ALK Resistance Mutations May Predict Efficacy of Lorlatinib in NSCLC

Treatment of patients with advanced non-small cell lung cancer (NSCLC) who harbor anaplastic lymphoma kinase (ALK) gene rearrangements is rapidly evolving and includes different ALK-targeting tyrosine kinase inhibitors (TKIs). Currently five ALK TKIs are approved by the FDA, including the first-generation TKI crizotinib, the second-generation TKIs alectinib, brigatinib, and ceritinib, and the third generation lorlatinib. While second-generation ALK TKIs are effective following crizotinib failure, these agents have recently moved into the first-line setting based on favorable efficacy and safety.  Although they are highly effective and may induce long-lasting responses, most patients eventually develop acquired resistance. In a phase II trial, the third-generation ALK- and ROS1- targeting TKI lorlatinib showed activity in ALK-positive patients, including patients with brain metastases, who previously failed on crizotinib and/or second-generation TKIs. Among patients who previously received only crizotinib, the objective response rate (ORR) was 69%, but the ORR was lower (39%) among those who failed two or more TKIs. An analysis of the study, recently published in the Journal of Clinical Oncology, evaluated the potential for ALK resistance mutations to serve as a biomarker for lorlatinib sensitivity in previously treated patients with ALK-mutated NSCLC.

Genotyping of baseline plasma and tumor tissue samples from 189 patients enrolled on this trial revealed detectable ALK resistance mutations in 24% of patients. Among 59 patients who received lorlatinib after crizotinib failure, there was no significant difference in outcomes between patients with ALK resistance mutations and those without these mutations. However, in patients who had previously been treated with at least one second-generation ALK-targeting TKI, lorlatinib was found to be more effective in patients with ALK mutations than in those without these mutations. Patients with ALK mutations had an ORR of 62% and 69% in plasma and tissue respectively, while the ORR for patients without ALK mutations was 32% and 27%. Patients with ALK mutations also had prolonged progression-free survival (PFS) on lorlatinib compared to those without ALK mutations by tumor genotyping (11.0 months vs 5.4 months; HR 0.47), though a similar effect was not observed by plasma genotyping (7.3 months vs 5.5 months; HR 0.81).

The efficacy of lorlatinib in patients with ALK resistance mutations did not vary based on the type of mutation present. The most common ALK mutation detected among the trial population was G1202R/del, which is associated with resistance to both first-generation and second-generation ALK TKIs. In these patients, lorlatinib demonstrated an ORR of 57% and a median PFS of 8.2 months. More than one ALK mutation was detected in approximately a third of patients, which may indicate compound ALK mutations or heterogeneous resistance mechanisms, and may impact efficacy of loraltinib. Indeed, although numbers are small, patients with more than one ALK mutation appear to have lower response to lorlatinib and shorter duration of response.

The authors concluded that, among patients with ALK-positive NSCLC who have been previously treated with at least one second-generation ALK TKI, presence of ALK resistance mutations predicts for increased efficacy of lorlatinib. This new biomarker may help select patients who may benefit from lorlatinib. Furthermore, authors highlighted the importance of additional research of plasma versus tissue genotyping for detection of ALK mutations and other potential biomarkers that may help to optimize sequencing of next-generation ALK inhibitors.

J Clin Oncol. 2019 March 20. [Epub ahead of print.]

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