Alpha-Emitting RYZ101 Meets Phase 3 PFS End Point in Advanced GEP-NETs

The investigational radiopharmaceutical therapy RYZ101 (actinium-225 [²²⁵Ac]-Dotatate) significantly improved progression-free survival (PFS) in patients with somatostatin receptor–positive (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that progressed after lutetium-177 (¹⁷⁷Lu; Lutathera)-based therapy.¹

According to topline results from the phase 3 ACTION-1 trial (NCT05477576), the study met its primary end point of PFS as assessed by blinded independent central review, with a statistically significant and clinically meaningful improvement in the RYZ101 arm compared with standard-of-care treatment.

Safety findings were consistent with the known safety profile of RYZ101. Detailed efficacy and safety results, including the magnitude of the PFS benefit, are expected to be presented at a future medical meeting.

“¹⁷⁷Lu-based therapy is widely used in GEP-NETs, but unfortunately the vast majority of patients will eventually progress. Determining the optimal treatment after ¹⁷⁷Lu has been an important question for my patients, and until now there has been no randomized [p]hase 3 evidence to guide it,” Simron Singh, MD, medical oncologist in the Odette Cancer Centre at Sunnybrook Health Sciences Centre and professor of medicine at the University of Toronto, stated in a news release. “ACTION-1 provides the first [p]hase 3 results for an alpha-based targeted [radiopharmaceutical therapy], and a clinically meaningful improvement in [PFS] is a crucial development in improving the care of patients with GEP-NETs.”

RYZ101: Mechanism of Action and Prior Findings

RYZ101 is an investigational targeted radiopharmaceutical therapy consisting of dotatate bound to ²²⁵Ac, an alpha-particle-emitting radioisotope. The use of an alpha-emitting isotope distinguishes RYZ101 from ¹⁷⁷Lu-based radiopharmaceutical therapy. Whereas both approaches use a targeting molecule to deliver radiation to tumor cells expressing somatostatin receptors, RYZ101 uses ²²⁵Ac to deliver alpha-particle radiation. ²²⁵Ac emits high-energy, short-range alpha particles that can induce double-stranded DNA damage in cancer cells, potentially leading to cell death.

Earlier clinical data came from a phase 1b trial involving 17 patients with GEP-NETs whose disease progressed after ¹⁷⁷Lu-based treatment. In that study, RYZ101 was reported to be well tolerated, with no treatment-related serious adverse events or treatment discontinuations due to adverse events.²

ACTION-1 Trial Design

ACTION-1 is a global, randomized, open-label phase 3 trial evaluating RYZ101 in patients with inoperable, advanced, well-differentiated, SSTR+ GEP-NETs whose disease progressed following ¹⁷⁷Lu-based therapy.³

In the phase 3 portion, patients are randomized to receive RYZ101 or standard-of-care treatment consisting of high-dose or high-frequency long-acting somatostatin analogues, everolimus (Afinitor), or sunitinib (Sutent). The primary end point is PFS assessed by blinded independent central review. Secondary end points include overall survival and additional measures of efficacy and safety.

Regulatory Status and Next Steps

Following the positive interim analysis, the sponsor plans to engage with the FDA to discuss next steps toward a potential regulatory submission. Patients enrolled in the trial will continue to be followed for overall survival, providing additional information on longer-term outcomes.

REFERENCES

1. Bristol Myers Squibb Announces Positive Topline Results from the Interim Analysis of Phase 3 ACTION-1 for RYZ101, RayzeBio’s Radiopharmaceutical Therapy, in Patients with GEP-NETs. News release. Bristol Myers Squibb. October 12, 2026. Accessed October 12, 2026. https://tinyurl.com/3r4w3jtr

2. Strosberg JR, Morris M, Ulaner GA, et al. 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. J Clin Oncol. 2025;43(4_suppl):661-661. doi:10.1200/jco.2025.43.4_suppl.661

3. Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy (ACTION-1). ClinicalTrials.gov. Updated October 5, 2026. Accessed October 12, 2026. https://tinyurl.com/36ueaan4