Author: [AUTHOR] Published on 2/11/2022 5:00:00 AM
FDA Approves KIMMTRAK (Tebentafusp-tebn) for the Treatment of HLA-A*02:01-Positive Adult Patients with Unresectable or Metastatic Uveal Melanoma
On January 25, 2022, the US Food and Drug Administration (FDA) approved KIMMTRAK (tebentafusp-tebn) for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. < read more
The approved recommended dosage of KIMMTRAK is 20 mcg intravenously (IV) on Day 1, 30 mcg IV on Day 8, 68 mcg IV on Day 15, and 68 mcg IV once every week thereafter until unacceptable toxicity or disease progression occur. Administer the first three infusions of KIMMTRAK in an appropriate healthcare setting by intravenous infusion over 15-20 minutes. Monitor patients during the infusion and for at least 16 hours after the infusion is complete. Dosage interruption or permanent discontinuation may be required based on individual safety and tolerability.
Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated.
Additional information regarding dosage and administration as well as warnings and precautions about CRS, skin reactions, elevated liver enzymes, and embryo-fetal toxicity can be found in the full prescribing information linked below.
Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
MOA: Tebentafusp-tebn is a bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor CD3 T cell engager.
General PK: After a single dose administration, tebentafusp-tebn C
max and AUC
0-7d increased in an approximately dose proportional manner from 20 to 68 mg (0.3 to 1 times the approved recommended dose). The steady-state geometric mean (% CV) C
max of tebentafusp-tebn is 13 ng/mL (34.6%) and AUC
0-7d is 4.6 ng.day/mL (23%) following administration of the approved recommended dosage in patients with metastatic uveal melanoma with no accumulation.
Distribution: Tebentafusp-tebn geometric mean (% CV) steady-state volume of distribution is 7.56 L (24%).
Elimination: The geometric mean clearance of tebentafusp-tebn is 16.4 L/d (CV: 24.5%) and median terminal half-life is 7.5 hours (range: 6.8-7.5 hours).
Metabolism: Tebentafusp-tebn is expected to be catabolized into small peptides and amino acids.
PD: Lymphocyte counts declined the day after the first 3 doses and returned to baseline prior to subsequent doses. Serum levels of cytokines (IFN-γ, TNFα, IL-2, IL-6, IL-10 and IL-1RA) and chemokines (CXCL9, CXCL10, CXCL11, hepatocyte growth factor, and monocyte chemoattractant protein-1) were increased during the first three doses of KIMMTRAK with peak levels between 8 to 24 hours after treatment with KIMMTRAK and levels returned to baseline prior to subsequent doses. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the first 3 doses.
Immunogenicity: Treatment-emergent anti-drug antibodies (ADA) against tebentafusp-tebn were detected in 33% and 29% of patients receiving tebentafusp-tebn across all doses in study IMCgp100-102 and -202, respectively. The median onset time to ADA formation was 6-9 weeks after tebentafusp-tebn treatment. The ability of these binding ADAs to neutralize tebentafusp-tebn is unknown. Median titer in the ADA-positive subgroup was 8192 across the 67 treatment cycles. The exposure (AUC
0-7d) of tebentafusp-tebn decreased by 97% and terminal half-life decreased to 10-14 minutes in patients with ADA titers greater than 8192. Exploratory analyses with limited data suggest that formation of ADA does not appear to have clinically significant effect on frequency or severity of hypersensitivity related adverse reactions and no observed sign of decreased overall survival.
Use in Specific Populations
No clinically significant difference in the PK of tebentafusp-tebn was identified based on weight (43 to 163 kg), sex (48% female), age (23 to 91 years), or mild to moderate renal impairment based on creatinine clearance (CLcr) estimated by C-G formula (CLcr 30 to 89 mL/min) or mild hepatic impairment as measured by total bilirubin (TB) and aspartate aminotransferase (AST) (TB ≤ upper limit of normal (ULN) and AST > ULN or TB > 1 to 1.5x ULN and any AST).
Tebentafusp-tebn has not been studied in patients with severe (CLcr < 30 mL/min) renal impairment or in patients with moderate (TB >1.5 to 3x ULN, any AST) to severe (TB > 3 to 10x ULN, any AST) hepatic impairment.
Drug Interaction Studies
Elevation of certain proinflammatory cytokines may suppress CYP450 enzyme activities.
Efficacy and Safety
Efficacy of KIMMTRAK was evaluated in IMCgp100-202, a randomized, open-label, multicenter trial that enrolled patients with metastatic uveal melanoma and were HLA-A*02:01 genotype positive identified by a central assay. The major efficacy outcome was overall survival (OS). Additional efficacy outcomes were investigator-assessed progression free survival (PFS) and objective response rate (ORR) per RECIST 1.1. Additional information regarding efficacy trial can be found in the full prescribing information linked below.
The most common adverse reactions (occurring in ≥ 30%) are CRS, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache and vomiting.
The most common laboratory abnormalities (occurring in ≥ 50%) are decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
