RYZ101 Improves Progression-Free Survival in Previously Treated GEP-NETs

The investigational radiopharmaceutical therapy RYZ101 (225Ac-DOTATATE) produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) vs investigator’s choice of standard of care in patients with somatostatin receptor (SSTR)–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that had progressed following lutetium-177 (Lu177)–based therapy, meeting the primary end point of the planned interim analysis of the phase 3 ACTION-1 trial (NCT05477576), according to topline results announced by Bristol Myers Squibb.¹ Safety results were consistent with the known safety profile of RYZ101.

What did the ACTION-1 interim analysis show?

At the planned interim analysis, ACTION-1 met its primary end point, demonstrating a statistically significant and clinically meaningful improvement in PFS by BICR with RYZ101 vs investigator’s choice of standard of care. The safety profile of RYZ101 was consistent with that previously observed for the agent.

Detailed results are expected to be presented at a future medical meeting. The developers noted that these are the first results from a phase 3 trial of an alpha-isotope–based targeted radiopharmaceutical therapy in any indication.

“The improvement in [PFS] is a defining moment for RYZ101 and for the patients we built this program around—people with advanced GEP-NETs whose cancer has progressed after Lu177-based therapy and who have few remaining options,” said Amreen Husain, MD, chief medical officer of RayzeBio, in the news release.¹ “These are the first results from a phase 3 trial of an alpha-isotope based targeted RPT [225Ac] in any indication, and we are moving with urgency to bring these data to the FDA and, ultimately, provide a novel option for patients.”

Why is treatment after lutetium-177 therapy an unmet need?

Lu177-based radiopharmaceutical therapy has shown significant clinical benefit and is approved for adult patients with SSTR-positive GEP-NETs, but most patients invariably progress following treatment, with few effective treatment options available.

“Lu177-based therapy is widely used in GEP-NETs, but unfortunately, the vast majority of patients will eventually progress. Determining the optimal treatment after Lu177 has been an important question for my patients, and until now there has been no randomized phase 3 evidence to guide it,” said Simron Singh, MD, a medical oncologist at the Odette Cancer Centre, Sunnybrook Health Sciences Centre, professor of medicine at the University of Toronto, and principal investigator of the ACTION-1 study, in the news release.¹ “ACTION-1 provides the first [phase 3] results for an alpha-based targeted RPT, and a clinically meaningful improvement in [PFS] is a crucial development in improving the care of patients with GEP-NETs.”

What is the ACTION-1 trial design?

ACTION-1 is a randomized phase 3 trial evaluating RYZ101 vs investigator’s choice of standard of care—high-dose or high-frequency long-acting somatostatin analogues, everolimus (Afinitor), or sunitinib (Sutent)—in patients with SSTR-positive GEP-NETs who have progressed following Lu177-based therapy.² The primary end point was PFS by BICR.

Patients currently enrolled will continue to receive care consistent with the study protocol, and they will be followed for overall survival. GEP-NETs are rare tumors, with an estimated 18,000 patients diagnosed annually in the US and a prevalence of fewer than 200,000 patients; somatostatin receptor type 2 is expressed in 80% to 90% of GEP-NET tumors, and metastatic disease is present at diagnosis in the majority of cases.

What is RYZ101, and what are the next steps?

RYZ101 is an investigational, targeted radiopharmaceutical therapy comprising DOTATATE bound to actinium-225 (225Ac), a highly potent alpha-emitting radioisotope that emits a high-energy, short-range alpha particle capable of causing double-stranded DNA damage in cancer cells. In a phase 1b trial of 17 patients with disease progression who had previously received Lu177, RYZ101 was well tolerated, with no treatment-related serious adverse events (AEs) or discontinuations due to any AE. The agent is also being evaluated in earlier-stage trials in hormone receptor–positive metastatic breast cancer. The FDA granted RYZ101 orphan drug designation for the treatment of GEP-NETs in August 2026.

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/2fke9svb
2. 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://clinicaltrials.gov/study/NCT05477576