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PURPOSE: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. METHODS: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. RESULTS: The WERA matrix overlooked an active screening area of 821 postal code areas - representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity - with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog - characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. CONCLUSIONS: The WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.
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Acessibilidade aos Serviços de Saúde , Oncologia , Neoplasias , Medicina de Precisão , Humanos , Alemanha , Acessibilidade aos Serviços de Saúde/organização & administração , Neoplasias/terapia , Oncologia/organização & administração , Institutos de Câncer/organização & administração , População RuralRESUMO
Research into bispecific antibodies, which are designed to simultaneously bind two antigens or epitopes, has advanced enormously over the past two decades. Owing to advances in protein engineering technologies and considerable preclinical research efforts, bispecific antibodies are constantly being developed and optimized to improve their efficacy and to mitigate toxicity. To date, >200 of these agents, the majority of which are bispecific immune cell engagers, are in either preclinical or clinical evaluation. In this Review, we discuss the role of bispecific antibodies in patients with cancer, including history and development, as well as innovative targeting strategies, clinical applications, and adverse events. We also discuss novel alternative bispecific antibody constructs, such as those targeting two antigens expressed by tumour cells or cells located in the tumour microenvironment. Finally, we consider future research directions in this rapidly evolving field, including innovative antibody engineering strategies, which might enable more effective delivery, overcome resistance, and thus optimize clinical outcomes.
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Anticorpos Biespecíficos , Neoplasias , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Engenharia de Proteínas/métodosRESUMO
BACKGROUND: NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-ß). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors. METHODS: Patients received NIS793 (0.3-1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3-30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20-30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). RESULTS: Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-ß/NIS793 complexes and depleted active TGF-ß in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-ß target genes and signatures and increased immune signatures. CONCLUSIONS: In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-ß pathway inhibition. TRIAL REGISTRATION NUMBER: NCT02947165.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Renais , Neoplasias Pulmonares , Adulto , Humanos , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Fator de Crescimento Transformador betaRESUMO
Volumetric absorptive microsampling (VAMS) has emerged as a minimally invasive alternative to conventional sampling. However, the applicability of VAMS must be investigated clinically. Therefore, the feasibility of at-home sampling was investigated for the kinase inhibitors nilotinib, cabozantinib, dabrafenib, trametinib and ruxolitinib and evaluated regarding the acceptance of at-home microsampling, sample quality of at-home VAMS and incurred sample stability. In addition, clinical validation including three different approaches for serum level predictions was performed. For this purpose, VAMS and reference serum samples were collected simultaneously. Conversion of VAMS to serum concentration was based either on a linear regression model, a hematocrit-dependent formula, or using a correction factor. During the study period 591 VAMS were collected from a total of 59 patients. The percentage of patients who agreed to perform VAMS at home ranged from 50.0 % to 84.6 % depending on the compound. 93.1 % of at-home VAMS were collected correctly. Regarding the drug stability in dried capillary blood, no stability issues were detected between on-site and at-home VAMS. Linear regression showed a strong correlation between VAMS and reference serum concentrations for nilotinib, cabozantinib, dabrafenib and ruxolitinib (r 0.9427 - 0.9674) and a moderate correlation for trametinib (r 0.5811). For clinical validation, the acceptance criteria were met for all three approaches for three of the five kinase inhibitors. Predictive performance was not improved by using individual hematocrit instead of population hematocrit and was largely independent of conversion model. In conclusion, VAMS at-home has been shown to be feasible for use in routine clinical care and serum values could be predicted based on the measured VAMS concentration for nilotinib, cabozantinib, and dabrafenib.
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Coleta de Amostras Sanguíneas , Teste em Amostras de Sangue Seco , Humanos , Estudos de ViabilidadeAssuntos
Radioisótopos do Iodo , Proteínas Proto-Oncogênicas c-ret , Pirazóis , Piridinas , Neoplasias da Glândula Tireoide , Humanos , Radioisótopos do Iodo/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots-regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.
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OBJECTIVE: Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a highly selective and sensitive method for the quantification of kinase inhibitors, yet not widely available in clinical routine for therapeutic drug monitoring (TDM). To provide a more accessible alternative, a high-performance liquid chromatography method with ultraviolet/diode array detection (HPLC-UV/DAD) to quantify cabozantinib, dabrafenib, nilotinib and osimertinib, was developed and validated. Results were compared to LC-MS/MS. METHOD: After liquid-liquid-extraction and reconstitution of the residue in 20 mM potassium dihydrogen phosphate (KH2PO4) (pH4.6), acetonitrile and methanol (50:25:25,v/v/v), chromatographic separation was achieved in 20.0 min using a Luna® C18(2)-HST column (100 × 2 mm, 2.5 µm), protected by a C18 guard column (4 × 2 mm) (column temperature: 30 °C, autosampler: 10 °C). Mobile phase A and B consisted of 20 mM KH2PO4 (pH4.9) and acetonitrile (9:1,v/v) and acetonitrile:20 mM KH2PO4 (pH4.9) (7:3,v/v), respectively. Gradient elution was performed at 200 µL/min. Analytes were quantified at 250, 280 and 330 nm, using sorafenib as internal standard. RESULTS: Calibration curves were linear (35-2,000 ng/mL). Method validation assays met requirements by U.S. Food and Drug Administration and European Medicines Agency. Compared to the more sensitive and specific LC-MS/MS, HPLC-UV/DAD showed a good correlation and a strong positive association (Kendall's tau 0.811¬-0.963, p < 0.05). Bland-Altman-plots revealed 100% (cabozantinib), 98.6% (dabrafenib), 98.6% (nilotinib) and 96.2% (osimertinib) of relative differences inside the limits of agreement. Regulatory agency criteria for sample reanalysis and cross validation were met (±20%-criterion:100% (cabozantinib), 94.3% (dabrafenib), 92% (nilotinib) and 84.6% (osimertinib). CONCLUSION: The developed HPLC-UV/DAD method is "fit-for-TDM" in clinical routine and serves as a genuine alternative to LC-MS/MS.
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Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Acetonitrilas , Acrilamidas , Anilidas , Compostos de Anilina , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Humanos , Imidazóis , Indóis , Oximas , Piridinas , Pirimidinas , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
Personalized dosing of kinase inhibitors (KI) might be beneficial in oral anti-cancer therapy to overcome individual pharmacokinetic variability. Volumetric absorptive microsampling (VAMS) has emerged as an attractive alternative compared to conventional invasive sampling methods enabling remote and frequent specimen collection. Therefore, an LC-MS/MS VAMS method was developed and validated to monitor drug exposure of ten KI from 20 µL dried capillary blood. The assay includes the KI cabozantinib, dabrafenib, nilotinib, and osimertinib with a calibration range of 6-1500 ng/mL and afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib and trametinib within a range of 2-500 ng/mL. Using acetonitrile containing isotope labelled internal standards (IS) as solid-liquid extraction solvent, analytes and IS were detected by multiple reaction monitoring (MRM) after electro-spray ionization (ESI) in positive ionization mode after chromatographic separation using a phenyl-hexyl column. The method was validated according to the FDA and EMA guidelines for bioanalytical method validation and in accordance with the guideline of the International Association for Therapeutic Drug Monitoring and Clinical Toxicology for dried blood spot-based methods. The calibration model was linear and reproducible for all KI (R2> 0.994). Furthermore, the validation demonstrated that the VAMS method is accurate, precise, and sensitive. The method fulfilled the acceptance criteria for matrix effects, recovery, carry over, selectivity as well as for the haematocrit effect and all substances proved to be stable in dried condition for at least six weeks at room temperature. In vitro experiments using spiked venous blood were conducted to establish a VAMS-to-plasma conversion factor for each analyte for comparison of VAMS and plasma concentrations. The method was successfully used in a real-life setting demonstrating its applicability in clinical routine. VAMS concentrations of afatinib, cabozantinib, dabrafenib, nilotinib, ruxolitinib and trametinib were assessed in capillary blood samples collected from either trained healthcare professionals or patients at home.
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Coleta de Amostras Sanguíneas , Espectrometria de Massas em Tandem , Coleta de Amostras Sanguíneas/métodos , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos/métodos , Humanos , Espectrometria de Massas em Tandem/métodosRESUMO
Blinatumomab is a first-in-class immunotherapy based on the bispecific T-cell engager (BiTE®) immune-oncology platform, which redirects CD3+ T cells to kill CD19+ target cells. The objective of this analysis was to describe the correlation between B- and T-cell kinetics and response to blinatumomab in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL). The clinical efficacy of treatment with blinatumomab in patients with r/r NHL was recently investigated in a phase 1 dose-escalation and expansion trial (NCT00274742) wherein 76 patients received blinatumomab by continuous intravenous infusion at various doses (0.5-90 µg/m2/day). B-Cell depletion and expansion of CD3+, CD4+, and CD8+ T cells was analyzed in patients stratified per clinical response (complete response [CR], n = 16; partial response [PR], stable disease [SD], or progressive disease [PD], n = 54) for at least 4 weeks (additional 4 weeks after clinical benefit) from the date of administration of blinatumomab until dose-limiting toxicity or PD. B-cell depletion kinetics were faster in patients who had a CR than in patients who did not have a complete response (PR, SD, or PD). T-cell expansion (T-cell counts exceeding the baseline level on day 22) was more pronounced in patients with CR than in patients without CR. T-cell expansion in patients with CR correlated with increased T-cell counts of both CD4+ and CD8+ T cells compared with patients without CR. Patients with r/r NHL who achieved a CR had faster B-cell depletion and increased expansion of CD3+, CD4+, and CD8+ T cells than patients who did not achieve a CR.
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Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfoma não Hodgkin/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos B/imunologia , Humanos , Linfoma não Hodgkin/imunologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Linfócitos T/imunologia , Resultado do TratamentoRESUMO
B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.
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Antígeno de Maturação de Linfócitos B/genética , Deleção de Genes , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Idoso , Antígenos de Neoplasias/metabolismo , Variações do Número de Cópias de DNA/genética , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Mieloma Múltiplo/diagnóstico por imagemRESUMO
Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE®) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 µg/d; cIV: n = 16, 5-80 µg/d). The SC maximum tolerated dose was 172.0 µg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov).
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Anticorpos Biespecíficos , Antineoplásicos Imunológicos , Neoplasias de Próstata Resistentes à Castração , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/uso terapêutico , Antígenos de Superfície/imunologia , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Complexo CD3/imunologia , Glutamato Carboxipeptidase II/imunologia , Imunoterapia , Infusões Intravenosas , Injeções Subcutâneas , Dose Máxima Tolerável , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Resultado do TratamentoRESUMO
Immuno-oncology approaches have entered clinical practice, with tremendous progress particularly in the field of T cell-engaging therapies over the past decade. Herein, we provide an overview of the current status of bispecific T cell engager (BiTE) therapy, considering the unprecedented new indication for such therapy in combating minimal (or measurable) residual disease in patients with acute lymphoblastic leukaemia, and the development of novel approaches based on this concept. Key aspects that we discuss include the current clinical data, challenges relating to treatment administration and patient monitoring, toxicities and resistance to treatment, and novel strategies to overcome these hurdles as well as to broaden the indications for BiTE therapy, particularly to common solid cancers. Elucidation of mechanisms of resistance and immune escape and new technologies used in drug development pave the way for new and more-effective therapies and rational combinatorial approaches. In particular, we highlight novel therapeutic agents, such as bifunctional checkpoint-inhibitory T cell engagers (CiTEs), simultaneous multiple interaction T cell engagers (SMITEs), trispecific killer engagers (TriKEs) and BiTE-expressing chimeric antigen receptor (CAR) T cells (CART.BiTE cells), designed to integrate various immune functions into one molecule or a single cellular vector and thereby enhance efficacy without compromising safety. We also discuss the targeting of intracellular tumour-associated epitopes using bispecific constructs with T cell receptor (TCR)-derived, rather than an antibody-based, antigen-recognition domains, termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs), which might broaden the armamentarium of T cell-engaging therapies.
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Imunoterapia Adotiva , Imunoterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Anticorpos Biespecíficos/imunologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/imunologiaRESUMO
Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell-independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell-dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro, and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. SIGNIFICANCE: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.
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Anticorpos Biespecíficos/efeitos adversos , Adesão Celular/efeitos dos fármacos , Células Endoteliais/imunologia , Síndromes Neurotóxicas/imunologia , Linfócitos T/imunologia , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Encéfalo/patologia , Adesão Celular/imunologia , Linhagem Celular , Criança , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Feminino , Humanos , Incidência , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/imunologia , Masculino , Microvasos/citologia , Microvasos/imunologia , Microvasos/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
Blinatumomab, the first-in-class CD3/CD19 bispecific T-cell engager antibody construct, has recently been approved for treating patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia. However, the clinical proof of concept of blinatumomab efficacy was initially demonstrated in patients with R/R B-cell non-Hodgkin lymphoma (B-NHL) in the MT103-104 phase 1 dose-escalation and expansion trial (NCT00274742), which defined 60 µg/m2 per day as the maximum tolerated dose (MTD). The clinically most relevant adverse effects were neurologic symptoms and cytokine release syndrome. Currently, there are no data on long-term outcomes and toxicity for B-NHL patients receiving blinatumomab treatment, so we performed a single-center, long-term follow-up analysis of 38 patients who participated in the MT103-104 phase 1 trial. We found no evidence for long-term toxicities, especially no blinatumomab-induced neurocognitive impairments. For the entire study population, the median overall survival (OS) was 4.6 years. Remarkably, patients who had received ≥60 µg/m2 per day and responded to blinatumomab achieved a median OS of 7.7 years. Of note, 6 of the surviving patients treated at the MTD have been treatment-free for more than 7 years. In contrast, patients who were treated at dose levels below the MTD had a median OS of only 1.1 years. These results indicate that 60 µg/m2 per day seems to represent the targeted dose level of blinatumomab required for durable remission in R/R B-NHL. Here, we provide the first clinical evidence that blinatumomab lacks long-term toxicity and has the potential to induce sustained remissions in patients with R/R B-NHL.
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Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/mortalidade , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Retratamento , Resultado do TratamentoRESUMO
BACKGROUND: Increasing knowledge of cancer genomes has triggered the development of specific targeted inhibitors, thus providing a valuable therapeutic pool. METHODS: In this report, the authors analyze the presence of targetable alterations in 136 tumor samples from 92 patients with melanoma using a comprehensive approach based on targeted DNA sequencing and supported by RNA and protein analysis. Three topics of high clinical relevance are addressed: the identification of rare, activating alterations; the detection of patient-specific, co-occurring single nucleotide variants (SNVs) and copy number variations (CNVs) in parallel pathways; and the presence of cancer-relevant germline mutations. RESULTS: The analysis of patient-matched blood and tumor samples was done with a custom-designed gene panel that was enriched for genes from clinically targetable pathways. To detect alterations with high therapeutic relevance for patients with unknown driver mutations, genes that are untypical for melanoma also were included. Among all patients, CNVs were identified in one-third of samples and contained amplifications of druggable kinases, such as CDK4, ERBB2, and KIT. Considering SNVs and CNVs, 60% of patients with metastases exhibited co-occurring activations of at least 2 pathways, thus providing a rationale for individualized combination therapies. Unexpectedly, 9% of patients carry potentially protumorigenic germline mutations frequently affecting receptor tyrosine kinases. Remarkably two-thirds of BRAF/NRAS wild-type melanomas harbor activating mutations or CNVs in receptor tyrosine kinases. CONCLUSIONS: The results indicate that the integrated analysis of SNVs, CNVs, and germline mutations reveals new druggable targets for combination tumor therapy.
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Biomarcadores Tumorais/genética , GTP Fosfo-Hidrolases/genética , Regulação Neoplásica da Expressão Gênica , Melanoma/patologia , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/patologia , Estudos de Casos e Controles , Quinase 4 Dependente de Ciclina/genética , Variações do Número de Cópias de DNA , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Melanoma/genética , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor ErbB-2/genética , Neoplasias Cutâneas/genéticaRESUMO
OBJECTIVES: Domatinostat (4SC-202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. METHODS: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1-14 with 7 days off or continuously days 1-21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty-four patients were treated with domatinostat. RESULTS: No formal maximum tolerated dose (MTD) was determined. One dose-limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment-related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. CONCLUSION: Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.
Assuntos
Benzamidas/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Feminino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidade , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.
Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Suspensão de Tratamento/estatística & dados numéricos , Idoso , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. RESULTS: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression () was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.5 (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (≤4.5; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). CONCLUSION: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation.