Lazertinib (Lazcluze): FDA Approval, Licensing in Türkiye, and Reimbursement Status

• FDA Approved: Yes (first approval date: August 19, 2024)
• Brand Name: Lazcluze
• Active Ingredient: Lazertinib
• Administration: Oral film-coated tablet
• Class: EGFR tyrosine kinase inhibitor
• Category: Targeted agent
• Manufacturer: Janssen Biotech, Inc.
• Availability in Türkiye: Can be obtained through TEB (Turkish Pharmacists' Association).
• Cancers for Which It Is Approved: Advanced or metastatic non-small cell lung cancer (NSCLC) positive for EGFR exon 19 deletions or exon 21 L858R mutations

What Is Lazcluze and How Does It Work?

Lazcluze contains lazertinib, a tyrosine kinase inhibitor used to treat advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

How Does It Work?

Lazertinib works by inhibiting EGFR tyrosine kinase activity. EGFR is a protein that controls cell growth and division. In lung cancer cells, EGFR is often overactive, leading to uncontrolled cancer cell growth. Blocking EGFR activity with lazertinib reduces cancer cell growth and spread.

Lazertinib (Lazcluze) FDA Approval History

• May 19, 2021: Updated data on amivantamab combined with lazertinib showed durable responses and clinical activity in patients with EGFR-mutated non-small cell lung cancer relapsing after osimertinib.
• September 9, 2021:New data on Rybrevant (amivantamab-vmjw) combined with lazertinib showed early activity in patients with non-small cell lung cancer progressing after osimertinib and platinum-based chemotherapy.
• July 26, 2022: Janssen announced new data supporting the safety and efficacy of Rybrevant combined with lazertinib in patients with EGFR-mutated non-small cell lung cancer.
• June 4, 2023: New long-term CHRYSALIS data showed that median progression-free survival had not been reached after 33.6 months of follow-up with first-line RYBREVANT® plus lazertinib in treatment-naive patients with advanced EGFR-mutated non-small cell lung cancer.
• October 23, 2023:The landmark phase 3 MARIPOSA trial showed that RYBREVANT® (amivantamab-vmjw) plus lazertinib reduced the risk of disease progression or death by 30% compared with osimertinib in EGFR-mutated non-small cell lung cancer.
• October 23, 2023: The phase 3 MARIPOSA-2 trial showed that RYBREVANT® (amivantamab-vmjw) and lazertinib, given with or without chemotherapy after osimertinib, reduced the risk of disease progression or death by 56% and 52%, respectively.
• June 3, 2024: Notable results from PALOMA-2 showed clinically meaningful tumor responses and an improved safety profile with subcutaneous amivantamab plus lazertinib in EGFR-mutated non-small cell lung cancer.
• August 20, 2024:The FDA approved Rybrevant (amivantamab-vmjw) combined with Lazcluze (lazertinib) for patients with advanced EGFR-mutated lung cancer.

Licensing in Türkiye

Lazcluze, containing lazertinib, can be imported into Türkiye under an authorization for use of medicines from abroad, as a medicine not licensed by the Turkish Ministry of Health. This process is managed through the Turkish Pharmacists' Association (TEB).

Access to Medicines from Abroad:

• For patients needing treatment, their treating medical oncologist must request authorization from the Turkish Ministry of Health for use of a medicine from abroad.
• Once authorized, Lazcluze can be obtained from abroad through the Turkish Pharmacists' Association (TEB).
• This is an official process intended to facilitate and accelerate patients' access to treatment.
• Lazcluze is not reimbursed by SGK (Social Security Institution); patients must finance the medicine themselves.

Mechanisms of Resistance

• Development of New EGFR Mutations: Secondary mutations such as C797S may prevent lazertinib binding to EGFR, making the drug ineffective.
• MET Gene Amplification: Cells can bypass EGFR signaling and generate alternative growth signals through MET, triggering resistance to EGFR-targeted drugs.
• Activation of Alternative Signaling Pathways: Pathways such as HER2, RAS, RAF, MEK, PI3K, AKT, and mTOR may activate and sustain cell growth independently of EGFR. These mechanisms allow cancer cells to survive through different routes.
• Phenotypic Transformation: In some patients, EGFR-mutated NSCLC may change its cellular characteristics and evolve into another tumor type through transformation to small cell lung cancer (SCLC). This is generally associated with losses in RB1 and TP53.
• Increased Drug Efflux: Drug transporters in the cell membrane, such as P-glycoprotein (P-gp), may increase pumping of lazertinib out of cells, reducing its intracellular activity.

Absorption

• Lazertinib has high bioavailability when taken orally.
• Maximum plasma concentration (Tmax): Peak levels are reached within 2-6 hours.
• Interaction with fatty foods: Taking it with fatty foods may increase absorption without a clinically meaningful change.
• Intestinal absorption: It is absorbed by passive diffusion from the intestine and may be expelled by P-glycoprotein (P-gp).
• pH sensitivity: Medicines that reduce stomach acid, such as proton pump inhibitors, may reduce absorption.
• For optimal absorption, lazertinib is recommended to be taken with water, with or without food.

Distribution

• Widely distributed in tissues (volume of distribution: 2,091 L)
• Can cross the blood–brain barrier and may be effective against brain metastases
• Plasma protein binding: 66-82%
• Readily crosses cell membranes (lipophilic structure)

Metabolism

• Metabolized in the liver by CYP3A4.
• Main metabolic pathways: oxidation and conjugation.
• It has no active metabolite; the drug itself is the active component.
• Use cautiously in patients with liver impairment, because slower metabolism may increase plasma drug levels.

Elimination 

• Lazertinib is generally eliminated through urine and feces.
• However, elimination is mainly through the hepatobiliary system (liver, bile, intestine, and feces).
• Urinary elimination is low, indicating that kidney function is not a determining factor in its clearance.

Dose Range 

• Recommended dose: 240 mg/day (a single oral dose)
• Dose reductions: If adverse reactions develop, the dose may be reduced to 160 mg/day or 120 mg/day.
• Overdose risk: QT prolongation, neurological adverse reactions, and hepatotoxicity may occur.
• Liver/Kidney Impairment: Dose adjustment may be needed in severe impairment.

Drug Interactions 

• Interaction with CYP3A4 Inhibitors (Slower Metabolism): Lazertinib is broken down in the liver by CYP3A4. Medicines that strongly inhibit this enzyme may increase blood levels of lazertinib and raise toxicity risk. Examples include ketoconazole, ritonavir, and clarithromycin. Dose reduction should be considered if these medicines are used.
• Interaction with CYP3A4 Inducers (Faster Metabolism): These medicines stimulate CYP3A4, causing faster breakdown of lazertinib and potentially reducing its effectiveness. Examples include rifampin, carbamazepine, phenytoin, and St. John's wort. Avoid the combination if possible; a dose increase may be planned if necessary.
• Interaction with Acid-Reducing Medicines (Reduced Absorption): Intestinal absorption of lazertinib depends on stomach acid. Proton pump inhibitors or H2 receptor blockers increase gastric pH, reducing absorption. Examples include omeprazole, pantoprazole, and ranitidine. These medicines should be taken several hours before or after lazertinib.
• Combination with QT-Prolonging Medicines (Cardiac Risk): Lazertinib may affect heart rhythm and prolong the QT interval. Combining it with medicines with the same effect increases arrhythmia risk. Examples include amiodarone, citalopram, and levofloxacin. Heart rhythm should be monitored by ECG during combined use.
• P-glycoprotein Inhibitors/Inducers (Effects on Intracellular Levels): Lazertinib may be affected by the P-gp transporter system. Inhibitors may increase intracellular drug levels, while inducers may decrease them. Medicines that may affect this include verapamil (inhibitor) and rifampin (inducer). Use under observation and adjust the dose if needed.
• Combination with Other Targeted Agents (High Interaction Risk): When lazertinib is combined with other targeted agents, such as other TKIs or monoclonal antibodies, the pattern of effects may become complex. If a combination is planned, the medicines' metabolic pathways and mechanisms should be carefully assessed.

Precautions

• Liver Impairment: Lazertinib is metabolized in the liver. Dose adjustment may be necessary in severe liver impairment.
• Kidney Impairment: Use cautiously in mild to moderate kidney impairment. Data in severe kidney impairment are limited.
• Risk of QT Prolongation:Lazertinib may affect heart rhythm and cause QT prolongation. ECG and electrolyte levels should be monitored in patients with heart disease.
• Pulmonary Toxicity (ILD/Pneumonitis): Interstitial lung disease (ILD) may rarely develop. If breathing difficulties or cough occur, stop treatment and assess the patient.
• Hypersensitivity Reactions: Allergic reactions and skin rashes may occur. Stop treatment for severe reactions.
• Pregnancy and Breastfeeding: Use during pregnancy is not recommended because it may harm the fetus. It must not be used during breastfeeding.
• Interactions with Other Medicines: It may interact with CYP3A4 inhibitors and inducers. Tell the physician about all medicines being taken.

Adverse Reactions 

• Diarrhea: 20-25%
• Constipation: 15-20%
• Nausea: 15%
• Vomiting: 10-12%
• Loss of appetite: 10-15%
• Stomatitis (mouth sores): 5-10%
• Rash: 25-30%
• Itching: 10-15%
• Dry skin: 10%
• Allergic skin reactions (rash, redness, hives): 5-10%
• Headache: 10-12%
• Paresthesia (numbness, tingling): 5-8%
• Muscle pain: 10%
• Joint pain: 5%
• QT prolongation (risk of abnormal heart rhythm): 2-5%
• Venous thromboembolism (blood clots in veins): 1-3%
• Pulmonary toxicity: <1%
• Elevated liver enzymes (increased SGOT/SGPT): 8-12%
• Impaired kidney function: <1%
• Dry eyes: 5%
• Visual disturbances (blurred vision, light sensitivity): 3-5%
• Fatigue: 20%
• Taste disturbances (dysgeusia): 5%
• Dizziness: 8-10%
• Dry mouth: 5-8%