A comprehensive review on Brigatinib – A wonder drug for targeted cancer therapy in non-small cell lung cancer

Abstract

The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using -[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90 mg of brigatinib for 7 days and then 180 mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.

In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition

“…Since pyrimidine nucleotides are essential for the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), pyrimidine bearing compounds have been widely investigated for diverse activities including anticancer activity in the regular literature and patents field [29][30][31][32]. Brigatinib ( Figure 2) with bisanilino-pyrimidine structure is a novel anaplastic lymphoma kinase (ALK) inhibitor, which was found effective in the treatment of NSCLC [33]. Abemaciclib, imatinib, nilotinib, nimustine, osimertinib, pazopanib and rociletinib ( Figure 2) are another pyrimidine-based anticancer agents [34,35].…”

Drug-Related Pneumonitis in Cancer Treatment during the COVID-19 Era

“…ALK inhibitors, either first (crizotinib), second (alectinib, ceritinib, brigatinib) or third generation (lorlatinib), can also lead to lung interstitial toxicity. Several hypotheses have been suggested to better clarify the mechanisms responsible for pulmonary toxicity exerted by ALK-TKIs with particular regard to crizotinib, but they all derive from case reports and retrospective studies [ 51 ]. In a systematic review conducted by Pellegrino and colleagues, pulmonary adverse events attributed to crizotinib occurred in 1.8% of cases, 1.1% attributed to ceritinib, 2.6% to alectinib, 1.8% to lorlatinib and 7% to brigatinib, which was therefore identified as the ALK inhibitor with the highest percentage of ILD [ 47 ].…”

“…Across all studies of brigatinib, at a starting dose of 90 mg once daily, 4.5% of patients experienced any grade event of pneumonitis with a median time to onset of 2 days. Three percent of patients had grade 3 or higher events that led to drug discontinuation [ 48 , 51 ]. In a recent study by Hwang et al in patients with NSCLC treated with ALKs, COP was the most common pattern (64% of the sample), followed by HP and AIP.…”

Safety and efficacy of anaplastic lymphoma kinase tyrosine kinase inhibitors in non‑small cell lung cancer (Review)

“…Crizotinib is considered as a first-generation inhibitor of ALK indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive or c-ros oncogene 1 (ROS1)-positive ( 25 ). Crizotinib was approved by the US FDA in 2011.…”

“…Brigatinib is a tyrosine kinase inhibitor with broad-spectrum activity against ALK, ROS1, the insulin-like growth factor-1 receptor (IGF-1R), and Fms-like tyrosine kinase 3 (FLT-3), as well as EGFR deletions and point mutations, including L1152R, V1180L, G1202R, R1275Q, T790M, C797S, and L858R ( 24 , 25 , 50 ). Brigatinib has a 12-fold higher potency than crizotinib for inhibiting ALK.…”