Update on Lorlatinib: Role in Reducing the Risk of Disease Progression in ALK-Positive NSCLC

Abstract

Lorlatinib is an oral third-generation inhibitor of anaplastic lymphoma kinase (ALK) with activity in advanced ALK-positive non-small cell lung cancer (NSCLC) in both the first and subsequent line setting. Superior systemic and intracranial efficacy of lorlatinib over crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI), in treatment-naïve patients with advanced ALK-positive NSCLC was demonstrated by the phase 3 CROWN trial. Lorlatinib retains anti-tumor effect against single and some compound ALK resistance mutations after disease progression on first- and second-generation ALK TKIs. Currently, alectinib, brigatinib, ceritinib, crizotinib and lorlatinib are approved for treatment of advanced ALK-positive NSCLC. However, no head-to-head studies have directly compared lorlatinib to second-generation ALK inhibitors. Herein, we aim to provide an overview of the efficacy and safety of lorlatinib and discuss where lorlatinib stands in the therapeutic approach to advanced ALK-positive NSCLC.

Unraveling the Post-Translational Modifications and therapeutical approach in NSCLC pathogenesis

“…showed that Everolimus is an mTORC1 inhibitor, increasing radiosensitivity in NCI-H661 NSCLC cells through altering EMT [114] . Inhibitors such as dabrafenib, encorafenib and vemurafenib (BRAF inhibitors) [115] , Abemaciclib (CDK4/6 inhibitors) [116] , Lorlatinib (ALK inhibitors) [117] has been reported. The various PTMs and its inhibitor drug are given in Table 1 .…”

Recent Advances in the Management of Adverse Events Associated with Lorlatinib

“…The mechanism of acquired resistance has been widely reported, often due to the development of compound ALK mutations and bypass signaling and changes in cell types. 6 , 34 Yoda et al 35 reported that ALK C1156Y/L1198F and G1202R/L1196M were the most common compound mutations for lorlatinib resistance. In addition, ALK I1171S/G1269A, L1196M/D1203N, G1202R/F1174L, G1202R/L1196M and D1203N/I1171N mutations are other potential resistance mechanism that have been reported.…”

“… 4 With the understanding of the molecular biology of NSCLC, numerous small molecular tyrosine kinase inhibitors (TKIs) have been successfully approved as targeted therapies in patients with oncogene-driven mutations, which are tremendous advances in NSCLC treatment. 5 , 6 In comparison with traditional platinum-based chemotherapy, TKIs significantly improved overall survival (OS) and quality of life in NSCLC patients with oncogenic driver mutations. 7 …”

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…Receptor tyrosine kinase inhibitors have been used clinically in cancer therapy since 2001 [ 298 ]. Lorlatinib is an inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) kinase, which is approved by the FDA for patients with ALK-positive NSCLC [ 299 , 300 ]. Recently, Nielsen et al showed that neutrophils treated with conditioned medium from the pancreatic cancer cell line KPC mT4 and bone-marrow-derived neutrophils from the KPC mouse model with pancreatic tumors had increased non-receptor tyrosine kinase FES activity [ 233 ].…”