OBJECTIVES: Since approval of the first ALK inhibitor (ALKi) crizotinib in 2011, patients with ALK-positive NSCLC have demonstrated improved outcomes compared with chemotherapy. Second-generation (2^nd-gen) ALKis were subsequently approved, allowing the possibility of sequencing these agents to extend patient benefit and improve outcomes. Our objective was to conduct an SLR describing the evidence base of sequencing ALKis and associated outcomes.

METHODS: An SLR was conducted in PubMed, Embase, and Cochrane through July 17, 2017; conference abstracts (3 meetings, past 2 years) were also searched. The search was limited to English-language studies of humans with no date limit, and included terms for disease, treatment, study type, and outcomes of interest. Titles and abstracts were reviewed according to predefined inclusion/exclusion criteria by two independent researchers. Data extraction included study design, patient characteristics, line/sequence of therapy, and outcomes, including median overall survival (mOS).

RESULTS: Of 504 unique articles/abstracts, 82 met inclusion criteria; 48 clinical trials (CTs), and 34 observational studies (obs-studies). Fifteen studies (5 CTs, 10 obs-studies) described results of a 2^nd-gen ALKi after initial crizotinib, and 1 obs-study described results of a 2^nd-gen ALKi after an initial 2^nd-gen ALKi. In studies of a 2^nd-gen ALKi after initial crizotinib, 1 study reported mOS as 48.6 months from initiation of crizotinib; mOS from diagnosis of advanced NSCLC ranged from 49.4-89.6 months. Median OS ranged from 15.5-22.7 months with a single ALKi. Studies were heterogeneous in terms of study design, data source, sample size, observation timeframe, and outcomes collected.

CONCLUSIONS: Subsequent use of ALKis may clinically benefit patients progressing on an initial ALKi. Crizotinib-led sequences have a broader evidence base and more mature clinical outcomes than 2^nd-gen-led sequences. No evidence was found directly comparing different ALKi sequences. It is important to characterize the evidence that is available on various ALKi sequences.