Poster presentation at the ASCO Genitourinary Cancers Symposium titled, “[225Ac]Ac-AKY-1189, a Nectin-4-Targeted Radiopharmaceutical, in Patients With Previously Treated Locally Advanced or Metastatic Solid Tumors: Phase 1b NECTINIUM-2 Study”

[225Ac]Ac-AKY-1189, a Nectin-4-Targeted Radiopharmaceutical, in Patients With Previously Treated Locally Advanced or Metastatic Solid Tumors: Phase 1b NECTINIUM-2 Study Timothy A. Yap1, Omar Alhalabi1, Yang Lu1, Brandon R. Mancini2, Harshad R. Kulkarni2, Kristin Plichta3, Serguei A. Castaneda4, Frankis Almaguel4, Randy Yeh5, Ryan Reddy6, David Benjamin6, Abhishek Tripathi7, Phillip Kuo8, Ying-Hui Huang9, Janet K. Horton9, Matthew Galsky5 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2BAMF Health, Grand Rapids, MI, USA; 3University of Iowa, Iowa City, IA, USA; 4Biogenix Molecular, Miami, FL, USA; 5Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Hoag Memorial Hospital Presbyterian, Newport Beach, CA, USA; 7City of Hope Medical Center, Duarte, CA, USA; 8Kuo Radiology LLC, Tucson, AZ, USA; 9Aktis Oncology, Boston, MA, USA BACKGROUND • Nectin-4 is a clinically validated target in metastatic urothelial carcinoma (mUC) and is overexpressed across multiple additional solid tumor types, supporting broad therapeutic potential.1-9 • AKY-1189 is a high-affinity, selective Nectin-4-targeted miniprotein radioconjugate that demonstrates rapid plasma clearance with favorable normal tissue biodistribution and dosimetry in humans when radiolabeled with 68Ga or 177Lu.10 • In preclinical urothelial carcinoma models, a single administration of [225Ac]Ac-AKY-1189 induced tumor regression or stasis, with target- dependent antitumor activity observed at well-tolerated dose levels. • These data supported clinical investigation of [225Ac]Ac-AKY-1189. CONCLUSIONS • NECTINIUM-2 is a first-in-human study evaluating [225Ac]Ac-AKY-1189, a Nectin-4-targeted alpha-emitting radiopharmaceutical, in patients with previously treated locally advanced or metastatic solid tumors. • This trial aims to define a safe and biologically active dose and to characterize early clinical activity in Nectin-4-expressing tumors. References: 1) Challita-Eid PM, et al. Cancer Res. 2016;76(10):3003-13. 2) Powles T, et al. N Engl J Med. 2024;390(10):875-88. 3) M-Rabet M, et al. Ann Oncol. 2017;28:769-76. 4) Fabre-Lafay S, et al. BMC Cancer. 2007;7:73. 5) Mabwell Press Release. 2024. 6) Zhang J, et al. Oncol Lett. 2019;18(2):1163-70. 7) Kobecki J, et al. Int J Mol Sci. 2023;24(21):15900. 8) Sanders C, et al. Oncotarget 2022;13:1166-73. 9) Takano A, et al. Cancer Res. 2009;69(16):6694-703. 10) Sathekge M, et al. Eur J Cancer. 2024;211(suppl 1):114539. Acknowledgments: Medical writing and poster production support were provided by Acumen Medical Communications, funded by Aktis Oncology. For more information, contact Janet Horton, MD: [email protected] STUDY DESIGN NECTINIUM-2 (NCT07020117) is a first-in-human, Phase 1b, multicenter, open-label study evaluating [225Ac]Ac-AKY-1189. TPS902 CURRENT STATUS • NECTINIUM-2 is actively enrolling in the United States. • Dose escalation is ongoing. OBJECTIVES Primary Objectives • Part 1: Evaluate the safety and tolerability of [225Ac]Ac-AKY-1189 • Part 2: Determine the objective response rate by tumor type to [225Ac]Ac -AKY-1189, utilizing RECIST v1. 1 Secondary Objectives • Evaluate safety and tolerability • Characterize pharmacokinetics and dosimetry • Determine preliminary antitumor activity PATIENT POPULATION Inclusion Criteria Exclusion Criteria • Age ≥18 years • Histologically or cytologically confirmed locally advanced or metastatic solid tumors • ≥1 measurable lesion per RECIST v1. 1 • ECOG performance status 0-1 • Adequate end-organ function • Documented progression on prior systemic therapies in the metastatic setting • Tumor uptake confirmed by [64Cu]Cu-AKY-1189 PET/CT • Prior radiopharmaceutical therapy • Investigational therapy within 4 weeks • Anticancer therapy or external beam radiotherapy within 3 weeks • Prior Nectin-4-targeted therapy except enfortumab vedotin New York, NY Houston, TX Pittsburgh, PA Grand Rapids, MI Iowa City, IA Miami, FL Duarte, CA Irvine, CA Brain Metastasis Bone Metastasis Liver MetastasisLung Metastasis 1 hr 3 hr Tumors Biodistribution of [68Ga]Ga-AKY-1189 in a patient with mUC AKY-1189 high-affinity Nectin-4-targeting miniprotein Nectin-4 [64Cu]Cu-AKY-1189 Imaging • PET/CT imaging for patient selection • Imaging agent with suitable half-life for assessment of biodistribution and dosimetry Targeted Alpha Therapy [225Ac]Ac-AKY-1189 • Tumor-targeted alpha particle emission • High-energy, short path length • Localized tumor cell killing Patient Screening & Imaging Selection • Advanced or metastatic solid tumors • Nectin-4 uptake assessed by [64Cu]Cu-AKY-1189 PET/CT ◦ Tumor uptake confirms eligibility • Target engagement • Biodistribution and dosimetry assessment Dose 1 Dose 2 Dose 3 Dose 4 Dose 5 Part 1: Dose Escalation • Up to 30 patients with locally advanced or metastatic solid tumors (mUC, TNBC, HR+BC, cervical, CRC, H&N, NSCLC) • Ascending dose levels of [225Ac]Ac-AKY-1189 • Up to 6 treatment cycles • Dose escalation guided by safety and tolerability • Determine MTD/MAD • Establish RP2D Part 2: Dose Expansion • Enrollment at RP2D • 3 cohorts of Nectin-4-positive solid tumors by [64Cu]Cu-AKY-1189 PET/CT • Evaluation of clinical activity and safety Cohort 1 mUC Cohort 3 Basket Cohort 2 TNBC mUC = metastatic urothelial carcinoma; TNBC = triple-negative breast cancer; HR+BC = hormone receptor-positive breast cancer; CRC = colorectal cancer; H&N = head and neck cancer; MAD = multiple ascending dose; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; RP2D = recommended Phase 2 dose Backfill Dose Level Before MTD / MAD Nectin-4-positive solid tumors (n = 30) MTD / MAD Dose Level Nectin-4-positive solid tumors (n = 30)

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