14 Stomach Wall 76 54 99 14 Right colon 78 57 102 14 Rectum 81 59 104 14 Heart Wall 1,190 690 2,040 392 Kidneys 988 615 1,820 305 Liver 934 556 1,660 319 Lungs 626 328 910 175 Pancreas 76 54 99 14 Salivary Glands 1,520 900 2,370 452 Red Marrow 807 398 1,450 303 Osteogenic Cells 1,280 922 1,860 227 Spleen 3,668 1,740 9,060 1881 Thymus 75 54 99 14 Thyroid 693 315 1,510 347 Urinary Bladder Wall 76 55 99 14 Total Body 140 111 167 16 Table 3. Study FPX-01-01: [225Ac]-FPI-1434 Radiation Absorbed Dose Estimates by Target Organ (Dosimetry-Evaluable Subjects, N=13) * mGy-Eq to denote a relative biologic effectiveness (RBE) value of 3.4 for alpha emitters has been applied. [111In]-FPI-1547 Whole Body Planar Scintigraphy Anterior Posterior Anterior Posterior Anterior Posterior ~1 hr ~24 hr ~65 hr Anterior Posterior ~168 hr [111In]-FPI-1547 SPECT/CT Coronal Axial Demographics Therapeutic Administration Radiation absorbed doses estimated in “real-time” for the planned therapeutic activity based on time-integrated activity from [111In]-FPI-1547 planar biodistribution converted to values for [225Ac]-FPI-1434 • Administered activity was not to exceed protocol-defined thresholds of 18 Gy (kidneys), 31 Gy (liver), and 16.5 Gy (lungs) using an RBE value of 3.4 for all calculations Patients received ~5mCi (185 MBq) [111In]-FPI-1547 for imaging Therapeutic administrations of [225Ac]-FPI-1434 were 10, 20 and 40 kBq/kg body-weight with a protein mass-dose range ~0.01-0.04 mg/kg. Regions of Interest CT-based organ volume Time Activity Curves and Time-integrated Activity Residence Time Calculation In-111 to Ac-225 values OLINDA/EXM 2.1-2.2 (Hermes Medical Solutions) No DLTs, treatment-related SAEs, or dose interruption/modification were reported in Cohorts 1-3 100% of patients imaged were eligible based on imaging to receive [225Ac]-FPI-1434. Prospective and personalized treatment planning for targeted alpha therapy of IGF-1R expressing tumors is an important safety checkpoint to estimate risk to critical organs. Dosimetric results well within pre-specified limits in a single-dose regimen up to 40 kBq/kg. [225Ac]-FPI-1434 demonstrated a manageable safety profile with no drug-related serious adverse events and/or dose limiting toxicity in administered activity up to 40 kBq/kg body- weight. Recruitment to multi-dose and cold antibody cohorts ongoing. Mean Min Max Cohort 1 (10 kBq/kg) N=4 884 797 984 Cohort 2 (20 kBq/kg) N=4 1840 1290 2290 Cohort 3 (40 kBq/kg) N=4 3394 2400 4179 Table 2. [225Ac]-FPI-1434 Administration (kBq) Objectives The aim of this phase 1 study (NCT03746431) is to evaluate the safety and tolerability of [111In]-FPI-1547 and [225Ac]-FPI-1434 in patients with advanced refractory solid tumors that express IGF-1R based on imaging assessment and to determine the Recommended Phase 2 Dose (RP2D) of [225Ac]-FPI-1434. Patient- specific dosimetry is employed for treatment planning to confirm the protocol- specified administered activity does not exceed radiation absorbed dose limits for selected organs of interest. [225Ac]-FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody, a proprietary bifunctional chelate, and the alpha-emitting radionuclide actinium-225 (Ac-225) which binds to the external domain of the insulin-like growth factor type 1 receptor (IGF-1R), a receptor tyrosine kinase expressed by a majority of cancer cells. Internalization of the radioimmunoconjugate causes tumor cell death primarily through double stranded DNA breaks induced by alpha particles emitted from the decay of Ac-225. An indium-111 imaging analog, [111In]-FPI-1547, with the identical antibody and bifunctional chelate as [225Ac]-FPI-1434 is used for patient selection based on quantification of IGF-1R expressing targets and organ- based dosimetry prior to therapy. Ac-225 Decay Median Age (range) 61.0 (36-78) years Gender, n (%) Male 9 (75%) Female 3 (25%) Race, n (%) White 10 (83%) Asian 1 (8%) Not reported 1 (8%) Tumor type, n (%) Prostate cancer 6 (50%) Colorectal cancer 3 (25%) Adrenocortical carcinoma 1 (8%) Fibromyxoid sarcoma 1 (8%) Ovarian cancer 1 (8%) Baseline ECOG, n (%) 0 7 (58%) 1 5 (42%) Table 1. Study FPX-01-01: Patient Characteristics Safety Population Treated with [225Ac]-FPI-1434 [N=12] All Grades (≥2pts) , n (%) Thrombocytopenia 5 (42%) Neutropenia 4 (33%) Fatigue 4 (33%) Lymphocyte count decrease 3 (25%) White blood cell count decrease 3 (25%) Nausea 2 (17%) Grade 3, n (%) *Neutropenia 1 (8%) *Lymphocyte count decrease 1 (8%) *White blood cell count decrease 1 (8%) No Grade 4 AEs observed Table 5. Study FPX-01-01: Most Common FPI-1434-related AEs Patients, n (%) Any Adverse Events (AEs) 12 (100%) Serious Adverse Events (SAEs) 1 (8%) FPI-1434-related AEs 8 (67%) FPI-1547-related AEs 1 (8%) FPI-1434-related SAEs 0 (0%) FPI-1547-related SAEs 0 (0%) Table 4. Study FPX-01-01: Post-Treatment Safety Events Safety Population – Cohorts 1-3 (N=12) Patients with evaluable [111In]-FPI-1547 Image Data for Dosimetry N=13 Patients treated with [225Ac]-FPI-1434 N=12 Dosimetry for the first 3 cohorts of [225Ac]-FPI-1434 administered as a single dose * Gr 3 WBC decrease , neutropenia, lymphopenia were attributed to the same patient. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Planar scintigraphy x4 225Ac 111In days SPECT/CT x2 Dosimetry Assessment Evaluation of IGF-1R target expression and biodistribution [111In]-FPI-1547 ~5 mCi [225Ac]-FPI-1434 Therapy 4-Arm DOTA Chelator PEG3 Linker FPI-1175 Imaging [111In]-FPI-1547 4-Arm DOTA Chelator PEG3 Linker FPI-1175 Therapy [225Ac]-FPI-1434 Eligible per imaging but not treated due to rapid disease progression N=1

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