According to results of an exploratory analysis, 50% of patients with ALK gene fusionpositive advanced non-small cell lung cancer (NSCLC) also characterized by 1 or more ALK resistance mutations to crizotinib responded to treatment with alectinib.1

Although alectinib, a small-molecule tyrosine kinase inhibitor, is currently approved by the US Food and Drug Administration (FDA) for the treatment of all patients with metastatic ALK-positive NSCLC,2  its initial FDA approval in 2015 was based on the results of 2 single-arm phase 2 clinical trials showing benefit in adult patients with ALK gene fusion-positive advanced NSCLC who had experienced disease progression on crizotinib.  

In this study, next-generation sequencing was performed on available specimens of circulating tumor cell-free DNA (ctDNA) collected from patients enrolled in those 2 studies following progression on crizotinib but prior to treatment with alectinib (187 individuals) and postprogression on alectinib (48 individuals).

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Of the 187 patients in the former group, single-nucleotide variants in ALK were detected in 48 patients (25.7%). The baseline characteristics were similar, including central nervous system lesions of those with and without point mutations in ALK, with exceptions including race and performance status. Compared with the subgroup without ALK mutations, there were higher percentages of patients in the ALK mutation subgroup of Asian race (33.3% vs 17.3%), and a performance status of 1 or higher (81.3% vs 64.1%).

Notably, 34 different ALK point mutations were identified in the ALK mutation subgroup, with specimens from 35% and 67% characterized by more than 1 ALK mutation and a known ALK resistance mutation to crizotinib, respectively.

Half of the patients with disease characterized by a known ALK resistance mutation to crizotinib (32 individuals), achieved an investigator-assessed partial response to alectinib.

Median investigator-assessed progression-free survival (PFS) was shorter in the ALK-mutation subgroup compared with the subgroup without an ALK mutation (5.6 months vs 10.3 months, respectively), and the objective response rates to alectinib for the ALK mutation vs no ALK mutation subgroups were 48% and 55%, respectively, when assessed by the investigator, and were 35% and 45%, respectively, when assessed by an independent review committee.

Corresponding disease-control rates were 85% and 89% (investigator-assessed) and 83% and 85% (independent review) for those in the ALK mutation and no ALK mutation subgroups, respectively.

Regarding the 49 patients from whom ctDNA specimens were collected following disease progression on alectinib, 16 distinct ALK mutations, including those known to be associated with alectinib resistance (eg, G1202R), were identified in 47% of patients, with no ALK mutations observed in the remaining 53%.

ALK mutations appearing during treatment with alectinib included I1171N and I1171S, G1202R, G1269A, and L1196M.

Limitations of this analysis identified by the study authors included the absence of comparator arms from the 2 studies, as well the lack of matched tumor specimens.

In their concluding remarks, the study authors noted that “further research is needed to determine non-ALK mediated mechanisms of resistance.”

Disclosure: Some of the authors of the featured study disclosed financial relationships with pharmaceutical and medical device companies. For a full list of disclosures, please refer to the original study.

References

  1. Noé J, Lovejoy A, Ou S-H I, et al. ALK mutation status before and after alectinib treatment in locally advanced or metastatjc ALK-positive NSCLC: Pooled analysis of two prospective trials [published online November 8, 2019] J Thorac Oncol. doi: 10.1016/j.jtho.2019.10.015
  2. Alectinib (Alecensa®) [package insert]. South San Francisco, CA: Genentech, Inc.; 2018.