Search Results (36)

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have become first-line therapies for advanced non-small cell lung cancer (NSCLC) with ALK rearrangements. This study investigates ALK-TKI-associated adverse events (AEs), focusing on identifying hepatotoxicity signals and previously undocumented safety concerns. Using disproportionality analysis of 56,864 reports from the FDA Adverse Event Reporting System (FAERS) database, we systematically classified AEs via the Medical Dictionary for Regulatory Activities (MedDRA). At the System Organ Class (SOC) level, crizotinib exhibited a significantly stronger signal for eye disorders, ceritinib was uniquely linked to gastrointestinal disorders, and loratinib was predominantly associated with metabolism and nutrition disorders. Several AEs previously undocumented in drug labels were identified, including pericardial effusion, elevated C-reactive protein, hemolytic anemia, hemoptysis, and decreased hemoglobin. Furthermore, crizotinib, ceritinib, and alectinib were significantly associated with hepatotoxicity, marked by elevated alanine aminotransferase, aspartate aminotransferase, and hepatic enzyme levels. These findings highlight the need for vigilant monitoring of unlabeled AEs and potential label updates, particularly for hepatotoxicity risks associated with crizotinib, ceritinib, and alectinib. Full article

The formulation process for some drugs can be challenging, due to their unfavorable physical and mechanical properties and poor water solubility. Powder technology has made a significant impact in regard to the modification of the particles in active pharmaceutical ingredients (APIs) to produce high-quality granules. Spherical particles are preferred over other shapes, due to their high tap and bulk density, reduced dustiness, better flowability, strong anti-caking properties, and better mechanical performance during tableting. The present study investigates the possibility of obtaining spherical crystals of ceritinib, a drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer, which belongs to BCS class IV drugs and has a platy crystal shape. Ceritinib spheres were prepared by spherical agglomeration, in a ternary system, and quasi-emulsion solvent diffusion, with the addition of polyvinylpyrrolidone, as well as a combination of these two methods. With the combined method of spherical crystallization, crystals with the most favorable morphology and the narrowest distribution of particle sizes were obtained, which was the reason for further optimization. The influence of different impeller geometries and mixing rates on the morphology of the obtained crystals was examined and the optimal conditions for the process were selected. Using empirical correlations and a visual criterion, the process was scaled up from a 0.1 L to a 1 L batch crystallizer. The obtained crystals were characterized by light and scanning electron microscopy. The addition of a bridging liquid and/or a polymer additive did not change the internal structure of the ceritinib crystals, which was confirmed by X-ray powder diffraction. Full article

Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib’s cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations. Full article

Background and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC). Tracing ALK’s discovery, from its fusion with nucleolar phosphoprotein (NPM)-1 in anaplastic large cell non-Hodgkin’s lymphoma (ALCL) in 1994, the review elucidates the subsequent impact of ALK gene alterations in various malignancies, including inflammatory myofibroblastoma and NSCLC. Approximately 3–5% of NSCLC patients exhibit complex ALK rearrangements, leading to the approval of six ALK-tyrosine kinase inhibitors (TKIs) by 2022, revolutionizing the treatment landscape for advanced metastatic ALK + NSCLC. Notably, second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib. Methods: To ensure comprehensiveness, we extensively reviewed clinical trials on ALK inhibitors for NSCLC by 2023. Additionally, we systematically searched PubMed, prioritizing studies where the terms “ALK” AND “non-small cell lung cancer” AND/OR “NSCLC” featured prominently in the titles. This approach aimed to encompass a spectrum of relevant research studies, ensuring our review incorporates the latest and most pertinent information on innovative and alternative therapeutics for ALK + NSCLC. Key Content and Findings: Beyond exploring the intricate details of ALK structure and signaling, the review explores the convergence of ALK-targeted therapy and immunotherapy, investigating the potential of immune checkpoint inhibitors in ALK-altered NSCLC tumors. Despite encouraging preclinical data, challenges observed in trials assessing combinations such as nivolumab-crizotinib, mainly due to severe hepatic toxicity, emphasize the necessity for cautious exploration of these novel approaches. Additionally, the review explores innovative directions such as ALK molecular diagnostics, ALK vaccines, and biosensors, shedding light on their promising potential within ALK-driven cancers. Conclusions: This comprehensive analysis covers molecular mechanisms, therapeutic strategies, and immune interactions associated with ALK-rearranged NSCLC. As a pivotal resource, the review guides future research and therapeutic interventions in ALK-targeted therapy for NSCLC. Full article

Following the results of the CROWN phase III trial, the third-generation macrocyclic ALK inhibitor lorlatinib has been introduced as a salvage option after the failure of a first-line TKI in ALK-rearranged NSCLC, while its precise role in the therapeutic algorithm of ROS1 positive disease is still to be completely defined. The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood–brain barrier penetration are the reasons for the growing popularity and interest in this molecule. Nevertheless, the major vulnerability of this drug resides in a peculiar profile of related collateral events, with neurological impairment being the most conflicting and debated clinical issue. The cognitive safety concern, the susceptibility to heterogeneous resistance pathways, and the absence of a valid alternative in the second line are strongly jeopardizing a potential paradigm shift in this oncogene-addicted disease. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses. Full article

Raman spectroscopy is a useful tool for polymorphic form-monitoring during the crystallization process. However, its application to solute concentration estimation in two-phase systems like crystallization is rare, as the Raman signal is influenced by various changing factors in the crystallization process. The development of a robust calibration model that covers all variations is complex and represents a major challenge for the implementation of Raman spectroscopy for in-line monitoring and control of the solution crystallization process. This paper describes the development of a Raman-based calibration model for estimating the solute concentration of the active pharmaceutical ingredient ceritinib. Several different calibration approaches were tested, which included both temperature and spectra of clear solutions and slurries/suspensions. It was found that the concentration of the ceritinib solution could not be accurately predicted when suspended crystals were present. To overcome this challenge, the approach was enhanced by including additional variables related to crystal size and solid concentration obtained via in-line process microscopy (chord-length distribution percentiles D10, D50 and D90) and turbidity. Partial least squares regression (PLSR) and artificial neural network (ANN) models were developed and compared based on root mean square error (RMSE). ANN models estimated the solute concentration with high accuracy, with the prediction error not exceeding 1% of the nominal solute concentration. Full article

Ceritinib (CER) is a potent drug that has been recently approved by the Food and Drug Administration for the treatment of patients with non-small cell lung cancer harboring the anaplastic lymphoma kinase mutation gene. The existing methods for the quality control of CER are very limited and suffer from limited analytical throughput and do not meet the requirements of the green analytical principles. This study presented the first-ever development and validation of three innovative green and high-throughput microwell spectrophotometric methods (MW-SPMs) for the quality control of CER in its dosage form (Zykadia^® capsules). These MW-SPMs were based on the formation of colored N-vinylamino-substituted haloquinone derivatives of CER upon its reactions with each of chloranil, bromanil, and 2,3-dichloro-1,4-naphthoquinone in the presence of acetaldehyde. The optimized procedures of the MW-SPMs were established, and their analytical performances were validated according to the ICH. The linear range of the MW-SPMs was 5–150 µg/mL, with limits of quantitation of 5.3–7.6 µg/mL. The accuracy and precision of the MW-SPMs were proved, as the average recovery values were 99.9–101.0%, and the relative standard deviations did not exceed 1.8%. The three methods were applied to the determination of CER content in Zykadia^® capsules and drug content uniformity testing. The greenness of the MW-SPMs was proved using three different metric tools. In addition, these methods encompassed the advantage of high-throughput analysis. In conclusion, the three methods are valuable tools for convenient and reliable application in the pharmaceutical quality control units for CER-containing capsules. Full article

Background and Objectives: Ceritinib (CER) is a potent drug of the third-generation tyrosine kinase inhibitor class. CER has been approved for the treatment of patients with non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase (ALK) mutation gene. In the literature, there is no green and high-throughput analytical method for the quantitation of CER in its dosage form (Zykadia^® capsules). This study describes, for the first time, the development and validation of two novel one-step and green microwell spectrophotometric methods (MW-SPMs) for the high-throughput quantitation of CER in Zykadia^® capsules. Materials and Methods: These two methods were based on an in microwell formation of colored derivatives upon the reaction of CER with two different benzoquinone reagents via two different mechanisms. These reagents were ortho-benzoquinone (OBQ) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and their reactions proceeded via condensation and charge transfer reactions, respectively. The reactions were carried out in 96-well transparent plates, and the absorbances of the colored reaction products were measured with an absorbance microplate reader at 540 and 460 nm for reactions with OBQ and DDQ, respectively. The optimum conditions of reactions were established, their molar ratios were determined, and reaction mechanisms were postulated. Under the refined optimum reaction conditions, procedures of MW-SPMs were established and validated according to the guidelines of the International Council on Harmonization. Results: The limits of quantitation were 6.5 and 10.2 µg/well for methods involving reactions with OBQ and DDQ, respectively. Both methods were applied with great reliability to the determination of CER content in Zykadia^® capsules and their drug uniformity. Greenness of the MW-SPMs was evaluated using three different metric tools, and the results proved that the two methods fulfil the requirements of green analytical approaches. In addition, the simultaneous handling of a large number of samples with microvolumes in the proposed methods gave them the advantage of a high-throughput analysis. Conclusions: The two methods are valuable tools for rapid routine application in pharmaceutical quality control units for the quantitation of CER. Full article

Because of the specific thermodynamic properties of active pharmaceutical ingredients, the process of crystallization often meets implementation challenges in the pharmaceutical industry. Therefore, it is essential to select the appropriate method and system for the crystallization of a drug. Ceritinib, an active ingredient in the treatment of lung cancer, was formed as a result of pH modification during the cooling crystallization of ceritinib dihydrochloride solution. By carrying out processes in various solvent systems, several polymorphs were produced. A combination of forms B and C was generated in the ethanol–water system, resulting in smaller crystals. The acetone–water system produced pure form A, which has larger crystals and is more applicable for forthcoming studies. To additionally enhance granulometric properties, ceritinib form A was recrystallized in tetrahydrofuran at different temperatures using antisolvent crystallization. Crystallization at a higher saturation temperature results in larger and more compact crystals, which enhances filtration and drying. Full article

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. Therefore, the dose was not optimized in some cases and was modified post-marketing (e.g., ceritinib, dasatinib, niraparib, ponatinib, cabazitaxel, and gemtuzumab-ozogamicin). The FDA recognized the drawbacks of this approach and, in 2021, launched Project Optimus, which provides the framework and guidance for dose optimization during the clinical development stages of anticancer agents. Since dose optimization is crucial in clinical development, especially of targeted therapies, it is necessary to identify the role of pharmacological tools such as pharmacogenomics, therapeutic drug monitoring, and pharmacodynamics, which could be integrated into all phases of drug development and support dose optimization, as well as the chances of positive clinical outcomes. Full article

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. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges. Full article

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. Results: Twenty-eight targeted agents were used to treat 80 patients with advanced STS and a known pre-specified genetic alteration. MDM2 inhibitors were the most-studied drug (n = 19), followed by crizotinib (n = 9), ceritinib (n = 8), and ⁹⁰Y-OTSA (n = 8). All patients treated with the MDM2 inhibitor achieved a treatment response of stable disease (SD) or better with a treatment duration of 4 to 83 months. For the remaining drugs, a more mixed response was observed. The evidence is low because most studies were case reports or cohort studies, where only a few STS patients were included. Conclusions: Many targeted agents can precisely target specific genetic alterations in advanced STS. The MDM2 inhibitor has shown promising results. Full article

Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body’s proteins, it leads to various autoimmune disorders. Additionally, when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells. Full article

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. Full article

The 5-year survival rate of non-small-cell lung cancer (NSCLC) is still low (<21%) despite recent improvements. Since conventional therapies have a lot of side effects, combined therapy is strongly recommended. Here, we report a patient with advanced NSCLC who received combined therapy, including ceritinib, photobiomodulation (PBM), ACGL (Antrodia cinnamomea (A. cinnamomea), and Ganoderma lucidum (G. lucidum)). Based on combined therapy, suitable doses of A. cinnamomea, G. lucidum, and PBM are important for tumor inhibition. This case report presents clinical evidence on the efficacy of combined therapy in advanced NSCLC patients, including computed tomography (CT) scan, magnetic resonance imaging (MRI), carcinoembryonic antigen (CEA), and blood tests. The effective inhibition of human lung adenocarcinoma cells is demonstrated. Our case highlights important considerations for PBM and ACGL applications in NSCLC patients, the side effects of ceritinib, and long-term health maintenance. Full article