Sponsor: Immunocore Ltd (industry)
Phase: 3
Start date: June 5, 2024
Planned enrollment: 680
Brenetafusp (IMC‑F106C; PRAME‑A02) is an investigational, off‑the‑shelf TCR bispecific (ImmTAC) being developed by Immunocore to treat PRAME‑positive solid tumors in HLA‑A*02:01–positive patients. It is in a first‑in‑human phase 1/2 basket trial (NCT04262466) with multiple expansion cohorts and a registrational phase 3 trial in first‑line advanced/metastatic cutaneous melanoma (PRISM‑MEL‑301; NCT06112314). (clinicaltrials.ucsd.edu)
Brenetafusp is a soluble, high‑affinity T‑cell receptor specific for a PRAME peptide presented by HLA‑A02:01, fused to an anti‑CD3 single‑chain antibody. It redirects and activates polyclonal T cells to kill PRAME‑expressing tumor cells. The relevant HLA‑A02:01‑restricted PRAME epitope includes PRAME300–309 (ALYVDSLFFL), a well‑characterized peptide presented on tumor cells; HLA‑A*02:01 is present in a substantial fraction of the U.S. population. (oncologypro.esmo.org)
Ongoing pivotal program: - PRISM‑MEL‑301 (phase 3): brenetafusp + nivolumab vs standard nivolumab regimens (nivolumab or nivolumab/relatlimab) in previously untreated HLA‑A*02:01‑positive advanced melanoma; primary endpoint PFS by BICR; first patient randomized June 18, 2024; estimated primary completion October 2027. (ascopubs.org)
Safety monitoring and inpatient observation during initial “step‑up” dosing are part of the ImmTAC class management strategy, based on prior experience. Trial sites list typical key exclusions (e.g., uncontrolled autoimmune disease, active infections). (clinicaltrials.ucsd.edu)
Notes: All clinical data above reflect interim conference abstracts and sponsor updates available as of October 7, 2025; no peer‑reviewed full manuscripts of these efficacy data were identified. (ascopubs.org)
Last updated: Oct 2025
Goal: Evaluate whether adding the PRAME-targeted TCR-CD3 bispecific brenetafusp (IMC-F106C) to nivolumab improves outcomes versus standard nivolumab-based regimens in previously untreated, advanced melanoma patients who are HLA-A*02:01-positive.
Patients: Adults with unresectable stage III or stage IV melanoma, HLA-A*02:01-positive, measurable disease by RECIST 1.1, ECOG 0–1, with known BRAF V600 status, and adequate tumor tissue. Key exclusions include prior systemic therapy for advanced melanoma, active or untreated CNS metastases, significant cardiopulmonary comorbidity, active autoimmune disease requiring immunosuppression, hypersensitivity to study drugs, and prior life-threatening toxicity to PD-(L)1 or LAG-3 inhibitors.
Design: Global, randomized, controlled phase 3 trial with parallel arms. Allocation is randomized among two experimental dose levels of brenetafusp plus nivolumab versus active comparator control consisting of nivolumab alone or nivolumab plus relatlimab, aligned with standard-of-care regimens. Approximately 680 participants will be enrolled. Primary intent is treatment with blinded independent central review for radiographic endpoints.
Treatments: Experimental arms: brenetafusp plus nivolumab. Brenetafusp (IMC-F106C; PRAME-A02) is an off-the-shelf soluble T-cell receptor–CD3 bispecific (ImmTAC) that targets PRAME peptide presented by HLA-A*02:01, redirecting polyclonal T cells to kill PRAME-expressing tumor cells. Early-phase studies in melanoma and ovarian cancer show manageable safety dominated by low-grade cytokine release syndrome and rash, with signals of disease control and ctDNA molecular responses; limited combination data with anti–PD-1 suggest activity and biological synergy. Nivolumab is an anti–PD-1 antibody standard in first-line melanoma; the control arm allows either nivolumab monotherapy or nivolumab plus the anti–LAG-3 antibody relatlimab, consistent with current practice. Dosing: brenetafusp weekly for 13 weeks then every 2 weeks through Week 51 then every 4 weeks; nivolumab every 4 weeks. Control: nivolumab 480 mg Q4W or nivolumab 480 mg plus relatlimab 160 mg Q4W.
Outcomes: Primary: progression-free survival by BICR per RECIST 1.1. Key secondary endpoints include overall survival, overall response rate by BICR, safety (AEs, SAEs, and treatment modifications), pharmacokinetics of brenetafusp (Cmax), anti-drug and neutralizing antibodies to brenetafusp, exploratory association of intratumoral immune contexture (CD3+/CD163+ ratio) with PFS in the brenetafusp arms, and health-related quality of life. Follow-up spans approximately 45 months for most efficacy and safety measures and up to 57 months for OS and late safety.
Burden on patient: Moderate. Visit intensity is higher in the brenetafusp arms due to weekly infusions during the first 13 weeks, then biweekly through one year, transitioning to every 4 weeks thereafter; control arms receive Q4W infusions. Expect additional pharmacokinetic sampling during early cycles (predose and multiple postdose draws in Weeks 1–3), immunogenicity blood tests, and protocol-mandated tumor assessments by imaging at standard intervals. Archival or fresh tumor tissue is required, and some participants may undergo fresh biopsies for adequacy or exploratory biomarkers. The frequency of early visits, infusion times with postdose monitoring for cytokine release syndrome, travel requirements, and serial blood sampling contribute to moderate burden compared with standard nivolumab-based therapy, which is less visit-intensive early on.
Last updated: Oct 2025
Inclusion Criteria:
* Participants must be HLA-A\*02:01-positive
* Participants must have histologically confirmed Stage IV or unresectable Stage III melanoma
* Archived or fresh tumor tissue sample that must be confirmed as adequate
* Participants must have measurable disease per RECIST 1.1
* Participant must have BRAF V600 mutation status determined
* Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
* Male and female participants of childbearing potential who are sexually active with a non-sterilized partner must agree to use highly effective methods of birth control from the study screening date until 5 months after the final dose of study intervention
Exclusion Criteria:
* Participants with a history of a malignant disease other than those being treated in this study
* Participants with untreated, active, or symptomatic central nervous system (CNS) metastases or carcinomatous meningitis
* Hypersensitivity to IMC-F106C, nivolumab, relatlimab, or any associated excipients
* Participants with clinically significant pulmonary disease or impaired lung function
* Participants with clinically significant cardiac disease or impaired cardiac function
* Participants with active autoimmune disease requiring immunosuppressive treatment
* Participants with any medical condition that is poorly controlled or that would, in the Investigator's or Sponsor's judgment, adversely impact the participant's participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results
* Participants who received prior systemic anticancer therapy for unresectable or metastatic melanoma
* Participants with a history of a life-threatening AE related to prior anti-PD-(L)1 or anti-LAG-3
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St Louis, Missouri, 63110, United States
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