Tebentafusp

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.

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 in

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 illne