Proactive Treatment Targeting ctDNA-Positive Patients

The MIRI trial, led by the UCLA Jonsson Comprehensive Cancer Center, is a single-arm Phase 2 study targeting estrogen receptor-positive breast cancer patients who are imaging-negative for metastasis but have detectable circulating tumor DNA (ctDNA) in the blood. The trial will begin on April 30, 2026, at UCLA in the U.S., with patients receiving a combination of imlunestrant (1 daily dose) and abemaciclib (2 daily doses) every 28 days for up to 12 cycles. The key objective is to verify whether treatment can be initiated at the molecular minimal residual disease (MRD) stage, before clinical relapse, to potentially block relapse pathways.

Combination Strategy Targeting Different Pathways

Inluriyo (imlunestrant) is an oral estrogen receptor antagonist and selective estrogen receptor degrader (SERD) developed by Eli Lilly and Company (LLY), which inhibits ER and ESR1 variant receptor signaling. Verzenio (abemaciclib), also from the same company, is a CDK4/CDK6 inhibitor that blocks cell cycle progression. It was first approved in the U.S. in 2017 and its adjuvant indication for high-risk HR-positive/HER2-negative early breast cancer was expanded on March 3, 2023. Therefore, this combination simultaneously suppresses both hormonal dependency and cell cycle signaling in tumor growth, but the 48.6% incidence of Grade 3 or higher adverse events in the EMBER-3 trial highlights an important safety criterion for long-term use in MRD patients.

Expanding Approved Assets to Early Disease

On September 25, 2025, the FDA approved Inluriyo for the treatment of ESR1-mutant ER-positive/HER2-negative progressive or metastatic breast cancer following endocrine therapy, along with the co-approval of Guardant360 CDx as a companion diagnostic. In the pivotal Phase 3 EMBER-3 trial, the median progression-free survival for patients with ESR1 mutations was 5.5 months with Inluriyo versus 3.8 months with fulvestrant or exemestane, with a hazard ratio of 0.62. MIRI aims to shift this late-stage data forward to ctDNA-positive patients post-adjuvant therapy, representing a new Phase 2 development stage rather than an approved indication.

Primary Endpoints and Competitive Landscape

The primary endpoint is the ctDNA clearance rate after 12 cycles of treatment, with safety, ctDNA re-emergence post-treatment, and 1-year distant relapse-free survival (DRFS) as secondary evaluation criteria. Current standard adjuvant therapies include tamoxifen or aromatase inhibitors, while high-risk patients are treated with Verzenio combinations or Novartis (NVS)'s Kisqali (ribociclib) combinations. Kisqali received FDA approval on September 17, 2024, for high-risk HR-positive/HER2-negative stage 2–3 early breast cancer. In the metastatic ESR1-mutant market, Menarini Group's Orserdu (elacestrant) has been competing since January 27, 2023. The global breast cancer treatment market is projected to reach USD 34.59 billion in 2025, with Verzenio's 2025 revenue of USD 5.307 billion illustrating the commercial leverage of MRD-based indication expansion.