Rybrevant Adverse Reactions

Summary of the safety profile: 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 12 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy.
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 as follows 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. (See Table 12.)

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Summary of the safety profile: In the dataset of amivantamab in combination with carboplatin and pemetrexed (N=301), the most frequent adverse reactions in all grades were rash (83%), neutropenia (57%), nail toxicity (53%), infusion related reactions (51%), fatigue (43%), stomatitis (39%), nausea (43%), thrombocytopenia (40%), constipation (40%), oedema (40%), decreased appetite (33%), hypoalbuminaemia (32%), alanine aminotransferase increased (26%), aspartate aminotransferase increased (23%), vomiting (22%), and hypokalaemia (20%). Serious adverse reactions included rash (2.7%), venous thromboembolism (2.3%), thrombocytopenia (2.3%) and ILD (2.0%). Eight percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (2.7%), rash (2.3%), ILD (2.3%), and nail toxicity (1.0%).
Table 13 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with chemotherapy.
The data reflects exposure to amivantamab in combination with carboplatin and pemetrexed in 301 patients with locally advanced or metastatic non-small cell lung cancer. Patients received amivantamab 1,400 mg (for patients <80 kg) or 1,750 mg (for patients ≥80 kg) weekly for 4 weeks. Starting at Week 7, patients received amivantamab 1,750 mg (for patients <80 kg) or 2,100 mg (for patients ≥80 kg) every 3 weeks. The median exposure to amivantamab in combination with carboplatin and pemetrexed was 7.7 months (range: 0.0 to 28.1 months).
Adverse reactions observed during clinical studies are listed as follows 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. (See Table 13.)

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Summary of the safety profile: In the dataset of amivantamab in combination with lazertinib (N=421), the most frequent adverse reactions in all grades were rash (89%), nail toxicity (71%), infusion-related reactions (63%), hypoalbuminaemia (48%), hepatotoxicity (47%), oedema (47%), stomatitis (43%), venous thromboembolism (37%), paraesthesia (lazertinib) (34%), fatigue (32%), diarrhoea (29%), constipation (29%), dry skin (26%), pruritis (24%), decreased appetite (24%), hypocalcaemia (21%), nausea (21%) and other eye disorders (21%). The most frequent serious adverse reactions included venous thromboembolism (11%), pneumonia (4.0%), rash (3.1%), ILD/pneumonitis (2.9%), hepatotoxicity (2.4%), COVID-19 (2.4%), and IRR and pleural effusion (2.1%). Twenty-three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to Rybrevant discontinuation were rash (5.5%), infusion related reactions (4.5%), nail toxicity (3.6%), ILD (2.9%) and VTE (2.9%).
Table 14 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with lazertinib.
The data reflects exposure to amivantamab in combination with lazertinib in 421 patients with locally advanced or metastatic non-small cell lung cancer. Patients received amivantamab 1,050 mg (for patients <80 kg) or 1,400 mg (for patients ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter. The median exposure to study treatment in the amivantamab and lazertinib combination group was 18.5 months (range: 0.2 to 31.4 months).
Adverse reactions observed during clinical studies are listed as follows 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. (See Table 14.)

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Description of selected adverse reactions: Infusion-related reactions: In patients treated with amivantamab monotherapy, infusion-related reactions occurred in 67% of patients. 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 (see Precautions).
In patients treated with amivantamab in combination with carboplatin and pemetrexed, infusion-related reactions occurred in 50% of patients. Greater than 94% of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 60 minutes (range 0-7 hours), and the majority occurring within 2 hours of infusion start. Occasionally an IRR can occur at re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks.
In patients treated with amivantamab in combination with lazertinib, infusion-related reactions occurred in 63% of patients. Ninety-four percent of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 1 hour, 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 (see Precautions). Occasionally an IRR can occur at re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks.
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 treated with amivantamab monotherapy, 2.3% of patients treated with amivantamab in combination with carboplatin and pemetrexed and 3.1% of patients treated with amivantamab in combination with lazertinib, including 1 (0.2%) fatal case. 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 (see Precautions).
Venous thromboembolic (VTE) events with concomitant use with lazertinib: When Rybrevant is used in combination with lazertinib, VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in 37% of the 421 patients receiving Rybrevant in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 11% of patients receiving Rybrevant in combination with lazertinib and deaths occurring in 0.5% of patients receiving Rybrevant in combination with lazertinib. For information on prophylactic anticoagulants and management of VTE events, see Dosage & Administration and Precautions.
In patients receiving Rybrevant in combination with lazertinib, the median time to first onset of a VTE event was 84 days. VTE events led to Rybrevant treatment discontinuation in 2.9% of patients.
Skin and nail reactions: Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 76% of patients treated with amivantamab alone. 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. Nail toxicity occurred in patients treated with amivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 1.8% of patients.
Rash (including dermatitis acneiform), occurred in 83% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 14% of patients. Rash leading to amivantamab discontinuation occurred in 2.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with carboplatin and pemetrexed. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 4.3% of patients (see Precautions).
Rash (including dermatitis acneiform), occurred in 89% of patients treated with amivantamab in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 27% of patients. Rash leading to amivantamab discontinuation occurred in 5.5% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with lazertinib. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 11% of patients (see Precautions).
Eye disorders: Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab alone. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All events were Grade 1-2.
Eye disorders, including keratitis (0.3%), occurred in 11% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Other reported adverse reactions included growth of eyelashes, visual impairment, uveitis, and other eye disorders. All events were Grade 1-2 (see Precautions).
Eye disorders, including keratitis (2.6%) occurred in patients treated with amivantamab in combination with lazertinib. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. Most events were Grade 1-2 (see Precautions).
Special populations: Elderly: There are limited clinical data with amivantamab in patients 75 years of age or over (see Pharmacology: Pharmacodynamics under Actions). 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 clinical studies of patients with locally advanced or metastatic NSCLC treated with amivantamab, 4 of the 1,862 (0.2%) participants who were treated with Rybrevant and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab antibodies. There was no evidence of an altered pharmacokinetic, efficacy, or safety profile due to anti-amivantamab antibodies.
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.