Lorlatinib Tablets LuciLorla 100mg&25mg

[Product Name] Lorlatinib Tablets

[English Name] Lorlatinib Tablets

[Other Names] Lorlatinib / Boruina / ALK / ROS1 TKI / LORBRENA

[Specification] 25 mg × 30 tablets/box; 100 mg × 30 tablets/box

[Manufacturer] Lucius Pharmaceutical (Laos) Co., Ltd.

[Overview]

Lorlatinib is a novel, third-generation tyrosine kinase inhibitor (TKI) that targets Anaplastic Lymphoma Kinase (ALK) and the receptor tyrosine kinase c-ros oncogene 1 (ROS1). One of the key factors limiting the efficacy of traditional ALK/ROS TKIs is the emergence of acquired resistance mutations—specifically the ALK G1202R and ROS1 G2032R resistance mutations—though these are, of course, not the only mechanisms of resistance. Another critical factor is the limited efficacy of these drugs against central nervous system (CNS) metastases due to the presence of the blood-brain barrier.

[Indications]

Indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is positive for Anaplastic Lymphoma Kinase (ALK).

[Dosage and Administration]

Recommended Adult Dosage for NSCLC Treatment:

100 mg orally once daily. Continue treatment until disease progression or until unacceptable toxicity occurs.

May be taken with or without food.

[Adverse Reactions]

The most common side effects of Lorlatinib include: swelling of the arms, legs, hands, and feet (edema); numbness and tingling sensations in the joints or limbs (peripheral neuropathy); difficulty thinking or confusion; difficulty breathing; fatigue; weight gain; joint pain; mood changes; feelings of sadness or anxiety; diarrhea; etc.

Lorlatinib may cause a decrease in male fertility.

[Contraindications]

Concomitant use with strong CYP3A inducers.

Hypersensitivity to Lorlatinib or to any of the excipients in the formulation.

[Precautions]

Myelosuppression: Anemia (typically mild) commonly occurs with the use of Lorlatinib. Mild thrombocytopenia and lymphopenia have also been observed. Cardiovascular Effects: PR interval prolongation and atrioventricular (AV) block, including Grade 3 events, have occurred infrequently in patients receiving lorlatinib. Some patients required pacemaker placement. Monitor ECG prior to initiating lorlatinib treatment and periodically thereafter. Withhold treatment, and resume at a reduced dose (if a pacemaker was not placed) or at the same dose (for patients with a pacemaker). Permanently discontinue in patients without a pacemaker upon recurrence.

Central Nervous System (CNS) Effects: CNS effects (including seizures, hallucinations, and changes in cognitive function, mood [including suicidal ideation], speech, mental status, and sleep) may occur in patients receiving lorlatinib. Overall, CNS effects occurred in slightly more than half of the patients treated with lorlatinib. In one study, nearly one-third of patients receiving lorlatinib (at any dose) experienced cognitive effects; a small subset of these events were severe (Grade 3 or 4). Nearly one-quarter of patients experienced mood effects; severe events occurred infrequently. Speech effects, hallucinations, and changes in mental status were also reported, including rare severe events. Seizures have been observed, sometimes in conjunction with other neurological findings. Changes in sleep were also reported. The median time to onset of any CNS reaction was 1.2 months (range: 1 day to 1.7 years). Depending on the severity, CNS adverse events may require treatment interruption, dose reduction, or permanent discontinuation.

Hepatotoxicity: Severe hepatotoxicity occurred in the majority of healthy subjects receiving a single dose of lorlatinib in combination with multiple doses of rifampin (a strong CYP3A inducer). Grade 3 or 4 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were common, and Grade 2 elevations were also reported. ALT or AST elevations occurred within 3 days and resolved to within the normal range within 15 days (range: 7 to 34 days); the median time to recovery was 7 days for subjects with Grade 2 ALT or AST elevations, and 18 days for subjects with Grade 3 or 4 ALT or AST elevations. Lorlatinib is contraindicated in patients taking strong CYP3A inducers. Before initiating lorlatinib treatment, discontinue strong CYP3A inducers for at least 3 plasma elimination half-lives of the strong CYP3A inducer. Avoid concomitant use of lorlatinib with moderate CYP3A inducers; if concomitant use with moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin levels at least 3 times within the first 48 hours and during the first week after initiating lorlatinib. Based on the relative importance of each drug, discontinue either lorlatinib or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity.

Hyperlipidemia: Elevations in serum cholesterol and triglycerides may occur in patients treated with lorlatinib. Grade 3 or 4 elevations in total cholesterol and triglycerides have been reported. The median time to onset (for both hypercholesterolemia and hypertriglyceridemia) is 15 days. Typically, within 21 days of initiating lorlatinib treatment, most patients with hypercholesterolemia and hypertriglyceridemia require the initiation of lipid-lowering therapy. Assess serum cholesterol and triglycerides prior to initiating lorlatinib, and monitor serum cholesterol and triglycerides periodically at 1 and 2 months after starting lorlatinib. Initiate lipid-lowering therapy (or increase the dose) for patients with hyperlipidemia. Depending on the severity, hyperlipidemia may require interruption or dose reduction of lorlatinib treatment.

Pulmonary Toxicity: Lorlatinib may cause rare, severe, or life-threatening pulmonary adverse reactions associated with interstitial lung disease (ILD)/pneumonitis, including Grade 3 and 4 events. Promptly evaluate new or worsening respiratory symptoms suggestive of ILD/pneumonitis (e.g., dyspnea, cough, fever). If ILD/pneumonitis is suspected, immediately withhold lorlatinib; permanently discontinue lorlatinib for any grade of ILD/pneumonitis that is considered related to the drug. Drug-Drug Interactions: Significant interactions may exist, requiring adjustments to dosage or frequency, additional monitoring, or the selection of alternative therapies.

ALK-Positive Status: Lorlatinib is approved for use in patients with metastatic non-small cell lung cancer (NSCLC) whose tumors test positive for abnormalities in the Anaplastic Lymphoma Kinase (ALK) gene.

Pregnancy: Based on its mechanism of action and data from animal reproduction studies, Lorlatinib may cause fetal harm when administered during pregnancy. Assess the pregnancy status of females of reproductive potential prior to initiating treatment. Females of reproductive potential should avoid pregnancy and use effective non-hormonal methods of contraception during treatment and for at least 6 months following the last dose of Lorlatinib. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months following the last dose of Lorlatinib.

[Safety and Efficacy]

Studies have demonstrated that patients with advanced non-small cell lung cancer (NSCLC)—specifically those positive for ALK (Anaplastic Lymphoma Kinase) or ROS1 (Receptor Tyrosine Kinase c-ros Oncogene 1) abnormalities—including those with brain metastases, exhibit a clinical therapeutic response to Lorlatinib. In a Phase 1 clinical trial, patients who were either treatment-naïve or had experienced disease progression following treatment with a single tyrosine kinase inhibitor achieved an overall response rate of 46% after undergoing dose-escalation therapy with the drug. The median progression-free survival was 1.4 months, and a reduction in the volume of brain metastases was observed.

On April 27, 2017, Pfizer announced that its next-generation ALK/ROS1 inhibitor, Lorlatinib, had been granted Breakthrough Therapy Designation by the FDA. This designation applies to the treatment of ALK-positive, metastatic NSCLC in patients whose disease has progressed following prior treatment with one or more ALK inhibitors. The granting of this designation was based on efficacy and safety data derived from an ongoing Phase 1/2 clinical study. On October 17, 2017, Pfizer presented the complete Phase II clinical trial data for Lorlatinib at the WCLC 2017 conference:

For ALK-positive, treatment-naïve NSCLC (non-small cell lung cancer) patients, the ORR (Objective Response Rate) reached as high as 90%, with an intracranial ORR of 75%;

For ALK-positive patients previously treated with Crizotinib, the ORR was 69%, with an intracranial ORR of 68%;

For ALK-positive patients previously treated with ALK inhibitors other than Crizotinib, the ORR was 33%, with an intracranial ORR of 42%;

For ALK-positive patients previously treated with 2–3 different ALK inhibitors, the ORR was 39%, with an intracranial ORR of 48%;

For ROS1-positive patients who had undergone prior treatment, the ORR was 36%, with an intracranial ORR of 56%.

The trial results demonstrated that the drug exhibits clinically meaningful activity in treating both pulmonary tumors and brain metastases in patients with advanced ALK-positive and ROS1-positive NSCLC.

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F) for short-term transport.