Lazertinib

The co-administration of multiple doses of 160 mg lazertinib once daily increased rosuvastatin (BCRP substrate) C_max by 2.24-fold and AUC by 2.02-fold. Narrow therapeutic index medicinal products that are BCRP substrates (e.g., sunitinib) should be used with caution, as lazertinib may increase the plasma concentrations of these medicinal products.

The co-administration of multiple doses of rifampicin (strong CYP3A4 inducer) decreased lazertinib C_max by 72% and AUC by 83% in healthy subjects. The co-administration of lazertinib with strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John’s wort) should be avoided. The co-administration of lazertinib with moderate CYP3A4 inducers may also decrease lazertinib plasma concentrations and hence moderate CYP3A4 inducers (e.g. bosentan, efavirenz, modafinil) should be used with caution.

Induction of CYP1A2 cannot be excluded. Therefore, caution is advised when co-administering with substrates of CYP1A2 (e.g., tizanidine).

The co-administration of multiple doses of 160 mg lazertinib once daily increased midazolam (CYP3A4 substrate) C_max by 1.39-fold and AUC by 1.47-fold. Narrow therapeutic index medicinal products that are CYP3A4 substrates (e.g., cyclosporine, everolimus, pimozide, quinidine, sirolimus, tacrolimus) should be used with caution, as lazertinib may increase the plasma concentrations of these medicinal products.

Based on population pharmacokinetics (PK) analysis, no dose adjustment is required for patients with severe renal impairment. Data in patients with severe renal impairment are limited. The PK of lazertinib in patients with end stage renal disease is unknown. Caution is required in patients with end-stage renal disease.

The PK of lazertinib in patients with severe hepatic impairment is unknown. Caution is required in patients with severe hepatic impairment.

There are no data from the use of lazertinib in pregnant women. Studies in animals have shown reproductive toxicity (reduced embryo-foetal survival and foetal body weight). Based on its mechanism of action and animal data, lazertinib may cause foetal harm when administered to a pregnant woman. Lazertinib should not be used 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 lazertinib or its metabolites are excreted in human milk or affects milk production. Because the risk to the breast-feeding child cannot be excluded, female patients should be advised not to breast-feed during treatment and for 3 weeks after the last dose of lazertinib.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to use effective contraception during treatment and up to 3 weeks after treatment.

Male patients with female partners of reproductive potential should be advised to use effective contraception (e.g., condom) and not donate or store semen during treatment and for 3 weeks after the last dose of lazertinib.

Fertility

There are no data on the effect of lazertinib on human fertility. Studies in animals have shown that lazertinib has effects on reproductive organs in females (decreased numbers of oestrus cycles and corpora lutea) and males (degenerative changes in the testis) and may impair female and male fertility.

Lazertinib has minor influence on the ability to drive and use machines. If patients experience treatment-related symptoms (such as fatigue) 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 (89%), nail toxicity (71%), infusion-related reaction (amivantamab) (63%), hypoalbuminaemia (amivantamab) (48%), hepatotoxicity (47%), oedema (amivantamab) (47%), stomatitis (43%), venous thromboembolism (37%), paraesthesia (34%), fatigue (32%), constipation (29%), diarrhoea (29%), dry skin (26%), decreased appetite (24%), pruritus (24%), hypocalcaemia (21%), other eye disorders (21%) and nausea (21%).

The most frequent serious adverse reactions included venous thromboembolism (11%), pneumonia (4.0%), rash (3.1%), interstitial lung disease/pneumonitis (2.9%), COVID-19 (2.4%), hepatotoxicity (2.4%), pleural effusion (2.1%), infusion-related reaction (amivantamab) (2.1%), respiratory failure (1.4%), fatigue (1.2%), oedema (amivantamab) (1.2%), hypoalbuminaemia (amivantamab) (1.2%), and hyponatraemia (1.2%).

The most frequent adverse reactions leading to any treatment discontinuation in patients receiving lazertinib in combination with amivantamab were rash (6%), infusion-related reaction (amivantamab) (4.5%), nail toxicity (3.6%), interstitial lung disease/pneumonitis (2.9%), venous thromboembolism (2.9%), pneumonia (1.9%) and oedema (amivantamab) (1.7%).

Tabulated list of adverse reactions

The table below summarises the adverse reactions that occurred in patients receiving lazertinib in combination with amivantamab.

The data reflects exposure to lazertinib in 421 patients who received lazertinib in combination with amivantamab in MARIPOSA. The median exposure to lazertinib 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 (≥1/1 000 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 lazertinib in combination with amivantamab:

^a grouped terms
^b applicable only to amivantamab.

Description of selected adverse reactions

Venous thromboembolism

Venous thromboembolic (VTE) events, including deep vein thrombosis (14.5%) and pulmonary embolism (PE) (17.3%), were reported in 37% of patients receiving lazertinib in combination with amivantamab. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 11% and deaths occurring in 0.5% of patients receiving lazertinib in combination with amivantamab.

In patients receiving lazertinib in combination with amivantamab, the median time to first onset of a VTE event was 84 days. VTE events led to any treatment discontinuation in 2.9% of patients.

Interstitial lung disease (ILD)/pneumonitis

Interstitial lung disease or ILD-like adverse reactions (e.g., pneumonitis) have been reported with the use of lazertinib in combination with amivantamab as well as with other EGFR inhibitors. ILD or pneumonitis was reported in 3.1% of patients treated with lazertinib in combination with amivantamab, including 0.2% fatal cases. 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 has occurred. Rash occurred in 89% of patients treated with lazertinib in combination with amivantamab. Most cases were Grade 1 or 2, with Grade 3 events occurring in 27% of patients. Rash leading to any treatment discontinuation occurred in 6% 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 lazertinib in combination with amivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 11% of patients.

Eye disorders

Eye disorders, including keratitis (2.6%), occurred in patients treated with lazertinib in combination with amivantamab. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. Most events were Grade 1-2.

Hepatotoxicity

Hepatotoxicity-related reactions occurred in 47% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3-4 hepatotoxicity occurring in 9% of patients. Most events were related to elevations of serum transaminases (36% alanine aminotransferase increased and 29% aspartate aminotransferase increased). Most patients with elevations of transaminases were able to continue study treatment without modification of study treatment while a small number were managed with a dose interruption or with a dose reduction. There were no cases of liver failure or fatal cases of hepatotoxicity in clinical studies.

Paraesthesia

Paraesthesia occurred in 34% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3 paraesthesia occurring in 1.7% of patients. Most patients with paraesthesia had resolution with dose interruption or dose reduction.

Stomatitis

Stomatitis occurred in 43% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3 stomatitis occurring in 2.4% of patients.

Diarrhoea

Diarrhoea occurred in 29% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3 diarrhoea occurring in 2.1% of patients.

Special populations

Elderly

There are limited clinical data with lazertinib in patients 75 years of age or over. Older patients (≥65 years of age) reported more Grade 3 or higher adverse events compared to patients <65 years of age (81% vs. 70%). While the rates of drug interruptions and dose reductions were similar, the rate of adverse events leading to any treatment discontinuation was higher in patients ≥65 years of age compared to patients <65 years of age (47% vs. 25%).