Pooled Efficacy and Safety Analysis of the Phase III Studies of Alectinib vs. Crizotinib in Untreated ALK-Positive Non-Small Cell Lung Cancer

ALK (anaplastic lymphoma kinase) gene gives instructions for coding a protein called ALK tyrosine kinase receptor, that is a cell membrane receptor involved in the regulation of cell growth. Alterations (i.e. rearrangements) of this gene may result in increased growth of the tumor cells. Altered forms of the ALK gene have been found in some types of cancer, including 3-5% of cases of non-small cell lung cancer (NSCLC), and in some anaplastic large cell lymphoma. Patients with tumors harboring such alterations of the ALK gene and protein are highly sensitive to a class of drugs called ALK inhibitors (i.e. ALK tyrosine kinase inhibitors [TKI]). To date, three generations of ALK inhibitors have revolutionized the treatment and the natural history of this disease. Crizotinib, a first-generation ALK TKI, was the first among these drugs to demonstrate to prolong the survival as compared with chemotherapy in patients with pretreated and treatment-naïve ALK-positive metastatic NSCLC. It represented the standard of care, until the development of further-generation ALK inhibitors, like Alectinib, Brigatinib and Ceritinib. These latter became new treatment options, at first as a sequential therapy after disease progression to Crizotinib. Nonetheless, to date Alectinib, Brigatinib and Lorlatinib are available as first line therapy options, after having been compared to Crizotinib in phase 3 studies. They led to increased objective response rate (ORR), intracranial disease control and progression-free survival (PFS) as compared to the first-generation agent. Finally, the third-generation TKI Lorlatinib, first approved at disease progression to second-generation TKIs, has been investigated as first line treatment within the CROWN phase III trial, with impressive results. In many countries, Alectinib represents the first line standard of care for patients with ALK-positive disease, based on strong efficacy and safety results. To date, no data of comparison between further-generation ALK TKIs are available. Three randomized controlled trials compared Alectininb to Crizotinib: the ALEX trial (NCT02075840), the ALESIA trial (NCT02838420, conducted in Asian population) and the J-ALEX trial (JapicCTI-132316, conducted in Japanese population). To date, an analysis describing efficacy and safety of Alectinib as first line therapy by pooling together the population enrolled in each single trial has not been conducted. In this complex scenario, providing patient-level data about a worldwide used drug, to investigate predictors of activity, would be of great importance when treating a patient with a newly diagnosed ALK-positive metastatic NSCLC.