BMS Reports Phase 3 PFS Benefit with RYZ101 in Advanced GEP-NETs

Bristol Myers Squibb (BMS) has announced positive topline results from the planned interim analysis of the Phase 3 ACTION-1 trial evaluating RYZ101 (²²⁵Ac-DOTATATE) in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with investigator-selected standard care.

Developed by RayzeBio, a BMS company, RYZ101 is an investigational targeted radiopharmaceutical therapy being evaluated in patients with somatostatin receptor-positive (SSTR+) GEP-NETs whose disease has progressed following lutetium-177 (Lu-177)-based radiopharmaceutical therapy. The findings address an important treatment gap in a population with limited options after disease progression on an established treatment approach.

Phase 3 ACTION-1 Trial Meets Primary Endpoint

The randomized Phase 3 ACTION-1 trial (NCT05477576) compared RYZ101 with investigator-selected standard care, including high-dose or high-frequency long-acting somatostatin analogues, everolimus, or sunitinib.

The planned interim analysis demonstrated a statistically significant and clinically meaningful improvement in PFS, assessed by blinded independent central review. BMS also reported that safety results were consistent with the known safety profile of RYZ101.

However, the company has not disclosed numerical PFS results, including median PFS, the hazard ratio, or confidence intervals. These data will be necessary to assess the magnitude and precision of the treatment effect. Detailed findings are expected to be presented at a future medical meeting.

Participants currently enrolled in ACTION-1 will continue to receive care according to the study protocol and will be followed for overall survival. The trial’s interim PFS result therefore does not establish whether RYZ101 improves overall survival.

Actinium-225 Provides a Different Radiopharmaceutical Approach

RYZ101 combines DOTATATE, which targets somatostatin receptors expressed on certain neuroendocrine tumor cells, with actinium-225 (²²⁵Ac), a radioactive isotope that emits high-energy, short-range alpha particles.

These particles can cause double-stranded DNA damage in cancer cells, potentially leading to cell death. This mechanism provides the rationale for evaluating RYZ101 in patients whose tumors progress after Lu-177-based radiopharmaceutical therapy. However, the mechanistic differences between alpha- and beta-emitting therapies do not, by themselves, establish comparative clinical superiority.

In an earlier Phase 1b trial involving 17 patients with GEP-NETs that had progressed following Lu-177-based treatment, RYZ101 was reported to be well tolerated. No treatment-related serious adverse events or dose discontinuations due to adverse events were reported in that study.

FDA Discussions Planned Following Positive Results

The U.S. Food and Drug Administration granted RYZ101 Orphan Drug Designation for GEP-NETs in August 2026. Following the positive interim findings, RayzeBio plans to engage with the FDA to discuss next steps toward a potential regulatory submission.

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. The milestone may also provide further clinical evidence for the development of actinium-225-based treatments.

RYZ101 is additionally being evaluated in earlier-stage clinical trials for hormone receptor-positive metastatic breast cancer.

Addressing an Unmet Need in GEP-NETs

GEP-NETs are rare tumors arising in the gastrointestinal tract or pancreas. BMS estimates that approximately 18,000 people are diagnosed with these tumors annually in the United States. Somatostatin receptor type 2 (SSTR2) is expressed in an estimated 80–90% of GEP-NET tumors.

Lu-177-based radiopharmaceutical therapy is an established treatment option for eligible patients with SSTR-positive GEP-NETs. However, many patients eventually experience disease progression, and effective subsequent treatment options remain limited.

The ACTION-1 findings provide Phase 3 evidence supporting further investigation of RYZ101 in this post-Lu-177 treatment setting. Its eventual clinical role will depend on the detailed efficacy and safety data, continued overall survival follow-up, and regulatory assessment. RYZ101 remains investigational.

Clinical Interpretation

The ACTION-1 results represent an important clinical development for patients with SSTR-positive GEP-NETs whose disease progresses following Lu-177-based radiopharmaceutical therapy. By meeting its primary endpoint against investigator-selected standard care, RYZ101 has demonstrated a positive Phase 3 PFS result in a population with limited treatment options. However, the absence of numerical PFS data prevents assessment of the magnitude and precision of the benefit. Detailed safety findings and continued overall survival follow-up will be important in defining its clinical value. The findings support further development, but they do not yet establish RYZ101’s comparative benefit or its future role in routine clinical practice.

Reference

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, Bristol Myers Squibb, 12 October 2026

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 ID NCT05477576