Actinium-225 DOTATATE (RYZ101) / BMS - LARVOL DELTA

RYZ101 (225Ac-DOTATATE) in patients with estrogen receptor-positive, human epidermal growth factor receptor 2–negative, locally advanced and unresectable, or metastatic breast cancer progressing after prior therapy: The phase 1b/2 TRACY-1 study. (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT06590857 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Alpha radioligand therapy in neuroendocrine neoplasms: current landscape and spotlight on RYZ101. (PubMed, Future Oncol) - "While the advent and regulatory approval of beta emitting RLT such as 177Lu-DOTATATE has offered a valuable therapeutic option for patients with NETs, there is still very significant room to tap the maximal therapeutic potential of RLT. Yet, other alpha RLT agents are currently being investigated in both RLT-naïve as well-pre-treated patient populations. While long-term safety and efficacy data are awaited, alpha RLT agents such as RYZ101 offer a unique opportunity to enhance the therapeutic promise of RLT in NETs."

Journal • Review • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor

Study of RYZ101 in Combination with SoC in Subjects with SSTR+ ES-SCLC (clinicaltrials.gov) - P1 | N=31 | Recruiting | Sponsor: RayzeBio, Inc. | Trial completion date: Dec 2026 ➔ Mar 2029 | Trial primary completion date: Mar 2025 ➔ Mar 2027

Trial completion date • Trial primary completion date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • PD-L1 • SSTR

AcTRESS: A Phase I Study to Assess the Tolerability of 225Ac-DOTATATE in Patients with Refractory and Relapsing Multiple Myeloma Expressing Somatostatin Receptors (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Jules Bordet Institute | N=30 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Hematological Malignancies • Multiple Myeloma • Oncology

ACTION-1: Study of RYZ101 Compared with SOC in Pts W Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov) - P3 | N=288 | Recruiting | Sponsor: RayzeBio, Inc. | Trial primary completion date: Jul 2025 ➔ Dec 2025

Trial primary completion date • Carcinoid Tumor • Endocrine Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

Phase 1b portion of the ACTION-1 phase 1b/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177 Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings. (ASCO-GI 2025) - P3 | "RYZ101 was well tolerated, and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy and a manageable safety profile. Part 2 (phase 3) of the ACTION-1 trial is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing after 177Lu-labeled SSAs."

Clinical • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • SSTR • SSTR2

TRACY-1: Trial of 225Ac-DOTATATE (RYZ101) in Subjects with ER+, HER2-negative Unresectable or Metastatic Breast Cancer Expressing SSTRs. (clinicaltrials.gov) - P1/2 | N=124 | Recruiting | Sponsor: RayzeBio, Inc. | Trial completion date: Jul 2029 ➔ Jan 2033 | Trial primary completion date: May 2028 ➔ Oct 2028

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

RYZ101 (225Ac-DOTATATE) ± pembrolizumab in estrogen receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced and unresectable or metastatic breast cancer progressing after prior therapy: the phase 1b/2 TRACY-1 study (SABCS 2024) - "Concomitant amino acid IV infusions (containing L-arginine and L-lysine) will be co-infused with RYZ101 for renal protection. The study is expected to begin enrolment in July 2024."

IO biomarker • Metastases • P1/2 data • Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • SSTR • SSTR2

ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors progressing after 177Lu somatostatin analogue therapy: Phase 1b safety/efficacy (NANETS 2024) - P3 | "Longer-term safety and efficacy data will be presented. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs."

Clinical • P1 data • Endocrine Cancer • Fatigue • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • SSTR • SSTR2

TRACY-1: Trial of 225Ac-DOTATATE (RYZ101) Alone and with Pembrolizumab in Subjects with ER+, HER2-negative Unresectable or Metastatic Breast Cancer Expressing SSTRs (clinicaltrials.gov) - P1/2 | N=172 | Recruiting | Sponsor: RayzeBio, Inc.

Combination therapy • Metastases • New P1/2 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

RYZ101 (225Ac-DOTATATE) + Carboplatin + Etoposide + Atezolizumab in Somatostatin Receptor Expressing Extensive-Stage Small-Cell Lung Cancer (IASLC-WCLC 2024) - P1 | "Preliminary pharmacokinetic findings indicate clearance and half-life comparable to previous studies of RYZ101 and 177 Lu-DOTATATE. Conclusions : There were no DLTs reported at DL1 (6.5 MBq) and the dose of RYZ101 has been escalated to the next dose level. The study is actively enrolling patients to receive RYZ101 at DL2 (8.3 MBq) and additional safety data will be presented once mature."

Back Pain • Cardiovascular • Fatigue • Heart Failure • Hematological Disorders • Infectious Disease • Influenza • Lung Cancer • Musculoskeletal Pain • Neutropenia • Oncology • Pain • Respiratory Diseases • Small Cell Lung Cancer • Solid Tumor • SSTR • SSTR2

ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov) - P3 | N=288 | Recruiting | Sponsor: RayzeBio, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Metastases • Carcinoid Tumor • Endocrine Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177 Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings. (ASCO 2024) - P3 | "RYZ101 was well tolerated and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Longer-term safety and efficacy data will be presented."

Clinical • P1 data • Endocrine Cancer • Fatigue • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • SSTR • SSTR2

Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: safety and efficacy findings (SNMMI 2024) - P3 | "RYZ101 was well tolerated and a fixed dose of 10. 2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy."

Clinical • P1 data • Endocrine Cancer • Fatigue • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • SSTR • SSTR2

Bristol Myers' RayzeBio halts radiotherapy trial enrollment after isotope runs scarce (Fierce Pharma) - "Thanks to a shortage of the isotope actinium, RayzeBio has temporarily halted new patient enrollment in its ACTION-1 phase 3 study, a RayzeBio spokesperson confirmed over email....All patients currently enrolled in ACTION-1 will continue to receive treatment, RayzeBio's spokesperson stressed. The company plans to resume new patient enrollment in the third quarter."

Enrollment status • Trial suspension • Gastrointestinal Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor

Bristol Myers Squibb to Present Data at ASCO & EHA from More Than 130 Studies Across 25 Diseases Supporting Expansion into New Indications, Demonstrating Long-Term Survival, and Highlighting Novel Modalities and Research Platforms (Businesswire) - "Multiple subgroup analyses from the Phase 1/2 TRANSCEND CLL 004, Phase 1 TRANSCEND NHL 001 (MCL cohort) and Phase 2 TRANSCEND FL studies reinforcing the deep and durable responses with Breyanzi (lisocabtagene maraleucel), demonstrating consistent clinical outcomes in relapsed/refractory chronic lymphocytic leukemia (CLL), relapsed/refractory mantle cell lymphoma (MCL) and relapsed/refractory follicular lymphoma (FL) across a broad study population. (ASCO/EHA)....Safety and efficacy data from the Phase 1b portion of the ACTION-1 trial of RYZ101 (an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors) in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy. (ASCO)."

P1 data • P1/2 data • P2 data • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Neuroendocrine Tumor • Oncology • Solid Tumor

Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC (clinicaltrials.gov) - P1 | N=31 | Recruiting | Sponsor: RayzeBio, Inc. | Trial primary completion date: Apr 2024 ➔ Mar 2025

Combination therapy • Trial primary completion date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • PD-L1 • SSTR

AcTRESS: A Phase I Study to Assess the Tolerability of 225Ac-DOTATATE in Patients With Refractory and Relapsing Multiple Myeloma Expressing Somatostatin Receptors (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: Jules Bordet Institute

New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology

ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov) - P3 | N=288 | Active, not recruiting | Sponsor: RayzeBio, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Carcinoid Tumor • Endocrine Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC (clinicaltrials.gov) - P1 | N=31 | Recruiting | Sponsor: RayzeBio, Inc. | Phase classification: P1b ➔ P1

Combination therapy • Phase classification • Lung Cancer • Oncology • Solid Tumor • PD-L1 • SSTR

Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings (ESMO 2023) - P1b | "Initial data suggest promising efficacy. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2MBq q8w for 4 cycles with standard of care in pts with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs."

Clinical • P1 data • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • SSTR • SSTR2

ACTION-1: A randomized Phase Ib/3 trial of RYZ101 compared with SoC in SSTR+ well-differentiated GEP-NET with progression following Lu-177 SSA (NANETS 2023) - P3 | N=NA | "In Phase 3, patients will be randomized (1:1) to receive RYZ101 at a fixed dose of 10.2 MBq (275 µCi) every 8 weeks for up to 4 cycles or investigator's choice SoC (everolimus, sunitinib, or high-dose long-acting SSA); crossover to RYZ101 is permitted at time of centrally reviewed progression. Primary endpoint (Phase 3): progression-free survival (PFS) by blinded independent central review (BICR) using RECIST v1.1. Secondary endpoints: overall survival; objective response rate and best overall response (BICR and investigator assessment); duration of response; disease control rate; PFS (investigator assessment); safety."

P3 data

ACTION-1: Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (clinicaltrials.gov) - P3 | N=288 | Recruiting | Sponsor: RayzeBio, Inc.

Metastases • Trial completion date • Trial primary completion date • Carcinoid Tumor • Endocrine Cancer • Hepatology • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

Bristol Myers Squibb Completes Acquisition of RayzeBio, Adding Differentiated Actinium-Based Radiopharmaceutical Platform (Businesswire) - "Bristol Myers Squibb...announced today that it has successfully completed its acquisition of RayzeBio, Inc...With the completion of the acquisition, RayzeBio shares have ceased trading on the NASDAQ Global Market and RayzeBio is now a wholly owned subsidiary of Bristol Myers Squibb...This transaction brings a promising pipeline of RPTs to Bristol Myers Squibb, including RayzeBio’s lead program RYZ101 (²²⁵Ac-DOTATATE), which targets somatostatin receptor 2 (SSTR2), over-expressed in GEP-NETs and extensive stage small cell lung cancer (ES-SCLC)...The platform has the potential to be a significant IND engine to generate a number of candidates and comes with a state-of-the-art RPT manufacturing facility, which is expected to begin operating in the first half of 2024....Bristol Myers Squibb’s previously announced tender offer to acquire all of the outstanding shares of RayzeBio common stock for a purchase price of $62.50 per share in..."

Commercial • M&A • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor

Bristol Myers Squibb Adds Premier Radiopharmaceutical Platform with Acquisition of RayzeBio (Businesswire) - "Bristol Myers Squibb...and RayzeBio, Inc...announced a definitive merger agreement under which Bristol Myers Squibb will acquire RayzeBio for $62.50 per share in cash, for a total equity value of approximately $4.1 billion, or $3.6 billion net of estimated cash acquired. The transaction was unanimously approved by both the Bristol Myers Squibb and RayzeBio Boards of Directors....RayzeBio is completing construction of a state-of-the-art in-house manufacturing facility in Indianapolis, Indiana, and GMP drug production is expected to begin in the first half of 2024. The transaction is expected to be treated as a business combination and to be dilutive to Bristol Myers Squibb’s non-GAAP diluted earnings per share by approximately $0.13 in 2024. Bristol Myers Squibb expects to finance the acquisition with primarily new debt issuance."

M&A • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor