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Small molecular kinase inhibitors play a key role in modern cancer therapy. Protein kinases are essential mediators in the growth and progression of cancerous tumors, rendering involved kinases an increasingly important target for therapy. However, kinase inhibitors are almost insoluble in water because of their hydrophobic aromatic nature, often lowering their availability and pharmacological efficacy. Direct drug functionalization with polar groups represents a simple strategy to improve the drug solubility, availability, and performance. Here, we present a strategy to functionalize secondary amines with oligoethylene glycol (OEG) phosphate using a one‐pot synthesis in three exemplary kinase inhibiting drugs Ceritinib, Crizotinib, and Palbociclib. These OEG‐prodrug conjugates demonstrate superior solubility in water compared to the native drugs, with the solubility increasing up to 190‐fold. The kinase inhibition potential is only slightly decreased for the conjugates compared to the native drugs. We further show pH dependent hydrolysis of the OEG‐prodrugs which releases the native drug. We observe a slow release at pH 3, while the conjugates remain stable over 96 h under physiological conditions (pH 7.4). Using confocal microscopy, we verify improved cell uptake of the drug‐OEG conjugates into the cytoplasm of HeLa cells, further supporting our universal solubility approach. [ABSTRACT FROM AUTHOR]

The development of a quantitative in-line UV spectroscopic method for monitoring of solute concentration during the crystallization process of the active pharmaceutical ingredient (API), ceritinib is described. The method is based on artificial neural networks (ANN). A seeded cooling crystallization process of ceritinib from tetrahydrofuran was studied as a model system. The model was constructed from collected ATR-UV spectra and temperature records within the metastable zone. The collected spectra were preprocessed with the first derivative using the Savitzky-Golay filter. ANN models with different architectures were created and the optimal architecture was chosen based on the root mean square error of prediction (RMSEP) criterion. In addition, ANN models were compared with the models obtained by the linear partial least squares regression (PLSR). Due to the nonlinear relationship in the data set, ANN models predict the solution concentration with higher accuracy compared to linear models. The developed models were successfully used in real-time solution concentration measurement during ceritinib crystallization along with a supersaturation control module developed in-house. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumor (IMT) is an intermediate malignant neoplasm, and approximately 50% of patients are anaplastic lymphoma kinase positive (ALK+). Given this unique trait, ALK tyrosine kinase inhibitors (TKIs), initially developed for ALK+ nonsmall cell lung carcinoma, were expected to be effective. Subsequently, crizotinib, a first-generation ALK-TKI, was approved by the U. S. Food and Drug Administration, and other generations of ALK-TKIs have since been tested for their efficacy. In this study, we report a case of unresectable IMT who showed a partial response to ceritinib, a second-generation ALK-TKI, allowing conversion surgery to be performed. Furthermore, the patient was found to have a rare ALK translocation, sequestosome 1 (5)-ALK (20), detected by next-generation sequencing. In conclusion, this case presents real-world evidence to establish the role of ceritinib as a first-line treatment for ALK+ IMT, which can contribute to further studies on ALK+ IMT.

IntroductionIn patients with NSCLC harboring oncogenic ALK or ROS1 rearrangements, tyrosine kinase inhibitors have yielded high response rates and improvements in progression-free survival compared with cytotoxic chemotherapy; however, acquired resistance eventually develops. In preclinical models, ALK and MEK coinhibition was able to overcome ALK inhibitor resistance.MethodsA phase 1 study of the ALK/ROS1 inhibitor ceritinib and the MEK inhibitor trametinib in patients with refractory NSCLC harboring ALK or ROS1 fusions was initiated. A three plus three dose-escalation scheme was used. Two dose levels were investigated. The primary end point was to determine the safety and tolerability of the combination.ResultsNine patients (n = 8 ALK+, n = 1 ROS1+) were enrolled in the study and completed at least one cycle of therapy. The most common adverse events (all grades) were diarrhea (n = 9; 100%), rash (n = 8; 89%), abdominal pain (n = 5; 56%), and elevated aspartate transaminase/alanine transaminase level (n = 4; 44%). The overall response rate was 22%, whereas disease control rate was 56%. Median duration of response was 7.85 months. The median progression-free survival was 3.0 months (95% confidence interval: 1.5-7.0 mo). The median overall survival was 8.9 months (95% confidence interval: 2.0-not reached).ConclusionsData from this trial indicate that the combination of ceritinib and trametinib had no unexpected toxicities and that a tolerable dose could be identified. A subset of patients seemed to obtain clinical benefit from this treatment after progression on prior ALK/ROS1 inhibitor treatment.ClinicalTrials.gov Identifier: NCT03087448.

The development of a quantitative in-line UV spectroscopic method for monitoring of solute concentration during the crystallization process of the active pharmaceutical ingredient (API), ceritinib is described. The method is based on artificial neural networks (ANN). A seeded cooling crystallization process of ceritinib from tetrahydrofuran was studied as a model system. The model was constructed from collected ATR-UV spectra and temperature records within the metastable zone. The collected spectra were preprocessed with the first derivative using the Savitzky-Golay filter. ANN models with different architectures were created and the optimal architecture was chosen based on the root mean square error of prediction (RMSEP) criterion. In addition, ANN models were compared with the models obtained by the linear partial least squares regression (PLSR). Due to the nonlinear relationship in the data set, ANN models predict the solution concentration with higher accuracy compared to linear models. The developed models were successfully used in real-time solution concentration measurement during ceritinib crystallization along with a supersaturation control module developed in-house.

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. [ABSTRACT FROM AUTHOR]

Opinion statement: Inflammatory myofibroblastic tumor (IMT), characterized by intermediate malignancy and a propensity for recurrence, has presented a formidable clinical challenge in diagnosis and treatment. Its pathological characteristics may resemble other neoplasms or reactive lesions, and the treatment was limited, taking chemotherapies as the only option for those inoperable. However, discovering anaplastic lymphoma kinase (ALK) protein expression in approximately 50% of IMT cases has shed light on a new diagnostic approach and application of targeted therapies. With the previous success of combating ALK+ non-small-cell lung cancers with ALK tyrosine kinase inhibitors (TKIs), crizotinib, a first-generation ALK-TKI, was officially approved by the U.S. Food and Drug Administration in 2020, to treat unresectable ALK+ IMT. After the approval of crizotinib, other ALK-TKIs, such as ceritinib, alectinib, brigatinib, and lorlatinib, have proven their efficacy on ALK+ IMT with sporadic case reports. The sequential treatments of targeted therapies in may provide the insight into the choice of ALK-TKIs in different lines of treatment for unresectable ALK+ IMT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alexandria TM Lee,1 Saihong Ignatius Ou1,2 1University of California Irvine School of Medicine, Department of Medicine, Orange, CA, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, USACorrespondence: Saihong Ignatius Ou, University of California Irvine School of Medicine, Department of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, 200 South Manchester, Suite 400, Orange, CA, 92868, USA, Email siou@hs.uci.eduAbstract: 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). In addition, three randomized phase 3 trials in the crizotinib-refractory setting were also conducted by next-generation ALK TKIs that were developed earlier before the superiority of next-generation ALK TKIs was demonstrated in order to secure the approval of these ALK TKIs in the crizotinib-refractory setting. These three crizotinib-refractory randomized trials were: ASCEND-5 (ceritinib), ALUR (alectinib), and ALTA-3 (brigatinib). The outcome of the ATLA-3 trial was recently presented closing out the chapter where next-generation ALK TKIs were investigated in the crizotinib-refractory setting as they have replaced crizotinib as the standard of care first-line treatment of advanced ALK+ NSCLC. This editorial summarizes the results of next-generation ALK TKIs in randomized crizotinib-refractory trials and provides a perspective on how natural history of ALK+ NSCLC may potentially be altered with sequential treatment. ALTA-3 compared brigatinib to alectinib, showing that both achieved near identical blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (19.2– 19.3 months). Importantly, 4.8% of brigatinib-treated patients developed interstitial lung disease (ILD) while no alectinib-treated patients developed ILD. Dose reduction and discontinuation due to treatment-related adverse events were 21% and 5%, respectively, for brigatinib-treated patients compared to 11% and 2%, respectively, for alectinib-treated patients. Upon analysis of these findings, we speculate that brigatinib may have a diminishing role in the treatment of advanced ALK+ NSCLC.Keywords: ALTA-3, ALUR, ASCEND-5, brigatinib, alectinib, ceritinib, crizotinib, advanced ALK+ NSCLC

Ceritinib is an anti-cancer of drug used in treatment of non-small cell lung cancer. A high-performance thin layer chromatography (HPTLC) method has been developed for ceritinib, which is stability indicating and simple, precise, and discriminating. The stationary phase used was aluminum-backed silica gel60 F254 plates with chloroform: methanol: glacial acetic acid as the mobile phase in the ratio of 8.5:1.5:0.5 (V/V/V). The retention factor was found to be 0.34 ± 0.02. The densitometric scanning was performed at 277 nm. The linear range for analysis was 100-600 ng band-1, which gave good linear relationship with regression coefficient of 0.998. Method accuracy was proved by the recovery studies. The detection limit and quantification limit were 7.38 and 10.03 ng band-1, respectively. Stress degradation studies like hydrolysis under different pH conditions, photolytic, thermal, and oxidative degradation were carried out as per ICH Q1A (R2) and Q1B guidelines. The method established was found to be robust, and thus it can be used as a stability-indicating method. [ABSTRACT FROM AUTHOR]

The possibility of spherical agglomeration was investigated for two active pharmaceutical ingredients from different classes of the Biopharmaceutics Classification System. The effects of different batch crystallization solvent systems on the granulometric properties and structures of dronedarone hydrochloride and ceritinib were investigated. Light and stereomicroscopy were used to determine the size and shape of the agglomerates, while X‐ray powder diffraction was applied to assess the changes in polymorphic form. Since the change in the solvent system had no effect on the crystal structure but did alter the size and shape of the crystals, dissolution experiments were carried out to determine drug release profiles. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in approximately 3–5% of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement (ALK–TKIs) have shown significant efficacy and improved the survival of patients with NSCLC exhibiting ALK rearrangement. However, almost all patients exhibit disease progression during TKI therapy owing to resistance acquired through various molecular mechanisms, including both ALK-dependent and ALK-independent. Here, we review the mechanisms underlying resistance to second-generation ALK–TKIs, and the clinical management strategies following resistance in patients with ALK rearrangement-positive NSCLC. Treatment strategies following the failure of second-generation ALK–TKIs failure should be based on resistant mechanisms. For patients with ALK mutations who exhibit resistance to second-generation ALK–TKIs, lorlatinib is the primary treatment option. However, the identification of resistance profiles of second-generation ALK–TKIs can aid in the selection of an appropriate treatment strategy. In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK–TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy could be the alternative treatment options. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. The co-amorphous materials exhibited physical stability for up to 4 months under dry conditions (40 °C). Further, co-amorphous materials maintained the supersaturation for 24 hrs and improved solubility as well as dissolution of CRT. CRT:RTH 1:1 CAMs improved the permeability of CRT by 2 fold, estimated by employing the everted gut sac method. The solubility advantage of CAMs was also reflected in pharmacokinetic parameters, with a 3.1-fold and 2-fold improvement of CRT:RTH 2:1 in CRT exposure (AUC 0-t) and plasma concentration (Cmax) compared to the physical mixture, respectively. [ABSTRACT FROM AUTHOR]

Abstract Background Alectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking. Case presentation. We report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2–3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake. Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome. Conclusions Close monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.

In the present study, the first electrochemical investigation of ceritinib, which is a small-molecule tyrosine kinase inhibitor used as a new generation targeted anticancer drug, was described. For this purpose, a commercially available boron-doped diamond electrode pretreated cathodically was used. Using cyclic voltammetry, ceritinib presented two pairs of oxidation/reduction peaks in aqueous solution. The electrode process is controlled by a mixed diffusion and adsorption mechanism. The effects of pH and nature of the supporting electrolyte in the absence and the presence of anionic surfactant, sodium dodecylsulfate (SDS), pre-concentration variables and other instrumental parameters were demonstrated on the current response of ceritinib. It was observed that the addition of 8 × 10−4 mol L−1 SDS to the ceritinib solution prepared in 0.1 mol L−1 HNO3 improved the sensitivity of the stripping voltammetric measurements. By applying square-wave adsorptive stripping voltammetry (after 30 s pre-concentration at open-circuit condition), the calibration curves were linear for both oxidation peaks, Ia (at ~ + 0.99 V) and IIa (at ~ + 1.20 V) in the concentration range from 0.075 to 2.0 µg mL−1 (1.34 × 10−7–3.58 × 10−6 mol L−1), with detection limits of 0.014 µg mL−1 (2.50 × 10−8 mol L−1) for Ia, and 0.011 µg mL−1 (1.97 × 10−8 mol L−1) for IIa. The applicability of the developed methodology using the electrochemical signal IIa was verified by analysis of commercial capsule formulations and model human urine samples. [ABSTRACT FROM AUTHOR]

Abstract Background Anaplastic lymphoma kinase (ALK) fusion is a prognostic indicator for patients with non‐small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitors (TKIs). The real‐world data of ALK TKIs remain a major concern. Methods Patients with ALK‐positive advanced NSCLC, who received crizotinib or alectinib treatment in first line, were retrospectively reviewed. ALK status was detected using immunohistochemistry (IHC) or next‐generation sequencing (NGS). Clinical outcomes have been comprehensively analyzed between TKIs, ALK fusions, EML4‐ALK variants, and next‐generation TKIs after crizotinib failure. Results One hundred sixty‐eight patients were successively enrolled (crizotinib, n = 109; alctinib, n = 59). Alectinib showed consistent superiority in progressive‐free survival (PFS) over crizotinib (hazard ratio [HR]: 0.43, 95% confidential interval [CI]: 0.24–0.77, p = 0.004). Multivariate Cox regression showed chemotherapy (CT) prior to TKIs or synchronous chemotherapy seemed not to improve PFS compared to ALK inhibitors alone (p > 0.05). And, alectinib was superior to crizotinib in prolonging intracranial PFS (HR 0.12, 95% CI: 0.03–0.49, p = 0.003). Patients in EML4 group had a better prognosis than those in non‐EML4 group after alectinib administration (HR 0.13, 95% CI: 0.03–0.60, p = 0.009). TP53 co‐mutations were relatively common (34.0%) and associated with adverse outcome in ALK‐positive patients (adjusted HR 2.22, 95% CI: 1.00–4.92, p = 0.049). After crizotinib failure, 33 patients received a sequential application of next‐generation ALK TKIs. Compared to ceritinib and brigatinib, alectinib might have better PFS (p = 0.043). Conclusion Our results revealed alectinib had better PFS and higher intracranial efficacy compared to crizotinib in ALK‐positive NSCLC, and might improve PFS by comparison with ceritinib and brigatinib after crizotinib failure.

Key points Ceritinib showed fierce lethality to the planktonic and persistent S. aureus. Ceritinib were highly effective in MRSA biofilm eradication and inhibition. The bactericidal mechanisms of ceritinib were showed by membrane breaking and ROS activation.

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. [ABSTRACT FROM AUTHOR]

Keywords: anaplastic lymphoma kinase (ALK); brigatinib; ceritinib; crizotinib; photosensitivity EN anaplastic lymphoma kinase (ALK) brigatinib ceritinib crizotinib photosensitivity 285 290 6 05/11/23 20230501 NES 230501 To the Editor, The U.S. Food and Drug Administration (FDA) has approved five anaplastic lymphoma kinase (ALK) inhibitors (i.e., crizotinib, ceritinib, alectinib, brigatinib, lorlatinib) since 2011 to treat ALK-positive, metastatic non-small cell lung cancer. 6 e Patient concomitant medications were not considered to be contributing confounders as photosensitivity improved/resolved upon interruption of ALK inhibitor and worsened/recurred upon resumption of ALK inhibitor (positive rechallenge), while other drug(s) labeled for photosensitivity were continued throughout clinical course. [Extracted from the article]