A few pills twice a day keep ALK-positive non-small-cell lung cancer at bay

Abstract

Non-small-cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. A number of oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements being one of the most attractive (1). In the past 10 years, we have learned that the presence of such molecular event is associated with some specific pathological and clinical features, including a preferential seeding into the central nervous system (CNS) and, most importantly, anticipates response to anti-ALK agents (2-4). Front-line crizotinib, the first-in-class ALK-inhibitor, prolonged median progression-free survival (PFS) of 4 months respect to standard platinum-pemetrexed (11.9 vs. 7.0 months; HR =0.45, P<0.001), nearly doubling the probability of achieving responses [response rate (RR): 75% vs. 45%] and preserving quality of life, as demonstrated in the PROFILE 1014 trial (5). However, the drug does not definitively cure any patient and, within the first year of therapy, cancer eventually re-growths due to the occurrence of acquired resistance, with the CNS as the dominant site of progression (6). The new generation and FDA-approved ALK-inhibitors, ceritinib, alectinib and brigatinib, are more potent and brain-penetrable than crizotinib and retain activity against a wide spectrum of ALK resistance mutations (6). In single-arm studies, all these drugs resulted effective in crizotinib-failure setting, particularly in patients with brain metastases (BMs) (7-11). Furthermore, sequential use of crizotinib followed by ceritinib or alectinib produced a combined PFS exceeding 18 months (12,13). This is the reason why, the standard of care for advanced ALK positive NSCLC should include crizotinib followed by a second generation ALK inhibitor. However, it remains unclear whether upfront use of a second-generation ALK inhibitor could translate into a more durable benefit than the one observed with sequential approach.In a recent issue of The Lancet, Hida and colleagues reported results of the J-ALEX, a phase 3 randomized Japanese trial directly comparing alectinib to crizotinib in 207 ALK rearranged NSCLCs who had never received an ALK inhibitor (14). Notably, the study also included individuals previously exposed to one line of chemotherapy and with asymptomatic BMs, regardless of prior radiation therapy (RT). Stratification was done according to ECOG performance status (0/1 vs. 2), treatment line (first vs. second) and disease stage (IIIB vs. IV). The study met its primary end-point of PFS by independent review, demonstrating an impressive reduction in the risk of progression of 66% for patients treated with alectinib (PFS: not reached, NR vs. 10.2 months; HR =0.34, P<0.0001). In addition, alectinib had greater intracranial activity (HR for PFS 0.16) also delaying the onset of BMs (HR for time to BMs onset 0.41), had a numerically higher RR (92% vs. 79%) and a more favorable safety profile than crizotinib [grade 3-4 adverse events (AEs): 26% vs. 52%]. Importantly, the PFS improvemen...