Introduction
Imdelltra (tebentafusp-tebn) is a novel bispecific T-cell engager (BiTE) immunotherapy approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. As the first FDA-approved T-cell redirecting therapy for metastatic uveal melanoma, Imdelltra represents a significant advancement in the treatment of this rare but aggressive form of ocular cancer that has historically had limited therapeutic options.
Mechanism of Action
Imdelltra is a bispecific gp100 peptide-HLA-directed CD3 T-cell engager that binds simultaneously to CD3 on T-cells and gp100 peptide presented by HLA-A*02:01 on uveal melanoma cells. This dual binding creates an immunological synapse between T-cells and tumor cells, leading to T-cell activation, proliferation, and targeted cytotoxicity against gp100-expressing melanoma cells. The drug redirects existing T-cells to recognize and eliminate tumor cells regardless of their native T-cell receptor specificity.
Indications
Imdelltra is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. This indication received accelerated approval based on overall response rate and duration of response, with continued approval contingent upon verification of clinical benefit in confirmatory trials.
Dosage and Administration
Initial Dose: 20 mcg intravenously over 15-30 minutes Step-up Dosing: 30 mcg on day 2, 54 mcg on day 3 Maintenance Dose: 68 mcg intravenously weekly beginning on day 8Dose modifications are required for cytokine release syndrome (CRS) and other adverse reactions. Treatment should be administered by healthcare providers experienced in the management of immunotherapy-related adverse events. HLA-A*02:01 status must be confirmed prior to initiation.
Pharmacokinetics
Absorption: Administered intravenously with complete bioavailability Distribution: Steady-state volume of distribution approximately 6-8 L Metabolism: Primarily proteolytic degradation via catabolic pathways Elimination: Half-life of approximately 6 hours with clearance of 10-15 L/day Special Populations: No clinically significant differences observed based on age, sex, race, or mild to moderate renal/hepatic impairmentContraindications
- History of severe hypersensitivity to tebentafusp-tebn or any component of the formulation
- Patients who are not HLA-A*02:01 positive
- Active uncontrolled infection
- Concurrent administration with other T-cell redirecting therapies
Warnings and Precautions
Boxed Warning: Cytokine Release Syndrome (CRS) - can be life-threatening or fatal. Requires close monitoring and management according to established guidelines. Additional Warnings:- Skin reactions including rash, pruritus, and skin edema
- Elevated liver enzymes requiring monitoring
- Neurological toxicity including headache and dizziness
- Increased risk of infections
- Embryo-fetal toxicity
Drug Interactions
- Immunosuppressants: May reduce efficacy of Imdelltra
- CYP substrates: Theoretical potential for increased exposure due to cytokine-mediated suppression
- Live vaccines: Contraindicated during treatment
- Other T-cell activating therapies: Increased risk of CRS and neurotoxicity
Adverse Effects
Very Common (≥20%):- Cytokine release syndrome (92%)
- Rash (83%)
- Pyrexia (76%)
- Pruritus (69%)
- Fatigue (56%)
- Nausea (39%)
- Chills (37%)
- Headache (33%)
- Hypothyroidism (32%)
- Edema (27%)
- Grade 3-4 CRS (1%)
- Elevated transaminases (15%)
- Skin reactions requiring intervention (8%)
- Neurological events (3%)
Monitoring Parameters
Prior to each dose:- Complete blood count with differential
- Comprehensive metabolic panel including liver function tests
- Assessment for CRS symptoms
- Skin examination
- Neurological assessment
- Vital signs every 30 minutes
- Continuous monitoring for CRS symptoms
- Thyroid function tests monthly
- Regular assessment for delayed adverse events
- Tumor response assessment per RECIST 1.1 criteria
Patient Education
- Understand the risk of CRS and report fever, chills, dizziness, or difficulty breathing immediately
- Report skin changes, itching, or rash
- Maintain hydration and monitor for fever
- Use effective contraception during treatment and for 1 week after final dose
- Inform all healthcare providers about Imdelltra therapy
- Carry patient safety card provided by manufacturer
- Avoid live vaccines during treatment
- Report any neurological symptoms promptly
References
1. FDA Approval Letter: Imdelltra (tebentafusp-tebn). April 2024 2. Nathan P, et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2021;385(13):1196-1206 3. Imdelltra [package insert]. Waltham, MA: Immunocore Limited; 2024 4. Middleton MR, et al. Tebentafusp: A First-in-Class TCR-Anti-CD3 Bispecific T Cell Engager for Metastatic Uveal Melanoma. J Clin Oncol. 2022;40(16):1756-1765 5. NCCN Clinical Practice Guidelines in Oncology: Uveal Melanoma. Version 2.2024 6. ClinicalTrials.gov: IMCgp100-102 (NCT03070392) and IMCgp100-202 (NCT02570308)