The efficacy and safety of ALK inhibitors in the treatment of ALK‐positive non‐small cell lung cancer: A network meta‐analysis

Abstract

PurposeThe current study was carried out to compare the effectiveness and safety of different ALK inhibitors in treating ALK+ NSCLC.MethodsProgression‐free survival (PFS), disease control rate (DCR), overall response rate (ORR), and intracranial ORR and DCR have been aggregated to appraise the effectiveness of each ALKi. The discontinuation rate due to adverse events (AEs) was pooled to evaluate their safety. Bayesian network meta‐analyses were used to compare the ORR, DCR, PFS, and discontinuation rate of patients treated with alectinib, ceritinib, crizotinib, and chemotherapy.ResultsCompared with chemotherapy, ALK inhibitors significantly prolonged PFS [hazard ratio (HR) and 95% confidence interval (CI): alectinib, 0.50 (0.43‐0.58); ceritinib, 0.75 (0.69‐0.83); crizotinib, 0.71 (0.66‐0.76)]. The ORRs were significantly higher for ALK inhibitors than for chemotherapy [odds ratio (OR) and corresponding 95% CI: alectinib, 11.69 (4.29‐36.56); ceritinib, 7.85 (3.44‐19.27); crizotinib, 6.04 (3.33‐11.71)]. The discontinuation rates were lower for ALK inhibitors than for chemotherapy [OR and corresponding 95% CI: alectinib, 0.42 (0.12‐1.36); ceritinib, 0.52 (0.20‐1.35); crizotinib, 0.70 (0.30‐1.62)].Conclusions ALK+ NSCLC patients treated with ALKi tend to have longer PFS than those treated with chemotherapy. ALKi‐naïve patients tended to response better than their ALKi‐pretreated counterparts. Alectinib appeared to be preferable for treating brain metastases due to its high intracranial efficacy. Patients treated with alectinib or ceritinib tended to have higher ORR and DCR than patients with similar baselines treated with crizotinib or chemotherapy. No significant differences in discontinuation rate were found for alectinib, ceritinib, crizotinib, and chemotherapy.

Comparative Efficacy of Targeted Therapies in Patients with Non-Small Cell Lung Cancer: A Network Meta-Analysis of Clinical Trials

“…Also, a recent network meta-analysis of ALK inhibitors showed consistent findings among treatments in both ORR and PFS outcomes [23]. In Fan et al's study, a remarkable improvement in ORR was shown: the ORs (95%CI) for crizotinib, ceritinib, and alextinib were 11.69 (4.29-36.56), 7.85 (3.44-19.27), and 6.04 (3.33-11.71), compared to chemotherapy, respectively [23]. The superior efficacy of alectinib in PFS might be associated with the resistance to crizotinib among ALK-positive NSCLC patients, which reduces therapeutic response to crizotinib [24,25].…”

“…In a large medical chart review of 1471 participants with ALK-positive NSCLC among a total of 27,375 recorded subjects from seven countries, crizotinib showed a significant improvement in complete response (odds ratio (OR) = 2.65, 95% CI = 1.69-4.15) and reduction of recurrence/progression (odds ratio = 0.38, 95% CI = 0.24-0.59) compared to controls [22]. Also, a recent network meta-analysis of ALK inhibitors showed consistent findings among treatments in both ORR and PFS outcomes [23]. In Fan et al's study, a remarkable improvement in ORR was shown: the ORs (95%CI) for crizotinib, ceritinib, and alextinib were 11.69 (4.29-36.56), 7.85 (3.44-19.27), and 6.04 (3.33-11.71), compared to chemotherapy, respectively [23].…”

Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme

“…A cell-based method using the P450-Glo CYP3A4 Assay and Screening System with Luciferin-IPA together with the CellTiter-Glo Luminescent Cell Viability Assay was used to measure CYP3A4 inhibition in intact HepG2-CYP3A4 cells [27]. HepG2-CYP3A4 cells were seeded on a transparent 96-well plate at a density of 8.0 × 10 4 cells/well and cultured for 24 h. The cells were then washed once with 1× PBS and treated with Opti-MEM solutions of ensartinib (5,10,15, and 25 µM) or a model inhibitor (10 µM ketoconazole). After a 10 min pre-incubation under standard conditions, the CYP3A4 substrate luciferin-IPA was quickly added to all cells other than background samples at a final concentration of 2 µM and the plates were then incubated for 45 min at room temperature.…”

“…Ensartinib (X-396) is a third-generation TKI (Figure 1) that is a potent inhibitor of mutated anaplastic lymphoma kinase (ALK); deregulation of this enzyme has been found to be a meaningful target in 3-7% of all NSCLC cases [3]. Ensartinib is currently undergoing phase II and III clinical trials for the treatment of NSCLC [4]; preclinical investigations have shown that it is more active than the approved ALK inhibitors crizotinib, alectinib, and ceritinib and that it retains activity even in models with ALK mutations that confer resistance to these agents [5]. During treatment, many patients develop drug resistance and initially sensitive tumor cells stop responding to the applied drugs.…”

Efficacy of Crizotinib, Ceritinib, and Alectinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Meta-Analysis of Clinical Trials

“…Since the initial development of ALK inhibitors, subsequent clinical trials on the efficacy of the ALK inhibitors have been published [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Several systematic reviews and meta-analyses have also been reported [30][31][32][33]. However, Fan J et al mainly investigated the efficacy and safety of alectinib, although they reported the findings of ORR and DCR for alectinhib in the ALK inhibitor-naïve or crizotinib-resistant patients [31].…”