Spotlight on the treatment of ALK-rearranged non-small-cell lung cancer.

Abstract

Lung cancer is the leading cause of cancer-related mortality, both worldwide and in the USA. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. At the turn of 21st century, platinum based cytotoxic chemotherapy was shown to offer modest survival benefit in metastatic NSCLC and remained the only viable treatment option for a long time. Over the past decade, the therapeutic landscape of NSCLC has expanded dramatically owing to the discovery of various driver mutations. Several molecularly targeted agents and immune checkpoint inhibitors are now a part of the therapeutic armamentarium against this genetically complex disease. ALK gene encodes for a member of insulin receptor superfamily transmembrane receptor tyrosine kinase [1]. In 2007, chromosomal rearrangement involving ALK gene on chromosome 2 and EML4 gene on chromosome 5 was first found to have potent transforming activity in NSCLC. Subsequently, preclinical studies suggested that this fusion gene might be the driver mutation and potentially be a therapeutic target of NSCLC [2]. Approximately, 3– 7% of patients with NSCLC harbor the EML4–ALK gene rearrangement, which is mutually exclusive with EGFR and KRAS mutations. ALK gene rearrangements are more common in younger patients with adenocarcinoma histology and those with minimal or no smoking history. There are reports of ALK gene rearrangement in patients with squamous cell and small-cell lung cancer; however, its clinical significance and potential as a therapeutic target in these histologic subtypes remain unknown. The testing modalities for ALK rearrangement in NSCLC include immunohistochemistry (IHC), FISH, and PCR; with the former two being the most commonly utilized modalities. However, there is a variable rate of discordance in response to ALK inhibition in IHC-negative but FISH-positive tumors, and therefore both IHC and FISH are currently recommended for ALK testing. Crizotinib, originally developed as a c-MET inhibitor, is the first-in-class ALK inhibitor to show activity in ALKrearranged NSCLC. In addition, it is also active in ROS1-rearranged lung cancer. Crizotinib received accelerated US FDA approval in 2011 based on a Phase I trial showing objective response rate (ORR) of 60% with a median progression free survival (PFS) of 9.7 months and 12-month overall survival of 74.8% in patients with ALK-rearranged NSCLC [3]. Subsequently, two randomized Phase III trials comparing crizotinib with standard chemotherapy in second line and first-line settings confirmed significantly higher response rates and longer PFS with crizotinib. No statistically significant overall survival difference was observed in either of these trials, largely accounted for by significant crossover between the two arms [4,5]. Despite the striking results with this first ALK inhibitor, the success in personalized therapy was fraught with several challenges. First, the majority of patients develop resistance to crizotinib within the first 12 months of treatment. Several resistance mechanisms have been implicated and are broadly divided into two categories: ALKdominant, and ALK-nondominant [6]. ALK-dominant mechanisms predominantly comprise second mutations in the ALK gene which include a gatekeeper mutation L1196M as well as other more recently reported mutations such