LORLADX Lorlatinib Tablets

[Product Name] Lorlatinib Tablets

[English Name] Lorlatinib Tablets

[Other Names] Lorlatinib / Boreina / LORBRENA

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

[Manufacturer] Bigbear Pharmaceutical Laos

[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 greater 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 certainly not the only mechanisms of resistance. Another key factor is the limited efficacy of these drugs against central nervous system (CNS) metastases due to the presence of the blood-brain barrier.

[Indications]

This product, as a monotherapy, is 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]

The recommended dosage of this product is 100 mg taken orally once daily (with or without food), until disease progression or the occurrence of intolerable toxicity.

The tablets should be swallowed whole; do not chew, crush, or split the tablets.

Take this product at approximately the same time each day. If a dose is missed, the missed dose may be taken unless the time to the next scheduled dose is within 4 hours. Do not take two doses at the same time to make up for a missed dose.

If vomiting occurs after taking this product, do not take an additional dose; continue with the recommended dose at the next scheduled administration time.

[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 lorlatinib. Mild thrombocytopenia and lymphopenia have also been observed.

Cardiovascular Effects: PR interval prolongation and atrioventricular (AV) block—including Grade 3 events—have occurred rarely in patients receiving lorlatinib. Some patients required pacemaker placement. Monitor ECG prior to initiating lorlatinib treatment and periodically thereafter. Discontinue 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 treatment in patients without a pacemaker if the event recurs.

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 were observed 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 were rare. Speech effects, hallucinations, and changes in mental status have also been reported, including rare severe events. Seizures have been observed, sometimes in conjunction with other neurological findings. Changes in sleep patterns have also been reported. The median time to onset for 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 who received lorlatinib in combination with multiple doses of rifampin (a strong CYP3A inducer). Grade 3 and 4 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were common, and Grade 2 elevations were also reported. ALT or AST levels rose within 3 days and returned to the normal range after 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 at least 3 times within the first 48 hours and during the first week after initiating lorlatinib. Discontinue lorlatinib or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity, based on the relative importance of each drug.

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) was 15 days. Typically, within 21 days of initiating lorlatinib treatment, most patients with hypercholesterolemia and hypertriglyceridemia require the initiation of lipid-lowering medication. Assess serum cholesterol and triglycerides prior to initiating lorlatinib, and monitor serum cholesterol and triglycerides periodically at 1 and 2 months after initiating lorlatinib. Initiate lipid-lowering medication (or increase the dose) for patients with hyperlipidemia. Depending on severity, hyperlipidemia may require interruption or dose reduction of lorlatinib treatment.

Pulmonary Toxicity: Rare, severe, or life-threatening pulmonary adverse reactions associated with interstitial lung disease (ILD)/pneumonitis, including Grade 3 and 4 events, may occur in patients taking lorlatinib. Promptly evaluate new or worsening respiratory symptoms suggestive of ILD/pneumonia (e.g., dyspnea, cough, fever). If ILD/pneumonia is suspected, immediately withhold Lorlatinib; for any grade of Lorlatinib-associated ILD/pneumonia, permanently discontinue the drug.

Drug-Drug Interactions: Significant interactions may exist, requiring dosage or frequency adjustments, additional monitoring, or the selection of alternative therapies.

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

Pregnancy: Based on its mechanism of action and data from animal reproduction studies, Lorlatinib may cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception during treatment and for at least 6 months after 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 after the last dose of Lorlatinib.

[Safety and Efficacy]

Studies have demonstrated that patients with advanced non-small cell lung cancer (NSCLC) that is positive for ALK (Anaplastic Lymphoma Kinase) or ROS1 (Receptor Tyrosine Kinase c-ros Oncogene 1)—including those with brain metastases—show a clinical therapeutic response to Lorlatinib. In a Phase 1 clinical trial, patients who were either treatment-naïve or whose disease had progressed following treatment with one tyrosine kinase inhibitor achieved an overall response rate of 46% following dose-escalation treatment 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, was granted Breakthrough Therapy Designation by the FDA for the treatment of ALK-positive, metastatic NSCLC (non-small cell lung cancer) in patients whose disease has progressed following prior treatment with one or more ALK inhibitors. This designation was granted 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.