Tebentafusp

KIMMTRAK is indicated as monotherapy for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

KIMMTRAK should be administered under the supervision of a physician experienced in the use of anti-cancer immunotherapy agents. Appropriate medicinal products, including anti-IL-6 treatment and resuscitation equipment should be available.

Posology Patients treated with KIMMTRAK must have HLA-A*02:01 genotype determined by a validated HLA genotyping assay. 6). Continue treatment until disease progression or unacceptable toxicity. Atypical responses similar to immune checkpoint inhibitors have been observed.

It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed. First three treatment doses First three doses of KIMMTRAK should be administered in a hospital setting with overnight monitoring for signs and symptoms of CRS for at least 16 hours.

Vital signs should be monitored pre-dose and at a minimum of every 4 hours until resolution of symptoms. If clinically indicated, more frequent monitoring or prolongation of hospitalisation should occur. If patients experience Grade 3 or 4 hypotension during any of the first three KIMMTRAK infusions, patients should be monitored every hour for at least 4 hours in an outpatient setting for the next three infusions.

, absence of Grade ≥ 2 hypotension requiring medical intervention), subsequent doses can be administered in appropriate out- patient ambulatory care setting. Observe patients for a minimum of 30 minutes following each infusion. Pre-medication To minimize the risk of hypotension associated with cytokine release syndrome (CRS), administer intravenous fluids prior to starting KIMMTRAK infusion based on clinical evaluation and the volume status of the patient.

For patients with pre-existing adrenal insufficiency on maintenance systemic corticosteroids, consider adjusting the corticosteroid dose to manage the risk of hypotension. Dose adjustments Evaluate for and treat other causes of fever, hypoxia and hypotension.

If CRS is suspected, identify and manage according to recommendations in Table 1. See Table 2 for management guidelines for acute skin reactions.

Table 1:

CRS Grading and Management Guidance CRS Grade* Management Grade 1 Temperature ≥ 38°C No hypotension or hypoxia Treat for symptoms as appropriate. Monitor for escalation in CRS severity Grade 2 Temperature ≥ 38°C Hypotension that responds to fluids and does not require vasopressors.

Oxygen requirement includes low flow nasal cannula (delivery of oxygen ≤ 6 L/min) or blow-by Symptom management as per Grade 1 in addition to the following measures: Administer bolus intravenous fluids as needed for hypotension Manage oxygen requirement with supplemental oxygen and additional respiratory support as needed.

g. dexamethasone 4 mg or equivalent) at least 30 minutes prior to next dose Grade 3 Temperature ≥ 38°C Require a vasopressor with or without vasopressin. g. 2 mg/kg/day methylprednisolone or equivalent) Increase monitoring to determine resolution or escalation in severity Consider administering tocilizumab.

Withhold KIMMTRAK until Grade ≤ 1. e. do not escalate) after appropriate risk versus benefit assessment and monitor patient accordingly. g. dexamethasone 4 mg or equivalent) at least 30 minutes prior to next dose Grade 4 Temperature ≥ 38°C Require multiple vasopressors.

g. CPAP, BiPAP, intubation and mechanical ventilation). al 2019). 4) Grade 2 or 3 Use local skin management and systemic antihistamine regimen. Topical corticosteroid treatment can be considered for symptomatic rash that does not respond to anti-pruritic regimen.

Consider systemic steroids for persistent or severe symptoms. 4) Grade 3 or 4a 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 clinically relevant adverse reactions Grade 3a Withhold KIMMTRAK until ≤ Grade 1 […]

Summary of safety profile The most common adverse drug reactions (≥ 30 %) in patients treated with KIMMTRAK were cytokine release syndrome (89 %), rash (83 %), pyrexia (76 %), pruritus (69 %), fatigue (64 %), nausea (49 %), chills (48 %), hypo/hyperpigmentation (47 %), abdominal pain (45 %), oedema (45 %), hypotension (39 %), dry skin (31 %), headache (31 %) and vomiting (30 %).

4 %), and hypotension (2 %). 4 %). The frequency of treatment discontinuation due to adverse reactions was 4 % in patients who received KIMMTRAK. 4 %). No treatment-related deaths were reported. Adverse reactions resulting in dose interruption occurred in 26 % of patients who received KIMMTRAK.

4 %). 1 %). 3 % of patients who received KIMMTRAK. 1 %). Tabulated list of adverse reactions Table 3 summarizes adverse reactions that occurred in 378 metastatic uveal melanoma patients from two clinical studies (IMCgp100-102 and IMCgp100-202) that received the recommended dosing KIMMTRAK dosing regimen of 20 micrograms on Day 1, 30 micrograms on Day 8 and 68 micrograms on Day 15 and 68 micrograms weekly thereafter.

The adverse drug reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term level. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. al 2019). Adjudicated CRS is provided in lieu of investigator reported CRS. 2 Some of the events may be associated with CRS or may be isolated reported events.

3 Includes blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatosis, drug eruption, eczema, eczema eyelids, erythema multiforme, exfoliative rash, interstitial granulomatous dermatitis, lichenification, lichenoid keratosis, palmar-plantar erythrodysaesthesia syndrome, papule, psoriasis, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, seborrhoea, seborrhoeic dermatitis, skin abrasion, skin erosion, skin exfoliation, skin irritation, skin plaque, solar dermatitis, toxic skin eruption, urticaria.

4 Includes fatigue and asthenia. 5 Includes achromotrichia acquired, ephelides, eyelash discolouration, eyelash hypopigmentation, hair colour changes, lentigo, pigmentation disorder, retinal depigmentation, skin depigmentation, skin discolouration, skin hyperpigmentation, skin hypopigmentation, solar lentigo, vitiligo.

6 Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, flank pain, gastrointestinal pain and hepatic pain. 7 Includes eye oedema, eye swelling, eyelid oedema, periorbital swelling, periorbital oedema, swelling of eyelid, pharyngeal oedema, lip oedema, lip swelling, face oedema, generalized oedema, localised oedema, oedema, oedema peripheral, peripheral swelling, swelling, swelling face.

8 […]

1.

KIMMTRAK is indicated as monotherapy for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

KIMMTRAK should be administered under the direction and supervision of a physician experienced in the use of anti-cancer agents and who is prepared to manage cytokine release syndrome in an environment where full resuscitation facilities are immediately available.

4). Patients treated with KIMMTRAK must have HLA-A*02:01 genotype determined by any validated HLA genotyping assay. 6). 1). Premedication To minimize the risk of hypotension associated with cytokine release syndrome (CRS), intravenous fluids should be administered prior to starting KIMMTRAK infusion based on clinical evaluation and the volume status of the patient.

3 For patients with preexisting adrenal insufficiency on maintenance systemic corticosteroids, adjusting the corticosteroid dose should be considered to manage the risk of hypotension. Dose adjustments No dose reductions of KIMMTRAK are recommended.

KIMMTRAK should be withheld or discontinued to manage adverse reactions as described in Table 1 and Table 2. If CRS is suspected, the symptoms should be identified and promptly managed according to recommendations in Table 1. See Table 2 for management guidelines for acute skin reactions.

Table 1:

CRS grading and management guidance CRS grade* Management Grade 1 Temperature ≥ 38 °C No hypotension or hypoxia • Continue treatment and provide symptomatic support. Monitor for escalation in CRS severity. Grade 2 Temperature ≥ 38 °C Hypotension that responds to fluids and does not require vasopressors Oxygen requirement includes low flow nasal cannula (delivery of oxygen ≤ 6 L/min) or blow-by • Continue treatment and administer bolus intravenous fluids and oxygen by low flow nasal canula or blow-by oxygen as needed.

g. 2 mg/kg/day methylprednisolone or equivalent). g. g. 2 mg/kg/day methylprednisolone or equivalent). g. g. CPAP, BiPAP, intubation and mechanical ventilation). , 2 mg/kg/day methylprednisolone or equivalent) * Based on American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading of CRS criteria (Lee et.

al 2019). 4) Grade 2 • Withhold KIMMTRAK until Grade ≤ 1 or baseline. , non-sedating long-acting antihistamine) • Administer topical corticosteroid treatment for symptomatic rash that does not respond to anti-pruritic regimen. • For persistent symptoms, administer systemic steroids • Resume KIMMTRAK escalation if the current dose is less than 68 mcg, or resume at same dose level if dose escalation has completed Grade 3 • Withhold KIMMTRAK until Grade ≤ 1 or baseline.

03). Special populations Paediatric population 6 The safety and efficacy of KIMMTRAK in children under the age of 18 years have not been established. No data are available. Elderly No dose adjustment is required for elderly patients (≥ 65 years of age).

Renal impairment Based on safety and efficacy analyses, dose adjustment is not necessary in patients with mild to moderate renal dysfunction. 2). Patients with history of cardiac disease KIMMTRAK has not been studied in patients with history of significant cardiac disease.

Patients with cardiac disease, QT prolongation and risk factors for cardiac failure should be monitored carefully (see section […]

Summary of safety profile The most common adverse drug reactions in patients treated with KIMMTRAK were cytokine release syndrome (88 %), rash (85 %), pyrexia (79 %), pruritus (72 %), fatigue (66 %), nausea (56 %), chills (55 %), abdominal pain (49 %), oedema (49 %), hypo/hyperpigmentation (48 %), hypotension (43 %), dry skin (35 %), headache (32 %) and vomiting (34 %).

Adverse reactions led to permanent discontinuation in 4 % of patients receiving KIMMTRAK. The most common adverse reaction that led to discontinuation of KIMMTRAK was cytokine release syndrome. Adverse reactions resulting in at least one dose interruption occurred in 26 % of KIMMTRAK-treated patients (dosed weekly) and resulted in a median of one skipped dose.

1 %; Grade 1-3). 2 % of patients in KIMMTRAK-treated group. 1 %; Grade 2-4). Tabulated list of adverse reactions Table 3 summarizes adverse reactions that occurred in 378 metastatic uveal melanoma patients from two clinical studies (IMCgp100-102 and IMCgp100-202) that received the recommended dosing KIMMTRAK dosing regimen of 20 micrograms on Day 1, 30 micrograms on Day 8 and 68 micrograms on Day 15 and 68 micrograms weekly thereafter.

The adverse drug reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term level. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. al 2019). Adjudicated CRS is provided in lieu of investigator reported CRS. 2 Some of the events may be associated with CRS or may be isolated reported events.

3 Includes fatigue and asthenia. 4 Includes achromotrichia acquired, ephelides, eyelash discolouration, eyelash hypopigmentation, hair colour changes, lentigo, pigmentation disorder, retinal depigmentation, skin depigmentation, skin discolouration, skin hyperpigmentation, skin hypopigmentation, solar lentigo, vitiligo.

5 Includes eye oedema, eye swelling, eyelid oedema, periorbital swelling, periorbital oedema, swelling of eyelid, pharyngeal oedema, lip oedema, lip swelling, face oedema, generalized oedema, localized oedema, oedema, oedema peripheral, peripheral swelling, swelling, swelling face.

Description of selected adverse reactions Cytokine release syndrome (CRS) In clinical study IMCgp100-202, cytokine release syndrome (adjudicated based on ASTCT consensus grading 2019) occurred in 89 % of KIMMTRAK treated patients. 8 % Grade 3 events.

Most commonly observed symptoms with CRS included chills, nausea, vomiting, fatigue, hypotension, and headache. Grade 3 events that 11 may be observed in association with CRS include tachycardia, hypoxia, angina pectoris, atrial flutter, and left ventricular dysfunction.

The majority (84 %) of episodes of CRS started the day of infusion. The median time to resolution of CRS was 2 days. 2 %) led to treatment discontinuation. All CRS symptoms were reversible and were mostly managed with intravenous fluids, antipyretics, or a single dose of corticosteroid.

8 %) received tocilizumab. 2, Table 1. Acute skin reactions In Study IMCgp100-202, acute skin reactions occurred in 91 % of patients treated with KIMMTRAK. including any grade rash (83 %), pruritis (69 %), erythema (25 %) and cutaneous oedema (27 %).

Most skin reactions were Grade 1 (28 %) or 2 (44 %) and some […]

1.

KIMMTRAK (tebentafusp) is indicated for:  the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. 1 Pediatrics Pediatrics (˂ 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

2 Geriatrics Geriatrics (≥ 65 years of age): Of the 410 patients with metastatic uveal melanoma treated with KIMMTRAK, 175 (43%) were 65 years of age and older and 38 (9%) were 75 years of age and older. Evidence from clinical studies suggests that use in the geriatric population is associated with no overall differences in safety or effectiveness.

1 Dosing Considerations  A positive HLA-A*02:01 genotype status is required for the selection of patients for treatment with KIMMTRAK [see WARNINGS AND PRECAUTIONS].  To minimize the risk of hypotension associated with cytokine release syndrome, administer intravenous fluids prior to starting KIMMTRAK based on clinical evaluation and the volume status of the patient [see WARNINGS AND PRECAUTIONS].

KIMMTRAK (tebentafusp) Page 5 of 29  For patients with pre-existing adrenal insufficiency on maintenance systemic corticosteroids, consider adjusting the corticosteroid dose given the risk of hypotension [see WARNINGS AND PRECAUTIONS].

2 Recommended Dose and Dosage Adjustment Recommended Dose 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].

Dosage Adjustment Cytokine Release Syndrome (CRS) Identify CRS based on clinical presentation [see WARNINGS AND PRECAUTIONS]. Evaluate for and treat other causes of fever, hypoxia and hypotension. If CRS is suspected, continue monitoring until resolution and manage according to recommendations in Table 1.

Table 1:

Recommended Management and Dose Modifications for Cytokine Release Syndrome (CRS) CRS Grade* Management Grade 1 Temperature ≥ 38°C No hypotension or hypoxia Treat for symptoms as appropriate. Monitor for escalation in CRS severity Grade 2 Temperature ≥ 38°C WITH Hypotension that responds to fluids and does not require vasopressors.

OR Oxygen requirement includes low flow nasal cannula (delivery of oxygen ≤ 6L/min) or blow- Symptom management as per Grade 1 in addition to the following measures: Administer bolus intravenous fluids as needed for hypotension Manage oxygen requirement with supplemental oxygen and additional respiratory support as needed.

Increase monitoring to determine resolution or KIMMTRAK (tebentafusp) Page 6 of 29 by escalation in severity If Grade 2 CRS symptoms do not rapidly improve to Grade ≤1 within 2–3 hours, then treat as Grade 3. g. g. g. al 2019)1 Acute Skin Reactions Recommended management and dose modifications for acute skin reactions is provided in Table 2.

1 Lee W, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release Syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625-38.

KIMMTRAK (tebentafusp) Page 7 of 29 Table 2:

Recommended Management and Dose Modifications for Acute Skin Reactions Adverse Reactions Severity of Adverse Reaction Management Acute Skin Reactions [See WARNINGS AND PRECAUTIONS] Grade 2 or 3* (Moderate to Severe) Withhold KIMMTRAK until < Grade 1 or baseline Use local skin management and systemic antihistamine regimen and oral steroids where required.

, 2 mg/kg/day methylprednisolone or equivalent) Elevated Liver Enzymes [See WARNINGS AND PRECAUTIONS] Grade 3 or 4* 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.

, do not escalate if other Grade 3 adverse reaction occurred during initial dose escalation; resume escalation once dosage is tolerated) […]

1 Adverse Reaction Overview The safety of KIMMTRAK was evaluated in study IMCgp100-202 (study 202), a randomized, open-label, active-controlled trial in 378 systemic therapy naive patients with metastatic uveal melanoma [see CLINICAL TRIALS].

Patients were randomized to receive either KIMMTRAK or investigator’s choice treatment (pembrolizumab, ipilimumab or dacarbazine). The most common adverse reactions (≥ 30 %) in patients treated with KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, hypo/hyperpigmentation, abdominal pain, edema, hypotension, dry skin, headache and vomiting.

Serious adverse reactions occurred in 28% of patients who received KIMMTRAK. 4%), and hypotension (2%). 4%) experienced a fatal adverse reaction (pulmonary embolism). 3% of patients who received investigator’s choice treatment. 4%). 5% of patients treated with investigator’s choice treatment (dosed every 3 weeks), with a median interruption duration of 14 and 21 days, respectively.

4%), alanine aminotransferase increase (2%), and aspartate aminotransferase increase (2%). KIMMTRAK (tebentafusp) Page 14 of 29 Adverse reactions leading to dose reduction occurred in 5% of patients who received KIMMTRAK. 4%), and rash (2%).

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.

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. The safety of KIMMTRAK was evaluated in study IMCgp100-202 (study 202), a randomized, open-label, active-controlled trial in 378 systemic therapy naive patients with metastatic uveal melanoma [see CLINICAL TRIALS].

Patients were randomized (2:1) to receive KIMMTRAK weekly by intravenous infusion according to the recommended intra-patient dosing regimen or Investigator’s choice treatment (pembrolizumab, ipilimumab, or dacarbazine) at the approved doses of these agents until disease progression or unacceptable toxicity [see DOSAGE AND ADMINISTRATION].

The median duration of exposure was 23 weeks in KIMMTRAK treated patients and 9 weeks with investigator’s choice treatment. Table 6 displays the adverse reactions observed in study IMCgp100-202 (study 202). 6 0 ALT = alanine aminotransferase; AST = aspartate aminotransferase a Investigator’s choice: i.

Dacarbazine: 1000 mg/m2 on Day 1 of each 21-day cycle ii. Ipilimumab: 3 mg/kg on Day 1 of each 21-day cycle for maximum of 4 doses iii. Pembrolizumab: 2 mg/kg up to maximum of 200 mg or 200 mg IV, where approved locally on Day 1 of each 21 -day cycle b Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal te nderness, epigastric discomfort, flank pain, gastrointestinal pain and hepatic pain c Some of the events may be associated with CRS or may be isolated reported events d Includes fatigue and asthenia e Includes eye edema, eye swelling, eyelid edema, periorbital swelling, periorbital edema, swelling of eyelid, pharyngeal edema, lip edema, […]

KIMMTRAK is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.