Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis

Abstract

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.

Keywords: ALK rearrangement; acquired resistance; brain metastasis; network meta-analysis.

Figure 1

Mechanisms of ALK translocation cancer progression. EML4-ALK translation triggers the initiation of the PI3K-AKT, RAS, and JAK/STAT signaling cascades that influence tumor growth, proliferation, and viability. ERK, extracellular signal-regulated kinase EML4-ALK, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase; PI3K, phosphatidylinositol-3 kinase; mTOR, STAT, signal transducer and activator of transcription. ALK, anaplastic lymphoma kinase; mammalian target of rapamycin; JAK, Janus kinase; MEK, mitogen-activated extracellular signal regulated kinase; RAS, reticular activating system.

Figure 2

Different pharmacological activities of (a) alectinib and (b) lorlatinib toward ALK fusion proteins with resistance mutations. (a) Resistance mutations (e.g., G1202R) prevent alectinib from combining with the ATP-binding domain of the ALK fusion protein. (b) Lorlatinib successfully associated with the ALK fusion protein’s ATP-binding pocket with resistance mutations, and downstream signals associated with tumor progression are downregulated; ATP, adenosine triphosphate; RM, resistance mutation; ALK, anaplastic lymphoma kinase.

Figure 3

Process diagram of the research selection.

Figure 4

Network map of the seven therapeutic groups: ensartinib, lorlatinib, brigatinib, alectinib, ceritinib, crizotinib, and chemotherapy. In this network map randomized controlled trials (RCTs) were represented by a solid line, with the breadth of the solid line correlated with the numbers of studies included. Broken lines represent no head-to-head RCTs and trial to comparison of treatments. n is the total number of patients in each group; Ensa, ensartinib; Lorl, lorlatinib; Brig, brigatinib; Alec, alectinib; Criz, crizotinib; Ceri, ceritinib; Chem, chemotherapy.

Figure 5

Comparison of the efficacies of chemotherapy, first-generation ALK inhibitors (crizotinib), second-generation ALK inhibitors (ceritinib, alectinib, brigatinib, and ensartinib), and third-generation ALK inhibitors (lorlatinib) in prolonging the PFS of (a) overall patients with ALK-p, ALK inhibitor-naive advanced NSCLC and (b) a subgroup of patients with CNS metastases. Data are expressed as hazard ratios (HRs) and 95% credible intervals (CrIs); ALK, anaplastic lymphoma kinase; ALK-p, anaplastic lymphoma kinase rearrangement positive; NSCLC, non-small cell lung cancer; CNS, central nervous system.