Tebentafusp

1 INDICATIONS AND USAGE KIMMTRAK is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. KIMMTRAK is a bispecific gp100 peptide-HLA-directed CD3 T cell engager indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma ( 1 , 2.1 ).

2 DOSAGE AND ADMINISTRATION Recommended dosage: 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 ( 2.2 ). Dilute and administer by intravenous infusion over 15-20 minutes ( 2.2 , 2.4 ). See Full Prescribing Information for instructions on preparation and administration of the diluted solution for intravenous infusion ( 2.2 , 2.4 ). Dosage interruption or permanent discontinuation may be required based on individual safety and tolerability ( 2.3 ). 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 a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (NCI CTCAEv4.03). Adverse Reaction Severity KIMMTRAK Dosage Modifications Cytokine Release Syndrome (CRS) [see Warnings and Precautions (5.1) ] Moderate defined as temperature ≥ 38°C with Hypotension that responds to fluids (does not require vasopressors) or Hypoxia requiring low flow nasal canula (≤ 6 L/min) or blow-by oxygen If hypotension and hypoxia do not improve within 3 hours or CRS worsens, escalate care and manage according to next higher level of severity For moderate CRS that is persistent (lasting 2-3 hours) or recurrent, administer corticosteroid premedication (e.g. dexamethasone 4 mg or equivalent) at least 30 minutes prior to next dose Severe defined as temperature ≥ 38°C with Hemodynamic instability requiring a vasopressor (with or without vasopressin) or Worsening hypoxia or respiratory distress requiring high flow nasal canula (> 6 L/min oxygen) or face mask Withhold KIMMTRAK until CRS and sequelae have resolved Administer intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent) Resume KIMMTRAK at same dose level (i.e., do not escalate if severe CRS occurred during initial dose escalation; resume escalation once dosage is tolerated) For severe CRS, administer corticosteroid premedication (e.g. dexamethasone 4 mg or equivalent) at least 30 minutes prior to next dose Life threatening defined as temperature ≥ 38°C with Hemodynamic instability requiring multiple vasopressors (excluding vasopressin) Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure Permanently discontinue KIMMTRAK Administer intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent) Skin Reactions [see Warnings and Precautions (5.2) ] Grade 2 or 3 a Withhold KIMMTRAK until ≤ Grade 1 or baseline Resume KIMMTRAK at same dose level (i.e., do not escalate if Grade 3 skin reactions occurred during initial dose escalation; resume escalation once dosage is tolerated) For persistent reactions not responding to oral steroids, consider intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent) Grade 4 a Permanently discontinue KIMMTRAK Administer intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent) Elevated Liver Enzymes [see Warnings and Precautions (5.3) ] Grade 3 or 4 a Withhold KIMMTRAK until ≤ Grade 1 or baseline. Resume KIMMTRAK at same dose level if the elevated liver enzymes occur in the setting of Grade 3 CRS; resume escalation if next administration is tolerated. If the elevated liver enzymes occur outside the setting of Grade 3 CRS resume escalation if the current dose is less than 68 mcg, or resume at same dose level if dose escalation has completed Administer intravenous corticosteroids if no improvement within 24 hours Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 a Withhold KIMMTRAK until ≤ Grade 1 or baseline Resume KIMMTRAK at same dose level (i.e., do not escalate if other Grade 3 adverse reaction occurred during initial dose escalation; resume escalation once dosage is tolerated) Grade 4 a Permanently discontinue KIMMTRAK 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: 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 2 below) 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 Gently homogenize the prepared solution by completing the following steps: 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. 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. Repeat (i) and (ii) an additional three times. Step 2- Preparation of KIMMTRAK Solution for Infusion Do not shake the KIMMTRAK vial. 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 3 below) and add to the prepared 100 mL infusion bag containing 0.9% Sodium Chloride Injection, USP plus Albumin (Human). 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 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.

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) ] The most common adverse reactions (occurring in ≥ 30%) are cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache and vomiting ( 6.1 ). 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 ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Immunocore at 1-844-IMMUNO1 (1-844-466-8661) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 4 summarizes 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 a Represents algorithmic identification of CRS cases based on ASTCT grading criteria (Lee et al. 2019). b Represents a composite of multiple related terms. Adverse Reactions KIMMTRAK (N=245) Investigator’s Choice (pembrolizumab, or ipilimumab, or dacarbazine) (N=111) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (% ) Immune system disorders Cytokine release syndrome a 89 0.8 2.7 0 Skin and subcutaneous tissue disorders Rash b 83 18 28 0 Pruritus 69 4.5 23 0 Dry skin 31 0 3.6 0 Skin Hypopigmentation b 28 NA 5 NA Erythema 24 0 0.9 0 Hair color changes b 20 NA 0 NA General disorders and administration site conditions Pyrexia 76 3.7 7 0.9 Fatigue b 64 6 42 0.9 Chills 48 0.4 3.6 0 Edema b 45 0 10 0 Gastrointestinal disorders Nausea 49 2 26 0.9 Abdominal pain b 45 2.9 33 3.6 Vomiting 30 1.2 9 0 Diarrhea 25 1.2 20 2.7 Vascular disorders Hypotension 39 3.3 2.7 0 Nervous system disorders Headache 31 0.4 10 0.9 Musculoskeletal and connective tissue disorders Arthralgia 22 0.8 16 0 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 5 summarizes the selected laboratory abnormalities observed in study IMCgp100-202. Table 5: Selected Laboratory Abnormalities (≥ 10%) worsening from baseline in patients who received KIMMTRAK versus Investigator’s Choice Alk Phos = Alkaline Phosphatase; AST=aspartate aminotransferase; ALT=alanine aminotransferase a The denominator used to calculate the rate varied from 242 to 245 for KIMMTRAK and 105 to 109 for IC based on the number of patients with a baseline value and at least one post-treatment value for the laboratory assessment. KIMMTRAK a (N=245) Investigator’s Choice a (pembrolizumab, or ipilimumab, or dacarbazine) (N=111) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (% ) HEMATOLOGY Lymphocyte count decreased 91 56 26 1.8 Hemoglobin decreased 51 0.8 20 0.9 Platelet count decreased 16 0 15 0.9 Neutrophil count decreased 14 2 8 1.8 CHEMISTRY Creatinine increased 87 0.4 73 0 Glucose increased 66 3.3 39 4.6 AST increased 55 13 39 1.9 ALT increased 52 9 29 1.8 Phosphate decreased 51 11 20 2 Albumin decreased 47 2.1 14 0.9 Calcium decreased 45 1.6 15 1.9 Lipase increased 37 15 28 6 Magnesium decreased 34 0 8 0 Alk phos increased 34 2.9 36 1.8 Sodium decreased 30 2.9 15 0.9 Potassium increased 29 1.6 15 0.9 Bilirubin increased 27 4.1 14 7 Amylase increased 23 4.1 18 1 Glucose decreased 18 0.4 4.6 0 Potassium decreased 17 0.8 8 0.9 Calcium increased 13 0 3.7 0

12.3 Pharmacokinetics After a single dose administration, tebentafusp-tebn C max and AUC 0-7d increased 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 max of tebentafusp-tebn is 13 ng/mL (34.6%) and AUC 0-7d is 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 cr 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 (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. Drug Interaction Elevation of certain proinflammatory cytokines may suppress CYP450 enzyme activities.