Lazcluze in combination with Amivantamab is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) characterized by epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.

Dosage and Administration

1. Patient Selection

Patients should be selected for first-line treatment of NSCLC with Lazcluze in combination with amivantamab based on the presence of EGFR exon 19 deletions or exon 21 L858R substitution mutations in tumor or plasma specimens.

If these mutations are not detected in a plasma specimen, testing of tumor tissue is recommended. Information on FDA-approved tests is available on the FDA website: http://www.fda.gov/CompanionDiagnostics.

2. Recommended Dosage and Administration

The recommended dosage of Lazcluze is 240 mg administered orally once daily, combined with amivantamab, with or without food. The tablets should be swallowed whole, not crushed, split, or chewed.

Treatment should continue until disease progression or the occurrence of unacceptable toxicity. Lazcluze should be administered any time prior to amivantamab when both are given on the same day. Refer to the amivantamab prescribing information for recommended dosing details.

3. Missed Dose

If a patient misses a dose of Lazcluze and it is within 12 hours of the scheduled time, the patient should be instructed to take the missed dose as soon as possible.

If more than 12 hours have passed, the patient should be advised to skip the missed dose and resume the next dose at the scheduled time.

4. Vomiting

If vomiting occurs at any time after taking Lazcluze, the patient should be instructed to take the next dose at the regularly scheduled time.

5. Concomitant Medications

When initiating treatment with Lazcluze in combination with amivantamab, anticoagulant prophylaxis should be administered to prevent venous thromboembolic events (VTE) during the first four months of treatment.

If no signs or symptoms of VTE are present during this period, discontinuation of anticoagulant prophylaxis may be considered at the discretion of the healthcare provider.

Additionally, patients should be advised to use alcohol-free emollient cream and limit sun exposure during and for two months after treatment.

Protective clothing and broad-spectrum UVA/UVB sunscreen are recommended to reduce the risk of dermatologic adverse reactions. Prophylactic measures, such as the use of oral antibiotics, may also be considered to mitigate the risk of these dermatologic reactions.

Contraindications to Lazcluze (Lazertinib):

There are no contraindications for the use of Lazcluze.

Warnings and Precautions

1. Venous Thromboembolic Events

The combination of Lazcluze with amivantamab has been associated with serious and potentially fatal venous thromboembolic events (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE). Most of these events occurred within the first four months of therapy.

In the MARIPOSA trial, VTEs were reported in 36% of patients receiving Lazcluze with amivantamab, with 10% experiencing Grade 3 and 0.5% experiencing Grade 4 events.

Additionally, there were two fatal cases of VTE (0.5%). A total of 7% of patients had VTEs that led to dose interruptions of Lazcluze, while 0.5% experienced VTEs that resulted in dose reductions, and 1.9% of patients permanently discontinued Lazcluze due to VTEs.

Recommendation: Administer prophylactic anticoagulation during the first four months of treatment. The use of Vitamin K antagonists is not recommended.

Monitor for VTE signs and symptoms and treat as appropriate. Withhold Lazcluze and amivantamab based on severity, and resume therapy once anticoagulant treatment has been initiated, at the discretion of the healthcare provider.

In case of VTE recurrence despite therapeutic anticoagulation, discontinue amivantamab permanently and continue Lazcluze at the discretion of the healthcare provider.

2. Interstitial Lung Disease (ILD)/Pneumonitis

Lazcluze, when used in combination with amivantamab, can cause interstitial lung disease (ILD)/pneumonitis. In the MARIPOSA trial, ILD/pneumonitis occurred in 3.1% of patients treated with this combination, with 1.0% experiencing Grade 3 and 0.2% experiencing Grade 4 events. There was one fatal case (0.2%) of ILD/pneumonitis, and 2.9% of patients permanently discontinued both Lazcluze and amivantamab due to ILD/pneumonitis.

Recommendation: Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold Lazcluze and amivantamab in patients with suspected ILD/pneumonitis, and permanently discontinue if ILD/pneumonitis is confirmed.

3. Dermatologic Adverse Reactions

The combination of Lazcluze and amivantamab can cause severe dermatologic reactions, including rash, dermatitis, acneiform pruritus, and dry skin.

In the MARIPOSA trial, rash occurred in 86% of patients, with 26% experiencing Grade 3 reactions. The median time to onset of rash was 14 days. Dose reductions and interruptions of Lazcluze due to rash occurred in 19% and 30% of patients, respectively, while 1.7% of patients permanently discontinued Lazcluze due to rash.

Recommendation: Administer alcohol-free emollient cream to reduce the risk of dermatologic reactions. Advise patients to limit sun exposure during treatment and for two months afterward, and to use protective clothing and broad-spectrum UVA/UVB sunscreen. Prophylactic measures, such as oral antibiotics, may also be considered. For Grade 3 reactions, administer oral steroids and consider dermatologic consultation.

4. Ocular Toxicity

Lazcluze, in combination with amivantamab, may cause ocular toxicity, including keratitis. In the MARIPOSA trial, ocular toxicity occurred in 16% of patients, with 0.7% experiencing Grade 3 or 4 toxicity.

Recommendation: Refer patients with new or worsening eye symptoms to an ophthalmologist promptly. Adjust or discontinue amivantamab based on severity and continue Lazcluze as appropriate.

5. Embryo-Fetal Toxicity

Based on animal studies and its mechanism of action, Lazcluze can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, lazertinib led to reduced embryofetal survival and fetal body weight in rats and malformations in rabbits at exposures equivalent to approximately 4 and 0.5 times, respectively, the human exposure at the recommended dose of 240 mg/day.

Recommendation: Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Female patients should use effective contraception during treatment and for three weeks after the last dose. Male patients with female partners of reproductive potential should also use effective contraception during treatment and for three weeks after the last dose.

Lazcluze (Lazertinib) Drug Interactions:

1. Effect of Other Drugs on Lazcluze

CYP3A4 Inducers:

It is advised to avoid the concomitant use of Lazcluze with strong or moderate CYP3A4 inducers. Consider alternative medications that do not have the potential to induce CYP3A4.

Lazertinib, the active ingredient in Lazcluze, is a substrate of CYP3A4. The concomitant use of Lazcluze with a strong or moderate CYP3A4 inducer may decrease the concentration of lazertinib, thereby reducing its efficacy​.

2. Effect of Lazcluze on Other Drugs

Certain CYP3A4 Substrates:

When Lazcluze is used in combination with a CYP3A4 substrate, monitor for any adverse reactions, particularly where minimal concentration changes may lead to serious effects, as recommended in the approved labeling for the CYP3A4 substrate. Lazertinib is a weak CYP3A4 inhibitor. Concomitant use of Lazcluze may increase the concentrations of CYP3A4 substrates, which could elevate the risk of adverse reactions related to these substrates​.

Certain BCRP Substrates:

Monitor for adverse reactions when Lazcluze is used in combination with BCRP substrates, where even minimal concentration changes may result in serious reactions. Lazertinib acts as a BCRP inhibitor, and its use may increase the concentrations of BCRP substrates, potentially leading to an elevated risk of adverse reactions​.

Special Populations

1. Renal Impairment

No dose adjustment is necessary for patients with mild or moderate renal impairment (eGFR 30 – 89 mL/min). However, Lazcluze has not been studied in patients with severe renal impairment or end-stage renal disease (eGFR < 30 mL/min)​.

2. Hepatic Impairment

No dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin ≤ 1.5×ULN and any AST) or moderate (total bilirubin ≤ 1.5 to 3×ULN and any AST) hepatic impairment. However, Lazcluze has not been studied in patients with severe hepatic impairment (total bilirubin > 3×ULN and any AST)​.

Mechanism of Action of Lazcluze (Lazertinib):

Lazertinib, the active component of Lazcluze, is a kinase inhibitor of the epidermal growth factor receptor (EGFR) that targets EGFR exon 19 deletions and exon 21 L858R substitution mutations at lower concentrations than wildtype EGFR.

In human NSCLC cells and mouse xenograft models, lazertinib demonstrated significant anti-tumor activity, particularly in combination with amivantamab, showing enhanced in vivo efficacy compared to either agent alone​.

Absorption:

Lazertinib reaches its maximum plasma concentration (Cmax) within 2 to 4 hours after administration. The presence of a high-fat meal does not significantly affect its pharmacokinetics​.

Distribution:

Lazertinib has a mean apparent volume of distribution of 2680 L (51%) and is approximately 99.2% bound to human plasma proteins​.

Elimination:

The mean terminal half-life of lazertinib is 3.7 days (56%), with a mean apparent clearance of 36.4 L/h (47%)​.

Metabolism and Excretion:

Lazertinib is primarily metabolized via glutathione conjugation, either enzymatically by glutathione-S-transferase (GST) or non-enzymatically, as well as by CYP3A4. Following a single oral dose, approximately 86% of the dose is recovered in feces (< 5% as unchanged) and 4% in urine (< 0.2% as unchanged