RYZ101 ACTION-1: BMS reports positive Phase 3 interim results

Bristol Myers Squibb says RYZ101 improved progression-free survival in ACTION-1, a Phase 3 trial in selected neuroendocrine tumors that had progressed after lutetium-based therapy.[1] The October 12 announcement reports a positive planned interim analysis, but gives no numerical estimate of the benefit or comparative adverse-event rates.[1]

Reader offer · IQON Labs

Buy 1, Get 1 20% Off

Pick any two research compounds. Take 20% off the lower priced one.

20% OFF

Applied automatically at checkout, no code needed

Claim my 20% off →

In every pair, the lower priced item is 20% off after other discounts; accessories excluded. For research use only.

Clinical research reporting, not treatment guidance. The IQON Labs research catalog is separate from the investigational medicine discussed here.

A trial for cancer that progressed after earlier targeted radiation

ACTION-1 addresses a particular point in treatment: the cancer has progressed after a radiopharmaceutical carrying lutetium-177.[2] Its registered main population consists of adults with advanced, inoperable, well-differentiated grade 1 or 2 gastroenteropancreatic neuroendocrine tumors, abbreviated GEP-NETs.[2] These tumors arise in the gastrointestinal tract or pancreas.[3]

Participants also need tumors that show somatostatin receptors on specialized imaging.[2] These receptors provide the target for a somatostatin analogue, a molecule designed to bind the same receptor as the natural hormone.[3] Attaching a radioactive isotope to that targeting molecule allows the treatment to deliver radiation to receptor-bearing tumor cells.[3]

The current registry requires prior disease control after lutetium therapy as well as adequate kidney function and blood counts.[2] These criteria narrow the question to selected patients whose tumors progressed after earlier control: can another receptor-targeted radiopharmaceutical delay further progression?[2]

What RYZ101 changes

RYZ101 combines the peptide-based targeting component DOTATATE with actinium-225, written as 225Ac-DOTATATE.[1][3] Actinium-225 emits alpha particles; the prior lutetium-177 treatments use a beta-emitting isotope.[3] The aim is to bring a different radiation source to tumors that retain the receptor target.[2][3]

Alpha particles deposit energy over a short range and can damage DNA.[1][3] That is the biological rationale for testing the drug.[1] Whether the resulting balance of tumor control and harm is better for patients requires a clinical comparison, which is the purpose of ACTION-1's randomized phase.[2]

The comparison is with standard care

The randomized phase compares RYZ101 with an investigator's choice among everolimus, sunitinib, octreotide or lanreotide.[2] It does not assign the control group to another course of lutetium treatment.[2] A positive ACTION-1 result therefore answers a different question from whether actinium is better than lutetium in a direct comparison.[2]

The trial is open label, meaning treatment assignment is known.[2] Its primary progression assessment is made by a separate, blinded independent central review.[1][2] Keeping those reviewers unaware of treatment assignment helps separate the imaging assessment from knowledge of which medicine a participant received.[2]

The October 5 registry update lists 343 participants as actual enrollment across ACTION-1.[2] That record spans the early phase, the randomized phase and an additional substudy.[2] The announcement does not identify the number analyzed in each randomized arm, so 343 cannot be used as the denominator for an interim benefit or safety calculation.[1][2]

Progression-free survival measures time to worsening or death

In ACTION-1, progression-free survival runs from randomization to either disease progression, assessed using standardized tumor-response criteria, or death from any cause, whichever comes first.[2] It asks how long participants remain alive without recorded progression.[2] Overall survival asks how long they remain alive, whether or not the cancer has progressed.[16]

BMS describes the interim PFS improvement as statistically significant and clinically meaningful.[1] Without a hazard ratio, confidence interval or median PFS for each arm, readers cannot judge its size or precision.[1] The release also omits the interim event count and data cutoff.[1] Participants will continue to be followed for overall survival; an overall-survival improvement has not been reported in this announcement.[1]

The registry defines an event-driven PFS assessment, with analysis tied to a target number of progression or death events.[2] That planned target does not reveal how many events were included in the interim result.[2] Nor does the registry's enrollment total show how long participants were followed.[2]

The earlier study gives risk context

An ACTION-1 poster presented at the 2024 American Society of Clinical Oncology meeting describes 17 treated participants in the uncontrolled Phase 1b portion, with a December 14, 2023 data cutoff.[3] That small study helped establish the regimen for later testing.[3] Its findings are historical context, separate from the new randomized result.[3]

The poster reports anemia, reduced lymphocyte counts and kidney-function adverse events, including severe events.[3] It also records treatment modifications for blood-count problems.[3]

The cohort had no randomized control group, and follow-up varied between participants.[3] Its blood and kidney findings make the larger trial's adverse-event comparison essential: any delay in progression needs to be weighed against effects on organs and blood cells.[3]

The full report must put benefit beside treatment burden

RayzeBio, a BMS company, sponsors ACTION-1 and funded the earlier poster.[1][2][3] The current announcement says detailed results are expected at a future medical meeting and that the company plans to discuss regulatory next steps with the FDA.[1] RYZ101 remains investigational.[1]

For patients whose disease progressed after lutetium therapy, the practical question is how much additional time without progression RYZ101 provides and at what cost in adverse effects.[1][2] Continued overall-survival follow-up addresses whether that disease control also helps patients live longer.[1]