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.

No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment. Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population. If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population. If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations.

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

Amivantamab as monotherapy

In the dataset of amivantamab intravenous formulation 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 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

Table 1 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy.

The data reflects exposure to amivantamab intravenous formulation 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 (≥1/1000 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 1. Adverse reactions in patients receiving amivantamab as monotherapy (N=380):

^* Grouped terms
^† Grade 3 events only

Amivantamab in combination with lazertinib

Overall, the safety profile of amivantamab subcutaneous formulation was consistent with the established safety profile of amivantamab 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 amivantamab (either intravenous or subcutaneous formulations) in combination with lazertinib (N=829), the most frequent adverse reactions of any grade (≥20% patients) were rash (87%), nail toxicity (68%), hypoalbuminaemia (49%), hepatotoxicity (43%), stomatitis (43%), oedema (42%), fatigue (34%), paraesthesia (29%), diarrhoea (26%), constipation (25%), dry skin (25%), nausea (24%), pruritus (24%), and decreased appetite (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 amivantamab subcutaneous formulation in combination with lazertinib, including ILD (4.2%), VTE (2.2%), hepatotoxicity (2.2%), and fatigue (1.5%). Seven percent of patients discontinued amivantamab subcutaneous formulation due to adverse reactions. In patients treated with amivantamab subcutaneous formulation in combination with lazertinib, the most frequent adverse reactions of any grade (≥1% patients) leading to discontinuation of amivantamab subcutaneous formulation were ILD (3.7%), rash (1.2%), and nail toxicity (1.0%).

Tabulated list of adverse reactions

The adverse reactions for amivantamab (either intravenous or subcutaneous formulation) when received in combination with lazertinib are summarised in Table 2.

The safety data below reflect exposure to amivantamab (either intravenous or subcutaneous formulation) in combination with lazertinib in 829 patients with locally advanced or metastatic NSCLC, including 421 patients in MARIPOSA, 202 patients in PALOMA-2 cohorts 1, 5 and 6, and 206 patients in PALOMA-3 subcutaneous arm. Patients received amivantamab (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 9.1 months (range: 0.1 to 31.4 months). Median duration on treatment for the subcutaneous formulation was 6.1 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 2. Adverse reactions for amivantamab (either intravenous or subcutaneous formulation) when received in combination with lazertinib (N=829):

^* 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], cohort 5 [N=77] 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.

Amivantamab in combination with carboplatin and pemetrexed

In the dataset of amivantamab (either intravenous or subcutaneous formulations) in combination with carboplatin and pemetrexed (N=444), the most frequent adverse reactions of any grade (≥20% patients) were rash (83%), nail toxicity (57%), neutropenia (56%), fatigue (46%), nausea (44%), stomatitis (42%), oedema (41%), thrombocytopenia (40%), constipation (39%), hypoalbuminaemia (36%), decreased appetite (32%), alanine aminotransferase increased (28%), aspartate aminotransferase increased (24%), and vomiting (23%).

Serious adverse reactions were reported in 19% of patients who received amivantamab subcutaneous formulation in combination with carboplatin and pemetrexed, including vomiting (2.8%), ILD (2.8%), nausea (2.1%), fatigue (2.1%), VTE (2.1%), neutropenia (2.1%), diarrhoea (1.4%), and hypocalcaemia (1.4%). 6% of patients discontinued amivantamab subcutaneous formulation due to adverse reactions. In patients treated with amivantamab subcutaneous formulation in combination with carboplatin and pemetrexed, the most frequent adverse reactions of any grade (≥1% patients) leading to discontinuation of amivantamab subcutaneous formulation were ILD (2.8%) and rash (1.4%).

Tabulated list of adverse reactions

The adverse reactions for amivantamab (either intravenous or subcutaneous formulation) when received in combination with carboplatin and pemetrexed are summarised in Table 3.

The safety data below reflect exposure to amivantamab (either intravenous or subcutaneous formulation) in combination with carboplatin and pemetrexed in 444 patients with locally advanced or metastatic NSCLC, including 151 patients in PAPILLON, 130 patients in MARIPOSA-2, 20 patients in CHRYSALIS, and 143 patients in PALOMA-2 cohorts 2 and 3b. Patients received amivantamab (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 7.4 months (range: 0.0 to 28.1 months). Median duration on treatment for the subcutaneous formulation was 6.9 months (range: 0.0 to 15.4 months) while median duration on treatment for the intravenous formulation was 7.7 months (range: 0.0 to 28.1 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).

Table 3. Adverse reactions for amivantamab (either intravenous or subcutaneous formulation) when received in combination with carboplatin and pemetrexed (N=444):

^* Grouped terms.
^a Frequency based on amivantamab intravenous studies only (CHRYSALIS [N=20], PAPILLON [N=151], MARIPOSA-2 [N=130]).
^b Frequency based on amivantamab subcutaneous studies only (PALOMA-2 cohorts 2 and 3B [N=143]).
^c Injection site reactions are local signs and symptoms associated with subcutaneous mode of administration.
^d Infusion-related reactions are systemic signs and symptoms associated with infusion of amivantamab intravenous.
^e Administration-related reactions are systemic signs and symptoms associated with administration of amivantamab subcutaneous.

Description of selected adverse reactions

Administration-related reactions

Administration-related reactions were reported in 14% of patients treated with amivantamab subcutaneous formulation in combination with lazertinib, and 7% of patients treated with amivantamab subcutaneous formulation in combination with carboplatin and pemetrexed. The most frequent signs and symptoms of administration-related reactions include dyspnoea, flushing, fever, chills, nausea, and chest discomfort. In patients treated with amivantamab subcutaneous formulation in combination with lazertinib, the median time to onset of first administration-related reactions was 1.9 hours (range: 0.0 to 176.5 hours), with most administration-related reactions (96%) being Grades 1 or 2 in severity. In patients treated with amivantamab subcutaneous formulation in combination with carboplatin and pemetrexed, the median time to onset of first administration-related reactions was 2.1 hours (range: 0.7 to 3.1 hours), with all administration-related reactions being Grades 1 or 2 in severity. In PALOMA-3, administration-related reactions were reported in 13% of patients treated with amivantamab subcutaneous formulation in combination with lazertinib compared to 66% when treated with amivantamab intravenous formulation in combination with lazertinib.

Injection site reactions

Injection site reactions occurred in 6% of patients treated with amivantamab subcutaneous formulation in combination with lazertinib and 3.5% of patients treated with amivantamab subcutaneous formulation in combination with carboplatin and pemetrexed. 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 amivantamab (either intravenous or subcutaneous formulation) in combination with lazertinib, including 2 (0.2%) patients with a fatal reaction, and 2.5% of patients treated with amivantamab (either intravenous or subcutaneous formulation) in combination with carboplatin and pemetrexed. 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 amivantamab 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 (0.7%) patients. Additionally, 336 (82%) of these 408 patients receiving amivantamab 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, for the direct comparison between arms, the incidence of VTE events was 9% for patients treated with amivantamab subcutaneous formulation in combination with lazertinib, versus 14% when treated with amivantamab 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 events was 17% for patients treated with amivantamab subcutaneous formulation in combination with lazertinib with all VTE events reported as Grade 1-2 and serious VTE events reported in 4.8% of these patients, compared to an overall incidence of 26% for patients treated with amivantamab intravenous formulation in combination with lazertinib with Grade 3 and Grade 4 VTE events reported in 10% and 2.6% of patients, respectively, and serious VTE events reported in 10% of these patients.

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin have occurred in patients treated with amivantamab (either intravenous or subcutaneous formulation). Rash occurred in 87% of patients treated with amivantamab in combination with lazertinib, leading to discontinuation of amivantamab in 0.6% of patients; and 83% of patients treated with amivantamab in combination with carboplatin and pemetrexed, leading to discontinuation of amivantamab in 0.5% of patients. Among patients treated with amivantamab in combination with lazertinib, most cases were Grade 1 or 2, with Grade 3 and Grade 4 reactions occurring in 22% and 0.1% of patients, respectively. Among patients treated with amivantamab in combination with carboplatin and pemetrexed, most cases were Grade 1 or 2, with Grade 3 reactions occurring in 14% of patients.

Eye disorders

Eye disorders occurred in patients treated with amivantamab (either intravenous or subcutaneous formulation), including keratitis in 1.9% of patients treated with amivantamab in combination with lazertinib and 0.2% of patients treated with amivantamab in combination with carboplatin and pemetrexed. 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. No overall differences in safety were observed between patients ≥65 years of age and patients <65 years of age.