Lorlatinib 100mg for the treatment of non-small cell lung cancer

Lorlatinib Instructions

Product Name: LuciLorla

Manufacturer: Lucius Pharmaceuticals

Chinese name: Lorlatinib

English name: Lorlatinib

Drug approval number: 07 L 0987/23

 

 

【Summary】

Lorlatinib is a third-generation ALK inhibitor. As a follow-up treatment for crizotinib resistance, it can inhibit the nine mutations that cause crizotinib resistance. It is particularly suitable for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who are resistant to other ALKs.

 

【Indications】

For the treatment of non-small cell lung cancer

 

【Specification】

100mg/capsule, 30 capsules/box.

 

【Storage】

Store at 20°C to 25°C (68°C to 77°F); short-distance transport is permitted at a temperature range of 15 to 30°C (59–86°F).

 

【Usage and Dosage】

Common adult doses for non-small cell lung cancer

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

It can be taken before or after meals.

 

【Adverse Reactions】

The most common side effects of lorlatinib include: swelling of the arms, legs, hands, and feet (edema); numbness and tingling feelings in the joints or arms and legs (peripheral neuropathy); trouble thinking or confusion; trouble breathing; fatigue; weight gain; joint pain; mood changes; feeling sad or anxious; and diarrhea.

Lorlatinib may cause decreased fertility in males. 

 

【Taboo】

Co-administration with strong CYP3A inducers.

Hypersensitivity to lorlatinib or any component of the formulation.

 

【Notes】

Myelosuppression: Anemia (usually mild) commonly occurs with lorlatinib. Mild thrombocytopenia and lymphocytopenia also occur.

Cardiovascular Effects: PR interval prolongation and atrioventricular block, including Grade 3 events, have rarely occurred in patients receiving lorlatinib. Some patients required pacemaker implantation. Monitor ECGs prior to initiating lorlatinib therapy and periodically thereafter. Withhold treatment and resume at a lower dose (if no pacemaker is implanted) or at the same dose in patients with pacemaker implantation. Permanently discontinue in patients without pacemakers for recurrence.

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

Hepatotoxicity: Severe hepatotoxicity occurred in most healthy subjects receiving doses of lorlatinib in combination with multiple doses of rifampin (a strong CYP3A inducer). Grade 3 and 4 elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were common, and grade 2 elevations were also reported. ALT or AST was elevated 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. Stop treatment with strong CYP3A inducers for at least 3 plasma half-lives (strong CYP3A inducers) prior to initiating lorlatinib treatment. Avoid concomitant use of lorlatinib with moderate CYP3A inducers; if concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin within 48 hours of starting lorlatinib and at least three times during the first week after starting lorlatinib. Discontinue lorlatinib or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity, based on the relative importance of each drug.

Hyperlipidemia: Elevated 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 (hypercholesterolemia and hypertriglyceridemia) is 15 days. Most patients with hypercholesterolemia and hypertriglyceridemia require initiation of lipid-lowering medications, usually 21 days after initiation of lorlatinib. Measure serum cholesterol and triglycerides prior to initiation of lorlatinib and periodically monitor serum cholesterol and triglycerides 1 month and 2 months after onset of lorlatinib. Administer lipid-lowering medications (or increase the dose) for patients with hyperlipidemia. Depending on the severity, hyperlipidemia may require interruption or dose reduction of lorlatinib therapy.

Pulmonary toxicity: Rare, severe, or life-threatening pulmonary adverse reactions associated with interstitial lung disease (ILD)/pneumonitis may occur with lorlatinib, 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, discontinue lorlatinib immediately; permanently discontinue lorlatinib-related ILD/pneumonitis of any severity.

Drug-Drug Interactions: Significant interactions may exist, requiring dose or frequency adjustments, additional monitoring, or selection of alternative therapy.

ALK Positive: Lorlatinib is approved for patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene.

Pregnancy: Based on the mechanism of action and data from animal reproduction studies, lorlatinib may cause fetal harm during pregnancy. Assess the pregnancy status of females of reproductive potential prior to initiating treatment. Females of reproductive potential should avoid becoming pregnant 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 shown that patients with advanced non-small cell lung cancer who are positive for ALK (anaplastic lymphoma kinase) or ROS1 (receptor tyrosine kinase c-ros oncogene 1), including those with brain metastases, have a clinical response to lorlatinib. In a phase I clinical trial, patients who had not received drug treatment or had worsening disease after using a tyrosine kinase inhibitor had a total effective response rate of 46% after dose escalation of the drug. The average survival time without worsening of the disease was 1.4 months, and the volume of brain metastases decreased.

On April 27, 2017, Pfizer announced that its new generation ALK/ROS1 inhibitor Lorlatinib was granted breakthrough drug status by the FDA for ALK-positive, metastatic NSCLC (non-small cell lung cancer) patients who had previously received one or more ALK inhibitors and whose disease progressed after treatment. This status was granted based on the efficacy and safety data of an ongoing Phase 1/2 clinical study.

On October 17, 2017, Pfizer announced the complete data of Lorlatinib's Phase II clinical trial at the WCLC2017 conference:

For ALK-positive patients with newly diagnosed NSCLC (non-small cell lung cancer), the ORR (objective response rate) was as high as 90%, and the intracranial ORR reached 75%;

For patients with ALK-positive disease who had previously received crizotinib, the ORR was 69%, with an intracranial ORR of 68%.

For patients with ALK-positive disease who had previously received ALK inhibitors other than crizotinib, the ORR was 33%, with an intracranial ORR of 42%.

For patients who were ALK-positive and had received 2-3 ALK inhibitors previously, the ORR was 39%, and the intracranial ORR reached 48%;

For previously treated patients with ROS1-positive disease, the ORR was 36%, and the intracranial ORR reached 56%.

Experimental results showed that the drug showed clinically significant activity in the treatment of lung tumors and brain metastases in patients with ALK-positive and ROS1-positive advanced NSCLC.