Considerations for Use of Tebentafusp, a BiTE Approved for Rare, High-Risk Uveal Melanoma

Tebentafusp-tebn (Kimmtrak; Immunocore Limited) is a bispecific T-cell engager (BiTE) approved by the FDA for the treatment of adult patients with HLA-A*02:01-positive unresectable or metastatic uveal melanoma, a rare malignancy with an annual incidence of approximately 5 cases per million people.¹ Approximately 91% of patients with uveal melanoma present with localized disease.² The 5-year risk for progression to metastatic disease varies by stage at initial presentation, with estimates of 3% to 5% for patients who present with stage 1 disease, to greater than 44% of patients with stage III disease at diagnosis.³ Upon progression to metastatic disease, the most common sites of metastasis are the liver, lung, bone, and skin.³

New England Cancer Specialists (NECS), an independent community oncology practice with 4 locations in Maine and New Hampshire, sees a proportional share of this small but high-risk patient population. Whether through its collaboration with regional academic medical centers or by local diagnosis, NECS has treated patients with metastatic uveal melanoma in most of its clinic locations.

Guidelines from the National Comprehensive Cancer Network (NCCN) for the workup of metastatic uveal melanoma recommend biopsy, baseline imaging, assessment of liver function, and HLA-A*02:01 genotypic testing. For patients in whom the bulk of disease is confined to the liver, liver-directed treatment modalities such as embolization, ablation, resection, or regional isolation perfusion are recommended. Conversely, for patients in whom the disease is not hepatically dominant, recommendations are systemic therapies or a clinical trial.⁴

Genotype testing for uveal melanoma patients involves a high-resolution whole-blood assay to determine the presence of HLA-A*02:01. Immunocore, the manufacturer of tebentafusp, provides guidance on navigating the nuances and interpretation of this testing.⁵ HLA-A*02:01 is the most prevalent cell surface marker in Caucasian populations and is present in approximately 45% of people with metastatic uveal melanoma in the United States and Europe.⁶ Human leukocyte antigens (HLAs) are cell surface molecules that regulate the body’s immune response to foreign substances by binding and presenting them to T cells, thus triggering an immune response to destroy the cell.⁶ Melanoma cells widely express a protein called glycoprotein 100 (gp100). These gp100 peptide molecules are bound to the end of HLA-A*02:01 molecules and presented on the surface of melanoma cells for immune cell detection.⁷

Mechanism of Action for Tebentafusp

For patients with metastatic uveal melanoma who test positive for HLA-A*02:01, NCCN recommended treatment options include tebentafusp (category 1 recommendation), immune checkpoint inhibitors (either in combination or as monotherapy), a clinical trial, or systemic chemotherapy.⁴ The remainder of this discussion will focus on patients who are candidates for tebentafusp.

As noted previously, approximately half of patients with metastatic uveal melanoma will express a gp100–HLA-A*02:01 complex on their cell surface.⁸ As a BiTE, tebentafusp has 2 unique binding locations. One arm of the drug binds to the gp100 antigen at the end of the HLA-A*02:01 antigen. The other arm of the drug binds to CD3, a receptor found on cytotoxic T cells. Once simultaneously bound, T cells release inflammatory cytokines, leading to direct lysis and death of uveal melanoma cells.⁸

Tebentafusp received FDA approval in January of 2022 following the publication of phase 3 trial (NCT03070392) data in the New England Journal of Medicine (NEJM), which demonstrated a statistically significant benefit in both overall survival (OS) and progression-free survival for tebentafusp compared with investigator’s choice of pembrolizumab (Keytruda; MSD International Business GmbH), ipilimumab (Yervoy; Bristol Myers Squibb), or dacarbazine in previously untreated patients with HLA-A*02:01 metastatic uveal melanoma.⁵ Three-year follow-up data published in NEJM in 2023 confirmed the efficacy benefit.⁹ Median OS at a minimum follow-up of 36 months was 21.6 months in the tebentafusp group vs 16.9 months in the control group (HR, 0.68; 95% CI, 0.54-0.87).⁹

Dosing and Administration

Tebentafusp is administered intravenously over 15 to 20 minutes every 7 days until progression or toxicity. The week 1 dose is 20 mcg, the week 2 dose is 30 mcg, and all subsequent weeks are 68 mcg. Drug preparation is somewhat unique, requiring a 2-step dilution process. In step 1, a small amount of albumin is added to a 100 mL bag of normal saline to create a 250 mcg/mL solution. This is done to prevent adsorption of tebentafusp to the infusion bag. After several gentle inversions of the albumin/saline dilution in the bag, the dose of tebentafusp is added to the bag, and the bag is gently inverted several times prior to administration using a tubing set containing a 0.2-micron in-line filter.

Because tebentafusp has an evidence-based indication supported by guidelines, patient access to tebentafusp in all cancer treatment settings—academic, community, rural, etc—is critical to reduce disparities in cancer care. Our practice uses a clinical pathways tool embedded in our electronic medical record (EMR). Clinical pathways assist in appropriate patient treatment selection, especially for rare disease states that a general oncologist in the community setting may see only once every several years. Navigating the melanoma disease state pathway prompts a physician to select whether a patient is positive or negative for HLA-A*02:01 to help ensure that all appropriate testing has been conducted prior to treatment selection.

Access, Adverse Events, and Support

Access to tebentafusp is limited not only by small patient populations and complexities of uveal melanoma testing, but also by the agent’s adverse event (AE) profile. Tebentafusp belongs to the broader class of drugs known as BiTEs. Since 2022, the FDA has approved 9 medications in this class; in addition to uveal melanoma, these drugs are used for common disease states such as lymphoma, multiple myeloma, and small cell lung cancer.¹⁰ Use of BiTEs is rapidly growing due to expanding clinical indications and greater comfort with their administration in the outpatient setting.^11,12

A brief review of the unique toxicities of this class will help illustrate the potential concerns of treatment initiation for a drug such as tebentafusp. By virtue of tebentafusp’s previously described mechanism of action, activation of the immune system via T-cell engagement leads to a cytokine excess that not only causes tumor cell death but also systemic manifestations known as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity (ICANS). Common signs and symptoms of CRS include fever, hypoxia, hypotension, tachycardia, headache, and myalgia. ICANS manifests as delirium, tremor, lethargy, confusion, aphasia, encephalopathy, and seizures. Although CRS and ICANS symptoms are early onset in nature, they are fortunately a short-lived phenomenon, largely confined to the first several doses of treatment, when tumor burden is largest. Rates of CRS and ICANS vary by T-cell engager product and can be mitigated with various preventive strategies, such as steroid and/or antihistamine premedication, prophylactic tocilizumab (Actemra; Genentech, Inc), and intravenous or oral hydration.¹³

For tebentafusp specifically, the primary early toxicity concern is CRS. Due to the agent’s potential for higher-grade CRS, package insert recommendations for tebentafusp suggest monitoring patients for 16 hours in an appropriate health care setting for the first 3 doses.¹⁴ Published incidence of all-grade CRS is high at 89%.¹² However, only 0.8% of patients experience grade 3/4 CRS.¹⁴ Most CRS events are grade 2 (76%), and the majority of events occur on the day of treatment (84%).¹² A recently published pooled safety analysis of 410 patients reports 0 patients as having experienced ICANS.¹⁵

Despite the lack of ICANS and low rate of grade 3 or 4 CRS, our practice has not yet begun to initiate tebentafusp patients in the outpatient setting like we have for all other BiTEs.¹² However, to reduce barriers to access, we look forward to developing a model that will allow us to initiate newly identified patients on tebentafusp in an all-outpatient setting.

Although much attention is paid to the toxicities associated with the initiation of BiTEs, it is also important to monitor later-onset AEs to ensure long-term safety. In addition to CRS, tebentafusp carries a risk of dermatologic toxicity (> 90%), hepatotoxicity (65% incidence of transaminitis), hematologic toxicity, and gastrointestinal toxicity.¹² In our practice, we utilize the EMR to embed drug-specific laboratory tests and AE monitoring guidance at appropriate time intervals in treatment order sets. This structured AE monitoring and management guidance is critical to ensuring that a patient safely remains on treatment and derives clinical benefit for as long as possible.

In addition to the clinical awareness and operational structure in place at NECS, our partnership with Immunocore has been especially important. Immunocore has collaborated with NECS on educational programs and provided in-service training for our clinical staff. From a pharmacist perspective, engaging with their medical science liaisons has allowed us to ask detailed questions about AE rates and management strategies. Immunocore’s website¹⁶ also offers excellent information about disease state, testing, efficacy, safety, and drug access. Kimmtrak Connect, Immunocore’s customized patient support program, helps patients navigate the complexities of treatment initiation and financial assistance. Immunocore has collaborated very closely with our internal patient advocates to help patients afford their treatment. Because tebentafusp is a very high-cost medication requiring weekly administration, mitigating financial toxicity is key to ensuring patients can access the therapy that is clinically most effective for them.

Optimizing the overall clinical benefit of a medication in an uncommon disease state involves an understanding of the treatment options, proactively identifying patients based on disease-specific markers and targets, leveraging the capabilities of the EMR to create safety structure, and partnering with the manufacturer to provide education and patient resources for care coordination and medication access. Across these various principles, NECS has been able to safely and effectively incorporate tebentafusp as a treatment option for our patients with metastatic uveal melanoma.

Author Information

Yonatan S. Resnick, PharmD, is vice president of pharmacy at New England Cancer Specialists, an independent community oncology practice with locations in Maine and New Hampshire.

References

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