The most common adverse reactions include edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough.[7]
Lorlatinib was approved for medical use in the United States in November 2018,[8][9] and in the European Union in May 2019.[5]
Medical uses
Lorlatinib is indicated for the treatment of adults with metastatic non-small cell lung cancer whose tumors are anaplastic lymphoma kinase (ALK)-positive.[4][5][6][7]
Contraindications
Lorlatinib must not be combined with strong inducers (i.e. activators) of the liver enzymes CYP3A4/5 if it can be avoided, as serious cases of liver toxicity have been observed under combination with the CYP3A4/5 inducer rifampicin.[4][10]
Lorlatinib is metabolized by the enzymes CYP3A4/5. Therefore, CYP3A4/5 inducers such as rifampicin, carbamazepine or St John's wort decrease its concentrations in the blood plasma and can reduce its effectiveness. Additionally, the combination of lorlatinib with rifampicin showed liver toxicity in studies. Inhibitors of these enzymes such as ketoconazole or grapefruit juice increase lorlatinib plasma concentrations, leading to higher toxicity. Lorlatinib is also a (moderate) CYP3A4/5 inducer, so that drugs that are metabolized by these enzymes are broken down more quickly when combined with lorlatinib. Examples include midazolam and ciclosporin.[4][10]
Interactions via other enzymes have only been studied in vitro. According to these findings, lorlatinib may inhibit CYP2C9, UGT1A1 and several transport proteins, induce CYP2B6, and has probably no relevant effect on CYP1A2.[10]
Lorlatinib is inactivated by oxidation, mainly through CYP3A4, and by glucuronidation, mainly through UGT1A4.[medical citation needed] Other CYPs and UGTs play a minor role.[medical citation needed] Lorlatinib and its metabolites are excreted with a half-life of 23.6 hours after a single dose; 47.7% into the urine (of which less than 1% in unchanged form), and 40.9% into the faeces (9.1% unchanged).[10]
Chemistry
Lorlatinib is a white to off-white powder. It has high solubility in 0.1 Mhydrochloric acid and very low solubility at a pH over 4.5.[11]
History
In November 2018, the US Food and Drug Administration (FDA) granted accelerated approval to lorlatinib for people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease.[8] Approval was based on a subgroup of 215 participants with ALK-positive metastatic NSCLC, previously treated with one or more ALK kinase inhibitors, enrolled in a non‑randomized, dose-ranging and activity-estimating, multi‑cohort, multicenter study (Study B7461001; NCT01970865).[8] The major efficacy measures were overall response rate (ORR) and intracranial ORR, according to RECIST 1.1, as assessed by an independent central review committee.[8]
In March 2021, the FDA granted regular approval to lorlatinib based on data from study B7461006 (NCT03052608), a randomized, multicenter, open-label, active-controlled trial conducted in 296 participants with ALK-positive metastatic non-small cell lung cancer who had not received prior systemic therapy for metastatic disease. Participants were required to have ALK-positive tumors detected by the VENTANA ALK (D5F3) CDx assay. Participants were randomized 1:1 to receive lorlatinib 100 mg orally once daily (n=149) or crizotinib 250 mg orally twice daily (n=147).
Society and culture
Legal status
In 2015, the FDA granted lorlatinib orphan drug status for the treatment of anaplastic lymphoma kinase (ALK)-positive or ROS1-positive non-small cell lung cancer.[13]
Lorlatinib was approved for medical use in the United States in November 2018,[8] and in the European Union in May 2019.[5][14][15]
Research
In June 2024, Pfizer announced positive longer-term follow-up results from the phase III CROWN study of lorlatinib in advanced non-small cell lung cancer showing that 60% of participants treated with lorlatinib were alive without disease progression after five years.[16][17][18]
References
^ ab"Lorviqua APMDS". Therapeutic Goods Administration (TGA). 26 May 2022. Archived from the original on 10 March 2024. Retrieved 10 March 2024.
^"Lorlatinib". NCI Drug Dictionary. National Cancer Institute. 2 February 2011. Archived from the original on 15 October 2020. Retrieved 27 December 2020.
^Solomon BJ, Liu G, Felip E, Mok TS, Soo RA, Mazieres J, et al. (May 2024). "Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study". Journal of Clinical Oncology: JCO2400581. doi:10.1200/JCO.24.00581. PMID38819031.
External links
Clinical trial number NCT01970865 for "A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations" at ClinicalTrials.gov