Amivantamab

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.

Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population.

Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population.

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab. 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 should be evaluated and appropriate treatment should be initiated as necessary. Amivantamab should be permanently discontinued in patients with confirmed ILD.

Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with amivantamab. Patients should be instructed to limit sun exposure during and for 2 months after amivantamab therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable. Alcohol-free emollient cream is recommended for dry areas. 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. Amivantamab should be dose reduced, interrupted, or permanently discontinued based on severity.

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

Eye disorders, including keratitis, occurred in patients treated with amivantamab. Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated.

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.

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.

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.

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.

Amivantamab may have moderate influence on the ability to drive and use machines (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

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 amivantamab 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

The table below summarises the adverse drug reactions that occurred in patients receiving amivantamab.

The data reflects exposure to amivantamab in 380 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received amivantamab 1,050 mg (for patients <80 kg) or 1,400 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); 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.

Adverse reactions in patients receiving amivantamab:

^* Grade 3 events only
^a Hypoalbuminaemia: blood albumin decreased, hypoalbuminaemia
^b Dizziness: dizziness, dizziness exertional, vertigo
^c Visual impairment: vision blurred, visual acuity reduced, visual impairment
^d Growth of eyelashes: growth of eyelashes, trichomegaly
^e Other eye disorders: blepharitis, conjunctival hyperaemia, corneal irritation, dry eye, episcleritis, eye disorder, eye pruritus, noninfective conjunctivitis, ocular hyperaemia
^f Interstitial lung disease: interstitial lung disease, pneumonitis
^g Stomatitis: aphthous ulcer, cheilitis, glossitis, lip ulceration, mouth ulceration, mucosal inflammation, stomatitis
^h Abdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort, gastrointestinal pain
ⁱ Rash: acne, dermatitis, dermatitis acneiform, erythema, erythema multiforme, folliculitis, impetigo, palmar-plantar erythrodysaesthesia syndrome, perineal rash, perioral dermatitis, pustule, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin lesion
^j Nail toxicity: ingrowing nail, nail bed infection, nail cuticle fissure, nail disorder, nail ridging, onychoclasis, onycholysis, paronychia
^k Dry skin: dry skin, eczema, eczema asteatotic, skin fissures, xeroderma
^l Oedema: eye oedema, eyelid oedema, face oedema, generalised oedema, localised oedema, oedema, oedema peripheral, periorbital oedema, periorbital swelling, peripheral swelling, swelling face
^m Fatigue: asthenia, fatigue

Description of selected adverse reactions

Infusion-related reactions

Infusion-related reactions occurred in 67% of patients treated with amivantamab. Ninety-eight percent of IRRs were Grade 1-2. Ninety-nine percent of IRRs occurred at the first infusion with a median time to onset of 60 minutes, and the majority occurring within 2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea, flushing, chest discomfort, and vomiting.

Interstitial lung disease

Interstitial lung disease or ILD-like adverse reactions have been reported with the use of amivantamab as well as with other EGFR inhibitors. Interstitial lung disease or pneumonitis was reported in 2.6% of patients. Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from the clinical study.

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 76% of patients treated with amivantamab. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 3% of patients. Rash leading to amivantamab discontinuation occurred in 0.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Paronychia occurred in patients treated with amivantamab. Most events were Grade 1 or 2, with Grade 3 paronychia occurring in 1.8% of patients.

Eye disorders

Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All events were Grade 1-2.

Other special populations

Elderly

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

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In a clinical study of patients with locally advanced or metastatic NSCLC treated with amivantamab, 3 (0.9%) of the 347 evaluable patients tested positive for anti-amivantamab antibodies. There was no evidence of an altered pharmacokinetic, efficacy, or safety profile due to anti-amivantamab antibodies.