RESUMO
Background: Capmatinib, a potent and selective MET tyrosine kinase inhibitor (TKI), holds promise as a therapeutic agent due to its potentially elevated intracranial efficacy in metastatic non-small cell lung cancer (NSCLC) patients harboring exon 14 skipping alterations in MET (MET Proto-Oncogene). This study aims to evaluate a targeted therapeutic approach to an MET exon 14 skipping (METex14) advanced NSCLC patient that progressed on Crizotinib and developed off target resistance alteration in PIK3CA. Case Discription: We present a case of advanced METex14 NSCLC patient wherein central nervous system (CNS) relapse occurred post complete surgical resection and remission of the lung tumor under first-line crizotinib treatment. Subsequent disease monitoring demonstrated a profound intracranial response to capmatinib in a crizotinib-resistant brain lesion. Molecular analysis unveiled the original METex14 D1028N driver mutation and a newly arisen PIK3CA bypass mutation, potentially contributing to off-target resistance. Conclusions: Before capmatinib was approved as a first line treatment option for metastatic NSCLC harboring somatic METex14 mutations, crizotinib conferred a potential option for targeted treatment. Switching to a selective MET-TKI like capmatinib with a better CNS penetration, it appears to be a promising approach for CNS metastasized NSCLC patients with METex14 mutations that failed on crizotinib. Further research is needed to more effectively understand and monitor resistance mechanisms using advanced diagnostic techniques such as DNA-based hybrid-capture (HC) next generation sequencing (NGS) to guide molecularly stratified therapy beyond the first line setting.
RESUMO
Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).
RESUMO
With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed in multiple cancer types. MET amplification and MET exon 14 skipping mutations induce protein autophosphorylation; however, the pathogenic mechanism and drug sensitivity of MET fusion remain unclear. The following report describes the clinical case of a patient diagnosed with squamous lung cancer bearing a TFG-MET gene fusion. In vitro assays demonstrated MET phosphorylation and oncogenic capacity due to the TFG-MET rearrangement, both of which were inhibited by crizotinib treatment. The patient was treated with crizotinib, which resulted in sustained partial remission for more than 17 months. Collectively, cellular analyses and our case report emphasize the potential of MET fusion as a predictive biomarker for personalized target therapy for solid tumors.
RESUMO
Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced NSCLC, respectively. Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: In the avelumab plus lorlatinib group (ALK-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (ALK-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses). Conclusions: Avelumab plus lorlatinib treatment in ALK-positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group. ClinicalTrialsgov identifier: NCT02584634.
RESUMO
BACKGROUND: Brigatinib is a next-generation tyrosine kinase inhibitor (TKI) targeting ALK and ROS1. The Barossa study is a multicenter, phase II basket study of brigatinib in patients with ROS1-rearranged solid tumors. ROS1 TKI-naive patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) were enrolled in cohort 1, and ROS1-rearranged NSCLC patients treated previously with crizotinib were enrolled in cohort 2. Patients with ROS1-rearranged solid tumors other than NSCLC were enrolled in cohort 3. PATIENTS AND METHODS: Eligible patients received brigatinib at the dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary endpoint was the objective response rate (RECIST 1.1) assessed by independent central review in cohorts 1 and 2. RESULTS: Between July 2019 and June 2021, 51 patients were enrolled into the study. Of the 51, 47 patients had ROS1-rearranged NSCLC; 28 and 19 of these patients were enrolled in cohort 1 and cohort 2, respectively. The remaining four patients had other ROS1-rearranged solid tumors, including rectal, brain, and pancreas tumor in one patient each, and primary unknown tumor in one patient. The confirmed objective response rate was 71.4% [95% confidence interval (CI) 51.3% to 86.8%] in cohort 1 (TKI-naive NSCLC patients) and 31.6% (95% CI 12.6% to 56.6%) in cohort 2 (NSCLC patients treated previously with crizotinib). The median progression-free survival was 12.0 months (95% CI 5.5-22.9 months) in cohort 1 and 7.3 months (95% CI 1.3-17.5 months) in cohort 2. None of the patients in cohort 3 showed any treatment response. Pneumonitis was observed in 9.8% of all the patients. CONCLUSIONS: Brigatinib was effective in TKI-naive patients with ROS1-rearranged NSCLC. The safety profile of brigatinib was consistent with that reported from previous studies.
RESUMO
Crizotinib (CRZ), one of anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), has emerged as a frontline treatment for ALK-positive (ALK+) lung adenocarcinoma. However, the overexpression of P-glycoprotein (P-gp, a mitochondrial adenosine triphosphate (ATP)-dependent protein) in lung adenocarcinoma lesions causes multidrug resistance (MDR) and limits the efficacy of CRZ treatment. Herein, a mitochondria-targeting nanosystem, zeolitic imidazolate framework-90@indocyanine green (ZIF-90@ICG), was fabricated to intervene in mitochondria and overcome drug resistance. Due to the zinc ion (Zn2+) interference of ZIF-90 and the photodynamic therapy (PDT) of ICG, this nanosystem is well suited for damaging mitochondrial functions, thus downregulating the intracellular ATP level and inhibiting P-gp expression. In addition, systematic bioinformatics analysis revealed the upregulation of CD44 in CRZ-resistant cells. Therefore, hyaluronic acid (HA, a critical target ligand of CD44) was further modified on the surface of ZIF-90@ICG for active targeting. Overall, this ZIF-90@ICG nanosystem synergistically increased the intracellular accumulation of CRZ and reversed CRZ resistance to enhance its anticancer effect, which provides guidance for nanomedicine design to accurately target tumours and induce mitochondrial damage and represents a viable regimen for improving the prognosis of patients with ALK-TKIs resistance. STATEMENT OF SIGNIFICANCE: The original aim of our research was to combat multidrug resistance (MDR) in highly aggressive and lethal lymphoma kinase-positive (ALK+) lung adenocarcinoma. For this purpose, a cascade-targeted system was designed to overcome MDR, integrating lung adenocarcinoma-targeted hyaluronic acid (HA), mitochondrion-targeted zeolitic imidazolate framework-90 (ZIF-90), the clinically approved drug crizotinib (CRZ), and the fluorescence imaging agent/photosensitizer indocyanine green (ICG). Moreover, using a "two birds with one stone" strategy, ion interference and oxidative stress induced by ZIF-90 and photodynamic therapy (PDT), respectively, disrupt mitochondrial homeostasis, thus downregulating adenosine triphosphate (ATP) levels, inhibiting MDR-relevant P-glycoprotein (P-gp) expression and suppressing tumour metastasis. Overall, this research represents an attempt to implement the concept of MDR reversal and realize the trade-offs between MDR and therapeutic effectiveness.
RESUMO
BACKGROUND: The predictive value of programmed death-ligand 1 (PD-L1) expression for the efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) remains underexplored. This study analyzed patients with advanced NSCLC harboring ROS1 rearrangements who received first-line crizotinib to evaluate the correlation between baseline PD-L1 expression and crizotinib efficacy. METHODS: In this study, the clinical data from 371 patients diagnosed with ROS1-rearranged NSCLC at Shanghai Chest Hospital between November 2017 and December 2022 were reviewed. The patients were categorized into three groups according to the baseline PD-L1 expression: tumor proportion score (TPS) <1%, TPS 1 %-49 %, and TPS≥50 %. The objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) following first-line crizotinib treatment were measured. RESULTS: A total of 64 patients were included in the analysis, with 16 patients in the TPS<1% group, 22 in the TPS 1 %-49 % group, and 26 in the TPS≥50 % group. The overall DCR was 100 %, and the overall ORR was 76.5 %. The ORRs were 81.2 % (13/16) in the TPS<1% group, 63.6 % (14/22) in the TPS 1 %-49 % group, and 84.6 % (22/26) in the TPS≥50 % group (p = 0.218). The median PFS across all patients was 20.21 months (95 % CI: 15.71-24.71), with a median PFS of 28.96 months (95 % CI: 19.87-38.04) in the TPS<1% group, 17.56 months (95 % CI: 12.25-22.86) in the TPS 1 %-49 % group, and 25.85 months (95 % CI: 18.52-33.17) in the TPS≥50 % group (p = 0.100). The median PFS for patients with CD74 fusion was 18.23 months (95 % CI: 15.24-21.22), while those with non-CD74 fusion exhibited a PFS of 16.49 months (95 % CI: 9.75-23.23) (p = 0.359). CONCLUSION: Patients with advanced ROS1-rearranged NSCLC were found to benefit from first-line crizotinib treatment, irrespective of baseline PD-L1 expression.
Assuntos
Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Rearranjo Gênico , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Humanos , Crizotinibe/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Proteínas Proto-Oncogênicas/genética , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proteínas Tirosina Quinases/genética , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , PrognósticoRESUMO
Perumal Kalaiyarasi JayachandranAnaplastic large cell lymphoma (ALCL) is the second most common type of peripheral T cell lymphoma and an aggressive mature T cell lymphoma. About 50 to 70% of systemic ALCLs are anaplastic lymphoma kinase positive (ALK +), the proportion even higher in the pediatric population. The 5-year survival after chemotherapy is around 70 to 80%. But there is a subgroup of ALK+ ALCL patients who are refractory to chemotherapy. Brentuximab vedotin is an approved agent for such patients. The activity of ALK inhibitors in ALK+ non-small cell lung cancer is well known and has been approved for use. The efficacy and safety of ALK inhibitors in ALK + ALCL are largely under-reported. Here we have reported our experience in the use of ALK inhibitors in relapsed refractory ALK+ ALCL.
RESUMO
Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.
Assuntos
Quinase do Linfoma Anaplásico , Apoptose , Proliferação de Células , Crizotinibe , Inibidores de Proteínas Quinases , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Crizotinibe/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/patologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Masculino , Feminino , Antineoplásicos/farmacologia , Pessoa de Meia-Idade , Movimento Celular/efeitos dos fármacos , Idoso , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Células Tumorais Cultivadas , Linhagem Celular Tumoral , Proteínas de Ligação a Calmodulina , Proteínas de Membrana , Proteínas do Tecido NervosoRESUMO
Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.
Assuntos
Crizotinibe , Citocromo P-450 CYP3A , Microssomos Hepáticos , Ratos Sprague-Dawley , Tramadol , Animais , Tramadol/farmacologia , Crizotinibe/farmacologia , Ratos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Citocromo P-450 CYP3A/metabolismo , Masculino , Interações Medicamentosas , Humanos , Espectrometria de Massas em Tandem , Família 2 do Citocromo P450/metabolismo , Família 2 do Citocromo P450/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Analgésicos Opioides/farmacologiaRESUMO
Background: MET exon 14 (METex14) skipping mutations are oncogenic drivers observed in approximately 3-4% of non-small cell lung cancers (NSCLC). Several distinct genetic alterations leading to METex14 have been reported but clinical significances of rare mutations are not well defined as well as outcomes of patients upon MET inhibitors (METi). Case presentation: This report presents the case of a patient with metastatic NSCLC harboring an uncommon MET mutational landscape including notably a novel METex14 mutation (R1022L). Dramatic but transient efficacy was observed under crizotinib, due to early occurrence of acquired both on- and off-target mechanisms of resistance such as MET D1246H mutation and wild-type KRAS amplification. Conclusion: Our case provides additional data on MET rare oncogenic variants and their sensitivity to METi. Systematic assessment of post-tyrosine kinase inhibitor tumor sample remains critical to identify on- and off-target mechanisms that may represent therapeutically targetable drivers in resistant patients.
RESUMO
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.
RESUMO
Background: Programmed cell death ligand 1 (PD-L1) is more readily expressed in ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancer (NSCLC) compared to NSCLC cases lacking driver gene mutations. Prior research has established a link between PD-L1 expression and reduced effectiveness of EGFR or ALK inhibitors in EGFR or ALK-positive NSCLC. Nonetheless, the relationship between initial PD-L1 levels and the clinical impact of first-line crizotinib therapy in ROS1-rearranged NSCLC is still uncertain. Methods: From January 2016 to December 2021, a total of 246 patients with ROS1 positive tumors were collected. Out of these, 82 patients with advanced ROS1-rearranged NSCLC, who were treated with crizotinib as their initial therapy, were selected for the study. The study aimed primarily to evaluate the objective response rate (ORR) and progression-free survival (PFS), and secondarily to assess disease control rate (DCR) and overall survival (OS). Results: Of the 82 advanced ROS1-rearranged NSCLC patients, 38 exhibited PD-L1 positivity, subdivided into 11 with high and 27 with low expression levels, while the remaining 44 showed no PD-L1 expression. The ORR for all included patients was 80.5%. No statistically significant variance in ORR was observed among ROS1-rearranged NSCLC patients across differing PD-L1 expression statuses. However, there was a statistically significant difference in DCR between PD-L1 negative group (100%) and high expression group (90.9%) (p=0.04). The median PFS spanned 26.4 months for the PD-L1 negative group, 16.6 for the low expression group, and 13.7 for the high expression group (p=0.001). Additionally, a notable statistical disparity was also observed in median PFS between the PD-L1 negative and positive groups (p=0.02). For the entire study population, the median OS was 53.0 months (95% CI 43.8 - 62.2). In the PD-L1-negative group, the median OS reached 57.2 months, compared to 53.0 months in the PD-L1-positive group, a difference lacking statistical significance (p=0.43). Conclusions: Our results suggest that for ROS1-positive NSCLC patients receiving crizotinib as first-line therapy, PD-L1 expression may serve as a negative prognostic marker for PFS rather than OS.
RESUMO
BACKGROUND: Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT). PROCEDURE: Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365 mg/m2 twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest. RESULTS: The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUCss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate. CONCLUSIONS: No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.
Assuntos
Quinase do Linfoma Anaplásico , Crizotinibe , Inibidores de Proteínas Quinases , Humanos , Crizotinibe/uso terapêutico , Crizotinibe/farmacocinética , Criança , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Feminino , Masculino , Adolescente , Pré-Escolar , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/patologia , Adulto Jovem , LactenteRESUMO
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 pHâ 3, while the conjugates remain stable over 96â h under physiological conditions (pHâ 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.
RESUMO
To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.
Assuntos
Crizotinibe , Citocromo P-450 CYP3A , Interações Medicamentosas , Microssomos Hepáticos , Polimorfismo Genético , Ratos Sprague-Dawley , Crizotinibe/farmacocinética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Animais , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Piridinas/farmacocinética , Pirazóis/farmacocinética , Pirazóis/farmacologiaRESUMO
Background: The c-met proto-oncogene (MET) serves as a significant primary oncogenic driver in non-small cell lung cancer (NSCLC) and has the potential to fuse with other genes, such as KIF5B, although it occurs infrequently. Only a limited number of reported cases have examined the clinical efficacy of crizotinib in patients with KIF5B-MET gene fusion, with no known data regarding acquired resistance to crizotinib and its potential mechanisms. In this report, we present the clinical progression of a female patient diagnosed with NSCLC and harboring a KIF5B-MET gene fusion. Case description: The patient initially exhibited partial response to first-line crizotinib treatment, albeit for a short duration and with limited efficacy. Subsequent disease progression revealed the emergence of a secondary MET mutation, specifically MET Y1230H, leading to acquired resistance to crizotinib. Conclusion: The reporting of this case is imperative for informing clinical practice, given the uncommon occurrence of NSCLC with MET fusion, displaying responsiveness to MET tyrosine kinase inhibitor therapy, as well as the emergence of the secondary Y1230H alteration as a potential resistance mechanism.
RESUMO
BACKGROUND: Crizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta-analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS). METHODS: We searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib. RESULTS: Fourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate). CONCLUSION: The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Proteínas Tirosina Quinases , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas , Crizotinibe/uso terapêutico , Crizotinibe/efeitos adversos , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Proteínas Proto-Oncogênicas/genética , Proteínas Tirosina Quinases/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas de Fusão Oncogênica/genética , Resultado do Tratamento , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Fusão GênicaRESUMO
BACKGROUND: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. METHODS: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. CONCLUSIONS: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. CLINICAL TRIAL INFORMATION: UMIN000031623.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-met , Humanos , Crizotinibe/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Pessoa de Meia-Idade , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Idoso , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Japão , Intervalo Livre de Progressão , Éxons , População do Leste AsiáticoRESUMO
Unecritinib (TQ-B3101) is a selective tyrosine kinase receptor inhibitor. In the study, in vitro metabolic experiments revealed that the hydrolysis of TQ-B3101 was mainly catalyzed by carboxylesterase 2 (CES2), followed by CES1. Next, a sensitive and reliable LC-MS/MS method was established for the simultaneous determination of TQ-B3101 and its metabolite crizotinib in rat plasma. To prevent in vitro hydrolysis of TQ-B3101, sodium fluoride, the CESs inhibitor at a concentration of 2â¯M, was immediately added after whole blood collection. Plasma samples were extracted by acetonitrile-induced protein precipitation method, and chromatographically separated on a Gemini C18 column (50â¯mm × 2.0â¯mm i.d., 5 µm) using gradient elution with a mobile phase of 0.1% formic acid and 5â¯mmol/L ammonium acetate with 0.1% formic acid. The retention times for TQ-B3101 and crizotinib were 2.61 and 2.38â¯min, respectively. The analytes were detected with tandem mass spectrometer by positive electrospray ionization, using the ion transitions at m/z 492.3 â 302.3 for TQ-B3101, m/z 450.3 â 260.3 for crizotinib, and m/z 494.0 â 394.3 for imatinib (internal standard). Method validation was conducted in the linear range of 1.00-800â¯ng/mL for the two analytes. The precision, accuracy and stabilities all met the acceptance criteria. The pharmacokinetic study indicated that TQ-B3101 was rapidly hydrolyzed to crizotinib with the elimination half-life of 1.11â¯h after a single gavage administration of 27â¯mg/kg to Sprague-Dawley rats, and the plasma exposure of TQ-B3101 was only 2.98% of that of crizotinib.