Abstract
BackgroundCrizotinib 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.MethodsSixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy.ResultsForty-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.ConclusionSecond-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.
Highlights
Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion
Second-generation ALK inhibitors produced a favourable efficacy in a cohort of crizotinib-treated ALK-positive advanced NSCLC patients
The efficacy of second-generation ALK inhibitors was higher in patient whose crizotinib treatment failure was due to intolerance than due to resistance
Summary
Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. The therapeutic strategy that targets this oncogenic fusion has greatly improved the prognosis of patients with advanced and metastatic disease, evidenced by an unprecedented 5-year survival rate of approximately 50% in ALK-positive NSCLC patients treated with an ALK inhibitor [3, 4]. The first-generation ALK inhibitor crizotinib was approved by the U.S Food and Drug Administration as a standard of care for advanced ALK-positive NSCLCs in 2011, and in 2014, it was proven to be superior to the platinum-based chemotherapy as the front-line treatment [5]. Crizotinib treatment leads to more adverse effect-related dose reduction and discontinuation than treatment with newer generation ALK inhibitors [7, 8]
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