Adverse reactions : תופעות לוואי

4.8   Undesirable effects
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 Adverse reactions
Infections and infestations
Common                                         Nasopharyngitis
Immune system disorders
Very common                                    Cytokine release syndrome1 Metabolism and nutrition disorders
Very common                                    Decreased appetite, hypomagnesaemia, hyponatraemia, hypocalcaemia, hypokalaemia
Uncommon                                       Tumour lysis syndrome
Psychiatric disorders
Very Common                                    Insomnia
Common                                         Anxiety
Nervous system disorders
Very common                                    Headache2 , dizziness, paraesthesia Common                                         Taste disorder
Cardiac disorders
Very common                                    Tachycardia2

Common                                            Arrhythmia2, atrial fibrillation2 Uncommon                                          Angina pectoris2, cardiac failure2 Vascular disorders
Very common                                       Hypotension2, flushing, hypertension Respiratory, thoracic and mediastinal disorders
Very common                                       Cough, dyspnoea
Common                                            Oropharyngeal pain, hypoxia2 Gastrointestinal disorders
Very common                                       Nausea2, vomiting2, diarrhoea, abdominal pain, constipation, dyspepsia
Skin and subcutaneous tissue disorders
Very common                                       Rash, pruritus, dry skin, hypo/ hyperpigmentation4, erythema
Common                                            Alopecia, night sweats Musculoskeletal and connective tissue disorders
Very common                                       Arthralgia, back pain, myalgia, pain in extremity Common                                            Muscle spasm
General disorders and administration site conditions
Very common                                       Pyrexia2, fatigue3, chills2, oedema5, Influenza like illness
Investigations
Very common                                       Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, lipase increased, anaemia, lymphocyte count decreased, blood phosphate decreased, blood creatinine increased
Common                                            Amylase increased, gamma glutamyltransferase increased, white blood cell count increased, blood alkaline phosphatase increased, blood glucose increased
Uncommon                                          Electrocardiogram QT prolonged 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il