KIMMTRAK Concentrate for solution for infusion Ref.[49841] Active ingredients: Tebentafusp

Traceability

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

Cytokine release syndrome (CRS)

Most patients experienced CRS following tebentafusp infusions. Diagnosis of CRS was most frequently based on pyrexia followed by hypotension and infrequently hypoxia. Other commonly observed symptoms with CRS included chills, nausea, vomiting, fatigue, and headache.

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 temperature generally occurred within the first 8 hours after tebentafusp infusion. CRS rarely (1.2%) led to treatment discontinuation.

Patients should be monitored for signs or symptoms of CRS for at least 16 hours following first three infusions of tebentafusp in a hospital setting with immediate access to medicinal products and resuscitative equipment to manage CRS. If CRS is observed, prompt treatment with supportive care including antipyretics, intravenous fluids, tocilizumab, or corticosteroids should be initiated to avoid escalation 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 of signs 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 be withheld 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 its mechanism of action and gp100 expression in normal melanocytes in the skin. Acute skin reactions mainly included rash, pruritus, erythema and cutaneous oedema (see section 4.8).

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

Acute skin reactions can be managed with antihistamine and topical corticosteroids. For persistent or severe symptoms, systemic steroids should be considered. Management of signs and symptoms of skin reactions may require temporary delays of subsequent tebentafusp treatments (see section 4.2, Table 2).

Cardiac disease

Cardiac events such as sinus tachycardia and arrhythmia have been observed in patients who have received tebentafusp treatment (see section 4.8). Patients with pre-existing cardiovascular disorders may be at increased risk for sequalae associated with CRS and should be monitored carefully. Any patient with signs or symptoms consistent with cardiac events should be evaluated and promptly treated. In addition, 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 predisposition to QT interval prolongation and in patients who are taking medicinal products that are known to prolong QT interval.

An electrocardiogram (ECG) should be performed in all patients before and after tebentafusp treatment during the first 3 weeks of treatment and subsequently as clinically indicated. If QTcF exceeds 500 msec or increases by ≥60 msec from baseline value tebentafusp treatment should be withheld and patients should 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 msec from baseline value. Depending on persistence and severity of the cardiac event and any associated CRS tebentafusp treatment should be withheld or discontinued (see section 4.2, Table 1).

Contraception

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

Excipients

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 CYP450 enzymes. The highest drug-drug interaction risk is during the first 24 hours of the first three doses of tebentafusp in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. These patients should be monitored for toxicity (e.g., warfarin) or drug concentrations (e.g., cyclosporine). The dose of the concomitant medicines should be adjusted as needed.

Women of childbearing potential / Contraception

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

Pregnancy

There are no data from the use of tebentafusp in pregnant women. Animal reproduction studies have not been conducted with tebentafusp (see section 5.3).

Tebentafusp is not recommended during pregnancy and in women of childbearing potential not using contraception. The pregnancy status in females of reproductive potential should be verified prior to initiating tebentafusp treatment.

Breast-feeding

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

Fertility

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

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

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. Adverse reactions requiring dosage interruption in ≥2% of patients included fatigue (3%; Grade 1--3), pyrexia (2.7%; Grade 1-3), 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 patients were cytokine release syndrome (1.9%; Grade 1-3), and hypotension (1.1%; 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.

Table 3. Adverse reactions in patients treated with KIMMTRAK monotherapy:

¹ 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, 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. The overall incidence of CRS included 12% Grade 1, 76% Grade 2 and 0.8% Grade 3 events. Most commonly observed symptoms with CRS included chills, nausea, vomiting, fatigue, hypotension, and headache. Grade 3 events that 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. CRS rarely (1.2%) led to treatment discontinuation. All CRS symptoms were reversible and were mostly managed with intravenous fluids, antipyretics, or a single dose of corticosteroid. 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 patients experienced Grade 3 (21%) events. Among patients with observed rash, patients commonly experienced rash (55%), rash maculo-papular (31%) and skin exfoliation (21%). Grade 3 adverse reactions 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, with decreasing 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 and median time to improvement to ≤ Grade 1 was 6 days.

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

Elevated liver enzymes

In Study IMCgp100-202 where 95% of patients had preexisting liver metastasis, ALT/AST increase to ≥ Grade 1 were observed in 65% of patients treated with KIMMTRAK. Elevations in bilirubin have been reported in 27% of patients and these were primarily associated with increase in size of liver 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 had improvement to ≤ Grade 1 within 7 days.

Immunogenicity

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 tebentafusp treatment.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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