The Evolution of Frontline Therapy in ALK-Positive Advanced NSCLC: Which ALK TKI to Use Upfront?

Jeffrey Zweig, MD, and Heather Wakelee, MD
Published: Monday, Jan 01, 2018

Therapeutic options for advanced anaplastic lymphoma kinase (ALK)–positive non–small-cell lung cancer have changed dramatically since the 2011 approval of crizotinib. Since then, 3 additional agents have received FDA approval for use in the second-line setting after progression on crizotinib: ceritinib, alectinib, and brigatinib. Other investigational ALK inhibitors are under evaluation. As these agents represent newer-generation, more potent ALK inhibitors, interest in their use in the frontline setting has quickly grown. Here, we review frontline trials of ceritinib and alectinib, with comparisons drawn with crizotinib, the only FDA-approved frontline choice until the recent approval of ceritinib. With several new promising options, we attempt to better answer the question of which ALK tyrosine kinase inhibitor (TKI) should be favored upfront.
Introduction The identification of the EML4-ALK fusion oncogene in 2007 as a driver of pathogenesis, in the 2% to 7% of patients with non– small-cell lung cancer (NSCLC) who express it, has led to the development over the last decade of several targeted anaplastic lymphoma kinase (ALK) inhibitors.1 The use of ALK inhibitors in advanced disease has transformed the treatment strategy of ALKpositive NSCLC, providing targeted therapeutic options that show significant progression-free survival (PFS) and overall survival (OS) benefit, with an impactful influence on patients and their disease course. There are currently 4 approved agents—crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig)—with several others in active development.2 Although crizotinib has historically represented the first-line agent of choice, it has quickly been challenged by the newer, more potent, second-generation ALK inhibitors ceritinib and alectinib, with ceritinib recently gaining FDA approval as a first-line option in May 2017. In order to best answer the question of which agent to use upfront, one must consider a variety of factors, including comparative trial data, adverse event (AE) profiles, and response rates, which will be reviewed here.
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