Tebentafusp-tebn Use in HLA-A*02:01–Positive Unresectable or Metastatic Uveal Melanoma

In January 2022, the FDA approved tebentafusp-tebn (Kimmtrak; Immunocore) for the treatment of adult patients with human leukocyte antigen (HLA)-A*02:01–positive unresectable or metastatic uveal melanoma.¹ The FDA approval was based on results from the IMCgp100 102 trial (NCT02570308), a phase 3, open-label, multicenter trial that included 378 patients with metastatic uveal melanoma.

Uveal melanoma is the most common intraocular cancer in adults and represents 3% to 5% of all melanomas, with an annual incidence in Europe and the United States at approximately 6 per 1 million individuals annually.² Additionally, up to 50% of patients with uveal melanoma will have metastases, predominantly in the liver. The median overall survival in the metastatic setting is approximately 1 year with current agents.

During several prior studies investi-gating the role of HLA in uveal melanoma, investigators were able to confirm that a high HLA class I expression (including HLA-A) is associated with a poor prognosis.³ In the United States and Europe, approximately 45% of individuals are HLA A*02:01 positive.⁴

During IMCgp100-102, patients were randomly assigned 2:1 to the tebentafusp-tebn group or the control group (investigator’s choice of therapy with single-agent pembrolizumab [82%], ipilimumab [13%], or dacarbazine [6%]). Adult patients with previously untreated HLA A*02:01–positive metastatic uveal melanoma, an ECOG score of 0 or 1 and at least 1 measurable lesion were included. Exclusion criteria for the patient population during the trial included symptomatic central nervous system metastases, active autoimmune disease and receiving steroids, or active systemic immunosuppressive treatment.

Among previously untreated patients with metastatic uveal melanoma, more patients treated with tebentafusp-tebn achieved 1-year overall survival than those in the control group (73% vs 59%, P < .001). Progression-free survival was also significantly higher in the tebentafusp-tebn group (31% vs 19% at 6 months, P = .01). Additionally, the percentage of patients who had an objective response rate was higher in the tebentafusp-tebn group at 9% vs 5% in the control group, with median duration of response at 9.9 months and 9.7 months, respectively.⁴

Mechanism of Action

Tebentafusp-tebn is representative of a new class of drug, termed immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC). The ImmTAC molecule is aT cell–redirecting bispecific fusion protein that uses an engineered high-affinity T-cell receptor to target any protein that is presented as a peptide-HLA complex on the target cell surface.

Tebentafusp-tebn consists of a soluble affinity-enhanced HLA-A*02:01-restricted T-cell receptor that is specific for the glycoprotein 100 (gp100) peptide and is fused to an anti-CD3 single-chain variable fragment. Glycoprotein 100 is expressed via HLA-A*02:01 on the surface of most uveal melanoma tumor cells, and tebentafusp-tebn binds to the HLA-A*02:01-gp100 complex on the target cell surface. This results in recruitment and activation of polyclonal T cells through CD3 to release cytokines and cytolytic mediators against the target uveal melanoma tumor cells.^5,6

Dosage and Administration

The selection of patients for treatment with tebentafusp-tebn for unresectable or metastatic uveal melanoma is based on a positive HLA-A*02:01 genotyping test, with the tebentafusp-tebn intravenous (IV) dosing scheduleas follows⁶:

• 20 μg IV on day 1

• 30 μg IV on day 8

• 68 μg IV on day 15

• 68 μg IV once every week thereafter

Patients should be treated with tebentafusp-tebn following the dosing schedule until unacceptable toxicity or disease progression occurs. Patients should be administered tebentafusp-tebn once weekly by IV infusion over a period of 15 to 20 minutes. During the first 3 doses of tebentafusp-tebn, patients are at highest risk of cytokine release syndrome (CRS), which may be serious or life-threatening; for this reason, monitoring during and for at least 16 hours following the infusion is required for the first 3 doses, with subsequent monitoring as clinically indicated following the third dose. If the patient does not experience grade 2 or worse hypotension during or after the third infusion, subsequent doses are better tolerated and a minimum of 30 minutes of monitoring is required following tebentafusp-tebn infusion.⁶

Adverse Events

The most common treatment-related adverse events (TRAEs) of any grade in the tebentafusp-tebn group were CRS (89%) with symptoms such as pyrexia (76%), chills (47%), hypotension (38%), and skin-related AEs such as rash (83%), pruritus (69%), and erythema (23%). The data also showed serious adverse events (AEs)occurred in 28% of patients receiving tebentafusp-tebn,including CRS (10%), rash (4.5%), pyrexia (2.4%),and hypotension (2%).

Fifty-seven percent of patients in the tebentafusp-tebn group experienced TRAEs in the first 4 weeks of treatment during dose escalation; however, the incidence is decreased with repeated doses.^4,6 AEs leading to dose reduction occurred in 5% of patients, with CRS (2.4%) and rash (2%) being the most common causes. AEs leading to permanent discontinuation occurred in 3.3% of patients and include anaphylactic reaction, brain edema, CRS, fatigue, hepatotoxicity, hypotension, and nausea, each occurring at 0.4%. No treatment related deaths were reported in either group.^4,6

During the trial, the most common laboratory abnormalities, occurring in 50% or more of patients, were decreased lymphocyte count and increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate levels.⁶

Warnings and Precautions

Tebentafusp-tebn has a black box warning for CRS, which may be serious or life-threatening. Patients should be monitored during and for at least 16 hours following the first 3 infusions, then as clinically indicated.⁶

Pregnancy and Lactation

Currently, there are no available data with tebentafusp-tebn in pregnant women. However, based on the drug’s mechanism of action, it may cause fetal harm when administered to a pregnant woman. Women taking tebentafusp-tebn should be advised of the potential risk to the fetus, and health care providers should verify the pregnancy status in women of reproductive potential prior to initiating treatment. Women of reproductive potential should also be advised to use effective contraception during treatment and for 1 week following the last dose of tebentafusp-tebn.⁶

There are also no available data on the presence of tebentafusp-tebn in human milk, the subsequent effect on a breastfed child, or the effects on milk production. As tebentafusp-tebn may be excreted in human milk, patients taking tebentafusp-tebn should also be advised not to breastfeed during treatment and for at least 1 week after the last dose.⁶

About the Author

Samantha Brongiel, PharmD, BCOP, is a clinical oncology pharmacist at Smilow Cancer Hospital and Yale New Haven Health System in Connecticut.

References

1. Center for Drug Evaluation and Research. FDA approves tebentafusp-tebn for unresectable or metastatic uveal melanoma. U.S. Food and Drug Administration. Published January 26, 2022. Accessed July 18, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tebentafusp-tebn-unresectable-or-metastatic-uveal-melanoma

2. Jager MJ, Shields CL, Cebulla CM, et al. Uveal melanoma. Nat Rev Dis Primers.2020;6(1):24. doi:10.1038/s41572-020-0158-0

3. Souri Z, Wierenga APA, Mulder A, Jochemsen AG, Jager MJ. HLA expression in uveal melanoma: an indicator of malignancy and a modifiable immunological target. Cancers (Basel). 2019;11(8):1132. doi:10.3390/cancers11081132

4. Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485

5. Kimmtrak HCP. KIMMTRAK (tebentafusp-tebn) - Official Physician Website. Accessed July 2022. https://www.kimmtrakhcp.com/?gclid=EAIaIQobChMIiKP4yYaB-QIVDY_ICh3qAA86EAAYASAAEgLKSvD_BwE

6. Tebentafusp-tebn. Prescribing information. U.S. Food and Drug Administration; 2022. Revised January 2022. Accessed July 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761228s000lbl.pdf