Are ALK rearrangement variants promising predictive biomarker of ALK tyrosine kinase inhibitors efficacy?

We read with interest the article by Woo et al. reporting ALK tyrosine kinase inhibitors (ALK-TKIs) efficacy in 51 ALK-positive patients with known EML4-ALK rearrangement variants (v) [1]. The authors report a better 2-year progression-free survival (PFS) rate with crizotinib in the v1/v2/others group (n1⁄4 24) compared with the v3a/b group (n1⁄4 20) (76% versus 26.4%, P1⁄4 0.034). This differential efficacy of crizotinib among ALK variants is supported by in vitro experiments. This is the first clinical report that supports the in vitro hypothesis previously raised by Heuckmann et al. who demonstrated the differential EML4-ALK variants sensitivity to ALK-TKIs according to the stability of the protein products [2]. However, we have some concerns about the clinical interpretation of these data and a potential technical issue. The overall survival (OS) curves of the v1/v2/others group and v3a/b group are stackable. The authors argued that this could be due to a low mortality rate and a larger proportion of heavily pretreated patients in the v1/v2/others group. However, two important confounding variables have been missed. First, oligoprogression as first progression event is common in crizotinib-treated ALK-positive lung cancer. Combining a local ablative therapy (LAT) and continuing crizotinib beyond progression can provide a clinical benefit and a disease control for months [3]. Continuing crizotinib beyond progression is commonly used when the clinical benefit is still observed. In two independent retrospective cohorts, 32.2% and 62% of patients were treated with crizotinib beyond progression resulting in a median OS of 32.2 and 29.6 months compared with 11.2 and 10.8 months in patients who did not received crizotinib beyond progression [4, 5]. As Woo et al. used RECIST criteria to define progression, they were unable to capture the clinical benefit of LAT and/or continuing crizotinib beyond progression. It would be very interesting if the authors could provide additional data about the profile of progression and the proportion of patients with oligoprogression that were treated with LAT and/or crizotinib beyond progression in the v1/v2/others and v3a/b groups. Second, next-generation ALK-TKIs are effective after crizotinib failure. The authors did not report the subsequent use in their patients of ceritinib and alectinib that are approved drugs in this setting. A larger number of patients treated with next-generation ALK-TKI after crizotinib failure in the V3a/b group could partly explain the lack of OS difference. Concerning the technical issue, the discovery of two new EML4-ALK variants is somewhat intriguing to our opinion. Indeed, EML4-ALK variants are detected using a multiplex RTPCR. This technology uses primers that are designed to amplify specifically a known mRNA sequence and is unable to uncover new (1⁄4unknown) variants. The authors did not mention the use of a sequencing technology able to describe new variants. Finally, although Woo et al. claimed in their conclusion that ‘stratification of patients with advanced ALK rearrangementpositive NSCLC by the variant-specific genotype should help to predict clinical responses to ALK inhibitors’, we believe that additional and more comprehensive data are needed to consider ALK rearrangement variants as potential predictive biomarkers of ALK-TKI efficacy.