Synonyms: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile | Lorbrena® | Lorviqua® | PF-06463922 | PF06463922

lorlatinib is an approved drug (FDA (2018), EMA (2019))

Compound class: Synthetic organic

Comment: Lorlatinib (PF-06463922) is a kinase inhibitor with action on ALK and ROS1 proto-oncogenes [3,7]. It is a reversible, ATP-competitive small molecule inhibitor. Lorlatinib is a third generation ALK inhibitor designed to have improved blood-brain barrier penetrance compared to older second generation ALK inhibitors such as the approved drugs ceritinib, alectinib, and brigatinib, with the aim of better targeting metastatic NSCLC lesions in the brain. Advanced generation ALK inhibitors are those which target acquired ALK mutations resistant to the original first generation inhibitor crizotinib, which occur in virtually all AKL-rearranged NSCLC tumours within a year of starting crizotinib therapy. In fact, the cyano group of lortatinib is highly selective for the ALK mutation L1196M [4]. Facchinetti et al. (2016) [1] review the progress in ALK inhibitor development and discuss the importance of targeting therapies based on individual patient tumour profiles. Shaw et al.(2016) [5] publish a case report of a patient with metastatic ALK-rearranged NSCLC whose tumours acquired sequential resistance to crizotinib, ceritinib and finally lorlatinib. However, the patient subsequently showed a resensitization to crizotinib. This patient was identified in a substudy of Phase 1/2 clinical trial NCT01970865, which is designed to compare lorlatinib against crizotinib in advanced NSCLC harbouring specific molecular alterations, such as the lorlatinib resistance-conferring mutation L1198F. The molecular biology behind this pheomenon is outlined in the Nature Reviews Cancer Research Highlight commentary by Shipman (2016) [6].

lorlatinib is commercially available from our sponsors