KIMMTRAK 100mcg / 0.5ml perfusive solution concentrate medication leaflet

KIMMTRAK 100 micrograms/0.5 mL concentrate for solution for infusion

One 0.5 mL vial contains 100 micrograms of tebentafusp, corresponding to a concentration beforedilution of 200 mcg/mL.

Tebentafusp is a fusion protein, produced by recombinant DNA technology in Escherichia coli cells.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless to slightly yellowish solution in a single-dose vial.

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 experiencedin the use of anti-cancer agents and who is prepared to manage cytokine release syndrome in anenvironment where full resuscitation facilities are immediately available. Hospitalisation isrecommended for at least the first three infusions of KIMMTRAK (see section 4.4).

Patients treated with KIMMTRAK must have HLA-A*02:01 genotype determined by any validated

HLA genotyping assay.

The recommended dose of KIMMTRAK is 20 micrograms on Day 1, 30 micrograms on Day 8,68 micrograms on Day 15, and 68 micrograms once every week thereafter (see section 6.6). Treatmentwith KIMMTRAK should be continued while patient is deriving clinical benefit and in the absence ofunacceptable toxicities (see section 5.1).

Premedication

To minimize the risk of hypotension associated with cytokine release syndrome (CRS), intravenousfluids should be administered prior to starting KIMMTRAK infusion based on clinical evaluation andthe volume status of the patient.

For patients with preexisting adrenal insufficiency on maintenance systemic corticosteroids, adjustingthe corticosteroid dose should be considered to manage the risk of hypotension.

No dose reductions of KIMMTRAK are recommended. KIMMTRAK should be withheld ordiscontinued 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 torecommendations 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 * Continue treatment and provide symptomatic

Temperature ≥ 38 °C support. Monitor for escalation in CRS

No hypotension or hypoxia severity.

Grade 2 * Continue treatment and administer bolus

Temperature ≥ 38 °C intravenous fluids and oxygen by low flownasal canula or blow-by oxygen as needed.

Hypotension that responds to fluids and doesnot require vasopressors * If hypotension and hypoxia do not improvewithin 3 hours or CRS worsens administer

Oxygen requirement includes low flow nasal high-dose intravenous corticosteroid (e.g.cannula (delivery of oxygen ≤ 6 L/min) or 2 mg/kg/day methylprednisolone orblow-by equivalent).

* For Grade 2 CRS that is persistent (lasting2--3 hours) or recurrent (occurrence of ≥

Grade 2 CRS with more than one dose),administer corticosteroid premedication (e.g.dexamethasone 4 mg or equivalent) at least30 minutes prior to next dose

Grade 3 * Withhold KIMMTRAK until CRS and

Temperature ≥ 38 °C sequelae have resolved

Require a vasopressor with or without * Administer high-dose intravenousvasopressin corticosteroid (e.g. 2 mg/kg/daymethylprednisolone or equivalent).

Require high flow nasal cannula (delivery ofoxygen > 6 L/min), face mask or non-rebreather * Administer tocilizumab as neededmask or Venturi mask - Patient weight ≤ 30 kg: 12 mg/kgintravenously over 1 hour

- Patient weight ≥ 30 kg: 8 mg/kgintravenously over 1 hour (maximum dose800 mg)

* Resume KIMMTRAK at same dose level(i.e., do not escalate if Grade 3 CRS occurredduring initial dose escalation; resumeescalation once dosage is tolerated)

* For Grade 3 CRS, administer corticosteroidpremedication (e.g. dexamethasone 4 mg orequivalent) at least 30 minutes prior to nextdose

Grade 4 * Permanently discontinue KIMMTRAK

Temperature ≥ 38 °C

* Administer intravenous corticosteroid (e.g.,

Require multiple vasopressors (excluding 2 mg/kg/day methylprednisolone orvasopressin) equivalent)

Requiring positive pressure (e.g. CPAP,

BiPAP, intubation and mechanical ventilation).

* Based on American Society for Transplantation and Cellular Therapy (ASTCT) consensus gradingof CRS criteria (Lee et. al 2019).

Table 2: Recommended management and dose modifications for acute skin reactions

Adverse reactions Severitya Management

Acute skin reactions Grade 2 * Withhold KIMMTRAK until Grade(see section 4.4) ≤ 1 or baseline.

* Administer antipruritic regimen(e.g., non-sedating long-actingantihistamine)

* Administer topical corticosteroidtreatment for symptomatic rash thatdoes not respond to anti-pruriticregimen.

* For persistent symptoms,administer systemic steroids

* Resume KIMMTRAK escalation ifthe current dose is less than 68 mcg,or resume at same dose level if doseescalation has completed

Grade 3 * Withhold KIMMTRAK until Grade≤ 1 or baseline.

* Administer topical corticosteroidand oral corticosteroids

* For persistent reactions notresponding to oral steroids, considerintravenous corticosteroid (e.g., 2mg/kg/day methylprednisolone orequivalent)

* Resume KIMMTRAK at same doselevel (i.e., do not escalate if Grade 3skin reactions occurred duringinitial dose escalation; resumeescalation once dosage is tolerated)

Grade 4 * Permanently discontinue

KIMMTRAK

* Administer intravenouscorticosteroid (e.g., 2 mg/kg/daymethylprednisolone or equivalent)a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 (NCI CTCAEv4.03).

The safety and efficacy of KIMMTRAK in children under the age of 18 years have not beenestablished. No data are available.

No dose adjustment is required for elderly patients (≥ 65 years of age).

Based on safety and efficacy analyses, dose adjustment is not necessary in patients with mild tomoderate renal dysfunction. No dose recommendations can be made for patients with severe renalimpairment because of the lack of pharmacokinetic data; therefore, dosing in patients with severe renalimpairment should be done with caution and careful monitoring (see section 5.2).

Patients with history of cardiac disease

KIMMTRAK has not been studied in patients with history of significant cardiac disease. Patients withcardiac disease, QT prolongation and risk factors for cardiac failure should be monitored carefully (seesection 4.4).

KIMMTRAK is for intravenous use. The recommended infusion period is 15 to 20 minutes.

KIMMTRAK requires dilution with sodium chloride 9 mg/mL (0.9 %) solution for injectioncontaining human albumin for intravenous infusion. Each vial of KIMMTRAK is intended for use assingle-dose only. Do not shake the KIMMTRAK vial.

For instructions on dilution and administration of the medicinal product, see section 6.6.

First three treatment doses

First three doses of KIMMTRAK should be administered in a hospital setting with overnightmonitoring for signs and symptoms of CRS for at least 16 hours. Vital signs should be monitored predose and at a minimum of every 4 hours until resolution of symptoms. If clinically indicated, morefrequent monitoring or prolongation of hospitalization should be performed.

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 threeinfusions.

Subsequent treatment doses

After 68 mcg dose level is tolerated (i.e., absence of Grade ≥ 2 hypotension requiring medicalintervention), subsequent doses can be administered in appropriate outpatient ambulatory care setting.

Patients should be observed for a minimum of 60 minutes following each infusion. For patients whohave received outpatient treatment with KIMMTRAK for at least 3 months and have not experiencedany interruptions greater than 2 weeks, outpatient monitoring following infusion may be decreased toa minimum of 30 minutes for subsequent doses.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Most patients experienced CRS following tebentafusp infusions. Diagnosis of CRS was mostfrequently based on pyrexia followed by hypotension and infrequently hypoxia. Other commonlyobserved symptoms with CRS included chills, nausea, vomiting, fatigue, and headache. CRS has beenassociated with organ dysfunction, including hepatic, renal, pancreatic, cardiac, and pulmonarydysfunction.

In the majority of cases, CRS started on the day of infusion with median time to resolution of 2 days.

Pyrexia was noted in nearly all cases of CRS, and in these patients, an increase in body temperaturegenerally occurred within the first 8 hours after tebentafusp infusion. CRS rarely (1.2 %) led totreatment discontinuation.

Patients should be monitored for signs or symptoms of CRS for at least 16 hours following first threeinfusions of tebentafusp in a hospital setting with immediate access to medicinal products andresuscitative equipment to manage CRS. If CRS is observed, prompt treatment with supportive careincluding antipyretics, intravenous fluids, tocilizumab, or corticosteroids should be initiated to avoidescalation to severe or life-threatening events and monitoring should be continued until resolution.

At subsequent doses, patients should be closely monitored after treatment for early identification ofsigns and symptoms of CRS (see section 4.2, Method of administration). Patients with co-morbidities,including cardiovascular disorders, may be at increased risk for sequalae associated with CRS.

Treatment with tebentafusp has not been studied in patients with clinically significant cardiac disease(see section 5.1). Depending on persistence and severity of CRS tebentafusp treatment should bewithheld or discontinued (see section 4.2, Table 1).

Acute skin reactions

Acute skin reactions have been reported with tebentafusp infusion, which may be based on itsmechanism of action and gp100 expression in normal melanocytes in the skin. Acute skin reactionsmainly included rash, pruritus, erythema and cutaneous oedema (see section 4.8).

Acute skin reactions typically occurred following each of the first three tebentafusp infusions anddecreased in severity and frequency over time. Majority of symptoms resolved without any systemiccorticosteroid or any long term sequalae.

Acute skin reactions can be managed with antihistamine and topical corticosteroids. For persistent orsevere symptoms, systemic steroids should be considered. Management of signs and symptoms of skinreactions may require temporary delays of subsequent tebentafusp treatments (see section 4.2, Table2).

Cardiac disease

Cardiac events such as sinus tachycardia and arrhythmia have been observed in patients who havereceived tebentafusp treatment (see section 4.8). Patients with pre-existing cardiovascular disorders maybe at increased risk for sequalae associated with CRS and should be monitored carefully. Any patientwith signs or symptoms consistent with cardiac events should be evaluated and promptly treated. Inaddition, appropriate treatment should be administered for any underlying CRS as a precipitating factor.

Cases of QT interval prolongation were reported following tebentafusp treatment (see section 4.8).

Tebentafusp treatment should be administered with caution in patients with history of or predispositionto QT interval prolongation and in patients who are taking medicinal products that are known to prolong

An electrocardiogram (ECG) should be performed in all patients before and after tebentafusp treatmentduring the first 3 weeks of treatment and subsequently as clinically indicated. If QTcF exceeds 500 msecor increases by ≥ 60 msec from baseline value tebentafusp treatment should be withheld and patientsshould be treated for any underlying precipitating factors including electrolyte abnormalities.

Tebentafusp treatment should be resumed once QTcF interval improves to <500 msec or is < 60 msecfrom baseline value. Depending on persistence and severity of the cardiac event and any associated CRStebentafusp treatment should be withheld or discontinued (see section 4.2, Table 1).

Women of childbearing potential have to use effective contraception during and for at least 1 weekafter last dose of tebentafusp treatment (see section 4.6)

This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially‘sodium-free’

No formal drug interaction studies have been performed with tebentafusp.

Initiation of tebentafusp treatment causes transient release of cytokines that may suppress CYP450enzymes. The highest drug-drug interaction risk is during the first 24 hours of the first three doses oftebentafusp in patients who are receiving concomitant CYP450 substrates, particularly those with anarrow therapeutic index. These patients should be monitored for toxicity (e.g., warfarin) or drugconcentrations (e.g., cyclosporine). The dose of the concomitant medicines should be adjusted asneeded.

Women of childbearing potential should use effective contraception during treatment with tebentafuspand for at least 1 week after last dose of tebentafusp.

There are no data from the use of tebentafusp in pregnant women. Animal reproduction studies havenot been conducted with tebentafusp (see section 5.3).

Tebentafusp is not recommended during pregnancy and in women of childbearing potential not usingcontraception. The pregnancy status in females of reproductive potential should be verified prior toinitiating tebentafusp treatment.

There is insufficient information on the excretion of tebentafusp/metabolites in human milk. A risk tothe newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment withtebentafusp.

No fertility studies have been conducted with tebentafusp (see section 5.3). The effect of tebentafuspon male and female fertility is unknown.

Tebentafusp has no or negligible influence on the ability to drive and use machines.

The most common adverse drug reactions in patients treated with KIMMTRAK were cytokine releasesyndrome (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. Themost common adverse reaction that led to discontinuation of KIMMTRAK was cytokine releasesyndrome.

Adverse reactions resulting in at least one dose interruption occurred in 26 % of KIMMTRAK-treatedpatients (dosed weekly) and resulted in a median of one skipped dose. Adverse reactions requiringdosage interruption in ≥ 2 % of patients included fatigue (3 %; Grade 1--3), pyrexia (2.7 %; Grade1-3), alanine aminotransferase increase (2.4 %; Grade 1-4), aspartate aminotransferase increase (2.4%; Grade 1-3) abdominal pain (2.1 %; Grade 1-3), and lipase increased (2.1 %; Grade 1-3).

Adverse reactions leading to at least one dose modification occurred in 4.2 % of patients in

KIMMTRAK-treated group. Adverse reactions which required dose modification in ≥ 1 % of patientswere cytokine release syndrome (1.9 %; Grade 1-3), and hypotension (1.1 %; Grade 2-4).

Table 3 summarizes adverse reactions that occurred in 378 metastatic uveal melanoma patients fromtwo 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 and68 micrograms on Day 15 and 68 micrograms weekly thereafter.

The adverse drug reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferredterm 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), veryrare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

Table 3: Adverse reactions in patients treated with KIMMTRAK monotherapy

Adverse reactions

Common Nasopharyngitis

Very common Cytokine release syndrome1

Very common Decreased appetite, hypomagnesaemia,hyponatraemia, hypocalcaemia, hypokalaemia

Uncommon Tumour lysis syndrome

Very Common Insomnia

Common Anxiety

Very common Headache2 , dizziness, paraesthesia

Common Taste disorder

Very common Tachycardia2

Common Arrhythmia2, atrial fibrillation2

Uncommon Angina pectoris2, cardiac failure2

Very common Hypotension2, flushing, hypertension

Very common Cough, dyspnoea

Common Oropharyngeal pain, hypoxia2

Very common Nausea2, vomiting2, diarrhoea, abdominal pain,constipation, dyspepsia

Very common Rash, pruritus, dry skin, hypo/ hyperpigmentation4,erythema

Common Alopecia, night sweats

Very common Arthralgia, back pain, myalgia, pain in extremity

Common Muscle spasm

Very common Pyrexia2, fatigue3, chills2, oedema5, Influenza likeillness

Very common Aspartate aminotransferase increased, alanineaminotransferase increased, blood bilirubinincreased, lipase increased, anaemia, lymphocytecount decreased, blood phosphate decreased, bloodcreatinine increased

Common Amylase increased, gamma glutamyltransferaseincreased, white blood cell count increased, bloodalkaline phosphatase increased, blood glucoseincreased

Uncommon Electrocardiogram QT prolonged1 CRS was adjudicated using the ASTCT consensus grading of CRS criteria (Lee et.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, haircolour changes, lentigo, pigmentation disorder, retinal depigmentation, skin depigmentation, skindiscolouration, skin hyperpigmentation, skin hypopigmentation, solar lentigo, vitiligo.

5 Includes eye oedema, eye swelling, eyelid oedema, periorbital swelling, periorbital oedema, swellingof eyelid, pharyngeal oedema, lip oedema, lip swelling, face oedema, generalized oedema, localizedoedema, oedema, oedema peripheral, peripheral swelling, swelling, swelling face.

In clinical study IMCgp100-202, cytokine release syndrome (adjudicated based on ASTCT consensusgrading 2019) occurred in 89 % of KIMMTRAK treated patients. The overall incidence of CRSincluded 12 % Grade 1, 76 % Grade 2 and 0.8 % Grade 3 events. Most commonly observed symptomswith CRS included chills, nausea, vomiting, fatigue, hypotension, and headache. Grade 3 events thatmay 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. CRS rarely (1.2 %) led to treatment discontinuation. All CRS symptoms werereversible and were mostly managed with intravenous fluids, antipyretics, or a single dose ofcorticosteroid. Two patients (0.8 %) received tocilizumab.

For clinical management of CRS, see section 4.2, 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 KIMMTRAK treated patientsexperienced Grade 3 (21 %) events. Among patients with observed rash, patients commonlyexperienced rash (55 %), rash maculo-papular (31 %) and skin exfoliation (21 %). Grade 3 adversereactions of rash were reported in 5 % of patients and included rash (2.4 %) and rash maculopapular(1.6 %).

Acute skin reactions typically occurred following each of the first three KIMMTRAK infusions, withdecreasing frequency of ≥ Grade 3 reactions (dose 1; 17 %, dose 2; 10 %, dose 3; 8 %, dose 4; 3 %).

The median time to onset of acute skin reactions was 1 day in the KIMMTRAK treated patients andmedian time to improvement to ≤ Grade 1 was 6 days.

For clinical management of acute skin reactions, see section 4.2, Table 2.

In Study IMCgp100-202 where 95 % of patients had preexisting liver metastasis, ALT/AST increaseto ≥ Grade 1 were observed in 65 % of patients treated with KIMMTRAK. Elevations in bilirubinhave been reported in 27 % of patients and these were primarily associated with increase in size ofliver metastasis. The majority Grade 3 or 4 ALT/AST elevations generally occurred within the first 3

KIMMTRAK infusions. Most patients experiencing Grade 3 or 4 ALT/AST elevations hadimprovement to ≤ Grade 1 within 7 days.

Treatment-emergent anti-drug antibodies (ADA) against tebentafusp were detected in 33 % and 29 %of patients receiving tebentafusp across all doses in study IMCgp100-102 and study IMCgp100-202,respectively. The median onset time to ADA formation was 6 to 9 weeks after start of tebentafusptreatment.

There was no evidence of ADA impact on safety or efficacy of tebentafusp, although the smallnumber of patients who developed high titer ADA precludes firm conclusions regarding their clinicalimpact.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no information on overdose with tebentafusp. In case of overdose, patients should be closelymonitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment shouldbe instituted immediately.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: not yetassigned

Tebentafusp is a bispecific fusion protein, comprised of a T cell receptor (TCR; targeting domain)fused to an antibody fragment targeting CD3 (cluster of differentiation 3; effector domain). The TCRend binds with high affinity to a gp100 peptide presented by human leukocyte antigen - A*02:01(HLA-A*02:01) on the cell surface of uveal melanoma tumour cells, and the effector domain binds tothe CD3 receptor on the polyclonal T cell.

An immune synapse is formed when the TCR targeting domain of tebentafusp binds to uvealmelanoma cells and the CD3 effector domain binds to polyclonal T cells. This immune synapse resultsin redirection and activation of polyclonal T cells regardless of their native TCR specificity.

Tebentafusp activated polyclonal T cells release inflammatory cytokines and cytolytic proteins, whichresult in direct lysis of uveal melanoma tumour cells.

Transient and clinically nonsignificant reduction in lymphocyte counts in blood was observed aftertreatment with tebentafusp. Lymphocytes decreased the day after the first 3 doses and returned tobaseline prior to subsequent doses.

After treatment with tebentafusp, transient increases in serum levels of proinflammatory cytokines andchemokines were observed in samples collected after the first three doses. Peak levels were observedbetween 8 to 24 hours after treatment with tebentafusp and levels returned to baseline prior tosubsequent doses.

Study IMCgp100-202: Previously untreated metastatic uveal melanoma

Study IMCgp100-202 was a randomised, open label, multicentre study that enrolled HLA-A*02:01positive metastatic uveal melanoma patients who were naïve to systemic therapy. Patient could nothave received previous systemic treatment or localized (liver--directed) therapy for metastatic uvealmelanoma except for a prior surgical resection of oligometastatic disease. Patient were excluded forpresence of symptomatic or untreated brain metastasis, symptomatic congestive heart failure, QTinterval corrected by Fridericia’s formula (QTcF) > 470 msec or congenital long QT syndrome, acutemyocardial infarction, or unstable angina pectoris less than 6 months prior to treatment initiation.

Patients were randomised (2:1) to receive tebentafusp weekly by intravenous infusion according to therecommended intra-patient dosing regimen section 4.2 or investigator’s choice treatment(pembrolizumab, ipilimumab, or dacarbazine) at the approved doses of these agents until diseaseprogression or unacceptable toxicity.

Patients could receive tebentafusp, pembrolizumab, or ipilimumab treatment beyond diseaseprogression if the patients were clinically stable, deriving clinical benefit and showed no signs ofunacceptable toxicity as determined by the investigator. Treatment breaks for up to 2 consecutiveweeks were allowed. Randomisation was stratified by lactate dehydrogenase (LDH) status, a knownprognostic factor for unresectable or metastatic UM.

The primary efficacy outcome was overall survival (OS) in all patients randomised in the study.

Tumour assessments were conducted every 12 weeks. Additional efficacy outcomes were investigatorassessed progression free survival (PFS) A total of 378 patients were randomised; 252 totebentafusp- treated group and 126 to the investigator’s choice treated group (pembrolizumab: 82 %;ipilimumab: 12 %; or dacarbazine: 6 %). The median age was 64 years (range 23 to 92 years); with49.5 % of patients ≥ 65 years, 87 % were white, 50 % were female. Baseline ECOG performancestatus was 0 (72 %) or 1 (20.4 %) or 2 (0.3 %), 36 % had elevated LDH level, and 95 % had livermetastasis.

In this study IMCgp100-202, 43 % of patients received treatment beyond progression with tebentafuspwith no new safety signals identified. Median duration of tebentafusp treatment beyond progressionwas 8 weeks. Of the total tebentafusp infusions during the study, 21.5 % was administered afterprogression.

After completion of the primary efficacy analysis, patients from the investigator’s choice arm werepermitted to crossover to the tebentafusp treatment. With a median duration of follow up of 22.4 months,the updated OS continued to favour the tebentafusp arm (HR= 0.58; 95% CI: 0.44, 0.77). At the time ofanalysis, 16 patients had crossed over to tebentafusp treatment.

The efficacy results are summarized in Table 4 and Figure 1. Figure 1 represents an analysis with 3years of follow-up. At the time of this analysis 16 patients from the control group have crossed-overto the tebentafusp treatment.

Table 4: Efficacy results in study IMCgp100-202

Primary and secondary KIMMTRAK Investigator`s choiceendpoints (N = 252) therapy(N = 126)

Overall survival (OS) 1

Number of deaths 87 (34.5 %) 63 (50 %)

Median months (95 % CI) 21.7 (18.6, 28.6) 16.0 (9.7, 18.4)

HR (95 % CI)2, 4 0.51 (0.37, 0.71)

Stratified log-rank p-value2 p = <0.0001

Progression free survival (PFS)3, 4

Number (%) of patients withevent 198 (78.6 %) 97 (77 %)

Median in months (95 % CI) 3.3 (3.0, 5.0) 2.9 (2.8, 3.0)

HR (95 % CI)4 0.73 (0.58, 0.94)

Stratified log-rank p-value2 p = 0.0139

Objective response rate (ORR)6n (%) 26 (10.3) 6 (4.8)95% CI 6.9, 14.8 1.8, 10.1

Complete Response (CR) 1 (0.4) 0

Partial Response (PR) 25 (9.9) 6 (4.8)

Stable Disease (SD)5 52 (20.6) 16 (12.7)

Median duration of response

Months (95% CI) 9.9 (5.6, 22.1) 9.7 (2.7, --)

CI = Confidence interval, HR = Hazard ratio1 At a prespecified interim analysis, 150 OS events were observed, and a p-value boundary fordeclaring efficacy (0.006) was determined by a Lan-Demets alpha spending function with O’Brien

Fleming type boundary.

2 Two-sided p-value based on log rank test stratified by LDH.3 As assessed by investigator using RECIST v1.1 criteria.

4 Hazard ratio is from a proportional hazards model stratified by LDH status5 Based on ≥24 weeks.6 Updated based on all patients having opportunity for at least 3 radiological assessments

Figure 1: Kaplan-Meier curves of overall survival in the study IMCgp100-202 (3-Year

Follow-up Analysis) - ITT Population

CI = confidence interval; HR = hazard ratio; IMCgp100 = tebentafusp; ITT = Intent-to-treat.

After 3 years of follow-up, tebentafusp continues to provide a substantial survival benefit comparedwith investigator’s choice.

Study IMCgp100-102: Previously treated metastatic uveal melanoma

Study IMCgp100-102 was an open-label, Phase 2 multicentre study conducted in 127 patients, whowere treated with the dosing scheme recommended in section 4.2. Patients were required to be

HLA-A*02:01 positive. Patients were eligible if they had experienced disease progression following atleast 1 or more prior lines of liver directed therapy or systemic therapy including immune check pointinhibitors in the metastatic setting. Patients were excluded for clinically significant cardiac disease andpresence of symptomatic or untreated brain metastasis.

Major efficacy outcome measures included confirmed ORR as assessed by Independent Central

Review (ICR) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Secondaryefficacy outcomes included PFS, DCR, DOR and OS.

The median age was 61 years, 50 % were female, 99 % were white, the ECOG performance score was0 (70 %) or 1 (30 %) and 96 % of patients had liver metastasis. Prior treatments includedimmunotherapy (73 % of patients) including immune checkpoint inhibitors (PD-1/PD-L1; 65 %;

CTLA-4; 31 %) and liver directed therapy 45%. Efficacy results from study IMCgp100-102 aresummarised in Table 5.

Table 5: Efficacy results in study IMCgp100-102

Primary and secondary endpoints KIMMTRAK(N = 127)

Confirmed objective response rate1 6 (4.7 %)(95% CI) (1.8 %, 10 %)

Complete response (CR) 0

Partial Response (PR) 6 (4.7 %)

Stable Disease (SD) 2 23 (18.1 %)

Median duration of response

Months (95% CI) 8.7 (5.6, 24.5)1 As assessed by independent central review using RECIST v1.1 criteria.2 Based on ≥24 weeks

The European Medicines Agency has waived the obligation to submit the results of studies with

KIMMTRAK in all subsets of the paediatric population in the treatment of ocular melanoma (seesection 4.2 for information on paediatric use).

The pharmacokinetics of tebentafusp appear linear and dose proportional over a dose range of 20 mcgto 68 mcg. Following weekly intravenous infusion in metastatic uveal melanoma patients, themaximum plasma concentrations (Cmax) reached 4.2 ng/mL - 13.7 ng/mL immediately at the end ofinfusion (T = 0.5 hours). No accumulation was observed with a weekly dosing regimen at the targettherapeutic doses.

Tebentafusp did not distribute extensively and displayed a volume of distribution comparable to bloodvolume (5.25 L).

The metabolic pathway of tebentafusp has not been characterised. Like other protein therapeutics,tebentafusp is expected to be degraded into small peptides and amino acids via catabolic pathways.

The excretion of tebentafusp is not fully characterised. Based on its molecular size that is close to theglomerular filtration size exclusion threshold, small amounts of tebentafusp may be excreted in theurine.

Following administration of tebentafusp in metastatic uveal melanoma patients the estimated systemicclearance was 4. 29 L/d, with a terminal half-life of 6 to 8 hours.

Population pharmacokinetic analysis indicated that there was no significant effect of weight (43 to163 kg), gender, race, and age (23 to 91 years) on tebentafusp clearance.

No formal pharmacokinetic studies of tebentafusp have been conducted in patients with renalimpairment.

No impact on safety or efficacy parameters was identified in patients with mild (creatinine clearance[CrCL] ranging 60 to 89 mL/min) to moderate (CrCL ranging 30 to 59 mL/min) renal impairment andno dose adjustments are recommended. There are limited data from patients (< 5%) with moderaterenal impairment and there is no information available from patients with severe renal impairment(CrCL < 30 mL/min).

No formal pharmacokinetic studies of tebentafusp have been conducted in patients with hepaticimpairment. Population PK analyses demonstrated that baseline and on treatment ALT/AST elevationsdid not impact tebentafusp pharmacokinetics. No dose adjustments based on ALT/AST levels arerecommended.

Tebentafusp is a human--specific protein and there are no relevant animal species in which nonclinicaltoxicology of tebentafusp could be tested.

No carcinogenicity, genotoxicity, or developmental and reproductive toxicity studies have beenconducted with tebentafusp.

Citric acid monohydrate (E330)

Di-sodium hydrogen phosphate (E339)

Mannitol (E421)

Trehalose

Polysorbate 20 (E432)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years.

From a microbiological point of view, once opened, the medicinal product should be diluted andinfused immediately.

After preparation of solution for infusion

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user.

Store and transport refrigerated (2 °C - 8 °C).

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Type I glass vial with a bromobutyl rubber stopper and an aluminium/plastic flip-off seal, containing0.5 mL concentrate.

Pack size of 1 vial.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

The solution for infusion should be prepared by a healthcare professional using proper aseptictechnique throughout the handling of this medicinal product

Use aseptic technique for dilution and preparation of dosing solutions.

Closed system transfer devices (CSTDs) must not be used for dose preparation of KIMMTRAKsolution for infusion.

Parenteral medicinal products and infusion bags should be inspected visually for particulate matter anddiscolouration prior to administration, whenever solution and container permit.

KIMMTRAK must be diluted prior to intravenous administration.

Ensure the following supplies are available prior to preparing KIMMTRAK for administration:

* 1 mL sterile syringes with graduations of 2 decimal places.

* Sterile needles.

* Human albumin; use concentration as per local availability. Local concentrations include butnot restricted to 4 % (40 g/L), 5 % (50 g/L), 20 % (200 g/L), 25 % (250 g/L).

* A 100 mL infusion bag containing sodium chloride 9 mg/mL (0.9 %) solution for injection:

o The infusion bag should be constructed of polyolefins (PO) [such as polyethylene (PE)and polypropylene (PP)] or polyvinyl chloride (PVC).

* A sterile, nonpyrogenic, low protein binding 0.2 micron in-line filter infusion set foradministration of the final infusion bag.

Dilution and Administration

A 2-step process is required for preparation of the final KIMMTRAK dose:

Step 1: Prepare the infusion bag

Using aseptic technique, prepare the infusion bag as follows:

a. Using a 1 mL syringe and a sterile needle, withdraw the calculated volume of human albumin intothe syringe (see Table 6 below) and add to the 100 mL infusion bag containing sodium chloride9 mg/mL (0.9 %) solution for injection to make a final human albumin concentration between225 mcg/mL and 275 mcg/mL.

Table 6: Examples of human albumin concentration and acceptable withdrawal volumes

Human albumin concentration Acceptable volume range for addition to 100 mLinfusion bag for human albumin concentrationbetween 225 mcg/mL to 275 mcg/ mL4 % (40 g/L) 0.63 mL (0.57 mL to 0.69 mL)5 % (50 g/L) 0.50 mL (0.45 mL to 0.55 mL)20 % (200 g/L) 0.13 mL (0.12 mL to 0.14 mL)25 % (250 g/L) 0.10 mL (0.09 mL to 0.11 mL)

b. Gently homogenize the diluted solution by completing the following steps:i. Invert the infusion bag so that the entry port is positioned at the top of the bag and tap theside of port tubing to ensure that any residual solution is released into the bulk solution.ii. Mix by gently rotating the bag lengthwise 360 degrees from the inverted position at least5 times. Do NOT shake the infusion bag.iii. Repeat (i) and (ii) an additional three times.

Step 2: Preparation of KIMMTRAK solution for infusion

c. Using a 1 mL syringe and a sterile needle, withdraw the required volume of KIMMTRAK100 micrograms/ 0.5 mL as per the dose required (shown in Table 6 below) and add to theprepared 100 mL infusion bag containing sodium chloride 9 mg/mL (0.9 %) solution forinjection, plus human albumin.

d. Do NOT flush the needle and syringe on transfer. Discard the vial containing the unused portionof KIMMTRAK in accordance with local requirements. Do not prepare more than one dosefrom the vial.

Table 7: KIMMTRAK volumes required for addition to infusion bag

Day of treatment Dose (mcg) of Volume (mL) of

KIMMTRAK KIMMTRAK

Day 1 20 0.10

Day 8 30 0.15

Day 15 and weekly 68 0.34thereafter

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

* Administer KIMMTRAK as intravenous infusion only.

* Immediately administer the infusion over 15 to 20 minutes through a dedicated intravenous line.

A sterile, nonpyrogenic, low protein binding 0.2 micron in line filter infusion set should beused. Administer the entire contents of the KIMMTRAK infusion bag to the patient.

* Upon completion of KIMMTRAK infusion, flush the infusion line with adequate volume ofsterile sodium chloride 9 mg/mL (0.9 %) solution for injection, to ensure that the entire contentsof the infusion bag are administered. Do not administer KIMMTRAK as an intravenous push orbolus. Do not mix KIMMTRAK with other drugs or administer other drugs through the sameintravenous line.

Storage of prepared infusion bag

* KIMMTRAK does not contain a preservative. The prepared infusion bag should beadministered within 4 hours from the time of preparation including the duration of infusion.

During the 4 hour window, the KIMMTRAK infusion bag should remain below 30 °C.

* If not used immediately, store the KIMMTRAK infusion bag in a refrigerator at 2 °C to 8 °C forup to 24 hours from the time of preparation which includes the time allowed for equilibration ofthe infusion bag to room temperature and the duration of the infusion.

* Once removed from the refrigerator, KIMMTRAK infusion bag must not be refrigerated again.

Discard unused KIMMTRAK solution beyond the recommended storage time.

Immunocore Ireland Limited

Unit 1, Sky Business Centre

Dublin 17, D17 FY82

Ireland

EU/1/22/1630/001

Date of first authorisation: 01 April 2022.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu