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1.
Lancet Oncol ; 25(6): 707-719, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38710187

RESUMO

BACKGROUND: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. METHODS: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. FINDINGS: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. INTERPRETATION: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. FUNDING: AstraZeneca and Daiichi Sankyo.


Assuntos
Imunoconjugados , Mutação , Neoplasias , Receptor ErbB-2 , Trastuzumab , Humanos , Feminino , Trastuzumab/uso terapêutico , Trastuzumab/efeitos adversos , Masculino , Receptor ErbB-2/genética , Pessoa de Meia-Idade , Idoso , Imunoconjugados/uso terapêutico , Imunoconjugados/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Adulto
2.
Gynecol Oncol ; 181: 162-169, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38211393

RESUMO

OBJECTIVE: HER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT. METHODS: Eligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints. RESULTS: Twenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1-4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2-40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4-67.8). Median DoR was 7.6 months (95% CI 5.6-12.3). Median PFS was 5.1 months (95% CI 1.7-7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1). CONCLUSIONS: Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).


Assuntos
Adenocarcinoma , Quinolinas , Neoplasias do Colo do Útero , Humanos , Feminino , Receptor ErbB-2/genética , Resultado do Tratamento , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Quinolinas/efeitos adversos , Diarreia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adenocarcinoma/tratamento farmacológico
3.
BMC Cancer ; 23(1): 182, 2023 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-36814246

RESUMO

BACKGROUND: An increasing number of trials indicate that treatment outcomes in cancer patients with metastatic disease are improved when targeted treatments are matched with druggable genomic alterations in individual patients (pts). An estimated 30-80% of advanced solid tumors harbor actionable genomic alterations. However, the efficacy of personalized cancer treatment is still scarcely investigated in larger, controlled trials due to the low frequency and heterogenous distribution of druggable alterations among different histologic tumor types. Therefore, the overall effect of targeted cancer treatment on clinical outcomes still needs investigation. STUDY DESIGN/METHODS: ProTarget is a national, non-randomized, multi-drug, open-label, pan-cancer phase 2 trial aiming to investigate the anti-tumor activity and toxicity of currently 13 commercially available, EMA-approved targeted therapies outside the labeled indication for treatment of advanced malignant diseases, harboring specific actionable genomic alterations. The trial involves the Danish National Molecular Tumor Board for confirmation of drug-variant matches. Key inclusion criteria include a) measurable disease (RECIST v.1.1), b) ECOG performance status 0-2, and c) an actionable genomic alteration matching one of the study drugs. Key exclusion criteria include a) cancer type within the EMA-approved label of the selected drug, and b) genomic alterations known to confer drug resistance. Initial drug dose, schedule and dose modifications are according to the EMA-approved label. The primary endpoint is objective response or stable disease at 16 weeks. Pts are assigned to cohorts defined by the selected drug, genomic alteration, and tumor histology type. Cohorts are monitored according to a Simon's two-stage-based design. Response is assessed every 8 weeks for the first 24 weeks, then every 12 weeks. The trial is designed similar to the Dutch DRUP and the ASCO TAPUR trials and is a partner in the Nordic Precision Cancer Medicine Trial Network. In ProTarget, serial fresh tumor and liquid biopsies are mandatory and collected for extensive translational research including whole genome sequencing, array analysis, and RNA sequencing. DISCUSSION: The ProTarget trial will identify new predictive biomarkers for targeted treatments and provide new data and essential insights in molecular pathways involved in e.g., resistance mechanisms and thereby potentially evolve and expand the personalized cancer treatment strategy. PROTOCOL VERSION: 16, 09-MAY-2022. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04341181. Secondary Identifying No: ML41742. EudraCT No: 2019-004771-40.


Assuntos
Neoplasias , Humanos , Dinamarca , Genômica , Neoplasias/patologia , Estudos Prospectivos , Resultado do Tratamento
4.
Br J Cancer ; 126(7): 1010-1017, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34903842

RESUMO

BACKGROUND: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy. METHODS: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04. RESULTS: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses. CONCLUSIONS: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition. CLINICAL TRIAL REGISTRATION: NCT03267316.


Assuntos
Antineoplásicos , Neoplasias , Anticorpos Monoclonais/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Proteína Acessória do Receptor de Interleucina-1/uso terapêutico , Dose Máxima Tolerável , Neoplasias/patologia
5.
Acta Oncol ; 61(12): 1499-1506, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36529989

RESUMO

BACKGROUND: This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across KRAS subtypes and in different KRAS subtypes across cancers, and to identify potentially actionable targets and patients who received targeted treatment matched to their genomic profile (GP). MATERIALS AND METHODS: In this descriptive and single-center study, we included 188 patients with solid tumors harboring KRAS mutations in codon 12, 13, 61, 117, or 146, referred to the Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark from mid-2016 to 2020. Genomic co-alterations were detected with whole-exome sequencing, RNA sequencing, SNP array, and mRNA expression array on fresh biopsies. The study is part of the Copenhagen Prospective Personalized Oncology study (NCT02290522). RESULTS: The majority of patients had colorectal cancer (60.1%), non-small cell lung cancer (11.2%), or pancreatic cancer (10.6%). Most tumors were KRAS-mutated in codon 12 or 13 (93.7%) including G12D (27.1%), G12V (26.6%), G12C (11.7%), and G13D (11.2%). A total of 175 different co-alterations were found, most frequently pathogenic APC and TP53 mutations (55.9% and 46.4%, respectively) and high expression of CEACAM5 (73.4%). Different cancers and KRAS subtypes showed different patterns of co-alterations, and 157 tumors (83.5%) had potentially actionable targets with varying evidence of targetability (assessed using ESMO Scale for Clinical Actionability of molecular Targets). Of the 188 patients included in the study, 15 (7.4%) received treatment matched to their GP (e.g., immunotherapy and synthetic lethality drugs), of whom one had objective partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CONCLUSION: Performing extensive genomic analysis in patients with known KRAS-mutated solid tumors may contribute with information to the genomic landscape of cancers and identify targets for immunotherapy or synthetic lethality drugs, but currently appears to have overall limited clinical impact, as few patients received targeted therapy matched to their GP.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Prospectivos , Neoplasias Pulmonares/genética , Mutação , Genômica , Códon
6.
Sociol Health Illn ; 44(2): 345-359, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34993996

RESUMO

This paper addresses selection practices in a Danish phase 1 unit specialised in precision medicine in the field of oncology. Where precision medicine holds the ambition of selecting genetically fit medicine for the patient, we find that precision medicine in the early trial setting is oriented towards selecting clinically and genetically fit patients for available treatment protocols. Investigating how phase 1 oncologists experience and respond to the moral challenges of selecting patients for early clinical trials, we show that inclusion criteria and patient categories are not always transparent to patients. Lack of transparency about inclusion criteria has been interpreted as morally problematic. Yet drawing on social science studies of 'unknowing', we argue that silence and non-transparency in interactions between oncologists and patients are crucial to respect the moral agency of patients at the edge of life and recognise them as belonging to the public of Danish health care. In the discussion, we consider the practice of placing 'unfit' patients on a waiting list for trial participation. Rather than representing an ethical and political problem, we argue, the waiting list can act as a valve enabling oncologists to navigate the scientific and as well as the moral uncertainties in phase 1 oncology.


Assuntos
Oncologia , Princípios Morais , Humanos , Oncologia/métodos , Medicina de Precisão/métodos
7.
Cytotherapy ; 22(4): 204-213, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32201034

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapeutic landscape and our perception of interactions between the immune system and tumor cells. Despite remarkable progress, disease relapse and primary resistance are not uncommon. Understanding the biological processes that tumor-infiltrating lymphocytes (TILs) undergo during ICI, how this affects the tumor microenvironment (TME) and, ultimately, clinical outcome is, therefore, necessary to further improve treatment efficacy. AIM: In the current study, we sought to characterize TILs from patients with metastatic solid tumors undergoing ICI correlating flowcytometric findings with clinical outcome. METHODS: In total, 20 patients with 10 different metastatic solid tumors treated with ICIs targeting programmed-cell death-1 (PD-1)/PD-L1 axis were included in this study. The phenotype of T cells deriving from biopsies obtained prior to treatment initiation and on-treatment was investigaded. Analyses were focused on T cells' degree of differentiation and activity and how they correlate with transcriptomic changes in the TME. RESULTS: Data indicate that patients benefitting from ICIs accumulate CD8+central memory T cells. TILs developed an effector-like phenotype over time, which was also associated with a cytolytic gene signature. In terms of modulation of T-cell responses, we observed that high expression of checkpoint molecules pre-treatment (i.e., PD-1, lymphocyte activation gene-3 [LAG-3], B and T-lymphocyte attenuator [BTLA] and T-cell immunoglobulin and mucin domain containing-3 [TIM-3]) was associated with similar gene signature and correlated to treatment benefit. Increasing expression of LAG-3 and BTLA in the CD8 compartment and their co-expression with PD-1 during treatment were, however, a common feature for patients who failed to respond to ICIs. CONCLUSIONS: Besides identifying immune profiles suggestive of response to ICI, our results provide a more nuanced picture regarding expression of checkpoint molecules that goes beyond T-cell anergy.


Assuntos
Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Fenótipo , Adulto , Idoso , Antígeno B7-H1/antagonistas & inibidores , Biópsia , Linfócitos T CD8-Positivos/imunologia , Feminino , Seguimentos , Humanos , Fatores Imunológicos/farmacologia , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
8.
Acta Oncol ; 56(7): 909-916, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28438067

RESUMO

BACKGROUND: Gene electrotrotransfer describes the use of electric pulses to transfer DNA to cells. Particularly skeletal muscle has potential for systemic secretion of therapeutic proteins. Gene electrotransfer to muscle using the integrin inhibitor plasmid AMEP (Antiangiogenic MEtargidin Peptide) was investigated in a phase I dose escalation study. Primary objective was safety. MATERIAL AND METHODS: Patients with metastatic or locally advanced solid tumors, without further standard treatments available, were treated with once-only gene electrotransfer of plasmid AMEP to the femoral muscle. Safety was monitored by adverse events registration, visual analog scale (VAS) after procedure and magnetic resonance imaging (MRI) of treated muscles. Pharmacokinetics of plasmid AMEP in plasma and urine was determined by quantitative polymerase chain reaction. Response was evaluated by positron emission tomography-computed tomography (PET-CT) scans. RESULTS: Seven patients were enrolled and treated at dose levels from 50 to 250 µg of plasmid AMEP, the study was terminated early due to cessation of plasmid production. Minimal systemic toxicity was observed and only transient mild pain was associated with the delivery of the electric pulses. MRI of the treated muscles revealed discrete intramuscular edema 24 h after treatment. The changes in the muscle tissue resolved within 2 weeks after treatment. Peak concentrations of plasmid AMEP was detected only in plasma within the first 24 hours after injection. Protein AMEP could not be detected, which could be due to the limit of detection. No objective responses were seen. CONCLUSIONS: Gene electrotransfer of plasmid AMEP was found to be safe and tolerable. No objective responses were observed but other DNA drugs may be tested in the future using this procedure.


Assuntos
Proteínas ADAM/genética , Inibidores da Angiogênese/administração & dosagem , Terapia Genética , Integrinas/antagonistas & inibidores , Proteínas de Membrana/genética , Músculo Esquelético/metabolismo , Neoplasias/terapia , Plasmídeos/administração & dosagem , Adulto , Idoso , Inibidores da Angiogênese/farmacocinética , Eletroporação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Plasmídeos/farmacocinética , Prognóstico , Distribuição Tecidual
9.
Ugeskr Laeger ; 186(9)2024 02 26.
Artigo em Dinamarquês | MEDLINE | ID: mdl-38445322

RESUMO

T-cell-based immunotherapy has recently evolved as a treatment option for a number of haematological malignancies and is also being developed in solid tumours. A common side effect of chimeric antigen T-cell therapy (CAR-T) and treatment with T-cell engagers is cytokine release syndrome (CRS), which is a potentially life-threatening condition characterized by release of inflammatory mediators. The treatment of CRS is similar to that of other hyper-inflammatory conditions and involves supportive treatment as well as immunosuppressive therapy. The risk of CRS can be mitigated by step-up dosing and immunosuppressive pre-treatment, as argued in this review.


Assuntos
Antineoplásicos , Receptores de Antígenos Quiméricos , Humanos , Síndrome da Liberação de Citocina , Imunoterapia , Imunossupressores/efeitos adversos
10.
Nat Med ; 30(6): 1645-1654, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38710951

RESUMO

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .


Assuntos
Neoplasias , Pirimidinas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Humanos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Feminino , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Pessoa de Meia-Idade , Adulto , Idoso , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Intervalo Livre de Progressão , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Morfolinas , Pirróis
11.
Lung Cancer ; 179: 107172, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36944283

RESUMO

BACKGROUND: Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling. METHODS: 44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Germline variants were selected according to association with inherited cancer using a 168-gene in silico panel, and variants classified according to ACMG/AMP classification as pathogenic (class 5) or likely pathogenic (class 4). RESULTS: In total, 16 patients (36%) were found to carry pathogenic or likely pathogenic variants in 13 cancer associated genes (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The germline PVs occurred in DNA repair pathways, including homologous recombination repair (HRR) (75%), nucleotide excision repair (6%), cell cycle regulatory (7%), base excision repair (6%), and hypoxic pathway (6%). Five (31%) patients with a germline PV had a first or second degree relative with mesothelioma compared to none for patients without a germline PV. Previously undiagnosed BRCA2 germline PVs were identified in two patients. Potential actionable targets based on the germline PVs were found in four patients (9%). CONCLUSION: This study revealed a high frequency of germline PVs in patients with mesothelioma. Furthermore, we identified germline PVs in two genes (NBN & RAD51B) not previously associated with mesothelioma. The data support germline testing in mesothelioma and provide a rationale for additional investigation of the HRR pathway as a potential actionable target.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Humanos , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Mesotelioma/genética , Mutação em Linhagem Germinativa , Células Germinativas , DNA Helicases/genética
12.
Sci Transl Med ; 15(695): eabp9229, 2023 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-37163618

RESUMO

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8+ and Ki67+CD8+ T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Linfócitos T CD8-Positivos/metabolismo , Neoplasias/patologia , Fibroblastos/patologia
13.
Nat Commun ; 14(1): 630, 2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36746967

RESUMO

HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, 'basket' trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR is 16% (95% CI 4.5-36.1%). The most common HER2 mutations are S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appear worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations are identified at progression in one responder. Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring HER2 mutations, the primary endpoint was not met and combinations may be explored.


Assuntos
Neoplasias do Sistema Biliar , Neoplasias da Mama , Quinolinas , Humanos , Feminino , Receptor ErbB-2/genética , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/induzido quimicamente , Diarreia/induzido quimicamente , Neoplasias da Mama/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento
14.
Adv Healthc Mater ; 11(1): e2100684, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34734500

RESUMO

Metastatic cancer spread is responsible for most cancer-related deaths. To colonize a new organ, invading cells adapt to, and remodel, the local extracellular matrix (ECM), a network of proteins and proteoglycans underpinning all tissues, and a critical regulator of homeostasis and disease. However, there is a major lack in tools to study cancer cell behavior within native 3D ECM. Here, an in-house designed bioreactor, where mouse organ ECM scaffolds are perfused and populated with cells that are challenged to colonize it, is presented. Using a specialized bioreactor chamber, it is possible to monitor cell behavior microscopically (e.g., proliferation, migration) within the organ scaffold. Cancer cells in this system recapitulate cell signaling observed in vivo and remodel complex native ECM. Moreover, the bioreactors are compatible with co-culturing cell types of different genetic origin comprising the normal and tumor microenvironment. This degree of experimental flexibility in an organ-specific and 3D context, opens new possibilities to study cell-cell and cell-ECM interplay and to model diseases in a controllable organ-specific system ex vivo.


Assuntos
Matriz Extracelular , Alicerces Teciduais , Animais , Reatores Biológicos , Camundongos , Perfusão , Proteoglicanas , Engenharia Tecidual
15.
Front Oncol ; 11: 558248, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33842304

RESUMO

Despite encouraging results with immune checkpoint inhibition (ICI), a large fraction of cancer patients still does not achieve clinical benefit. Finding predictive markers in the complexity of the tumor microenvironment is a challenging task and often requires invasive procedures. In our study, we looked for putative variables related to treatment benefit among immune cells in peripheral blood across different tumor types treated with ICIs. For that, we included 33 patients with different solid tumors referred to our clinical unit for ICI. Peripheral blood mononuclear cells were isolated at baseline, 6 and 20 weeks after treatment start. Characterization of immune cells was carried out by multi-color flow cytometry. Response to treatment was assessed radiologically by RECIST 1.1. Clinical outcome correlated with a shift towards an effector-like T cell phenotype, PD-1 expression by CD8+T cells, low levels of myeloid-derived suppressor cells and classical monocytes. Dendritic cells seemed also to play a role in terms of survival. From these findings, we hypothesized that patients responding to ICI had already at baseline an immune profile, here called 'favorable immune periphery', providing a higher chance of benefitting from ICI. We elaborated an index comprising cell types mentioned above. This signature correlated positively with the likelihood of benefiting from the treatment and ultimately with longer survival. Our study illustrates that patients responding to ICI seem to have a pre-existing immune profile in peripheral blood that favors good outcome. Exploring this signature can help to identify patients likely to achieve benefit from ICI.

16.
NPJ Breast Cancer ; 7(1): 44, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863913

RESUMO

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

17.
Cancer Discov ; 10(2): 198-213, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31806627

RESUMO

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Receptores de Estrogênio/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Antagonistas do Receptor de Estrogênio/farmacologia , Antagonistas do Receptor de Estrogênio/uso terapêutico , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento
18.
Ugeskr Laeger ; 181(20A)2019 Oct 14.
Artigo em Dinamarquês | MEDLINE | ID: mdl-31610836

RESUMO

This review summarises the current knowledge of anticancer therapy. More than 1,100 cancer drugs are currently under development in the United States. The increasing biological insight and platforms for high throughput screening of drugs have changed the developmental landscape of anticancer therapies from classical cytotoxic agents to targeted agents and immunotherapy. There is an increasing number of targeted agents, which are only efficacious in tumours harbouring specific genomic alterations in early clinical development. Furthermore, the landscape of immunotherapy broadens, and personalised immunotherapy is in development. The integration of genomic testing into early clinical oncology trials is increasing.


Assuntos
Antineoplásicos , Ensaios Clínicos Fase I como Assunto , Neoplasias , Humanos , Fatores Imunológicos , Imunoterapia , Oncologia , Neoplasias/tratamento farmacológico , Estados Unidos
19.
Oncotarget ; 10(14): 1388-1398, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30858924

RESUMO

PURPOSE: Access to genomic tumor material is required to select patients for targeted therapies. However, tissue biopsies are not always feasible and therefore circulating cell-free DNA (cfDNA) has emerged as an alternative. Here we investigate the utility of cfDNA for genomic tumor profiling in the phase I setting. STUDY DESIGN: Peripheral blood was collected from patients with advanced solid cancers eligible for phase I treatment. Patients failing the initial tissue biopsy due to inaccessible lesions or insufficient tumor cellularity (<10%) were included in the study. Genomic profiling of cfDNA including whole exome sequencing (WES) and somatic copy number alterations (SCNAs) analysis (OncoScan). RESULTS: Plasma cfDNA was pro- and retrospectively profiled from 24 and 20 patients, respectively. The median turnaround time was 29 days (N= 24, range 13-87 days) compared to tissue re-analyses of median 60 days (N= 6, range 29-98). Selected cancer-associated alterations (SCAAs) were identified in 70% (31/44) of patients, predominantly by WES due to the low sensitivity of OncoScan on cfDNA. Primarily, inaccessible cases of prostate and lung cancers could benefit from cfDNA profiling. In contrast, breast cancer patients showed a low level of tumor-specific cfDNA which might be due to cancer type and/or active treatment at the time of plasma collection. CONCLUSION: Plasma cfDNA profiling using WES is feasible within a clinically relevant timeframe and represents an alternative to invasive tissue biopsies to identify possible treatment targets. Especially, difficult-to-biopsy cancers can benefit from cfDNA profiling, but tumor tissue remains the gold standard for molecular analyses.

20.
Clin Cancer Res ; 25(4): 1239-1247, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30274980

RESUMO

PURPOSE: We evaluated the clinical benefit of tumor molecular profiling to select treatment in the phase I setting. EXPERIMENTAL DESIGN: Patients with advanced solid cancers and exhausted treatment options referred to a phase I unit were included in a prospective, single-center, single-arm open-label study (NCT02290522). Tumor biopsies were obtained for comprehensive genomic analysis including whole-exome sequencing and RNA sequencing. When possible, patients were treated with regimen matched to the genomic profile. Primary endpoint was progression-free survival (PFS). RESULTS: From May 2013 to January 2017, a total of 591 patients were enrolled, with 500 patients undergoing biopsy. Genomic profiles were obtained in 460 patients and a potential actionable target was identified in 352 (70%) of 500 biopsied patients. A total of 101 patients (20%) received matched treatment based on either gene mutations or RNA expression levels of targets available in early clinical trials or off-label treatment. Objective response according to RECIST1.1 was observed in 15 of 101 patients (0% complete response, 15% partial response), with a median PFS of 12 weeks (95% confidence interval, 9.9-14.4). CONCLUSIONS: Our study supports the feasibility of genomic profiling to select patients in the phase I setting and suggests that genomic matching can be beneficial for a minor subset of patients with no other treatment options. Randomized studies may validate this assumption.See related commentary by Ratain, p. 1136.


Assuntos
Genoma Humano/genética , Neoplasias/genética , Medicina de Precisão , Transcriptoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Intervalo Livre de Progressão , Análise de Sequência de RNA/métodos , Sequenciamento do Exoma/métodos , Adulto Jovem
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