RYZ101

Shows activity

Also known as:

225Ac-DOTATATE

Cancer types include:

breast cancer pancreas cancer small cell lung cancer stomach cancer

HealthScout AI Analysis

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Overview

RYZ101 (225Ac-DOTATATE) is an investigational, alpha‑emitting radiopharmaceutical that targets somatostatin receptor subtype 2 (SSTR2). It is being developed primarily for patients with advanced, well‑differentiated, SSTR2‑positive gastroenteropancreatic neuroendocrine tumors (GEP‑NETs) that have progressed after 177Lu‑labeled somatostatin analog therapy, and is also under study in SSTR‑positive extensive‑stage small cell lung cancer (ES‑SCLC) and ER‑positive breast cancer. The global ACTION‑1 study includes a completed phase 1b portion with efficacy and safety readouts and an ongoing phase 3 portion. (ascopubs.org)

Mechanism of action

Composition: Actinium‑225 (alpha emitter) chelated to DOTATATE, a somatostatin analog that binds SSTR2. (ascopubs.org)
Rationale: Alpha particles deliver very high linear energy transfer over a short path length, producing dense DNA double‑strand breaks that can increase tumor cell kill while limiting collateral damage compared with beta emitters. (ascopubs.org)
Preclinical data: High affinity for SSTR2 (Ki ≈ 0.057 nM) with efficient internalization; antitumor activity in SSTR‑expressing small cell lung cancer xenografts, including sustained regressions, and enhanced effect with carboplatin/etoposide. (jto.org)

Efficacy

GEP‑NETs (post‑177Lu‑SSA), ACTION‑1 phase 1b (ASCO 2025 update; data cutoff December 14, 2023; n=17 at 120 kBq/kg given q8w ×4 planned): - Confirmed objective response rate: 29.4% (1 complete response, 4 partial responses); an additional partial response was confirmed after cutoff.
- Disease control: 41.2% stable disease; 17.6% progressive disease.
- Median duration of response: not estimable (95% CI 9.26 months–NE).
- Median progression‑free survival: not estimable (95% CI 12.16 months–NE).
A fixed dose of 10.2 MBq q8w ×4 was selected as the phase 3 dose. The phase 3 portion is enrolling and will compare RYZ101 with investigator’s choice of everolimus, sunitinib, or high‑dose long‑acting SSA. (ascopubs.org)

Other tumor types under investigation - ES‑SCLC (first‑line, in combination with carboplatin/etoposide/atezolizumab): phase 1b, single‑arm, open‑label trial (NCT05595460), recruiting. Efficacy data have not yet been reported. (cdek.pharmacy.purdue.edu) - ER‑positive breast cancer (TRACY‑1): phase 1/2 study of RYZ101 alone and with pembrolizumab in SSTR‑expressing disease; preliminary imaging and a single‑patient therapeutic experience with 225Ac‑DOTATATE showing near‑complete response have been reported separately. (mayo.edu)

Safety

ACTION‑1 phase 1b (GEP‑NETs): - Most frequent treatment‑emergent adverse events: anemia (58.8%), nausea (58.8%), fatigue (52.9%).
- Grade ≥3 TEAEs in 29.4% (5 treatment‑related); serious AEs in 35.3%, none considered treatment‑related; no discontinuations due to TEAEs; one grade 5 hepatic failure deemed unrelated. Dose modifications/holds/delays occurred in 4 patients. (ascopubs.org)

Planned phase 3 safety evaluation is ongoing. No mature safety results are yet available for the ES‑SCLC combination study. (yalemedicine.org)

Ongoing clinical trials

ACTION‑1 (NCT05477576): Phase 1b/3 in post‑177Lu‑SSA SSTR2+ GEP‑NETs; phase 3 comparing RYZ101 (10.2 MBq q8w ×4) vs SoC. (yalemedicine.org)
NCT05595460: Phase 1b RYZ101 + carboplatin/etoposide/atezolizumab in untreated SSTR+ ES‑SCLC. (cdek.pharmacy.purdue.edu)
TRACY‑1 (Mayo Clinic): Phase 1/2 RYZ101 alone/with pembrolizumab in ER+, HER2‑negative SSTR‑expressing breast cancer. (mayo.edu)

Active trials using RYZ101

Found 3 active trials using this drug:

Phase 1b/2 Open-label Trial of 225Ac-DOTATATE (RYZ101) in Subjects with Estrogen Receptor-positive (ER+), Human Epidermal Growth Factor Receptor 2 (HER2)-negative, Locally Advanced and Unresectable or Metastatic Breast Cancer Expressing Somatostatin Receptors (SSTRs) and Progressed After Antibody-drug Conjugates And/or Chemotherapy (TRACY-1).

Sponsor: RayzeBio, Inc. (industry) Phase: 1/2 Start date: July 19, 2024

HealthScout AI summary: This trial enrolls adults with ER+, HER2-negative unresectable or metastatic breast cancer expressing somatostatin receptors (by SSTR-PET) who have progressed after antibody-drug conjugates and/or chemotherapy, and evaluates RYZ101 (225Ac-DOTATATE), an SSTR-targeted alpha-emitting radiopharmaceutical. Patients must have no prior radiopharmaceutical therapy and meet standard organ function criteria.

ClinicalTrials.gov ID: NCT06590857

Phase 1b Single Arm, Open-label Trial of RYZ101 in Combination With Carboplatin + Etoposide + Atezolizumab in Subjects With Somatostatin Receptor Expressing (SSTR+) Extensive Stage Small Cell Lung Cancer (ES-SCLC)

Sponsor: RayzeBio, Inc. (industry) Phase: 1 Start date: Oct. 10, 2022

HealthScout AI summary: Adults with extensive-stage SCLC that is SSTR-positive by PET (≥50% of measurable metastases SSTR+) and treatment-naive or ≤1 prior cycle of platinum/etoposide plus PD-L1 inhibitor receive first-line carboplatin/etoposide/atezolizumab combined with RYZ101 (225Ac-DOTATATE), an alpha-emitting radiopharmaceutical targeting SSTR2. Aims to define RP2D and assess safety/early activity of adding SSTR2-targeted alpha therapy to standard chemo-immunotherapy.

ClinicalTrials.gov ID: NCT05595460

Phase 1b/3 Global, Randomized, Controlled, Open-label Trial Comparing Treatment With RYZ101 to Standard of Care Therapy in Subjects With Inoperable, Advanced, SSTR+, Well-differentiated GEP-NETs That Have Progressed Following Prior 177Lu-SSA Therapy

Sponsor: RayzeBio, Inc. (industry) Phase: 3 Start date: March 24, 2022

HealthScout AI summary: Adults with inoperable, advanced, well-differentiated (G1–2) SSTR-positive GEP-NETs that progressed after prior 177Lu-SSA PRRT (with ≥6 months disease control) are randomized to RYZ101 (225Ac-DOTATATE, an SSTR2-targeted alpha-emitting radiopharmaceutical) versus investigator’s choice of everolimus, sunitinib, octreotide, or lanreotide. Key eligibility includes Krenning 3–4 on SSTR-PET, ECOG 0–2, and adequate organ function; excludes prior non–Lu-177 PRRT, radioembolization, significant cardiovascular disease, and cirrhosis.

ClinicalTrials.gov ID: NCT05477576