EMPIRE (NSABP FC-13): a biomarker-driven phase II platform trial evaluating cemiplimab-based immunotherapy in microsatellite-stable colorectal cancer with ctDNA-defined minimal residual disease.

Microsatellite-stable (MSS) colorectal cancer (CRC), which accounts for approximately 85% of cases annually, has demonstrated limited responsiveness to immune checkpoint blockade in the metastatic setting. Circulating tumor DNA (ctDNA) enables sensitive detection of minimal residual disease (MRD) following curative-intent therapy and identifies patients at high risk of recurrence who may benefit from additional treatment. The EMPIRE (NSABP FC-13) study is a multicenter, open-label, randomized phase II platform trial evaluating cemiplimab-based immunotherapy in patients with MSS CRC and ctDNA-defined MRD after definitive surgery and chemotherapy. Eligible patients have postoperative ctDNA positivity in the absence of radiographic recurrence and are allocated to one of three treatment arms: cemiplimab monotherapy; cemiplimab plus fianlimab (a lymphocyte activation gene-3 inhibitor); or cemiplimab plus REGN7075 (an EGFR×CD28 costimulatory bispecific antibody).

The primary endpoint is ctDNA clearance at 12 weeks assessed by tumor-informed assay, with secondary endpoints including recurrence-free survival, safety and tolerability, longitudinal ctDNA kinetics, and patterns of recurrence. Arms 2 and 3 use single-stage phase II designs, whereas Arm 1 follows a Simon two-stage design with early futility stopping. The study integrates comprehensive correlative analyses to characterize mechanisms of response and resistance.Clinical trial registration: The http://www.clinicaltrials.gov identifier is NCT07058012. Most colorectal cancer (CRC) tumors are classified as microsatellite-stable (MSS).

Although surgery and chemotherapy can address the disease in many patients, a substantial proportion will experience cancer recurrence despite cancer not being visible on routine scans at the time treatment ends. New blood tests that measure circulating tumor DNA (ctDNA) can detect very small amounts of remaining cancer, known as minimal residual disease (MRD), months before cancer becomes visible on imaging. Patients with detectable ctDNA after curative treatment, implying persistent microscopic disease still somewhere in the body, are at particularly high risk of relapse and may benefit from additional therapy before the cancer has a chance to gain an advantage.The EMPIRE trial (NSABP FC-13) is a clinical study designed to test whether new immunotherapy(ies) can eliminate this microscopic residual disease in patients with MSS CRC.

This study enrolls patients who have completed surgery and chemotherapy and who otherwise appear to be in remission (e.g. no evidence of cancer on scans), yet have detectable ctDNA in the blood. Patients are assigned to receive one of three immunotherapy-based treatments to activate the immune system.The main goal of the study is to determine whether treatment can clear ctDNA from the blood within 12 weeks, implying elimination of MRD. Additional goals include evaluating how long patients remain cancer-free, assessing treatment safety, and understanding how ctDNA levels change over time. By using blood tests to guide treatment decisions, the EMPIRE trial aims to develop a more personalized approach to prevent CRC recurrence.