Bristol Myers Squibb has announced positive topline results from the Phase 3 ACTION-1 trial of RYZ101 (actinium-225-DOTATATE) in patients with gastroenteropancreatic neuroendocrine tumors whose disease progressed following lutetium-177-based radiopharmaceutical therapy.
The planned interim analysis showed that ACTION-1 met its primary endpoint, with RYZ101 producing a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with investigator-selected standard-of-care treatment, according to Bristol Myers Squibb (BMS). PFS was assessed by blinded independent central review.
The October 12 announcement marks an important step for targeted alpha radiopharmaceutical therapy. According to BMS, ACTION-1 represents the first Phase 3 trial to report results for an alpha-isotope-based targeted radiopharmaceutical therapy in any indication.
However, the announcement remains a topline readout. The company has not yet disclosed the PFS hazard ratio, median PFS in either treatment group, response rates, subgroup analyses, or detailed adverse-event findings. Full results are expected to be presented at a future medical meeting.
ACTION-1 Targets a Major Treatment Question After Lutetium-177 Therapy
The Phase 3 ACTION-1 trial (NCT05477576) is evaluating RYZ101 in patients with advanced, well-differentiated, somatostatin receptor-positive (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with a lutetium-177-labelled somatostatin analogue.
Patients in the Phase 3 portion were randomized to receive RYZ101 or an investigator-selected standard-of-care option. Comparator treatments included high-dose or high-frequency long-acting somatostatin analogues, everolimus, or sunitinib.
This setting represents an important clinical challenge. Lutetium-177-based radiopharmaceutical therapy has become an established treatment approach for SSTR-positive GEP-NETs, but disease progression eventually occurs in most patients. Once that happens, the evidence supporting subsequent treatment selection is considerably more limited.
Simron Singh, MD, medical oncologist at the Odette Cancer Centre, Sunnybrook Health Sciences Centre, professor of medicine at the University of Toronto, and principal investigator of ACTION-1, said:
“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.”
Singh emphasized that ACTION-1 represents the first Phase 3 results for an alpha-based targeted radiopharmaceutical therapy, with the clinically meaningful improvement in progression-free survival marking an important development in the care of patients with GEP-NETs.
Moving From Beta to Alpha Radiation
RYZ101 is an investigational targeted radiopharmaceutical consisting of DOTATATE linked to actinium-225, an alpha-emitting radioisotope.
DOTATATE is designed to target somatostatin receptors expressed on neuroendocrine tumor cells. According to BMS, somatostatin receptor type 2 is expressed in approximately 80% to 90% of GEP-NET tumors.
Once the radiopharmaceutical binds to its target, the actinium-225 component delivers high-energy, short-range alpha radiation. These alpha particles can produce double-stranded DNA damage within cancer cells, potentially resulting in tumor cell death while limiting the distance over which radiation travels.
The approach therefore represents a different radiopharmaceutical strategy from lutetium-177 therapies, which use beta-emitting radionuclides.
For ACTION-1, the key question is particularly notable: can an SSTR-directed alpha-emitting radiopharmaceutical provide additional disease control in tumors that have already progressed after an SSTR-directed lutetium-177 treatment?
The interim Phase 3 findings suggest that it can improve PFS compared with the available standard-of-care options evaluated in the trial, although the magnitude of that benefit will remain unclear until the numerical results are reported.
Safety Consistent With Previous RYZ101 Experience
BMS reported that safety findings from the ACTION-1 interim analysis were consistent with the previously known safety profile of RYZ101. No additional detailed safety data were included in the topline announcement.
Earlier clinical experience came from a Phase 1b cohort involving 17 patients whose disease had progressed after prior lutetium-177 treatment. According to BMS, there were no treatment-related serious adverse events and no treatment discontinuations because of adverse events in that cohort.
Participants currently enrolled in ACTION-1 will continue treatment and follow-up according to the study protocol. The trial will also continue following patients for overall survival.
A Potential New Option in GEP-NETs
GEP-NETs are relatively rare malignancies that arise from neuroendocrine cells of the gastrointestinal tract and pancreas. BMS estimates that approximately 18,000 patients are diagnosed with GEP-NETs annually in the United States, with fewer than 200,000 people living with the disease.
The treatment landscape has expanded through somatostatin analogues, targeted therapies and radiopharmaceutical approaches, but management becomes increasingly difficult as patients progress through available lines of therapy.
That makes the post-lutetium-177 population studied in ACTION-1 particularly relevant.
Amreen Husain, MD, chief medical officer of RayzeBio, described the results as an important milestone for patients who have progressed following lutetium-177-based therapy. Husain said:
“The improvement in progression-free survival 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.”
She also emphasized the broader implications for the company’s radiopharmaceutical development program, adding, “This is the kind of impact we set out to deliver with actinium-based radiopharmaceuticals, and it is a
The US Food and Drug Administration granted RYZ101 Orphan Drug Designation for GEP-NETs in August 2026. Following the positive interim ACTION-1 results, RayzeBio, a BMS company, plans to discuss the findings and potential next regulatory steps with the FDA.
What Comes Next for RYZ101?
The next major milestone will be the presentation of the complete ACTION-1 dataset.
Detailed PFS results will be necessary to determine the magnitude and durability of the benefit and to understand how RYZ101 performed across clinically relevant patient groups. Overall survival follow-up, response data and a fuller characterization of hematologic, renal, and other toxicities associated with actinium-225 treatment will also be important for evaluating its potential place in the treatment sequence.
Still, the topline finding gives ACTION-1 broader significance beyond GEP-NETs. As the first reported Phase 3 results from an alpha-isotope-based targeted radiopharmaceutical program, the trial provides an important test of whether targeted alpha therapy can move from smaller early-phase studies into randomized late-stage oncology development.
For patients with SSTR-positive GEP-NETs who have already progressed following lutetium-177 therapy, the results may also begin to answer a more immediate question: what comes next after radiopharmaceutical therapy stops working?
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