These highlights do not include all the information needed to use KIMMTRAK ®safely and effectively. See full prescribing information for KIMMTRAK ®. KIMMTRAK ®(tebentafusp-tebn) injection, for intravenous use Initial U.S. Approval: 2022

WARNING: CYTOKINE RELEASE SYNDROME

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 [(see Dosage and Administration (2.2), see Warnings and Precautions (5.1)] .

1 INDICATIONS AND USAGE

KIMMTRAK is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for treatment of unresectable or metastatic uveal melanoma with KIMMTRAK based on a positive HLA-A*02:01 genotyping test of a whole blood sample [see Clinical Studies (14)] . Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics.

2.2 Recommended Dosage

The recommended dosage of KIMMTRAK administered intravenously is:

Treat patients 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.

If the patient does not experience Grade 2 or worse hypotension (requiring medical intervention) during or after the third infusion, administer subsequent doses in an appropriate ambulatory care setting, and monitor patients for a minimum of 30 minutes following each of these infusions [see Warnings and Precautions (5.1)] .

• 20 mcg on Day 1
• 30 mcg on Day 8
• 68 mcg on Day 15
• 68 mcg once every week thereafter

2.3 Dosage Modifications for Adverse Reactions

No dosage reduction for KIMMTRAK is recommended. Dosage modifications for KIMMTRAK for adverse reactions are summarized in Table 1.

Table 1: Dose Modifications for Adverse Reactions

2.4 Preparation and Administration

Preparation

Step 1: Preparation of the Infusion Bag

To prevent adsorption of tebentafusp-tebn to the infusion bag and other components of the drug delivery system, prepare an Albumin (Human) in 0.9% Sodium Chloride Injection, USP solution as follows:

Step 2- Preparation of KIMMTRAK Solution for Infusion

Administration

• A 2-step dilution process is required for preparation of the final KIMMTRAK dose for infusion.
• Use aseptic technique for dilution and preparation of intravenous infusion solutions.
• Visually inspect parenteral drug products and infusion bags for particulate matter and discoloration prior to administration, whenever solution and container permit.

3 DOSAGE FORMS AND STRENGTHS

Injection: 100 mcg/0.5 mL clear, colorless to slightly yellowish solution in a single-dose vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Cytokine Release Syndrome

Cytokine release syndrome (CRS), which may be life threatening, occurred in patients receiving KIMMTRAK. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS (≥ Grade 2) occurred in 77% of patients in Study IMCgp100-202 who received KIMMTRAK [see Adverse Reactions (6.1)] . Among patients who received KIMMTRAK, 23% received systemic corticosteroids for at least 1 infusion, 8% received supplemental oxygen during at least 1 infusion, and 0.8% received a vasopressor for at least 1 infusion. CRS led to permanent discontinuation in 1.2% of patients.

In Study IMCgp100-202, 60% of patients experienced ≥ Grade 2 CRS with more than 1 infusion, with the median number of events being 2 (range 1 - 12). The majority (84%) of episodes of CRS started the day of infusion. Among cases that resolved, the median time to resolution of CRS was 2 days.

Ensure that healthcare providers administering KIMMTRAK have immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK [see Dosage and Administration (2.2)] .

Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS [see Dosage and Administration (2.3)] .

5.2 Skin Reactions

Skin reactions, including rash, pruritus, and cutaneous edema occurred in patients treated with KIMMTRAK. In study IMCgp100-202, skin reactions occurred in 91% of patients treated with KIMMTRAK, including Grade 2 (44%) and Grade 3 (21%) events. Skin reactions included rash (83%), pruritus (69%), erythema (25%), and cutaneous edema (27%) [see Adverse Reactions (6.1)] .

The median time to onset of skin reactions was 1 day (range: 1 – 55 days). The median time to improvement to ≤ Grade 1 was approximately 6 days.

Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions [see Dosage and Administration (2.3)] .

5.3 Elevated Liver Enzymes

In Study IMCgp100-202, increases in alanine aminotransferase or aspartate aminotransferase were observed in 65% of patients treated with KIMMTRAK.

In patients experiencing ALT/AST elevations, 73% initially occurred within the first 3 infusions with KIMMTRAK. Most patients experiencing Grade 3 or 4 ALT/AST elevations had improvement to ≤ Grade 1 within 7 days. For events that were observed outside the setting of CRS, the median time to onset was 129 days. Grade 3 or greater elevations in liver enzymes outside the setting of CRS occurred in approximately 8% of patients.

Elevations in liver enzymes led to permanent discontinuation in 0.4% of patients receiving KIMMTRAK.

Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity [see Dosage and Administration (2.3)] .

5.4 Embryo-Fetal Toxicity

Based on the mechanism of action, KIMMTRAK may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with KIMMTRAK and for 1 week after the last dose [see Use in Specific Populations (8.1,8.3)] .

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Cytokine Release Syndrome [ see Boxed Warning, Warnings and Precautions (5.1)]
• Skin Reactions [ see Warnings and Precautions (5.2)]
• Elevated Liver Enzymes [ see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

First line metastatic uveal melanoma

The safety of KIMMTRAK was evaluated in study IMCgp100-202, a randomized (2:1), open-label, active-controlled trial in patients who had not received prior systemic therapy for metastatic or advanced uveal melanoma [see Clinical Studies (14)] . Patients received either KIMMTRAK administered at 20 mcg intravenously on Day 1, 30 mcg intravenously on Day 8, 68 mcg intravenously on Day 15, and 68 mcg intravenously once every week thereafter (N=245) or investigator’s choice treatment (N=111). The median duration of exposure was 5.3 months (range: 0.3 to 33 months) in patients treated with KIMMTRAK.

Serious adverse reactions occurred in 28% of patients who received KIMMTRAK. Serious adverse reactions occurring in ≥ 2% of patients were cytokine release syndrome (10%), rashes (4.5%), pyrexia (2.4%), and hypotension (2%). One patient (0.4%) experienced a fatal adverse reaction (pulmonary embolism).

Adverse reactions led to permanent discontinuation in 3.3% of patients who received KIMMTRAK. Adverse reactions that led to permanent discontinuation of KIMMTRAK were anaphylactic reaction, brain edema, cytokine release syndrome, fatigue, hepatotoxicity, hypotension, and nausea (each 0.4%).

Adverse reactions resulting in dosage interruption occurred in 25% of patients who received KIMMTRAK. Adverse reactions which required dosage interruption in ≥ 2% of patients included fatigue (3.7%), lipase increased (2.9%), pyrexia (2.4%), alanine aminotransferase increase (2%), and aspartate aminotransferase increase (2%).

Adverse reactions leading to dose reduction occurred in 5% of patients who received KIMMTRAK. Adverse reactions which required dosage reduction in ≥ 2% of patients were cytokine release syndrome (2.4%), and rashes (2%).

The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities in patient who received KIMMTRAK were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.

Table 4summarizes the adverse reactions observed in study IMCgp100-202.

Table 4: Adverse Reactions (≥20%) in Patients with Metastatic Uveal Melanoma Who Received KIMMTRAK in Study IMCgp100-202

Clinically relevant adverse reactions occurring in < 20% of patients who received KIMMTRAK included back pain, decreased appetite, constipation, hypertension, tachycardia or sinus tachycardia, dyspnea, paresthesia, dizziness, flushing, muscle spasms, myalgia, pain in extremity, alopecia, skin hyperpigmentation, influenza-like illness, oropharyngeal pain and night sweats.

Table 5summarizes the selected laboratory abnormalities observed in study IMCgp100-202.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

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 study IMCgp100-202, 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. The tebentafusp-tebn clearance increased in patients with high titer ADAs [see Clinical Pharmacology (12.3)] . 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on the mechanism of action, KIMMTRAK may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available data with KIMMTRAK in pregnant woman. No animal reproductive and developmental toxicity studies have been conducted with KIMMTRAK. Molecules of similar molecular weight can cross the placenta resulting in fetal exposure. Advise women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of tebentafusp-tebn in human milk, the effect on the breastfed child, or the effects on milk production. Because tebentafusp-tebn may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with KIMMTRAK and for at least 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

KIMMTRAK may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] .

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating KIMMTRAK treatment.

Contraception

Females

Advise female of reproductive potential to use effective contraception during treatment and for 1 week following the last dose of KIMMTRAK [see Use in Specific Populations (8.1)] .

8.4 Pediatric Use

Safety and efficacy of KIMMTRAK have not been established in pediatric patients.

8.5 Geriatric Use

Of the 245 patients with metastatic uveal melanoma treated with KIMMTRAK on IMCgp100-202, 47% were 65 years of age and older and 9% were 75 years of age and older. No overall differences in safety or efficacy were observed between patients ≥ 65 years of age compared to younger adult patients.

11 DESCRIPTION

Tebentafusp-tebn is a bispecific gp100 peptide-HLA-directed T cell receptor CD3 T cell engager. Tebentafusp-tebn has an approximate molecular weight of 77 kDa. Tebentafusp-tebn is produced by recombinant DNA technology in Escherichia colicells.

KIMMTRAK (tebentafusp-tebn) injection is supplied in a single-dose vial as a sterile, preservative-free, clear, colorless or slightly yellowish solution for intravenous administration by infusion.

Each single-dose vial contains tebentafusp-tebn (100 mcg), citric acid monohydrate (0.95 mg), di-sodium hydrogen phosphate (2.91 mg), mannitol (5 mg), polysorbate 20 (0.1 mg) trehalose (25 mg), and water for injection, with a pH of 6.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tebentafusp-tebn is a bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor CD3 T cell engager. The TCR arm binds to a gp100 peptide presented by human leukocyte antigen-A*02:01 (HLA-A*02:01) on the cell surface of uveal melanoma tumor cells.

In vitro, tebentafusp-tebn bound to HLA-A*02:01-positive uveal melanoma cells and activated polyclonal T cells to release inflammatory cytokines and cytolytic proteins, which results in direct lysis of uveal melanoma tumor cells.

12.2 Pharmacodynamics

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.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KIMMTRAK have not been fully characterized.

12.3 Pharmacokinetics

After a single dose administration, tebentafusp-tebn C maxand AUC 0-7dincreased in an approximately dose proportional manner from 20 to 68 mcg (0.3 to 1 times the approved recommended dose). Following administration of the approved recommended dosage in patients with metastatic uveal melanoma, the steady-state geometric mean (% CV) C maxof tebentafusp-tebn is 13 ng/mL (34.6%) and AUC 0-7dis 4.6 ng.day/mL (23%) 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.

Specific Populations

No clinically significant difference in the pharmacokinetics of tebentafusp-tebn were 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 (CL cr) estimated by C-G formula (CL cr30 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 (CL cr< 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.

Immunogenicity

Median titer in the ADA-positive subgroup was 8192 across the 67 treatment cycles. The exposure (AUC 0-7 days) of tebentafusp-tebn decreased by 97% and terminal half-life decreased to 10-14 minutes in patients with ADA titers greater than 8192.

Drug Interaction

Elevation of certain proinflammatory cytokines may suppress CYP450 enzyme activities.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with tebentafusp-tebn.

No studies have been conducted to evaluate the effects of tebentafusp-tebn on fertility.

14 CLINICAL STUDIES

Study IMCgp100-202: First line metastatic uveal melanoma

KIMMTRAK was evaluated in IMCgp100-202, a randomized, open-label, multicenter trial (NCT03070392) that enrolled patients with metastatic uveal melanoma (N=378). Patients were required to be HLA-A*02:01 genotype positive identified by a central assay. Patients were excluded if they received prior systemic therapy for metastatic or advanced uveal melanoma or localized liver-directed therapy. Prior surgical resection of oligometastatic disease was permitted. Patients with clinically significant cardiac disease or the presence of symptomatic or untreated brain metastasis were excluded.

Patients were randomized (2:1) to receive KIMMTRAK weekly by intravenous infusion administered at 20 mcg intravenously on Day 1, 30 mcg intravenously on Day 8, 68 mcg intravenously on Day 15, and 68 mcg intravenously once every week thereafter (N=252) or Investigator’s choice (N=126) of pembrolizumab, ipilimumab, or dacarbazine. Randomization was stratified by lactate dehydrogenase (LDH) level at study entry. Across both arms, patients stopped treatment for disease progression, unless the patient was otherwise deriving benefit, or for unacceptable toxicity.

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.

The median age was 64 years (range 23 to 92 years); 50% were female; 87% were White, and 12% were unreported or unknown race. The reported ethnicity was Hispanic or Latino in 2.4% of patients. Baseline ECOG performance status was 0 (73%), 1 (21%), or 2 (0.3%); 36% had elevated LDH level; and 94% had liver metastasis.

The efficacy results are summarized in Table 6and Figure 1.

Table 6: Efficacy Results in Study IMCgp100-202

Figure 1: Kaplan-Meier Curves of Overall Survival in Study IMCgp100-202

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Each KIMMTRAK (tebentafusp-tebn) injection carton (NDC 80446-401-01) contains:

The vial stopper is not made with natural rubber latex.

Storage and Handling

• One single-dose vial containing 100 mcg of tebentafusp-tebn in 0.5 mL of sterile, preservative-free, clear, colorless or slightly yellowish solution.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling ( Patient Information).

Cytokine Release Syndrome (CRS)

Inform patients of the risk of CRS, and to immediately contact their healthcare provider for signs and symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills, nausea, vomiting, fatigue, or headache) [see Warnings and Precautions (5.1)] .

Skin Reactions

Inform patients that rashes and skin reactions have occurred in patients who have received KIMMTRAK. Advise patients to contact their healthcare provider for signs and symptoms of progressive or intolerable skin reactions [see Warnings and Precautions (5.2)] .

Elevated Liver Enzymes

Inform patients that elevations in liver enzymes have occurred in patients who have received KIMMTRAK. Advise patients to contact their healthcare provider for signs and symptoms of liver toxicity (e.g., right sided abdominal pain, jaundice, scleral icterus) [see Warnings and Precautions (5.3)] .

Embryo-Fetal Toxicity

Lactation

Manufactured by: Immunocore Limited 92 Park Drive, Milton Park Abingdon, Oxfordshire United Kingdom, OX144RY License no: 2239

At: Baxter Oncology GmbH Kantstraβe 2 33790 Halle/Westfalen Germany

For: Immunocore Commercial LLC 181 Washington Street, Conshohocken, PA, US

• Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform females of the risk to a fetus [see Warnings and Precautions (5.4)and Use in Specific Populations (8.1)] .
• Advise females of reproductive potential to use effective contraception while on KIMMTRAK and for 1 week after the last dose [see Use in Specific Populations (8.1)and (8.3)] .

SPL PATIENT PACKAGE INSERT SECTION