Ceritinib

In light of the cocrystal structure of ceritinib with anaplastic lymphoma kinase (ALK)WT protein, a series of novel 2,4-diarylaminopyrimidine analogs (L1-L25) bearing a typical piperidinyl-4-ol moiety were designed and synthesized with improved biological and physicochemical properties. Satisfyingly, most compounds demonstrated moderate to excellent antitumor effects with IC50 values below 5 μM on ALK-positive Karpas299 and H2228 cells. In particular, L6 bearing the 1-(6-methoxy-pyridin-2-yl)-4-(morpholinomethyl)piperidinyl-4-ol moiety was detected as the optimal compound against ALK-dependent cell lines of Karpas299 (0...

OBJECTIVE: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making. MATERIALS AND METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework. RESULTS: Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included...

PURPOSE: Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase ( ALK ), deemed to be an oncogenic driver in NB. ALK inhibitors (ALKis), therefore, have the potential to be of therapeutic benefit. The purpose of this study is to report on their use in AON...

BACKGROUND: Interstitial lung disease (ILD) is a rare but life-threatening and fatal treatment-related pneumonitis. This study investigated the association between anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) and ILD. RESEARCH DESIGN AND METHODS: Cases of ILD that developed after treatment with an ALK-TKI in the Food and Drug Administration' s Adverse Event Reporting System (FAERS) data were assessed. We also described the clinical features of these cases and evaluated onset time, hospitalization, life-threatening condition, and fatality rate of ILD developed after treatment with an ALK-TKI...

In this study, we used molecular simulations to design Ceritinib (CRT) co-amorphous materials (CAMs) with concurrent improvement in solubility and bioavailability. Computational modeling enabled us to select the co-former by estimating the binding energy and intermolecular interactions. Rutin (RTH) was selected as a co-former for CRT CAMs using the solvent evaporation method to anticipate simultaneous improvement of solubility and bioavailability. The solid state characterization using DSC, XRPD, FT-IR, and a significant shift in Gordon Taylor experimental Tg values of co-amorphous materials revealed single amorphous phase formation and intermolecular interactions between CRT and RTH...

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As a second-generation selective oral anaplastic lymphoma kinase inhibitor, ceritinib is an effective first-line treatment for c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC). Its efficacy and safety for the treatment of crizotinib-resistant ROS1-rearranged NSCLC were explored in the study. A retrospective single-center study was conducted to investigate the efficacy of ceritinib in crizotinib-resistant ROS1-rearranged NSCLC. The objective response rate was the primary objective, while the disease control rate, progression-free survival and adverse events were secondary objectives...

Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS)...

Emerging evidence suggests that genetically highly specific triple-negative breast cancer (TNBC) possesses a relatively uniform transcriptional program that is abnormally dependent on cyclin-dependent kinase 7 (CDK7). In this study, we obtained an inhibitor of CDK7, N76-1, by attaching the side chain of the covalent CDK7 inhibitor THZ1 to the core of the anaplastic lymphoma kinase inhibitor ceritinib. This study aimed to elucidate the role and underlying mechanism of N76-1 in TNBC and evaluate its potential value as an anti-TNBC drug...

The competing roles of various next-generation ALK TKIs in the first and second line treatment setting of advanced ALK+ NSCLC were based on many phase 3 clinical trials in both the first-line and crizotinib-refractory settings. The approval of all next-generation ALK TKIs was first in the crizotinib-refractory setting, based on a large-scale Phase 2 trial, and was then followed by at least one global randomized phase 3 trial comparing to platinum-based chemotherapy (ASCEND-4) or to crizotinib (ALEX, ALTA-1L, eXalt3, CROWN)...

Drugs' safety and effectiveness are evaluated in randomized, dose-ranging trials in most therapeutic areas. However, this is only sometimes feasible in oncology, and dose-ranging studies are mainly limited to Phase 1 clinical trials. Moreover, although new treatment modalities (e.g., small molecule targeted therapies, biologics, and antibody-drug conjugates) present different characteristics compared to cytotoxic agents (e.g., target saturation limits, wider therapeutic index, fewer off-target side effects), in most cases, the design of Phase 1 studies and the dose selection is still based on the Maximum Tolerated Dose (MTD) approach used for the development of cytotoxic agents...

OBJECTIVE: To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK-positive non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK-positive NSCLC. METHODS: The effectiveness of ALKis was evaluated by assessing progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety...

Lung cancer is one of the most lethal malignancies in the world, with non-small cell lung cancer (NSCLC) accounting for approximately 80%-85% of all pathological types. Approximately 30%-55% of NSCLC patients develop brain metastases. It has been reported that 5%-6% of patients with brain metastases harbor anaplastic lymphoma kinase (ALK) fusion. ALK-positive NSCLC patients have shown significant therapeutic benefits after treatment with ALK inhibitors. Over the past decade, ALK inhibitors have rapidly evolved and now exist in three generations: first-generation drugs such as Crizotinib; second-generation drugs including Alectinib, Brigatinib, Ceritinib, and Ensartinib; and third-generation drugs like Lorlatinib...

AIM: To compare the efficacy and safety of alectinib with other ALK inhibitors in treating patients with metastatic or locally advanced ALK -positive NSCLC. METHODS: A systematic literature review was conducted up to November 2021. Network meta-analyses were performed using the frequentist method (random effects). GRADE evidence profile was conducted. RESULTS: 13 RCTs were selected. For overall survival, alectinib was found to reduce the risk of death compared with crizotinib...

BACKGROUND: The anaplastic lymphoma kinase (ALK) inhibitor treatment landscape is rapidly evolving, providing patients with ALK-positive (+) non-small cell lung cancer (NSCLC) with multiple therapy options, multiple lines of treatments, and prolonged survival. However, these recent treatment advances have resulted in additional increases in treatment costs. The objective of this article is to review the economic evidence of ALK inhibitors in patients with ALK+ NSCLC. METHODS: The systematic review was conducted in accordance with the Joanna Briggs Institute (JBI) systematic reviews of economic evaluation...

Background : Soft-tissue sarcoma (STS) is a heterogeneous group of sarcomas with a low incidence. The treatment of advanced disease is poor, and mortality is high. We aimed to generate an overview of the clinical experiences with targeted treatments based on a pre-specified target in patients with STS. Methods : A systematic literature search was conducted in PubMed and Embase databases. The programs ENDNOTE and COVIDENCE were used for data management. The literature was screened to assess the article's eligibility for inclusion...

ALK translocation amounts to around 3-7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management...

Anaplastic lymphoma kinase (ALK) rearrangements occur in ∼3%-6% of patients with advanced non-small-cell lung cancer (NSCLC). Small molecular drugs that effectively inhibit ALK gene have revolutionized the therapeutic paradigm for patients with ALK rearrangements, resulting in significant improvements in objective response rate, progression-free survival, and overall survival compared with classical platinum-based chemotherapy. Several ALK tyrosine kinase inhibitors (ALK-TKIs), including crizotinib, alectinib, ceritinib, brigatinib, ensartinib, and lorlatinib, have been recommended as standard first-line treatment for advanced NSCLC patients with ALK rearrangements...

BACKGROUND AND OBJECTIVE: Lung cancer is the most fatal malignant tumor in the world. Since the discovery of driver genes, targeted therapy has been demonstrated to be superior to traditional chemotherapy and has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The remarkable success of tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor ( EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) fusions has shifted the treatment from platinum-based combination chemotherapy to targeted therapy...

BACKGROUND: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are mainly used in the treatment of ALK-positive advanced non-small cell lung cancer (NSCLC), but a comprehensive clinical evaluation of ALK-TKIs is lacking. Hence, a comparison of ALK-TKIs for first-line treatment of ALK-positive advanced NSCLC is essential to provide rational drug use and a basis for improving national policies and systems. METHODS: According to the Guideline for the Administration of Clinical Comprehensive Evaluation of Drugs (2021) and the Technical Guideline for the Clinical Comprehensive Evaluation of Antitumor Drugs (2022), a comprehensive clinical evaluation index system of first-line treatment drugs for ALK-positive advanced NSCLC was established by literature review and expert interviews...