Metastatic uveal melanoma: Tebentafusp unobfuscated

By Warren R. Heymann, MD, FAAD
June 25, 2025
Vol. 7, No. 25

Oncodermatology is a full-time occupation comprised of two major components — novel therapies for cutaneous malignancies and adverse reactions to treatments for diverse cancers. A novel class of anticancer agents is termed ImmTACs — immune mobilizing monoclonal T-cell receptors against cancer. ImmTACs combine high-affinity recognition of MHC-presented tumor antigens with the simultaneous redirection and activation of non-tumor-specific T cells. (1) According to Dhillon, “Tebentafusp (tebentafusp-tebn; Kimmtrak^®) is a first-in-class, bispecific gp [glycoprotein]100 peptide-HLA-A*02:01 directed T cell receptor (TCR) CD3 T cell engager being developed by Immunocore for the treatment of uveal melanoma and malignant melanoma. The TCR arm of tebentafusp binds to HLA-A*02:01-positive uveal melanoma cells and activates polyclonal T cells, through CD3, to release inflammatory cytokines and cytolytic proteins, resulting in the direct lysis of tumour cells. In January 2022, tebentafusp received its first approval in the USA for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma, and in February 2022 received a Positive Opinion from the EU Committee for Medicinal Products for Human Use for the treatment of uveal melanoma.” (2)

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of nearly 5 cases per million individuals in the United States, and an approximate worldwide incidence of 6,500 cases per year. The five-year mortality from metastatic UM is 30%; 40% fatality rates occur in patients 10 to 15 years following the primary diagnosis. Colorectal and liver metastases are the leading causes of death. UM maintains a psychosocial burden on affected patients, greatly impacting their quality of life. (3.4) Current metastatic UM (mUM) therapy includes surgery, radio-embolization, chemoembolization, percutaneous hepatic melphalan infusion, systemic chemotherapy, and immunotherapy. (5) Immune check point inhibitors (anti-PD1/PD-L1, anti-CTLA4) have limited efficacy in patients with mUM. Tebentafusp studies have shown a significant and meaningful impact on overall survival in previously untreated patients with mUM. (6) A meta-analysis demonstrated that tebentafusp achieved a pooled objective response rate of 8% and a disease control rate of 51%. The median overall survival range of 16.8 to 25.5 months might seem low, but it is a meaningful improvement over historical benchmarks. (5)

This commentary focuses on tebentafusp and its cutaneous adverse effects.

According to Howlett et al., “Adverse events (AEs) can be grouped into two main categories: cytokine-mediated toxicity and skin toxicity. Cytokine-release-mediated AEs include pyrexia, chills and hypotension, usually occurring some hours after drug administration and are generally short-lived. In contrast to this, skin toxicities relate to the on-target off-tumour effect of gp100 expression in normal melanocytes and take somewhat longer to resolve — usually days. Most toxicities occur during the first cycle of treatment. In the phase III trial, Grade 3 and 4 AEs were seen in 44% of patients in the tebentafusp arm versus 17% in the control arm. There were no treatment-related deaths and only 2% of patients discontinued treatment with tebentafusp due to treatment-related AEs. This compared to a discontinuation rate of 5% in the control group.” (4)

Patients with a cytokine release syndrome are usually treated with antipyretic agents, intravenous fluids, glucocorticoids, or a combination of these therapies. In a phase III trial, 378 mUM patients were randomly assigned to either the tebentafusp group (252 patients) or a control group (126 patients who received pembrolizumab, ipilimumab, or dacarbazine); skin-related adverse events included a rash (83%), pruritus (69%), and erythema (23%). (7)

Rodriguez et al. reported on 6 patients with mUM who developed cutaneous AEs induced by tebentafusp. “All patients developed pruritus, which began after their first infusion of tebentafusp. Pruritus in patients 1 and 2 did not present with a concurrent rash and was well-controlled with antihistamines alone… Patients 3 and 4 developed morbilliform rashes affecting their face, trunk and extremities. With each subsequent infusion, erythema and pruritus increased. Symptoms were managed with pretreatment intravenous diphenhydramine, hydrocortisone 2.5% cream for the face, triamcinolone 0.1% cream for the body, and, as needed, oral or intravenous diphenhydramine. After three inpatient infusions, patients were adequately controlled as outpatients, with similar regimens (replacing intravenous diphenhydramine with oral hydroxyzine).” Patients 5 and 6 had more severe reactions — eczematous in the former and morbilliform in the latter — requiring clobetasol. The authors suggest that the high cutaneous AEs rate is because of gp 100 expression by melanocytes on normal skin. (8)

Tomsitz et al performed a prospective cohort study of 33 mUM patients treated with at least one dose of tebentafusp. Skin toxicity was observed in 78.8% of patients and was classified into 5 clinical categories: (1) symmetrical erythematous patches (83.8%), (2) hemorrhagic macules (11.8%), (3) urticarial lesions (7.4%), (4) bullous lesions (1.5%), and (5) skin (8.5%) and hair depigmentation (11.4%). Most lesions were on the face, often with periorbital involvement (69.1%), followed by the torso (67.6%), and upper extremities (36.7%). Most acute toxicities were noted within 20 hours of the infusion. Only symptomatic patients were treated with topical steroids. All early skin eruptions resolved quickly and without sequelae, except for blisters that healed with milia. Depigmentation appeared 8 to 19 weeks after treatment initiation. Histopathologic features were focal lymphocytic interface dermatitis with epidermal infiltration of CD8-positive lymphocytes. Patients with skin AEs had a significantly longer median overall survival compared to patients without any cutaneous events (34 versus 4 months, P < .001). (9)

Studies are underway to determine the utility of tebentafusp in patients with metastatic cutaneous melanoma recalcitrant to immune checkpoint inhibitors. (10) Regardless, even if the drug is not proven effective for cutaneous melanoma, given the high rate of cutanenous AEs with it, dermatologists will be consulted on patients being treated for mUM.

Point to Remember: Tebentafusp, a novel ImmTAC (immune mobilizing monoclonal T-cell receptors against cancer) approved for treating metastatic uveal melanoma, has a high incidence of cutaneous adverse reactions ranging from acute toxicity to depigmentation.

Our expert’s viewpoint

Scott Worswick, MD, FAAD
Professor of Dermatology
University of Southern California
Los Angeles, CA

Keeping up with the endless and exciting stream of new immunotherapies can be challenging. One of the newest drugs I’ve encountered lately in our cancer hospital (thanks to an ongoing trial of one of our oncologists) is tebentafusp, whose brand name is Kimmtrack. Its mechanism of action may be unfamiliar to you because it targets a glycoprotein found in uveal melanoma cells. Still, given its side effect profile, its name will become one you will recognize. Side effects typically occur quickly (usually within the first cycle) but do not necessitate withdrawing the drug. This is important because it provides a disease response rate of about 50% (much higher than what is expected for uveal melanoma with the medications we currently use for cutaneous melanoma).

To remember the side effects of tebentafusp, remember how this drug works. It activates T-cells, which then target melanocytes for destruction. As such, side effects can be grouped into those due to cytokine release (pyrexia or chills, hypotension), those resulting in cutaneous inflammation (morbilliform rash, erythema, dermatitis, urticaria, pruritus) and those directly due to melanocyte destruction (vitiligo, poliosis). Importantly, these side effects, while potentially uncomfortable, are rarely life-threatening and can be managed supportively using anti-histamines for pruritus, topical steroids for inflammation, and systemic steroids for more severe reactions.

To date, no reports of Stevens-Johnson syndrome have been reported with this agent. However, given its mechanism of action, reports of bullae as a side effect, and the histopathologic feature of CD8+ T-cells infiltrating the epidermis with an interface dermatitis, it seems possible that this may emerge as a potential side effect as more patients are treated with this drug. For now, though, patients with cutaneous reactions can be managed as described above with supportive care. They can be reassured that just as with PD1 inhibitors, a survival benefit is conferred to patients who receive tebentafusp and develop cutaneous reactions.

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References

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2. Dhillon S. Tebentafusp: First Approval. Drugs. 2022 Apr;82(6):703-710. doi: 10.1007/s40265-022-01704-4. PMID: 35364798.

3. Kulbay M, Marcotte E, Remtulla R, Lau THA, Paez-Escamilla M, Wu KY, Burnier MN Jr. Uveal Melanoma: Comprehensive Review of Its Pathophysiology, Diagnosis, Treatment, and Future Perspectives. Biomedicines. 2024 Aug 5;12(8):1758. doi: 10.3390/biomedicines12081758. PMID: 39200222; PMCID: PMC11352094.

4. Howlett S, Carter TJ, Shaw HM, Nathan PD. Tebentafusp: a first-in-class treatment for metastatic uveal melanoma. Ther Adv Med Oncol. 2023 Mar 21;15:17588359231160140. doi: 10.1177/17588359231160140. PMID: 36970111; PMCID: PMC10031621.

5. Dian Y, Liu Y, Zeng F, Sun Y, Deng G. Efficacy and safety of tebentafusp in patients with metastatic uveal melanoma: A systematic review and meta-analysis. Hum Vaccin Immunother. 2024 Dec 31;20(1):2374647. doi: 10.1080/21645515.2024.2374647. Epub 2024 Jul 14. PMID: 39004419; PMCID: PMC11249029.

6. Hassel JC, Stanhope S, Greenshields-Watson A, Machiraju D, Enk A, Holland C, Abdullah SE, Benlahrech A, Orloff M, Nathan P, Piperno-Neumann S, Staeger R, Dummer R, Meier-Schiesser B. Tebentafusp Induces a T-Cell-Driven Rash in Melanocyte-Bearing Skin as an Adverse Event Consistent with the Mechanism of Action. J Invest Dermatol. 2024 Jul 15:S0022-202X(24)01886-4. doi: 10.1016/j.jid.2024.03.048. Epub ahead of print. PMID: 39019150.

7. Nathan P, Hassel JC, Rutkowski P, Baurain JF, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R, Kirkwood JM, Joshua AM, Sacco JJ, Shoushtari AN, Orloff M, Piulats JM, Milhem M, Salama AKS, Curti B, Demidov L, Gastaud L, Mauch C, Yushak M, Carvajal RD, Hamid O, Abdullah SE, Holland C, Goodall H, Piperno-Neumann S; IMCgp100-202 Investigators. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2021 Sep 23;385(13):1196-1206. doi: 10.1056/NEJMoa2103485. PMID: 34551229.

8. Rodriguez I, Norman T, Guenther J, Smart K, Kwong A, Berry J, In GK, Worswick S. Cutaneous adverse effects induced by tebentafusp in patients with metastatic uveal melanoma: a case series and treatment insights. Clin Exp Dermatol. 2024 Mar 21;49(4):392-394. doi: 10.1093/ced/llad387. PMID: 37956104.

9. Tomsitz D, Kerl K, French LE, Heinzerling L. Clinical and pathological characterization of tebentafusp-associated skin toxicity: A cohort study with 33 patients. J Am Acad Dermatol. 2024 Aug 29:S0190-9622(24)02741-5. doi: 10.1016/j.jaad.2024.08.037. Epub ahead of print. PMID: 39216820.

10. Hamid O, Hassel JC, Shoushtari AN, Meier F, Bauer TM, Salama AKS, Kirkwood JM, Ascierto PA, Lorigan PC, Mauch C, Orloff M, Evans TRJ, Holland C, Edukulla R, Abedin SE, Middleton MR. Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study. J Immunother Cancer. 2023 Jun;11(6):e006747. doi: 10.1136/jitc-2023-006747. PMID: 37286303; PMCID: PMC10254987.

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