A retrospective study of alectinib versus ceritinib in patients with advanced non-small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed

Abstract

Background: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking.

Methods: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy.

Results: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib.

Conclusion: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Keywords: ALK; Alectinib; CNS; Ceritinib; Crizotinib; NSCLC; Treatment failure.

Fig. 1

(a) PFS between alectinib and ceritinb treatment groups (b) PFS between the treatment groups in terms of crizotinib treatment failure patterns

Fig. 2

PFS between alectinib and ceritinb in (a) subgroup of patients of crizotinib treatment failure due to intolerance (17 patients received alectinib and 8 patients received ceritinib in which 4 and 6 events were observed, respectively) and in (b) subgroup of patients of crizotinib treatment failure due to resistance (26 patients received alectinib and 14 patients received ceritinib in which 16 and 11 events were observed, respectively)

Fig. 3

a The relationship between PFS of crizotinib and subsequent alectinib/ceritinib in patients who underwent drug resistance in the two lines of treatment. b Cumulative incidence of systemic progression (black) and CNS progression (red) between the alectinib (solid line) and ceritinib (broken line) treatment