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:

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

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)] .

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

• 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.

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:

1. Using a 1 mL syringe with graduations of 2 decimal places and a sterile needle, withdraw the calculated volume of Albumin (Human) into the syringe (see Table 2below) and add to the 100 mL 0.9% Sodium Chloride Injection, USP bag constructed of polyolefins (PO) [such as polyethylene (PE) and polypropylene (PP)] or polyvinyl chloride (PVC) to make a final Albumin (Human) concentration of 250 mcg/mL.

   Table 2: Examples of Albumin (Human) Concentration and Volumes

   *Albumin (Human); use concentration as per local availability. Examples include but are not restricted to the following strengths: 5%, 20%, or 25%.
   Albumin (Human) concentration*	Albumin (Human) volume for addition to a 100 mL 0.9% Sodium Chloride Injection, USP Infusion Bag to prepare a concentration of 250 mcg/mL Albumin (Human) in 0.9% Sodium Chloride Injection, USP
   5% (50 g/L)	0.5 mL
   20% (200 g/L)	0.13 mL
   25% (250 g/L)	0.1 mL

2. Gently homogenize the prepared solution by completing the following steps:
   1. Invert the infusion bag so that the bag is upside down with the entry port positioned on top. Then tap the side of the port tubing to ensure that any residual solution is released into the bulk solution.
   2. Mix the prepared solution by gently rotating the bag lengthwise 360 degrees from the inverted position at least 5 times. Do not shake the infusion bag.
   3. Repeat (i) and (ii) an additional three times.

Step 2- Preparation of KIMMTRAK Solution for Infusion

1. Do not shake the KIMMTRAK vial.
2. Using a 1 mL syringe with graduations of 2 decimal places and a sterile needle, withdraw the required volume of KIMMTRAK 100 mcg/ 0.5 mL as per the dose required (shown in Table 3below) and add to the prepared 100 mL infusion bag containing 0.9% Sodium Chloride Injection, USP plus Albumin (Human).
3. Discard the single-dose vial containing the unused portion of KIMMTRAK in accordance with local requirements. Do not prepare more than one dose from the vial.

   Table 3: KIMMTRAK Volumes Required for Addition to the Infusion Bag

   Day of treatment	Dose (mcg) of KIMMTRAK	Volume (mL) of KIMMTRAK
   Day 1	20	0.1
   Day 8	30	0.15
   Day 15 and weekly thereafter	68	0.34

4. Mix the infusion bag by following the same procedure outlined in Step 1b.

Administration

• Immediately administer the diluted solution via intravenous infusion over 15-20 minutes through a dedicated intravenous line. A sterile, non-pyrogenic, low protein binding 0.2 micron in-line filter infusion set should be used. Administer the entire contents of the KIMMTRAK infusion bag.
• Administer the prepared infusion bag within 4 hours from the time of preparation including the duration of infusion. During the 4-hour window, the KIMMTRAK infusion bag should remain at room temperature.
• If not used immediately, store the KIMMTRAK infusion bag in a refrigerator at 2°C to 8°C (36°F to 46°F) and infuse within 24 hours from the time of preparation, which includes the storage time in the refrigerator, the time allowed for equilibration of the infusion bag to room temperature, and the duration of the infusion.
• Once removed from the refrigerator, do not refrigerate KIMMTRAK infusion bag again. Do not freeze. Discard unused KIMMTRAK solution beyond the recommended storage time.
• Do not mix KIMMTRAK with other drugs or administer other drugs through the same intravenous line.
• Upon completion of KIMMTRAK infusion, flush the infusion line with adequate volume of sterile 0.9% Sodium Chloride Injection, USP to ensure that the entire contents of the infusion bag are administered.

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)] .

6.1 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.

8.1 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.

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.

13.1 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.