RYBREVANT Solution for injection Ref.[115919] Active ingredients: Amivantamab

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.

Administration-related reactions

Administration-related reactions occurred in patients treated with Rybrevant subcutaneous formulation (see section 4.8).

Prior to the initial injection (Week 1 Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions. For subsequent doses, antihistamines and antipyretics should be administered.

Patients should be treated in a setting with appropriate medical support to treat administration-related reactions. At the first sign of administration-related reactions of any severity, injections should be interrupted, if ongoing, and post-injection medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the injection should be resumed. For Grade 4 or recurrent Grade 3 administration-related reactions, Rybrevant should be permanently discontinued (see section 4.2).

Interstitial lung disease

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab, including fatal events (see section 4.8). Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with Rybrevant should be interrupted pending investigation of these symptoms. Suspected ILD or ILD-like adverse reactions should be evaluated and appropriate treatment should be initiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILD or ILD-like adverse reactions (see section 4.2).

Venous thromboembolic (VTE) events with concomitant use with lazertinib

In patients receiving amivantamab in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), were reported (see section 4.8). Fatal events were observed with amivantamab intravenous formulation. Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.

Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability, treatment should be withheld until the patient is clinically stable. Thereafter, both drugs can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, Rybrevant should be discontinued. Treatment can continue with lazertinib at the same dose (see section 4.2).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable. Alcohol-free emollient cream is recommended for dry areas. A prophylactic approach to rash prevention should be considered. This includes prophylactic therapy with an oral antibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months of treatment. Non‑comedogenic skin moisturiser on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet should be considered beginning on Day 1 and continued for the first 12 months of treatment.

Prescriptions for topical and/or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. If skin reactions develop, topical corticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 or poorly-tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered. Patients presenting with severe rash that has an atypical appearance or distribution or lack improvement within 2 weeks should be referred promptly to a dermatologist. Rybrevant should be dose reduced, interrupted, or permanently discontinued based on severity (see section 4.2).

Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed.

Eye disorders

Eye disorders, including keratitis, occurred in patients treated with amivantamab (see section 4.8). Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for Grade 3 or 4 eye disorders, see section 4.2.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially "sodium-free" (see section 6.6).

Polysorbate content

This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 6 mg per 10 mL vial, or 8.4 mg per 14 mL vial. Polysorbates may cause hypersensitivity reactions.

No drug interaction studies have been performed. As an IgG1 monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact amivantamab are unlikely to be major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of amivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug-metabolising enzymes.

Vaccines

No clinical data are available on the efficacy and safety of vaccinations in patients taking amivantamab. Avoid the use of live or live-attenuated vaccines while patients are taking amivantamab.

Women of child-bearing potential/Contraception

Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment.

Pregnancy

There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug-associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product, the patient should be informed of the potential risk to the foetus (see section 5.3).

Breast-feeding

It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast-fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in the gastrointestinal tract of the breast-fed child and not absorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from amivantamab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

Rybrevant may have moderate influence on the ability to drive and use machines. Please see section 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment-related symptoms, including vision-related adverse reactions, affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

Summary of the safety profile

Rybrevant as monotherapy

In the dataset of amivantamab as monotherapy (N=380), the most frequent adverse reactions in all grades were rash (76%), infusion-related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), and constipation (23%). Serious adverse reactions included ILD (1.3%), IRR (1.1%), and rash (1.1%). Three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%).

Tabulated list of adverse reactions

Table 4 summarises the adverse drug reactions that occurred in patients receiving Rybrevant as monotherapy.

The data reflects exposure to Rybrevant intravenous formulation in 380 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received amivantamab 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg). The median exposure to amivantamab was 4.1 months (range: 0.0 to 39.7 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 4. Adverse reactions in patients receiving Rybrevant as monotherapy (N=380):

^* Grouped terms
^† Grade 3 events only

Rybrevant in combination with lazertinib

Overall, the safety profile of Rybrevant subcutaneous formulation was consistent with the established safety profile of Rybrevant intravenous formulation, with a lower incidence of administration-related reactions and VTEs observed with the subcutaneous formulation compared to the intravenous formulation.

In the dataset of Rybrevant (either intravenous or subcutaneous formulations) in combination with lazertinib (N=752), the most frequent adverse reactions of any grade (≥20% patients) were rash (87%), nail toxicity (67%), hypoalbuminaemia (48%), hepatotoxicity (43%), stomatitis (43%), oedema (42%), fatigue (35%), paraesthesia (29%), constipation (26%), diarrhoea (26%), dry skin (25%), decreased appetite (24%), nausea (24%), and pruritus (23%).

Clinically relevant differences between the intravenous and subcutaneous formulations, when given in combination with lazertinib, were observed for administration-related reactions (63% for intravenous vs. 14% for subcutaneous) and VTE (37% for intravenous vs. 11% for subcutaneous).

Serious adverse reactions were reported in 14% of patients who received Rybrevant subcutaneous formulation in combination with lazertinib, including ILD (4.2%), VTE (2.7%), hepatotoxicity (2.1%), and fatigue (1.5%). Seven percent of patients discontinued Rybrevant subcutaneous formulation due to adverse reactions. In patients treated with Rybrevant subcutaneous formulation in combination with lazertinib, the most frequent adverse reactions of any grade (≥1% patients) leading to discontinuation of Rybrevant subcutaneous formulation were ILD (3.6%) and rash (1.5%).

Tabulated list of adverse reactions

The adverse reactions for Rybrevant (either intravenous or subcutaneous formulation) when received in combination with lazertinib are summarised in Table 5.

The safety data below reflect exposure to Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib in 752 patients with locally advanced or metastatic NSCLC, including 421 patients in MARIPOSA, 125 patients in PALOMA-2 cohorts 1 and 6, and 206 patients in PALOMA-3 subcutaneous arm. Patients received Rybrevant (either intravenous or subcutaneous formulation) until disease progression or unacceptable toxicity. The median duration of treatment with amivantamab overall for both intravenous and subcutaneous formulations was 9.9 months (range: 0.1 to 31.4 months). Median duration on treatment for the subcutaneous formulation was 5.7 months (range: 0.1 to 13.2 months) while median duration on treatment for the intravenous formulation was
18.5 months (range: 0.2 to 31.4 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); and not known (frequency cannot be estimated from the available data).

Table 5. Adverse reactions for Rybrevant (either intravenous or subcutaneous formulation) when received in combination with lazertinib (N=752):

^* Grouped terms.
^a Applicable only to lazertinib.
^b Frequency based on amivantamab intravenous study only (MARIPOSA [N=421]).
^c Frequency based on amivantamab subcutaneous studies only (PALOMA-2 cohorts 1 and 6 [N=125] and PALOMA-3 subcutaneous arm [N=206]).
^d Injection site reactions are local signs and symptoms associated with subcutaneous mode of administration.
^e Infusion-related reactions are systemic signs and symptoms associated with infusion of amivantamab intravenous.
^f Administration-related reactions are systemic signs and symptoms associated with administration of amivantamab subcutaneous.

Description of selected adverse reactions

Administration-related reactions

Overall, administration-related reactions occurred in 14% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib. In PALOMA-3, administration-related reactions were reported in 13% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib compared to 66% when treated with Rybrevant intravenous formulation in combination with lazertinib. The most frequent signs and symptoms of administration-related reactions include dyspnoea, flushing, fever, chills, nausea, and chest discomfort. Median time to onset of first administration-related reactions was 2.1 hours (range: 0.0 to 176.5 hours). Most administration-related reactions (98%) were Grades 1 or 2 in severity.

Injection site reactions

Overall, injection site reactions occurred in 8% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib. All injection site reactions were Grade 1 or 2 in severity. The most frequent symptom of injection site reactions was erythema.

Interstitial lung disease

Interstitial lung disease (ILD) or ILD-like adverse reactions have been reported with the use of amivantamab as well as with other EGFR inhibitors. ILD was reported in 3.6% of patients treated with Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib, including 2 (0.3%) patients with a fatal reaction. Patients with a medical history of ILD, including drug-induced ILD or radiation pneumonitis, were excluded from PALOMA-2 and PALOMA-3.

Venous thromboembolic (VTE) events with concomitant use with lazertinib

VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in 11% of patients receiving Rybrevant subcutaneous formulation in combination with lazertinib in PALOMA-2 and PALOMA-3. Most cases were Grade 1 or 2, with Grade 3 events occurring in 3 (0.9%) patients. Additionally, 269 (81%) of these 331 patients receiving Rybrevant subcutaneous formulation took prophylactic anticoagulants with a direct oral anticoagulant or low molecular weight heparin within the first four months of study treatment. In PALOMA-3, the incidence of VTE reactions was 9% for patients treated with Rybrevant subcutaneous formulation in combination with lazertinib, compared to 13% when treated with Rybrevant intravenous formulation in combination with lazertinib, with similar rates of prophylactic anticoagulant use in both treatment arms (80% in the subcutaneous arm vs. 81% in the intravenous arm). For patients who did not receive prophylactic anticoagulants, the overall incidence of VTE was 17% for patients treated with Rybrevant subcutaneous formulation in combination with lazertinib with all VTE reactions reported as Grade 1-2 and serious VTE reactions reported in 4.8% of these patients, compared to an overall incidence of 23% for patients treated with Rybrevant intravenous formulation in combination with lazertinib with Grade 3 VTE reactions reported in 10% and serious VTE reactions reported in 8% of these patients.

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin have occurred in patients treated with Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib. Rash occurred in 87% of patients, leading to discontinuation of Rybrevant in 0.7% of patients. Most cases were Grade 1 or 2, with Grade 3 and Grade 4 reactions occurring in 23% and 0.1% of patients, respectively.

Eye disorders

Eye disorders, including keratitis (1.7%), occurred in patients treated with Rybrevant (either intravenous or subcutaneous formulation). Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders.

Special populations

Elderly

There are limited clinical data with amivantamab in patients 75 years of age or over (see section 5.1). No overall differences in safety were observed between patients ≥65 years of age and patients <65 years of age.

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.