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Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/etiologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Recidiva Local de Neoplasia/genética , Filogenia , Resultado do Tratamento , Fumar/genética , Fumar/fisiopatologia , Mutagênese , Variações do Número de Cópias de DNARESUMO
BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Colorretais , Inibidores Enzimáticos , Neoplasias Pulmonares , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Administração Oral , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêuticoRESUMO
This corrects the article DOI: 10.1038/nature22364.
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PURPOSE: A recent observational study suggested statins could reduce cancer diagnosis in patients with heart failure (HF). The findings need to be validated using robust epidemiological methods. This study aimed to evaluate the effect of statin treatment on the risk of cancer in patients with HF. METHODS: We conducted two target trial emulations using primary care data from IQVIA Medical Research Database-UK (2000 to 2019) with a clone-censor-weight design. The first emulated trial addressed the treatment initiation effect: initiating within 1 year versus not initiating a statin after the HF diagnosis. The second emulated trial addressed the cumulative exposure effect: continuing a statin for ≤3 years, 3-6 years, and >6 years after initiation. The study outcomes were any incident cancer and site-specific cancer diagnoses. Weighted pooled logistic regression models were used to estimate 10-year risk ratios (RR). 95% confidence intervals (CIs) were estimated using non-parametric bootstrapping. RESULTS: The first emulated trial showed that, compared to no statin, statins did not reduce the cancer risk in patients with HF (RR, 1.05; 95% CI, 0.94-1.15). The second emulated trial showed that, compared to treatment ≤3 years, statins with longer durations did not reduce the cancer risk (3-6 years: RR, 0.94; 95% CI, 0.70-1.33. >6 years: RR, 0.97; 95% CI, 0.79-1.26). No significant risk difference was observed on any site-specific cancer diagnoses. CONCLUSIONS: The results from the target trial emulations suggest that statin treatment is not associated with cancer risk in patients with HF.
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Insuficiência Cardíaca , Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Neoplasias/epidemiologia , Projetos de Pesquisa , Insuficiência Cardíaca/epidemiologia , CogniçãoRESUMO
INTRODUCTION: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. MATERIALS AND METHODS: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). RESULTS: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. CONCLUSION: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Segunda Neoplasia Primária , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Inibidores de Proteínas Quinases/efeitos adversos , Segunda Neoplasia Primária/genética , Éxons , MutaçãoRESUMO
The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
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Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem da Célula/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Evolução Molecular , Neoplasias Pulmonares/genética , Metástase Neoplásica/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Biópsia/métodos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Rastreamento de Células , Células Clonais/metabolismo , Células Clonais/patologia , Análise Mutacional de DNA , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Detecção Precoce de Câncer/métodos , Humanos , Limite de Detecção , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Reação em Cadeia da Polimerase Multiplex , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Cuidados Pós-Operatórios/métodos , Reprodutibilidade dos Testes , Carga TumoralRESUMO
Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.
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Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Pulmonares/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/terapia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/terapia , Ensaios Clínicos como Assunto , Consenso , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Medicina de Precisão , Resultado do TratamentoRESUMO
Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).
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Compostos de Anilina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/efeitos adversos , Neoplasias/tratamento farmacológico , Sulfonamidas/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Esquema de Medicação , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/epidemiologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologiaRESUMO
BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.
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Benzimidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Oxidiazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Progressão da Doença , Feminino , Humanos , Infusões Intravenosas , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Oxidiazóis/efeitos adversos , Oxidiazóis/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Fuso Acromático/efeitos dos fármacos , Reino UnidoRESUMO
BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).
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Carcinoma Pulmonar de Células não Pequenas/genética , Instabilidade Cromossômica , Heterogeneidade Genética , Neoplasias Pulmonares/genética , Mutação , Recidiva Local de Neoplasia/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Evolução Molecular , Exoma , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Filogenia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Análise de Sequência de DNA/métodosRESUMO
BACKGROUND: The development and rapid uptake of immune checkpoint inhibitors (CPI) has changed the outlook for patients with cancer. However, CPIs have different adverse event (AE) profiles to other systemic therapies, and prompt AE management is essential to assure optimal outcomes. In order to understand what and when adverse events are experienced, reported and managed during CPI treatment, a mixed methods study was conducted, including a case note review of patients who were receiving immunotherapy and semi-structured interviews with patients to understand their experience, management and reporting of AEs after receiving immune CPI treatment. METHODS: This mixed methods study was conducted at a large cancer hospital in the United Kingdom. A case note review identified how and where patients reported AEs. Data relating to patients with lung, bladder, prostate and head & neck cancers who received CPI treatment between 01/04/2015 and 31/07/2018 were extracted from e-prescribing databases and clinical data were included for analysis at a single time point (31 July 2018). Semi-structured interviews were conducted with patients receiving CPI treatment, exploring experience of AEs and reasons for delays in AE reporting and management. RESULTS: Sixty-two patients were included in the case note review, with 78 AEs being experienced by 36 patients (58%), including one patient experiencing 10 AEs. Serious AEs were experienced by 12 patients (19%) and ten AEs (17%) required oral steroids as treatment. The majority of AEs were reported to clinicians prior to further dosing, although milder AEs were often not addressed until subsequent clinic appointments. Interviews with 13 patients yielded major themes: variability, causality, decision making and impact. CONCLUSION: Most CPI-associated AEs are manageable if reported and treated promptly. Both the case note review and interviews found that reporting of non-serious AEs is often left until routine clinic visits, despite impacting patient experience, leaving the opportunity for AEs to be left unreported and implying a potential benefit for real time monitoring. Our study highlights a need to provide patients with reminders around AEs and their timely reporting even when apparently innocuous; patients must understand that AEs can occur at any cycle and even following treatment completion.
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Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Neoplasias/terapia , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisões , Feminino , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/terapia , Pesquisa Qualitativa , Reino Unido , Neoplasias da Bexiga Urinária/terapiaRESUMO
BACKGROUND: Neutropenia is associated with an increased risk of mortality and hospitalisation. Strategies, including the prescribing of colony-stimulating growth factors (CSFs), are adopted when a high risk (> 20%) of neutropenic complications are seen in the clinical trial setting. With a diverse treatment population that may differ from the patient groups recruited to studies, appropriate prescribing decisions by clinicians are essential. At present, results are conflicting from studies evaluating the risks of certain patient attributes on neutropenic events; we aimed to aggregate these associations to guide future management. DESIGN: A systematic review with a meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Studies were identified through a literature search using MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to December 1, 2017. Studies were included into a meta-analysis if they adjusted for confounders; analyses were conducted in STATA v 15.1 SE. RESULTS: A total of 4415 articles were retrieved by the search with 37 meeting the inclusion criteria and 12 eligible for meta-analysis. Meta-analysis was conducted for increasing age and yielded a pooled odds ratio of 1.39 (1.11, 1.76, I2 = 24.1%), in our subgroup analysis of 4814 patients. Odds ratios for studies were pooled that reported associations for one co-morbidity compared to none and resulted in an overall odds of 1.54 (CI 1.09-2.09, I2 = 13.1%), including 9189 patients in total. CONCLUSIONS: Results can enhance current guidance in prescribing primary prophylaxis for treatments that either fall marginally under the internationally recognised 20% neutropenia risk.
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Neoplasias/sangue , Neutropenia/induzido quimicamente , Humanos , Neoplasias/tratamento farmacológico , Neutropenia/terapiaRESUMO
Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Isoflavonas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagemRESUMO
BACKGROUND: Several prognostic indices have been devised to optimize patient selection for phase 1 oncology trials with no consensus as to the optimal score and none qualifying as a marker of treatment response. METHODS: Multivariate predictors of overall survival (OS) were tested on 118 referred patients to develop the Hammersmith Score (HS). The score's ability to predict OS, progression-free survival (PFS), and 90-day mortality (90DM) was compared with other prognostic indices. Changes in HS were recalculated during treatment. RESULTS: Albumin<35 g/L, lactate dehydrogenase>450 U/L, and sodium<135 mmol/L emerged as independent prognostic factors. These were used with equal weighting to devise the HS, a compound prognostic index ranging from 0 to 3. High (HS=2-3) score predicted worse OS (hazard ratio [HR]=6.5, P<.001), PFS (HR=2.8, P=.01), and 90DM (OR=9.0, P<.001). HS was a more accurate multivariate predictor of OS (HR=6.4, P<.001, C-index=0.72), PFS (HR=2.7, P=.03), and 90DM (area under the ROC curve 0.703) compared with other scores. Worsening of the HS during treatment predicted for shorter OS (P<.001). HS retained prognostic and predictive ability following external validation. CONCLUSIONS: HS is a simple, validated index to optimize patient selection and predict survival benefit from phase 1 oncology treatments. Prospective validation is ongoing.
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Ensaios Clínicos Fase I como Assunto , Neoplasias/mortalidade , Seleção de Pacientes , Valor Preditivo dos Testes , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/análise , Intervalo Livre de Doença , Feminino , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/terapia , Prognóstico , Reprodutibilidade dos Testes , Sódio/sangueRESUMO
AIMS: We aim to evaluate change in the use of prognostic guideline-directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non-cancer controls, including renin-angiotensin-system inhibitors (RASIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). METHODS AND RESULTS: We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12 months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non-cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR = 1.51, 95% CI = 1.35-1.68; beta-blockers: OR = 1.22, 95% CI = 1.08-1.37; MRAs: OR = 1.31, 95% CI = 1.08-1.59) and poor persistence (RASIs: OR = 2.04, 95% CI = 1.75-2.37; beta-blockers: OR = 1.35, 95% CI = 1.12-1.63; MRAs: OR = 1.49, 95% CI = 1.16-1.93), and higher risks for dose down-titration for RASIs (OR = 1.69, 95% CI = 1.40-2.04) and beta-blockers (OR = 1.31, 95% CI = 1.05-1.62). Cancer diagnosis was not associated with treatment initiation or dose up-titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. CONCLUSIONS: Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF.
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BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.
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BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.
Assuntos
Morfolinas , Neoplasias , Pirimidinas , Sulfonamidas , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Indóis , Inflamação/tratamento farmacológico , Genômica , Proteínas Mutadas de Ataxia Telangiectasia/genéticaRESUMO
A comprehensive evaluation of the total burden of morbidity endured by cancer survivors remains unavailable. This study quantified the burden of 144 health conditions and critical care admissions across 26 adult cancers and treatment modalities in 243,767 adults. By age 60, top conditions ranked by fold difference (cumulative burden in survivors divided by cumulative burden in controls) were haematology, immunology/infection and pulmonary conditions. Patients who had all three forms of treatment (chemotherapy, radiotherapy and surgery) experienced a high cumulative burden of late morbidities compared with patients who received radiotherapy alone. The top five cancers with the highest cumulative burden of critical care admissions by age 60 were bone (12.4 events per 100 individuals [CI: 11.6-13.1]), brain (9.0 [7.5-10.5]), spinal cord and nervous system (7.2 [6.7-7.8]), testis (6.7 [4.9-8.4]) and Hodgkin lymphoma (4.4 [3.6-5.1]). Conditions that were associated with high excess years-of-life-lost were haematological conditions (9.6 years), pulmonary conditions (8.6 years) and immunological conditions or infections (7.8 years). As the population of cancer survivors continues to grow, our results indicate that it is important to tackle long-term health consequences through enacting data-driven policies.
Assuntos
Sobreviventes de Câncer , Doença de Hodgkin , Masculino , Adulto , Humanos , Pessoa de Meia-Idade , Mortalidade Prematura , Morbidade , Hospitalização , Fatores de RiscoRESUMO
BACKGROUND: In those receiving chemotherapy, renal and hepatic dysfunction can increase the risk of toxicity and should therefore be monitored. We aimed to develop a machine learning model to identify those patients that need closer monitoring, enabling a safer and more efficient service. METHODS: We used retrospective data from a large academic hospital, for patients treated with chemotherapy for breast cancer, colorectal cancer and diffuse-large B-cell lymphoma, to train and validate a Multi-Layer Perceptrons (MLP) model to predict the outcomes of unacceptable rises in bilirubin or creatinine. To assess the performance of the model, validation was performed using patient data from a separate, independent hospital using the same variables. Using this dataset, we evaluated the sensitivity and specificity of the model. RESULTS: 1214 patients in total were identified. The training set had almost perfect sensitivity and specificity of >0.95; the area under the curve (AUC) was 0.99 (95% CI 0.98-1.00) for creatinine and 0.97 (95% CI: 0.95-0.99) for bilirubin. The validation set had good sensitivity (creatinine: 0.60, 95% CI: 0.55-0.64, bilirubin: 0.54, 95% CI: 0.52-0.56), and specificity (creatinine 0.98, 95% CI: 0.96-0.99, bilirubin 0.90, 95% CI: 0.87-0.94) and area under the curve (creatinine: 0.76, 95% CI: 0.70, 0.82, bilirubin 0.72, 95% CI: 0.68-0.76). CONCLUSIONS: We have demonstrated that a MLP model can be used to reduce the number of blood tests required for some patients at low risk of organ dysfunction, whilst improving safety for others at high risk.