Oncology · Medical Literature
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.
Abstract
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.
Clinical relevance
In patients with microsatellite-stable (MSS) colorectal cancer who remain ctDNA-positive (minimal residual disease) after curative-intent surgery and chemotherapy, can cemiplimab-based immunotherapy—as monotherapy or in novel combinations—achieve ctDNA clearance and delay or prevent radiographic recurrence? __SNAPSHOT__ {"studyDesign":"Multicenter, open-label, randomized Phase II platform trial (trial-in-progress / protocol publication); NCT07058012","setting":"Multicenter; NSABP Foundation sites across the United States; enrollment began September 2025 and is ongoing","sampleSize":"Arm 1 (cemiplimab monotherapy): up to 33 patients (Simon two-stage design); Arms 2 and 3 (combination regimens): up to 23 patients each (single-stage design); maximum planned total approximately 79 patients","population":"Adults ≥18 years with confirmed MSS or pMMR colorectal cancer (stage II–III or oligometastatic stage IV), ECOG performance status 0–1, ctDNA-positive by a CLIA-certified tumor-informed assay obtained within 2–12 weeks of completing all curative-intent therapy (surgery ± chemotherapy/chemoradiotherapy), and no radiographic evidence of recurrence at enrollment","intervention":"Three investigational arms administered IV every 3 weeks for up to 17 cycles (~1 year): Arm 1 — cemiplimab 350 mg monotherapy; Arm 2 — cemiplimab 350 mg + fianlimab 1600 mg (anti-LAG-3 antibody); Arm 3 — cemiplimab 350 mg + REGN7075 2700 mg (EGFRxCD28 costimulatory bispecific antibody)","comparator":"No placebo or standard-of-care comparator arm; single-arm efficacy assessment within each platform arm (inter-arm comparisons are exploratory)","primaryOutcome":"ctDNA clearance at 12 weeks from treatment initiation, assessed by tumor-informed assay, in the absence of radiographic recurrence","followUp":"Participants anticipated to remain on study approximately 18 months; treatment duration up to 1 year; long-term recurrence-free survival follow-up duration not yet fully specified in available protocol publications","fundingSource":"NSABP Foundation, Inc.; study drugs (cemiplimab, fianlimab, REGN7075) provided by Regeneron Pharmaceuticals (industry sponsor)"}
Key findings
This is a trial-in-progress publication (protocol paper); no efficacy, safety, or ctDNA clearance outcome data are yet available. The study was designed to detect a clinically meaningful ctDNA clearance rate: Arm 1 uses a Simon two-stage design (α=0.047, power=0.80) enrolling up to 33 patients; Arms 2 and 3 each use a single-stage design (α=0.05, power=0.78) enrolling up to 23 patients each. No primary outcome results, response rates, p-values, confidence intervals, hazard ratios, NNT, NNH, or adverse event frequencies are reported at this time. Secondary endpoints—including recurrence-free survival, longitudinal ctDNA kinetics, patterns of radiographic recurrence, and safety/tolerability—will be reported upon study completion.
Practice implications
EMPIRE (NSABP FC-13) addresses a critical and currently unmet clinical need: there are no approved therapies for MSS CRC patients who are ctDNA-positive (MRD-positive) after curative-intent treatment, a population known to carry a high risk of relapse. The trial's biomarker-enriched design—selecting patients based on postoperative ctDNA positivity without radiographic recurrence—is scientifically rational and represents an important methodological evolution in adjuvant oncology trial design, using ctDNA clearance at 12 weeks as an early surrogate of therapeutic activity rather than waiting for radiographic endpoints. The three-arm platform structure allows efficient simultaneous signal-finding across mechanistically distinct immunotherapy strategies: PD-1 blockade alone (cemiplimab), dual PD-1 and LAG-3 blockade (cemiplimab + fianlimab), and PD-1 blockade with EGFR×CD28 T-cell costimulation (cemiplimab + REGN7075). However, because this publication reports only the study design and rationale—not results—no conclusions about efficacy, safety, or clinical utility of any arm can be drawn at this time. Clinicians should recognize that MSS CRC has consistently resisted single-agent PD-1/PD-L1 blockade in the metastatic setting; whether the MRD-defined adjuvant context, lower tumor burden, and combination strategies will overcome this resistance is the central hypothesis under investigation. Findings from EMPIRE should not yet influence clinical practice; this trial represents hypothesis-generating science. IMPORTANT LIMITATION: Only the abstract (trial-in-progress/protocol publication) is available for review; the full manuscript in Future Oncology (PMID 42345857) may contain additional protocol details not captured here. __LIMITATIONS__ Trial-in-progress: no efficacy or safety results are available; this summary is based entirely on the study design and rationale.,The primary endpoint (ctDNA clearance at 12 weeks) is a surrogate marker; its correlation with clinical outcomes such as overall survival or durable recurrence-free survival in the MSS MRD-positive population has not been prospectively validated.,No placebo or standard-of-care comparator arm, which limits causal inference; each arm is assessed against a pre-specified historical null hypothesis rate rather than a concurrent control.,Small per-arm sample sizes (up to 33, 23, and 23 patients) provide adequate power only for signal detection, not definitive efficacy assessment; the study is explicitly designed as a Phase II screening trial.,Open-label design introduces risk of performance and ascertainment bias, particularly relevant for patient-reported and clinician-assessed endpoints.,Platform design allows arms to be added or removed, which may affect cross-arm comparability and interpretability over time.,Oligometastatic stage IV CRC is included alongside stage II–III disease, introducing prognostic heterogeneity within each arm.,Industry sponsorship (Regeneron providing investigational drugs) warrants acknowledgment, though the trial is investigator-initiated through the NSABP Foundation.,The ctDNA assay platform (tumor-informed) is specified, but assay standardization across CLIA-certified labs could introduce variability in the primary endpoint.,Generalizability is limited to patients who are ctDNA-positive after completing all curative-intent therapy; results will not apply to the broader MSS CRC population.,Funding source for the Future Oncology publication itself is not reported in the available abstract. __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ EMPIRE (NSABP FC-13) is an ongoing, biomarker-driven Phase II platform trial testing cemiplimab monotherapy and two novel cemiplimab-based combinations in MSS CRC patients with ctDNA-defined MRD after curative-intent treatment—a population with high recurrence risk and no currently approved adjuvant immunotherapy options. The trial is actively enrolling (as of September 2025) and no outcome data are yet available. Clinicians should not alter practice based on this publication; its significance lies in establishing a rigorous, ctDNA-enriched trial framework for a historically immunotherapy-resistant CRC subtype.