Last updated: June 28, 2026
Tebentafusp (Kimmtrak, tebentafusp-tebn, IMCgp100) is a first-in-class gp100 × CD3 bispecific T-cell engager developed by Immunocore on the ImmTAC (Immune-mobilising monoclonal TCR Against Cancer) platform. It is the only FDA-approved therapy for metastatic uveal melanoma in history — approved January 25, 2022 for HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma based on the IMCgp100-202 Phase 3 trial. Tebentafusp is also the first FDA-approved TCR-based bispecific in oncology, distinguishing the ImmTAC platform from antibody-based bispecific T-cell engagers (Janssen teclistamab BCMA, talquetamab GPRC5D; Amgen tarlatamab DLL3).
Mechanism of action:Tebentafusp is a fusion protein with two engineered halves: (1) an affinity-matured, soluble, HLA-A*02:01-restricted T cell receptor (TCR) that recognizes the gp100-derived nonameric peptide YLEPGPVTA presented on HLA-A*02:01, and (2) an anti-CD3 single-chain variable fragment (scFv) that engages T cells via the CD3 component of the T-cell receptor complex. When the soluble TCR end binds gp100/HLA-A*02:01 on a tumor cell and the anti-CD3 scFv end binds a polyclonal T cell, the two are brought into a productive immunological synapse and the T cell delivers cytolytic effector function (perforin, granzymes) against the tumor cell — redirected polyclonal T cell killing of gp100-presenting tumor cells. The affinity-matured TCR has picomolar affinity for its peptide-MHC target, several orders of magnitude tighter than natural TCRs (which are micromolar).
Regulatory status:FDA-approved in 1 indication: HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma (IMCgp100-202 Phase 3 trial NCT03070392, FDA regular approval January 25, 2022; EU EMA approval April 2022). Dosing: intra-patient dose escalation — 20 mcg Day 1, 30 mcg Day 8, 68 mcg weekly thereafter, given as a weekly IV infusion. First three infusions administered in inpatient or extended-monitoring outpatient setting; premedication (acetaminophen, IV corticosteroid, antihistamine) required before every dose to mitigate cytokine release syndrome. Package insert includes a CRS-monitoring boxed warning.
Uveal melanoma is the most common primary eye cancer in adults but is an extremely rare cancer overall — about 2,500 new cases per year in the United States. It arises from melanocytes in the uveal tract (choroid, ciliary body, iris) of the eye. Despite successful local treatment of the primary tumor (plaque brachytherapy, proton-beam radiation, or enucleation), about half of patients eventually develop metastases — usually liver-predominant, often years after the primary diagnosis. Historically, the prognosis for metastatic uveal melanoma was dismal: median overall survival was approximately 12 months, no FDA-approved systemic therapy existed for this disease, and unlike cutaneous (skin) melanoma, uveal melanoma is notoriously unresponsive to standard checkpoint immunotherapy — PD-1 and CTLA-4 inhibitors have objective response rates of only 5-15% as single agents in uveal melanoma, far below their cutaneous-melanoma performance.
Tebentafusp changed this. In the IMCgp100-202 Phase 3 trial, tebentafusp was randomized 2:1 against investigator's choice (pembrolizumab, ipilimumab, or dacarbazine) in 378 previously-untreated HLA-A*02:01-positive metastatic uveal melanoma patients. The primary endpoint, overall survival, showed a hazard ratio of 0.51 (median OS 21.7 vs 16.0 months) — a clinically meaningful and unprecedented OS benefit for this disease. Strikingly, the objective response rate was only about 9% — the OS benefit was achieved despite very few RECIST responses, a striking dissociation between ORR and OS that researchers have termed a "biological response" signal (the drug appears to convert progressive disease into stable disease with prolonged survival, rather than producing classic tumor shrinkage). This pattern is unusual in oncology and is one of the most distinctive aspects of the tebentafusp story.
The ImmTAC platform — not an antibody bispecific. Tebentafusp is the first FDA-approved member of Immunocore's ImmTAC class. Unlike antibody-based bispecific T-cell engagers (Janssen teclistamab and talquetamab in multiple myeloma; Amgen tarlatamab in SCLC), which target cell-surface antigens via Fab arms, ImmTAC molecules use an engineered soluble TCR to target intracellular antigens that are presented as peptides on Class I HLA molecules. This vastly expands the universe of accessible tumor antigens, because the vast majority of tumor-specific proteins (driver oncogene products, lineage antigens, mutated peptides) are intracellular and would be inaccessible to antibody bispecifics. The trade-off is that the patient must carry the matching HLA allele — for tebentafusp, HLA-A*02:01 — because TCR recognition is HLA-restricted. See the Tarlatamab (DLL3 BiTE) page for the sibling antibody-based T-cell engager class comparison.
Tebentafusp has 1 active FDA approval: the only FDA-approved therapy for metastatic uveal melanoma.
HLA-A*02:01-Positive Unresectable or Metastatic Uveal Melanoma (IMCgp100-202)
★ The ORR / OS Dissociation: A "Biological Response" Signal
In most oncology trials, the magnitude of the overall survival benefit tracks the magnitude of the objective response rate — if the drug shrinks more tumors, more patients live longer. Tebentafusp is one of the most striking counterexamples in modern oncology: OS HR 0.51 (a halving of mortality risk) achieved with an ORR of only ~9%. Most patients did not have RECIST-defined tumor shrinkage; many had stable disease, and a meaningful subset had what radiologists call "minor responses" (tumor shrinkage below the 30% RECIST threshold). Despite this, patients on tebentafusp lived substantially longer than patients on investigator's choice.
Researchers have proposed this represents a "biological response" signal — the drug appears to convert the natural history of the disease (rapidly progressive metastatic uveal melanoma) into a more indolent biology (stable or slowly progressive disease over many months), rather than producing classic shrink-the-tumor RECIST responses. This pattern has practical implications for oncologists choosing endpoints in tebentafusp trials and for patient counseling: a patient on tebentafusp may have "stable disease" on imaging for many months and still be deriving substantial OS benefit. Imaging response is not the right marker of tebentafusp benefit.
The mechanistic explanation likely involves a combination of the slow tumor doubling time typical of uveal melanoma and the ImmTAC mechanism (which engages polyclonal T cells against tumor cells without necessarily destroying every cell, leading to immune-mediated tumor control rather than complete eradication). This is one of the most discussed and least fully understood aspects of the tebentafusp story.
Curated subset of recruiting interventional tebentafusp trials in the ClinTrialFinder corpus as of June 28, 2026 (approximately 11 recruiting interventional trials total). Trials are grouped by clinical setting and ordered by phase and clinical significance.
Showing a curated subset of recruiting tebentafusp interventional trials in the ClinTrialFinder corpus as of June 28, 2026 (approximately 11 recruiting interventional trials total). For the latest list: view all recruiting tebentafusp trials on ClinicalTrials.gov.
Target: The gp100-derived nonameric peptide YLEPGPVTA presented on HLA-A*02:01 on tumor cells. gp100 (also called premelanosome protein, PMEL) is a melanocyte differentiation antigen normally expressed in melanosomes of melanocytes and overexpressed in melanoma (both uveal and cutaneous) and certain other lineage-related cancers (clear cell sarcoma). The HLA-A*02:01-restricted recognition is the basis for the HLA-A*02:01-positive eligibility requirement.
Mechanism step-by-step: (1) The tumor cell intracellularly produces gp100 protein as part of its melanocyte-lineage transcriptional program. (2) Proteasomal degradation generates peptide fragments including YLEPGPVTA, which is loaded onto HLA-A*02:01 in the endoplasmic reticulum and trafficked to the cell surface as a gp100/HLA-A*02:01 complex. (3) Tebentafusp's soluble TCR component binds gp100/HLA-A*02:01 on the tumor cell with picomolar affinity — several orders of magnitude tighter than a natural T-cell receptor (which binds at micromolar affinity). This affinity maturation is achieved by phage display engineering of the TCRβ chain. (4) Tebentafusp's anti-CD3 scFv component simultaneously binds the CD3 component of the T-cell receptor complex on any nearby polyclonal T cell (CD8+ or CD4+, naive or memory). (5) The two-armed engagement physically tethers the T cell to the tumor cell, forming a productive immunological synapse independent of the T cell's native TCR specificity. (6) The T cell delivers perforin and granzyme-mediated cytolytic effector function against the gp100-presenting tumor cell. (7) Cytokine release accompanies T cell activation — the source of the on-target cytokine release syndrome (CRS) seen in the safety profile.
Why ImmTAC differs from antibody-based bispecific T-cell engagers: Antibody bispecifics (such as tarlatamab DLL3 x CD3 in small cell lung cancer; teclistamab BCMA x CD3 and talquetamab GPRC5D x CD3 in multiple myeloma) target cell-surface antigens via their antibody Fab arms. Tebentafusp targets an intracellular antigen (gp100) via its engineered TCR arm — intracellular antigens vastly outnumber cell-surface antigens, including most driver oncogene products, lineage transcription factors, and mutated peptides. This is the central appeal of the ImmTAC platform: it accesses tumor antigens that are unreachable by antibody bispecifics. The trade-off is HLA restriction — ImmTAC molecules only work in patients carrying the matching HLA allele.
The Immunocore ImmTAC pipeline beyond tebentafusp: Tebentafusp is the first FDA-approved member of the class. Brenetafusp (IMC-F106C) is a PRAME x CD3 ImmTAC currently in Phase 3 (NCT06112314 PRISM-MEL) in HLA-A*02:01-positive cutaneous melanoma — PRAME is a cancer-testis antigen broadly expressed across many solid tumors, extending the TCR-bispecific concept beyond melanocyte lineage. Earlier-phase Immunocore ImmTAC programs target additional tumor antigens including MAGE-A4 (overlap with the afamitresgene autoleucel TCR-T territory in synovial sarcoma) and others. ClinTrialFinder does not currently have a dedicated TCR-bispecific mechanism hub — the closest existing hub is the antibody-based bispecific T-cell engager class (teclistamab, talquetamab, tarlatamab).
HLA-A*02:01 is a Class I HLA allele carried by approximately 40-50% of patients of Caucasian/European ancestry; the frequency is lower (but still meaningful, typically 15-25%) in patients of African, East Asian, and South Asian ancestry. Tebentafusp eligibility is binary: HLA-A*02:01-positive patients can receive tebentafusp; HLA-A*02:01-negative patients cannot.
How HLA typing is done: A simple blood draw is submitted for HLA typing by PCR-based sequence-specific oligonucleotide probe (SSOP), sequence-specific primer (SSP), or sequencing-based typing (SBT) — results typically return within days. The test is widely available at any cancer center, is inexpensive, and is the same test used for solid-organ transplant matching. Patients should request HLA typing as part of the metastatic uveal melanoma workup — or even earlier, at the initial uveal melanoma diagnosis — because tebentafusp eligibility depends on it.
What if the patient is HLA-A*02:01-negative? HLA-A*02:01-negative patients are not eligible for tebentafusp under the FDA label or in the current pivotal tebentafusp trial programs. Alternative options for metastatic uveal melanoma include:
See the Uveal Melanoma trials page for the full HLA-A*02:01-negative and HLA-A*02:01-positive trial landscape.
Tebentafusp is the only FDA-approved metastatic uveal melanoma therapy, but several other approaches are used in practice or in trials — some complementary, some competing.
⚠ Defining Tebentafusp Toxicity: Cytokine Release Syndrome (CRS)
Cytokine release syndrome (CRS) is the most distinctive tebentafusp toxicity and the basis for the FDA boxed warning. CRS was reported in approximately 89% of patients in the IMCgp100-202 Phase 3 trial, but the vast majority were Grade 1-2 (mild to moderate fever, hypotension, chills, tachycardia, hypoxia). Grade 3 or higher CRS was uncommon (approximately 1-3%). Onset is typically within the first hours after infusion and resolves within 24-48 hours.
CRS management has three layers built into the protocol: (1) Intra-patient dose escalation — 20 mcg Day 1, 30 mcg Day 8, 68 mcg Day 15 and weekly thereafter. Starting at one-third the maintenance dose lets the immune system adapt to the cytokine surge before reaching the full effector dose. (2) Inpatient or extended-monitoring outpatient setting for the first 3 infusions — patients are observed for CRS signs (fever, hypotension, hypoxia) for at least 16 hours after each of the first three doses, then transitioned to standard outpatient infusion for subsequent weekly doses. (3) Premedication before every dose — acetaminophen (paracetamol), an IV corticosteroid, and an antihistamine. Severe CRS (rare) is managed with IV fluids, supplemental oxygen, vasopressors, and tocilizumab.
In practice, the CRS-related logistics make the first 2-3 weeks of tebentafusp the most resource-intensive phase. After the dose escalation completes and the patient transitions to outpatient weekly 68 mcg infusions, the regimen becomes much more practical for long-term continuation.
The second-most-common tebentafusp toxicity is skin reactions — rash, pruritus (itching), periorbital edema (puffy eyelids), and dry skin. These reflect on-target gp100 expression in normal melanocytes (the same cell lineage the drug is designed to attack in tumors). Skin reactions are typically Grade 1-2, are most pronounced in the first 1-3 weeks of dosing, and are managed with topical or systemic corticosteroids, antihistamines, and standard rash care. Some patients also report transient depigmentation patches (vitiligo-like) as a longer-term sign of melanocyte targeting — analogous to the vitiligo seen with checkpoint immunotherapy in cutaneous melanoma, and considered (anecdotally) a possible favorable response indicator.
Because tebentafusp is dosed weekly and long-term, patients on continued therapy require regular monitoring of liver enzymes, blood pressure, and skin examination. The drug's "biological response" pattern means many patients remain on tebentafusp for many months with stable disease imaging — the long-term tolerability profile (manageable CRS once past the dose escalation, manageable skin reactions, fatigue) supports prolonged continuation in responding patients. Discontinuation typically follows clinical progression rather than cumulative toxicity.
What is Tebentafusp (Kimmtrak)?
Tebentafusp (brand name Kimmtrak, USAN tebentafusp-tebn, development code IMCgp100) is a first-in-class gp100 × CD3 bispecific T-cell engager developed by Immunocore on the ImmTAC (Immune-mobilising monoclonal TCR Against Cancer) platform. It is a fusion protein in which an affinity-matured, soluble HLA-A*02:01-restricted T cell receptor (TCR) recognizing the gp100-derived YLEPGPVTA peptide is fused to an anti-CD3 single-chain variable fragment (scFv). This TCR-mimetic architecture differentiates the ImmTAC platform from antibody-based bispecific T-cell engagers: antibody bispecifics target cell-surface antigens via Fab arms, while ImmTAC engages intracellular tumor antigens presented on Class I HLA — vastly expanding the universe of targetable tumor antigens. Tebentafusp received FDA regular approval on January 25, 2022 — the first FDA-approved therapy for metastatic uveal melanoma in history, and the first FDA-approved TCR-based bispecific in oncology — for HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma. The label is based on the IMCgp100-202 Phase 3 trial (NCT03070392), which demonstrated a hazard ratio for overall survival of 0.51 (median OS 21.7 vs 16.0 months) despite an objective response rate of only approximately 9% — a striking dissociation between ORR and OS that has been termed a "biological response" signal. EU EMA approval followed in April 2022. Dosing uses an intra-patient escalation schedule (20 mcg Day 1, 30 mcg Day 8, 68 mcg weekly thereafter) to mitigate cytokine release syndrome.
Which patients qualify for Tebentafusp?
Tebentafusp is FDA-approved for adults with HLA-A*02:01-positive unresectable or metastatic uveal melanoma — both criteria are required. (1) HLA-A*02:01-positive: a simple PCR-based blood test or sequencing-based HLA typing identifies whether the patient carries the HLA-A*02:01 allele. Approximately 40-50% of patients of Caucasian/European ancestry carry HLA-A*02:01; the frequency is lower in other ancestries. The test is widely available, inexpensive, and returns within days. HLA-A*02:01-negative patients are not eligible for tebentafusp; alternative options include checkpoint immunotherapy combinations (ipilimumab + nivolumab), liver-directed therapy (PHP / SCANDIUM-III), PRAME TCR-T (IMA203), and TIL therapy. (2) Unresectable or metastatic uveal melanoma: tebentafusp is approved for metastatic disease (any line), not the adjuvant or neoadjuvant setting — those uses are investigational only and are being tested in the ATOM Phase 3 (NCT06246149) and several Phase 2 neoadjuvant studies. Dosing: intra-patient dose escalation 20 mcg Day 1, 30 mcg Day 8, 68 mcg weekly thereafter; first 3 doses in inpatient or extended-monitoring outpatient setting with premedication (acetaminophen, IV corticosteroid, antihistamine) before transitioning to fully outpatient weekly dosing.
What is HLA-A*02:01 and why does it matter for Tebentafusp?
HLA-A*02:01 is a specific allele of the human leukocyte antigen (HLA) Class I molecule HLA-A. HLA Class I molecules present short intracellular peptides on the surface of every nucleated cell so that the immune system can survey what is being made inside the cell — including, in cancer, tumor-specific or tumor-associated peptides. Different people inherit different HLA alleles, and the specific allele determines which peptides can be presented. HLA-A*02:01 is the single most common HLA-A allele in patients of Caucasian/European ancestry — approximately 40-50% of these patients carry at least one HLA-A*02:01 allele. The frequency is lower (but still meaningful) in other ancestries. Tebentafusp's TCR component specifically recognizes the gp100-derived peptide YLEPGPVTA only when that peptide is presented on HLA-A*02:01 — so the drug only works in HLA-A*02:01-positive patients. The HLA typing test is a simple blood draw (PCR-based or sequencing-based), widely available at any cancer center, and typically returns results within days. Patients should request HLA typing as part of the uveal melanoma workup, both because tebentafusp eligibility depends on it and because several other investigational ImmTAC bispecifics (including brenetafusp / IMC-F106C, the PRAME bispecific in NCT06112314 PRISM-MEL Phase 3) and PRAME TCR-T therapies share the HLA-A*02:01 eligibility requirement. HLA-A*02:01-negative patients are not eligible for tebentafusp; alternative options are listed above.
What are the main side effects of Tebentafusp?
Tebentafusp's defining safety signal is cytokine release syndrome (CRS), reported in approximately 89% of patients in the IMCgp100-202 Phase 3 trial but almost always Grade 1-2 (mild to moderate fever, hypotension, chills, tachycardia, hypoxia). CRS is managed by the intra-patient dose escalation schedule (20 mcg Day 1, 30 mcg Day 8, 68 mcg weekly thereafter) — escalating the dose gradually over the first weeks of treatment lets the immune system desensitize to the cytokine surge. The first three doses are administered in an inpatient setting or under extended outpatient monitoring; subsequent weekly doses are given in standard outpatient infusion. Premedication before every dose is required and includes acetaminophen (paracetamol), an IV corticosteroid, and an antihistamine. Severe CRS is uncommon (Grade 3 or above approximately 1-3%) and is managed with IV fluids, supplemental oxygen, vasopressors, and (rarely) tocilizumab. The second-most-common toxicity is skin reactions — rash, pruritus (itching), and periorbital edema — reflecting on-target gp100 expression in normal melanocytes (the same cells the drug is designed to attack in tumors). Skin reactions are typically Grade 1-2, are most pronounced in the first 1-3 weeks of dosing, and are managed with topical or systemic corticosteroids and antihistamines. Other common adverse events: fever, hypotension, fatigue, nausea, chills, headache, vomiting, and transient liver enzyme elevations. The FDA label includes a CRS-monitoring boxed warning. See the Uveal Melanoma trials page for the full uveal trial landscape.
Is Tebentafusp being tested in other cancers beyond uveal melanoma?
Yes — tebentafusp is being tested in two major cross-cancer settings beyond its HLA-A*02:01-positive metastatic uveal melanoma label, and if either reads positive the indication could expand significantly. (1) Cutaneous melanoma post-immunotherapy: NCT05549297 TEBE-AM is a Phase 3 trial of tebentafusp vs investigator's choice in HLA-A*02:01-positive previously-treated advanced cutaneous melanoma after progression on checkpoint immunotherapy. Cutaneous melanoma also expresses gp100 (gp100 is a melanocyte differentiation antigen, expressed in both uveal and cutaneous melanocytes), so the same ImmTAC mechanism applies — the trial tests whether the OS benefit observed in uveal melanoma translates to the much larger cutaneous melanoma population. (2) Clear cell sarcoma: NCT06942442 is a Phase 2 trial of tebentafusp in HLA-A*02:01-positive patients with advanced clear cell sarcoma — the first non-melanoma cancer indication explored for the ImmTAC platform. Clear cell sarcoma is a rare soft tissue sarcoma that shares melanocytic differentiation features (and gp100 expression) with melanoma. If either trial reads positive, tebentafusp would expand beyond rare uveal melanoma into a much larger melanoma population (cutaneous) and a precedent-setting cross-cancer ImmTAC indication (sarcoma). In parallel, Immunocore's broader ImmTAC pipeline includes brenetafusp (IMC-F106C), a PRAME x CD3 bispecific currently in NCT06112314 PRISM-MEL Phase 3 in cutaneous melanoma — extending the TCR-bispecific concept beyond gp100 to PRAME, which is broadly expressed across solid tumors.
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