Lorlanib

Lorlatinib (Lorlatinib) instructions
Common name: Lorlatinib
Trade name: Lorbrena
All names: Lorlatinib, Lorlatinib, Lorbrena

Indications:
For the treatment of non-small cell lung cancer

Usage and dosage:
Usual dosage for adults to treat non-small cell lung cancer
Take 100 mg orally once a day. until disease progression or unacceptable toxicity.
Can be taken before or after meals.

Adverse reactions:
>10%:
Cardiovascular: edema (57%)
Central nervous system: peripheral neuropathy (47%; Grade 3/4: 3%), cognitive impairment (27% to 29%), fatigue (26%), mood disorders (23% to 24%), headache (18%), dizziness (16%), speech disorders (12% to 14%), sleep disorders (10%)
Dermatology: Rash (14%)
Endocrinology Metabolism: Hypercholesterolemia (96%), hypertriglyceridemia (90%), hyperglycemia (52%), hypoalbuminemia (33%), weight gain (24%), elevated amylase (22%), hyperkalemia (21%), hypomagnesemia (21%), Hypophosphatemia (21%)
Gastrointestinal tract: elevated serum lipase (24%), diarrhea (22%), nausea (18%), constipation (15%), vomiting (12%)
Hematology and oncology: anemia (52%; grade 3/4: 5%), Thrombocytopenia (23%; grade 3/4: <1%), lymphopenia (22%; grade 3/4: 3%) Liver: elevated serum aspartate aminotransferase (37%), elevated serum alanine aminotransferase (28%), elevated serum alkaline phosphatase (2 4%)
Neuromuscular and skeletal: arthralgia (23%), myalgia (17%), back pain (13%), limb pain (13%)
Ophthalmology: visual impairment (15%)
Respiratory system: dyspnea (27%), cough (18%) ), upper respiratory tract infection (12%)
Others: fever (12%)
1%-10%:
Cardiovascular: atrioventricular block (1%)
Central nervous system: hallucinations (7%), epilepsy (3%), mental status changes (2 %)
Respiratory system: pneumonia (3%), interstitial lung disease (≤2%), localized pneumonia (≤2%), respiratory failure (1%)

Contraindications:
Combined use with strong CYP3A inducers.
Hypersensitivity to lorlatinib or any component of the formulation.

Precautions:
Myelosuppression: Anemia (usually mild) commonly occurs with lorlatinib. Mild thrombocytopenia and lymphopenia also occur.
Cardiovascular Effects: PR interval prolongation and atrioventricular block, including Grade 3 events, occurred rarely in patients receiving lorlatinib. Some patients require a pacemaker. Monitor ECGs before initiating lorlatinib therapy and periodically thereafter. Discontinue treatment and resume treatment at a lower dose (if no pacemaker is inserted) or at the same dose in patients with a pacemaker. Permanently halts relapses in patients without a pacemaker.
Central Nervous System Effects: Central nervous system effects (including seizures, hallucinations, changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep) may occur in patients receiving lorlatinib. Overall, only more than half of patients treated with lorlatinib experienced central nervous system effects. In one study, nearly one-third of patients receiving lorlatinib (any dose) experienced cognitive effects; a small proportion of these events were serious (Grade 3 or 4). Mood effects occur in nearly a quarter of patients; serious events are rare. Speech effects, hallucinations, and mental status changes have also been reported, including rare serious 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 reactions 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 after doses of lorlatinib combined with multiple doses of rifampicin, a strong CYP3A inducer. Grade 3 and 4 elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are more common, and grade 2 elevations have also been reported. ALT or AST increased within 3 days and returned to the normal range after 15 days (range: 7 to 34 days); the median recovery time for subjects with grade 2 ALT or AST elevation was 7 days, and the median recovery time for subjects with grade 3 or 4 ALT or AST elevation was 18 days. Lorlatinib is contraindicated in patients taking strong CYP3A inducers. Discontinue treatment with strong CYP3A inducers for at least 3 plasma half-lives before initiating lorlatinib therapy (strong CYP3A inducers). Avoid concomitant use of lorlatinib with moderate CYP3A inducers; if concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin at least three times within 48 hours after starting lorlatinib and during the first week after starting lorlatinib. Discontinue lorlatinib or CYP3A inducers for persistent grade 2 or higher hepatotoxicity based on the relative importance of each agent.
Hyperlipidemia: Patients receiving lorlatinib may experience elevated serum cholesterol and triglycerides. Grade 3 or 4 elevations in total cholesterol and triglycerides have been reported. The median time to onset (hypercholesterolemia and hypertriglyceridemia) was 15 days. Typically, most patients with hypercholesterolemia and hypertriglyceridemia require initiation of lipid-lowering medication 21 days after initiating lorlatinib therapy. Measure serum cholesterol and triglycerides before starting lorlatinib, and monitor serum cholesterol and triglycerides regularly 1 and 2 months after the onset of lorlatinib. Use lipid-lowering drugs (or increase the dose) in patients with hyperlipidemia. Depending on severity, hyperlipidemia may require interruption of lorlatinib therapy or dose reduction.
Pulmonary Toxicity: Rare, serious, or life-threatening pulmonary adverse reactions related to interstitial pulmonary disease (ILD)/pneumonitis may occur with lorlatinib, including Grade 3 and 4 events. Promptly evaluate new or worsening respiratory symptoms suggestive of ILD/pneumonia (eg, dyspnea, cough, fever). Discontinue lorlatinib immediately if ILD/pneumonitis is suspected and permanently discontinue lorlatinib-related ILD/pneumonitis of any severity.
Drug-Drug Interactions: Significant interactions may exist that may require dose or frequency adjustment, additional monitoring, or the selection of alternative therapies.
ALK Positive: Lorlatinib is approved to detect patients with metastatic non-small cell lung cancer (NSCLC) who are positive for the abnormal anaplastic lymphoma kinase (ALK) gene.
Pregnancy: Based on data from mechanism of action and animal reproduction studies, lorlatinib may cause harm to the fetus during pregnancy. Assess the pregnancy status of females of reproductive potential before initiating treatment. Females of reproductive potential should avoid pregnancy and use an effective non-hormonal method of contraception during treatment and for at least 6 months after the last dose of lorlatinib. Male patients with a female partner of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose of lorlatinib.

Storage:
Store at 20°C to 25°C (68°F to 77°F); excursions allowed between 15°C to 30°C (59°F to 86°F).

Mechanism of action:
Lorlatinib is a new third-generation tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK) and the receptor tyrosine kinase c-ros proto-oncogene 1 (ROS1).

Safety and efficacy:
Studies have shown that patients with advanced non-small cell lung cancer, including those with brain metastases, who are ALK (anaplastic lymphoma kinase) or ROS1 (receptor tyrosine kinase c-ros proto-oncogene 1) positive, have a clinical response to lorlatinib. In phase I clinical trials, patients who were not treated with medication or who had used a tyrosine kinase inhibitor and whose condition worsened were treated with dose escalation of the drug, and the overall effective response rate was 46%. The average survival time without disease exacerbation was 1.4 months, and the size of brain metastases was reduced.
On April 27, 2017, Pfizer announced that its new generation ALK/ROS1 inhibitor Lorlatinib was granted breakthrough drug designation by the FDA for the treatment of ALK-positive, metastatic NSCLC (non-small cell lung cancer) that has progressed after treatment with one or more ALK inhibitors. This designation was granted based on efficacy and safety data from an ongoing Phase 1/2 clinical study.
On October 17, 2017, Pfizer announced the complete data of the Phase II clinical trial of Lorlatinib at the WCLC 2017 conference:
For ALK-positive patients with newly treated NSCLC (non-small cell lung cancer), the ORR (objective response rate) is as high as 90%, and the intracranial ORR reaches 75%;
For patients with ALK positivity and previous treatment with crizotinib, the ORR is 69%, and the intracranial ORR is 69%. Reached 68%;
For ALK-positive patients who had previously received treatment with other ALK inhibitors other than crizotinib, the ORR was 33%, and the intracranial ORR reached 42%;
For patients who were ALK-positive and had previously received 2-3 ALK inhibitors, the ORR was 39%, and the intracranial ORR reached 48%;
For ROS1-positive, previously treated patients, the ORR was 36%, and the intracranial ORR reached 56%.
Experimental results show that the drug shows clinically meaningful activity in the treatment of lung tumors and brain metastases in patients with ALK-positive and ROS1-positive advanced NSCLC.