A planned interim analysis of the radiopharmaceutical RYZ101 showed improved PFS by blinded independent central review vs standard of care.
Treatment with RYZ101 (225Ac-DOTATATE) led to a statistically significant and clinically meaningful progression-free survival (PFS) improvement by blinded independent central review (BICR) vs investigator’s choice of standard-of-care (SOC) therapy in patients with somatostatin receptor (SSTR)–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) whose disease had progressed after lutetium-177 (Lu-177)–based therapy, meeting the primary end point of the phase 3 ACTION-1 trial (NCT05477576).¹
Additionally, the safety profile of RYZ101 in ACTION-1 was reported to be consistent with the known safety profile of the agent. Detailed results from the trial are planned to be presented at a future medical meeting, and RayzeBio, the developer of RYZ101, plans to engage the FDA on next steps toward a regulatory submission for this agent in this indication.
“Lu177-based therapy is widely used in GEP-NETs, but unfortunately, the vast majority of patients will eventually progress,” Simron Singh, MD, a medical oncologist in the Odette Cancer Centre at the Sunnybrook Health Sciences Centre, a professor of medicine at the University of Toronto, and principal investigator of the ACTION-1 study, stated in a news release. “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. ACTION-1 provides the first phase 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.”
ACTION-1 is a global, randomized, open-label phase 1b/3 trial evaluating RYZ101 vs investigator-selected SOC in patients with inoperable, advanced, well-differentiated, SSTR-positive GEP-NETs that had progressed after Lu-177–labeled somatostatin analogue therapy.² Part 1 assessed safety, pharmacokinetics, and the recommended phase 3 dose, with dose-limiting toxicities during the first 56 days as the phase 1b primary end point. Part 2 compares the safety, efficacy, and pharmacokinetics of RYZ101 with SOC.
RYZ101 in Post–Lu-177 GEP-NETs: ACTION-1 Highlights
SOC options in the control arm include high-dose or high-frequency long-acting somatostatin analogues (octreotide or lanreotide), everolimus (Afinitor), or sunitinib (Sutent).1,2 The trial enrolled 343 patients, and its estimated primary completion date is in December 2026.²
Eligible patients were required to have histologically confirmed grade 1 or 2 GEP-NETs with a Ki-67 score of 20% or less. GEP-NETs needed to have arisen in the gastrointestinal tract or pancreas, and patients also needed to have an ECOG performance status of 0 to 2 and progressive disease following 2 to 4 cycles of Lu-177–labeled somatostatin analogue therapy. Additionally, patients needed to have achieved disease control for at least 6 months on prior Lu-177 therapy, with SSTR-positive PET imaging (Krenning score 3 or 4) and at least 1 measurable site of disease per RECIST 1.1 criteria. Prior radioembolization, uncontrolled diabetes, and significant cardiovascular disease were exclusion criteria, as was prior peptide receptor radionuclide therapy other than Lu-177.
RYZ101 is an investigational targeted radiopharmaceutical in which DOTATATE is bound to the alpha-emitting isotope actinium-225.¹ In a prior phase 1b study of 17 patients with disease progression who had been previously treated with Lu-177 and received treatment with RYZ101, no treatment-related serious adverse effects (AEs) were reported, and no discontinuations occurred due to AEs.
The FDA granted RYZ101 orphan drug designation for the treatment of patients with GEP-NETs in August 2026. Patients enrolled in ACTION-1 will continue to receive care per the trial protocol and will be followed for overall survival. Notably, RYZ101 is also being evaluated in earlier-stage trials in patients with hormone receptor–positive metastatic breast cancer.
