Lorviqua Mechanism of Action





Zuellig Pharma
Full Prescribing Info
Pharmacology: Pharmacodynamics: Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive, brain-penetrant, small molecule inhibitor of ALK and ROS1 tyrosine kinases that addresses mechanisms of resistance following previous treatment with ALK inhibitor therapy.
In nonclinical studies, lorlatinib potently inhibited catalytic activities of non-mutated ALK and a broad range of clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays. The ALK mutations analyzed included those conferring resistance to other ALK inhibitors, including alectinib, brigatinib, ceritinib, and crizotinib.
Lorlatinib demonstrated marked antitumor activity at low nanomolar free plasma concentrations in mice bearing tumor xenografts that express echinoderm microtubule-associated protein-like 4 (EML4) fusions with ALK variant 1 (v1), including ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T, are known to confer resistance to first and second generation ALK inhibitors. Lorlatinib is also capable of penetrating the blood-brain barrier and achieved efficacious brain exposure in mice and rat. In mice bearing orthotopic EML4-ALK or EML4-ALKL1196M brain tumor implants, lorlatinib caused tumor shrinkage and prolonged survival. The overall antitumor efficacy of lorlatinib was dose-dependent and strongly correlated with inhibition of ALK phosphorylation.
Clinical studies: ALK-positive advanced NSCLC previously treated with an ALK kinase inhibitor: The use of LORVIQUA in the treatment of ALK-positive advanced NSCLC previously treated with 1 or more ALK TKIs was investigated in Study B7461001, a single-arm, multicenter Phase ½ study. A total of 197 patients with ALK-positive advanced NSCLC previously treated with 1 or more ALK TKIs were enrolled in the Phase 2 portion of the study. Patients received LORVIQUA orally at the recommended dose of 100 mg once daily, continuously.
The primary efficacy endpoint in the Phase 2 portion of the study was ORR, including intracranial ORR, as per Independent Central Review (ICR) according to modified Response Evaluation Criteria in Solid Tumors (modified RECIST 1.1). Secondary endpoints included DOR, intracranial DOR, time-to-tumor response (TTR), and progression-free survival (PFS).
Patient demographics of the 197 ALK-positive advanced NSCLC patients previously treated with 1 or more ALK TKIs, were 59% female, 49% Caucasian, 36% Asian and the mean age was 53 years (range: 29 to 85 years) with 19% ≥65 years of age. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 or 1 in 97% of patients and 2 in 4% of patients. Brain metastases were present at baseline in 62% of patients. All 197 patients had received prior systemic therapy, 20% received 1, 28% received 2, 19% received 3, and 34% received 4 or more prior systemic therapies. Of the 197 patients, 44% received 1 prior ALK TKI, 33% received 2 prior ALK TKIs, and 23% received 3 or more prior ALK TKIs.
The main efficacy results for Study B7461001 are included in Tables 1 and 2. (See Tables 1 and 2.)

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Among the 93 patients with a confirmed objective response by ICR, the median TTR was 1.4 months (range: 1.1 to 11.0 months). Among the 70 patients with a confirmed objective tumor response by ICR, the median intracranial-TTR was 1.4 months (range: 1.1 to 6.2 months).
Pharmacokinetics: Absorption: Peak lorlatinib concentrations in plasma are rapidly reached with the median Tmax of 1.2 hours following a single 100 mg dose and 2.0 hours following 100 mg once daily multiple dosing.
After oral administration of lorlatinib tablets, the mean absolute bioavailability is 80.8% (90% CI: 75.7%, 86.2%) compared to intravenous administration.
Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher exposure compared to overnight fasting (AUCinf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%). Lorlatinib may be administered with or without food. The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (AUCinf ratio of 100.9%; 90% CI for the ratio: 97.6%, 104.3%). No dose adjustment is recommended when lorlatinib is taken with proton-pump inhibitors, H2-receptor antagonists or locally-acting antacids.
After multiple once daily dose administration, lorlatinib Cmax increased dose-proportionally and AUCtau increased slightly less than proportionally over the dose range of 10 to 200 mg once daily. At the 100 mg once daily lorlatinib dose, the geometric mean peak plasma concentration was 577 ng/mL and the AUC24 5650 ng·h/mL in patients with cancer. The geometric mean oral clearance was 17.7 L/h. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.
Distribution: In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to albumin to α1-acid glycoprotein.
Metabolism: In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
In plasma, a benzoic acid metabolite of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive.
Elimination: The plasma half-life of lorlatinib after a single 100 mg dose was 23.6 hours. Following oral administration of a 100 mg radiolabeled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in feces, with overall mean total recovery of 88.6%.
Unchanged lorlatinib was the major component of human plasma and feces, accounting for 44% and 9.1% of total radioactivity in plasma and feces, respectively. Less than 1% of unchanged lorlatinib was detected in urine.
Cardiac electrophysiology: QT interval: In Study B7461001, 2 patients (0.7%) had absolute Fridericia's correction QTc (QTcF) values >500 msec, and 5 patients (1.8%) had a change in QTcF from baseline >60 msec.
In addition, the effect of a single oral dose of lorlatinib (50 mg, 75 mg, and 100 mg) with and without 200 mg once daily itraconazole was evaluated in a 2-way crossover study in 16 healthy volunteers. No increases in the mean QTc interval were observed at the mean observed lorlatinib concentrations in this study.
In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily in Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.
PR interval: In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2-sided 90% upper CI: 19.4 ms). Among the 284 patients with PR interval <200 ms, 14% had PR interval prolongation ≥200 ms after starting lorlatinib. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1.0% of patients.
For those patients who develop PR prolongation, dose modification may be required (see Dosage & Administration).
Special populations: Hepatic impairment: As lorlatinib is metabolized in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT >2.5 x ULN, or if due to underlying malignancy, >5.0 x ULN or with total bilirubin > 1.5 x ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n=50). No dose adjustments are recommended for patients with mild hepatic impairment (see Dosage & Administration). Lorlatinib has not been studied in patients with moderate or severe hepatic impairment.
Renal impairment: Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Clinical studies excluded patients with serum creatinine >1.5 x ULN or estimated CLcr <60 mL/min. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild (n=103) or moderate (n=41) renal impairment (CLcr≥30 mL/min). Based on a renal impairment study, no dose adjustments are recommended for patients with mild or moderate renal impairment [absolute eGFR based on Modification of Diet in Renal Disease Study equation (MDRD) derived eGFR (in mL/min/1.73 m2) x measured body surface area/1.73 ≥30 mL/min]. In this study, lorlatinib AUCinf increased by 41% in subjects with severe renal impairment (absolute eGFR <30 mL/min) compared to subjects with normal renal function (absolute eGFR ≥90 mL/min). A reduced dose of LORVIQUA is recommended in patients with severe renal impairment, e.g. a starting dose of 75 mg taken orally once daily (see Dosage & Administration).
Elderly (≥65 years): Of the 295 patients in safety population in Study B7461001, 18.3% of patients were aged 65 years or older. Of the 215 patients in the efficacy population in Study B7461001, 17.7% of patients were aged 65 years or older. Although data are limited, no clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years and younger patients; no dose adjustments are recommended in elderly patients (see Dosage & Administration).
Gender, race, body weight, and phenotype: Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, or phenotypes for CYP3A5 and CYP2C19.
Toxicology: Preclinical Safety Data: Repeat-dose toxicity: The main toxicities observed were inflammation across multiple tissues (with increases in white blood cells), and changes in the pancreas (with increases in amylase and lipase), hepatobiliary system (with increases in liver enzymes), male reproductive system, cardiovascular system, kidneys and gastrointestinal tract, and peripheral nerves and the CNS (potential for cognitive functional impairment) (approximately 4.6 to 21 times the human clinical exposure at 100 mg based on AUC for all toxicities). Changes in blood pressure and heart rate, and QRS and PR interval prolongation were also observed in animals after acute dosing (approximately 2.6 times the human clinical exposure at 100 mg after a single dose based on Cmax). All target organ findings with the exception of the hepatic bile duct hyperplasia (approximately 7.1 to 21 times the human clinical exposure at 100 mg based on AUC) were partially to fully reversible.
Genotoxicity: Lorlatinib was not mutagenic in a bacterial reverse mutation (Ames) assay. Lorlatinib induced micronuclei via an aneugenic mechanism in human lymphoblastoid TK6 cells in vitro and in the bone marrow of rats. The exposure of animals at the no observed effect level for aneugenicity was approximately 16.5 times human clinical exposure at 100 mg based on AUC.
Carcinogenicity: Carcinogenicity studies have not been conducted with lorlatinib.
Reproductive toxicity: Effects on male reproductive organs (testis, epididymis, and prostate) were observed in animals (approximately 3.9 to 1.6 times the human clinical exposure at 100 mg based on AUC). The effects on male reproductive organs were fully or partially reversible.
In embryo-fetal toxicity studies increased embryo lethality, and lower fetal body weights were observed. Fetal morphologic abnormalities included rotated limbs, supernumerary digits, gastroschisis, malformed kidneys, domed head, high arched palate, and dilation of ventricles of the brain. The lowest doses with embryo-fetal effects in animals correlated with 0.6 to 1.1 times the human clinical exposure at 100 mg, based on AUC.
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