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

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)

Further reading

• ASCO 2025 GI abstract (ACTION‑1 phase 1b update): https://ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.661 (ascopubs.org)
• ASCO 2024 abstract (ACTION‑1 phase 1b): https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.3091 (ascopubs.org)
• NANETS 2024 summary (planned longer‑term data): https://www.endocrine-abstracts.org/ea/0108/ea0108c17 (endocrine-abstracts.org)
• ACTION‑1 trial pages (phase 3 details): https://www.yalemedicine.org/clinical-trials/a-randomized-controlled-open-label-study-of-ryz101-compared-with-standard-of-care-therapy-in-subje and https://www.dana-farber.org/clinical-trials/23-110 (yalemedicine.org)
• ES‑SCLC trial listing (NCT05595460): https://cdek.pharmacy.purdue.edu/trial/NCT05595460/ (cdek.pharmacy.purdue.edu)
• Radiology 2024 (SSTR2 imaging in ER+ breast cancer; single‑patient 225Ac‑DOTATATE therapy case): https://pubs.rsna.org/doi/abs/10.1148/radiol.233408 (pubs.rsna.org)
• Preclinical SCLC data: Journal of Thoracic Oncology (EP13.07‑05) and AACR 2023 abstract 5042. (jto.org)

Notes: Human efficacy and safety data to date are from the small, single‑arm phase 1b portion of ACTION‑1; randomized phase 3 results are not yet available as of October 7, 2025. (ascopubs.org)

Last updated: Oct 2025

Inclusion:

* Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs (Ki67 ≤20%) Eastern Cooperative Oncology Group (ECOG) status 0-2

* Progressive, SSTR-PET positive (i.e., Krenning score 3 or 4) GEP-NET (GI or pancreas) following 2-4 cycles of treatment with 177Lu-labeled SSA. Must have achieved disease control for at least 6 months following Lu-177 SSA. No time limit is defined between 177Lu-SSA treatment and randomization. There must be at least 1 SSTR-PET imaging-positive measurable site of disease (according to RECIST v1.1) and no RECIST v1.1 measurable metastatic lesions that are SSTR imaging-negative.

* Adequate renal function, as evidenced by estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\]) (Levey et al. 2009)

* Adequate hematologic function, defined by the following laboratory results:

* Part 2: Hemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); ANC ≥1000 cells/µL (≥1000 cells/mm3); platelets ≥75 x 109/L (75 x 103/mm3).

* Total bilirubin ≤3 x upper limit normal (ULN)

* Serum albumin ≥3.0 g/dL unless prothrombin time is within the normal range

Exclusion:

* Prior radioembolization

* Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure, left ventricular ejection fraction (LVEF) \<40% or QT interval corrected for heart rate using Fridericia's formula (QTcF) \>450 ms for males and \>470 ms for females.

* Resistant hypertension, defined as uncontrolled blood pressure (BP) \>140/90 mmHg while on optimal doses of at least 3 antihypertensive medications with 1 being a diuretic (Whelton et al. 2018)

* Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%

* PRRT other than Lu-177 SSA

* Any condition requiring systemic treatment with high-dose glucocorticoids within 14 days prior to first dose of study treatment and/or which cannot be stopped while on study. Inhaled or topical steroids are permitted.

* Prior history of liver cirrhosis or liver transplantation