Abstract
Simple SummaryThe prognosis of non-small cell lung cancer (NSCLC) is poor as more than half of the patients are diagnosed at an advanced stage. The outcomes have greatly improved in the recent two decades due to the introduction of target therapy. Anaplastic lymphoma kinase (ALK) rearrangement is the second most common driver mutation found in lung cancer, and several ALK inhibitors have shown excellent efficacy. However, head-to-head randomized controlled trials of these agents are lacking. We conducted this systematic review and network meta-analysis to indirectly compare the currently available ALK inhibitors. In summary, lorlatinib had the highest probability of the best progression-free survival in first-line treatment of ALK-positive NSCLC, followed by low-dose (300 mg twice daily) alectinib, high-dose (600 mg twice daily) alectinib, brigatinib, ensartinib, and ceritinib. Lorlatinib was associated with the best objective response rate and the highest probability of grade 3–5 adverse effects. Low-dose alectinib had the best safety profile.Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.
Highlights
Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is further classified into major subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma [1,2]
Compared to the first-generation anaplastic lymphoma kinase inhibitors (ALKIs), new-generation ALKIs significantly increased the progression-free survival (PFS) (hazard ratio (HR) = 0.41, 95% confidence interval (CI) = 0.34–0.49) and objective response rate (ORR) but did not lead to a higher incidence of grade 3–5 adverse effect (AE)
The patients who received brigatinib or lorlatinib had a higher risk of grade 3–5 AEs than those who received crizotinib; the patients who received alectinib had a better safety profile
Summary
Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is further classified into major subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma [1,2]. Some targetable driver mutations have been identified, with the most common types being epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, which are in general mutually exclusive. The discovery of these targetable genetic alterations has led to lung cancer treatments ranging from traditional cytotoxic therapy to the era of precision medicine with personalized small molecular inhibitors. Among these genetic driver mutations, as many as 5%–8% of NSCLC patients have ALK rearrangements, and mostly in younger never smokers [9]. ALK–EML4 fusion protein results in overactive signaling with the consequent up-regulation of cell growth, proliferation, survival, and tumor formation [12]
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