P84.23 The Safety and Toxicities of ALK -TKIs in ALK-Positive NSCLC: A Systematic Review and Pool Analysis

Abstract

The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) including crizotinib, alectinib, ceritinib and brigatinib are available for the first-line treatment of patients with positive non-small cell lung cancer (NSCLC) and show a promising response. Selecting a treatment with acceptable toxicities and has a lower influence on the quality of life of the patient is essential. However, the analysis of the toxicity and safety profiles among different first line ALK TKIs is lacking. We performed a systemetic review to evaluate the safety and tolerability profiles of the first-line ALK inhibitors according to ALK -TKI type. We extracted the data from prospective clinical trials searched in database and conducted a pooled analysis of severe AEs according to the type of ALK-TKIs. All statistical analyses were performed with the SPSS software. A total of 21 studies including 3418 patients were considered eligible for analysis. The frequencies of treatment-related death and AEs due to treatment withdrawn were 0.7% (24/3418) and 7.8 % (258/3308), respectively. The frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib, alectinib and brigatinib. One of the most common adverse events (AEs) observed with ALK inhibitors were gastrointestinal (GI) toxicities, such as nausea,vomiting and diarrhea. The frenquency of GI toxicities grade ≥ 3 in ceritinib group is significantly higher than in crizotinib group (5.6% vs. 1.2%, OR 4.825, 95% CI 2.907–8.008, P < 0.001) alectinib cohort (5.6% vs. 0.3%, OR 22.148, 95% CI 3.038–161.462, P < 0.001) and brigatinib group (5.6% vs 0.7%, OR 8.129, 95% CI 1.956–33.782, P=0.001). Hepatotoxicity of grade≥3 was significantly more frequent in patients treated with ceritinib, occured up to 24.1%(24.1% vs. 3.7%, OR 0.122, 95% CI 0.07–0.21, P < 0.001; 24.1% vs. 1.4%, OR 21.70, 95% CI 7.98–59.05, P < 0.001; 24.1% vs. 9.6%, OR 0.34 95% CI 0.27–0.42, P < 0.001). Significant difference of fatigue of grade ≥3 between ceritinib and other TKIs were detected (4.9% vs 0.9% OR 0.176, 95% CI 0.042–0.736, P=0.007; 4.9% vs0.7% OR 7.19, 95% CI 0.978–52.872, P=0.024; 4.9% vs 2.3% OR 0.46, 95% CI 0.29–0.74, P=0.001). It is more frequently in patients treated with crizotinib that occured neutropenia than any other group (12% vs 0.6% OR 21.07, 95% CI 5.2–85.2, P< 0.001; 12% vs1.1% OR 0.08, 95% CI 0.012–0.616, P=0.002; 12% vs 0% OR 1.09, 95% CI 1.08–1.11,P<0.001). Lung toxicity of grade ≥3 occured more often in brigatinib(6.1% vs 0% OR 2.46, 95% CI 2.22–2.71, P< 0.001; 6.1% vs2.8% OR 2.26, 95% CI 1.06–4.83, P=0.031; 6.1% vs 2.6% OR 2.46, 95%CI 1.33-4.54,P=0.003). Attention should be focused on ALK inhibitor-related SAEs although ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Statistically significant differences in some severe AEs among ceritinib, crizotinib alectinib and brigatinib were detected in this pool analysis.