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1.
Future Oncol ; 20(6): 297-306, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37916501

RESUMO

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research study called ARROW, which tested a medicine called pralsetinib in patients with non-small cell lung cancer (NSCLC), thyroid cancer, and other advanced solid tumours caused by a change in a gene called RET. For the purposes of this summary, only patients with NSCLC with a change in RET called fusion (RET fusion+) are highlighted. WHAT WERE THE RESULTS?: In total, 281 patients with RET fusion+ NSCLC had taken part in this study across the USA, Europe, and Asia. Patients were asked to take four pills (adding up to 400 mg) of pralsetinib each day and were checked for any changes in their tumours, as well as for any side effects. After an average of 8 months of treatment with pralsetinib, 72% of previously untreated patients and 59% of patients who had previously received chemotherapy had considerable shrinkage of their tumours. Among 10 patients with tumours which had spread to the brain (all of whom had received previous treatments), 70% had their tumours shrink greatly in the brain after treatment with pralsetinib. On average, patients lived with little to no tumour growth for 16 months. In previously untreated patients, the most common severe side effects that were considered related to pralsetinib treatment were decreased white blood cells (neutrophils and lymphocytes), increased blood pressure, and an increase in a blood protein called creatine phosphokinase. In previously treated patients, the severe side effects were decreased white blood cells (neutrophils, lymphocytes, and leukocytes), increased blood pressure, and low levels of red blood cells. In both untreated and previously treated patients, the most common severe side effects that required hospital attention were lung inflammation/swelling causing shortness of breath (pneumonitis) and lung infection (pneumonia). WHAT DO THE RESULTS MEAN?: Overall, the ARROW study showed that pralsetinib was effective in shrinking tumours in patients with RET fusion+ NSCLC regardless of previous treatment history. The recorded side effects were expected in patients receiving this type of medicine. Clinical Trial Registration: NCT03037385 (ARROW) (ClinicalTrials.gov).


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Pirazóis , Piridinas , Proteínas Proto-Oncogênicas c-ret/genética
2.
BMC Palliat Care ; 23(1): 124, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769564

RESUMO

BACKGROUND: Ex-ante identification of the last year in life facilitates a proactive palliative approach. Machine learning models trained on electronic health records (EHR) demonstrate promising performance in cancer prognostication. However, gaps in literature include incomplete reporting of model performance, inadequate alignment of model formulation with implementation use-case, and insufficient explainability hindering trust and adoption in clinical settings. Hence, we aim to develop an explainable machine learning EHR-based model that prompts palliative care processes by predicting for 365-day mortality risk among patients with advanced cancer within an outpatient setting. METHODS: Our cohort consisted of 5,926 adults diagnosed with Stage 3 or 4 solid organ cancer between July 1, 2017, and June 30, 2020 and receiving ambulatory cancer care within a tertiary center. The classification problem was modelled using Extreme Gradient Boosting (XGBoost) and aligned to our envisioned use-case: "Given a prediction point that corresponds to an outpatient cancer encounter, predict for mortality within 365-days from prediction point, using EHR data up to 365-days prior." The model was trained with 75% of the dataset (n = 39,416 outpatient encounters) and validated on a 25% hold-out dataset (n = 13,122 outpatient encounters). To explain model outputs, we used Shapley Additive Explanations (SHAP) values. Clinical characteristics, laboratory tests and treatment data were used to train the model. Performance was evaluated using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC), while model calibration was assessed using the Brier score. RESULTS: In total, 17,149 of the 52,538 prediction points (32.6%) had a mortality event within the 365-day prediction window. The model demonstrated an AUROC of 0.861 (95% CI 0.856-0.867) and AUPRC of 0.771. The Brier score was 0.147, indicating slight overestimations of mortality risk. Explanatory diagrams utilizing SHAP values allowed visualization of feature impacts on predictions at both the global and individual levels. CONCLUSION: Our machine learning model demonstrated good discrimination and precision-recall in predicting 365-day mortality risk among individuals with advanced cancer. It has the potential to provide personalized mortality predictions and facilitate earlier integration of palliative care.


Assuntos
Registros Eletrônicos de Saúde , Aprendizado de Máquina , Cuidados Paliativos , Humanos , Aprendizado de Máquina/normas , Registros Eletrônicos de Saúde/estatística & dados numéricos , Cuidados Paliativos/métodos , Cuidados Paliativos/normas , Cuidados Paliativos/estatística & dados numéricos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Medição de Risco/métodos , Neoplasias/mortalidade , Neoplasias/terapia , Estudos de Coortes , Adulto , Oncologia/métodos , Oncologia/normas , Idoso de 80 Anos ou mais , Mortalidade/tendências
3.
Curr Treat Options Oncol ; 23(12): 1721-1731, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36451063

RESUMO

OPINION STATEMENT: While cisplatin-based adjuvant chemotherapy has been the standard of care for the past two decades, the recent introduction of immunotherapy has heralded an important milestone in the adjuvant landscape of early-stage non-small cell lung cancer (NSCLC). The landmark approval of adjuvant atezolizumab based on disease-free survival (DFS) benefit in IMpower010 was swiftly followed by the recent data for use of adjuvant pembrolizumab in PEARLS/KEYNOTE-091, and similar trials involving other immune checkpoint inhibitors are eagerly anticipated. Although both atezolizumab and pembrolizumab demonstrated a significant DFS benefit in the intention-to-treat population, key subgroup analyses have raised questions about the role of predictive biomarkers such as PD-L1 expression and EGFR-mutation status. In this review, we examine the data from the two important trials (IMpower010 and PEARLS/KEYNOTE-091), discuss the controversies surrounding adjuvant immunotherapy including appropriate endpoints, biomarker selection and highlight key considerations in oncogene-driven NSCLC. Finally, we propose future directions including the impact of neoadjuvant therapy on developments in the adjuvant immunotherapy paradigm and role of minimal residual disease (MRD).


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Cisplatino/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Imunoterapia
4.
Palliat Med ; 35(8): 1578-1589, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34524044

RESUMO

BACKGROUND: The benefit of specialist palliative care for cancer inpatients is established, but the best method to deliver specialist palliative care is unknown. AIM: To compare a consult model versus a co-rounding model; both provide the same content of specialist palliative care to individual patients but differ in the level of integration between palliative care and oncology clinicians. DESIGN: An open-label, cluster-randomized trial with stepped-wedge design. The primary outcome was hospital length of stay; secondary outcomes were 30-day readmissions and access to specialist palliative care. ClinicalTrials.gov number NCT03330509. SETTING/PARTICIPANTS: Cancer patients admitted to the oncology inpatient service of an acute hospital in Singapore. RESULTS: A total of 5681 admissions from December 2017 to July 2019 were included, of which 5295 involved stage 3-4 cancer and 1221 received specialist palliative care review. Admissions in the co-rounding model had a shorter hospital length of stay than those in the consult model by 0.70 days (95%CI -0.04 to 1.45, p = 0.065) for all admissions. In the sub-group of stage 3-4 cancer patients, the length of stay was 0.85 days shorter (95%CI 0.05-1.65, p = 0.038). In the sub-group of admissions that received specialist palliative care review, the length of stay was 2.62 days shorter (95%CI 0.63-4.61, p = 0.010). Hospital readmission within 30 days (OR1.03, 95%CI 0.79-1.35, p = 0.822) and access to specialist palliative care (OR1.19, 95%CI 0.90-1.58, p = 0.215) were similar between the consult and co-rounding models. CONCLUSIONS: The co-rounding model was associated with a shorter hospital length of stay. Readmissions within 30 days and access to specialist palliative care were similar.


Assuntos
Oncologia , Cuidados Paliativos , Hospitais , Humanos , Tempo de Internação , Aceitação pelo Paciente de Cuidados de Saúde
5.
J Pathol Clin Res ; 10(2): e354, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38284983

RESUMO

This study analyzed whether extended molecular profiling can predict the development of epidermal growth factor receptor (EGFR) gene T790M mutation, which is the most frequent resistance alteration in non-small cell lung cancer (NSCLC) after treatment with the first-/second-generation (1G/2G) EGFR inhibitors (tyrosine kinase inhibitors [TKIs]), but only weakly associated with clinical characteristics. Whole exome sequencing (WES) was performed on pretreatment tumor tissue with matched normal samples from NSCLC patients with (n = 25, detected in tissue or blood rebiopsies) or without (n = 14, negative tissue rebiopsies only) subsequent EGFR p.T790M mutation after treatment with 1G/2G EGFR TKI. Several complex genetic biomarkers were assessed using bioinformatic methods. After treatment with first-line afatinib (44%) or erlotinib/gefitinib (56%), median progression-free survival and overall survival were 12.1 and 33.7 months, respectively. Clinical and tumor genetic characteristics, including age (median, 66 years), sex (74% female), smoking (69% never/light smokers), EGFR mutation type (72% exon 19 deletions), and TP53 mutations (41%) were not significantly associated with T790M mutation (p > 0.05). By contrast, complex biomarkers including tumor mutational burden, the clock-like mutation signature SBS1 + 5, tumor ploidy, and markers of subclonality including mutant-allele tumor heterogeneity, subclonal copy number changes, and median tumor-adjusted variant allele frequency were significantly higher at baseline in tumors with subsequent T790M mutation (all p < 0.05). Each marker alone could predict subsequent development of T790M with an area under the curve (AUC) of 0.72-0.77, but the small number of cases did not allow confirmation of better performance for biomarker combinations in leave-one-out cross-validated logistic regression (AUC 0.69, 95% confidence interval: 0.50-0.87). Extended molecular profiling with WES at initial diagnosis reveals several complex biomarkers associated with subsequent development of T790M resistance mutation in NSCLC patients receiving first-/second-generation TKIs as the first-line therapy. Larger prospective studies will be necessary to define a forecasting model.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Feminino , Idoso , Masculino , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos Prospectivos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Genômica , Biomarcadores
6.
Eur J Cancer ; 208: 114182, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38986421

RESUMO

PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Mutação , Triazinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Feminino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Triazinas/administração & dosagem , Triazinas/uso terapêutico , Triazinas/efeitos adversos , Adulto , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Idoso de 80 Anos ou mais , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Imidazóis
7.
Oncoimmunology ; 13(1): 2290787, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38170160

RESUMO

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Renais , Exantema , Neoplasias Renais , Neoplasias Pulmonares , Melanoma , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/genética , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Biomarcadores , Fadiga/induzido quimicamente , Fadiga/tratamento farmacológico , Exantema/induzido quimicamente , Exantema/tratamento farmacológico
8.
Appl Health Econ Health Policy ; 21(6): 841-855, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37747620

RESUMO

INTRODUCTION: There is a boom in imaging biomarker-driven companion and complementary diagnostics (CDx) for cancer, which brings opportunity for personalized medicine. Whether adoption of these technologies is likely to be cost-effective is a relevant question, and studies on this topic are emerging. Despite the growing number of economic evaluations, no review of the methods used, quality of reporting, and potential risk of bias has been done. We report a systematic review to identify, summarize, and critique the cost-effectiveness evidence for the use of biomarker-driven and imaging-based CDx to inform cancer treatments. METHODS: The Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Systematic literature searches until 30 December 2022 were performed in PubMed, Web of Science, Medline, Embase, and Scopus for economic evaluations of imaging biomarker-based CDx for cancer. The inclusion and exclusion of studies were determined by pre-specified eligibility criteria informed by the 'Patient, Intervention, Comparison, Outcome' (PICO) framework. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) was used to assess the quality of reporting, and the Bias in Economic Evaluation (ECOBIAS) was used to examine the potential risk of bias of included studies. RESULTS: A total of 12 papers were included, with eight model-based and four trial-based studies. Implementing biomarker-driven, imaging-based CDx was reported to be cost-effective, cost saving, or dominant (cost saving and more effective) in ten papers. Inconsistent methods were found in the studies, and the quality of reporting was lacking against the CHEERS reporting guideline. Several potential sources of 'risk of bias' were identified. These should be acknowledged and carefully considered by researchers planning future health economic evaluations. CONCLUSION: Despite favorable results towards the implementation of imaging biomarker-based CDx for cancer, there is room for improvement regarding the quantity and quality of economic evaluations, and that is expected as the awareness of current study limitations increases and more clinical data become available in the future.


Assuntos
Neoplasias , Humanos , Análise Custo-Benefício , Neoplasias/diagnóstico por imagem
9.
J Clin Invest ; 132(13)2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35579943

RESUMO

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.


Assuntos
Fator X , Neoplasias Pulmonares , Apoptose/genética , Linhagem Celular Tumoral , Receptores ErbB/genética , Fator X/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Processamento de RNA , RNA Mensageiro/genética , Motivos de Ligação ao RNA , Proteínas de Ligação a RNA/metabolismo
10.
Asia Pac J Clin Oncol ; 17(4): 388-395, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33502085

RESUMO

AIM: The significance and prioritization of early phase oncology trial continuation during a global pandemic is unknown. This study reported the outcomes, multiple challenges, and broad recommendations associated with the impact of the novel coronavirus disease 2019 (COVID-19) on oncology early phase 1 trials-and on drug development in Asia-based on the experiences and perspectives of Asian oncology phase 1 centers. METHODS: Between March and April 2020 during the initial period of outbreak, the impact of COVID-19 across oncology phase 1 sites in five Asian countries-China (Hong Kong), Japan, South Korea, Taiwan, and Singapore-was retrospectively analyzed. RESULTS: There was no trial termination or treatment discontinuation in all five countries. Although the most common impact was new patient enrollment being placed on hold, which was based on pharmaceutical sponsors' decision-making, the situation varied per site. Most sites had no restrictions in place that would limit their ability to fully comply with the requirements of conducting the early phase studies. The number of protocol deviations during the pandemic was largely dependent on domestic transportation status during the outbreak rather than the ability of the clinical trial centers. CONCLUSION: Determining the risk to benefits ratio of patients with cancer who are enrolled in early phase 1 clinical trials under the unusual circumstances of a global pandemic is important. Specific guidance or guidelines on the conduct of early phase 1 clinical trials during public health emergencies that are based on the recent lessons learned is urgently required.


Assuntos
COVID-19 , Desenvolvimento de Medicamentos , Neoplasias , Ensaios Clínicos Fase I como Assunto , Hong Kong , Humanos , Neoplasias/epidemiologia , Pandemias , Estudos Retrospectivos , SARS-CoV-2
11.
Lancet Respir Med ; 8(6): 561-572, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31954624

RESUMO

BACKGROUND: Resistance to first-generation and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is mediated by the emergence of the Thr790Met mutation in 50-60% of treated patients with non-small-cell lung cancer (NSCLC). We aimed to assess the safety and activity of nazartinib (EGF816), a third-generation EGFR TKI that selectively inhibits EGFR with Thr790Met or activating mutations (or both), while sparing wild-type EGFR, in patients with advanced EGFR-mutant NSCLC. METHODS: This phase 1 dose-escalation part of an open-label, multicentre, phase 1/2 study was conducted at nine academic medical centres located in Europe, Asia, and North America. Patients were included if they were aged 18 years or older and had stage IIIB-IV EGFR-mutant NSCLC (with varying statuses of EGFR mutation and previous therapy allowed), at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Nazartinib (at seven dose levels between 75 mg and 350 mg, in capsule or tablet form) was administered orally, once daily, on a continuous 28-day dosing schedule. A two-parameter Bayesian logistic regression model, guided by the escalation with overdose control principle, was implemented to make dose recommendations and estimate the maximum tolerated dose or recommended phase 2 dose of nazartinib (the primary outcome). This study is registered with ClinicalTrials.gov (NCT02108964); enrolment to phase 1 is complete and the study is ongoing. FINDINGS: By Aug 31, 2017, 180 patients (116 [64%] women; median age 60 years (52-69); 116 [64%] with ECOG performance status 1) received nazartinib across seven dose levels: 75 mg (n=17), 100 mg (n=38), 150 mg (n=73), 200 mg (n=8), 225 mg (n=28), 300 mg (n=5), and 350 mg (n=11). Seven dose-limiting toxicities were observed in six (3%) patients who received 150 mg, 225 mg, or 350 mg nazartinib once daily. Although the maximum tolerated dose was not met, the recommended phase 2 dose was declared as 150 mg once daily (tablet). The most common adverse events, regardless of cause, were rash (all subcategories 111 [62%] patients, maculopapular rash 72 [40%], dermatitis acneiform 22 [12%]), diarrhoea (81 [45%]), pruritus (70 [39%]), fatigue (54 [30%]), and stomatitis (54 [30%]), and were mostly grades 1-2. Any-cause grade 3-4 adverse events were reported in 99 (55%) patients across all doses, the most common being rash (all subcategories grouped 27 [15%]), pneumonia (12 [7%]), anaemia (ten [6%]), and dyspnoea (nine [5%]). Serious adverse events suspected to be drug-related occurred in 16 (9%) patients. INTERPRETATION: Nazartinib has a favourable safety profile, with low-grade skin toxicity characterised by a predominantly maculopapular rash that required minimal dose reductions. FUNDING: Novartis Pharmaceuticals Corporation.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nicotina/análogos & derivados , Idoso , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Nicotina/efeitos adversos , Nicotina/uso terapêutico , Resultado do Tratamento
12.
Ann Acad Med Singap ; 46(9): 333-338, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29022033

RESUMO

INTRODUCTION: We reviewed changes in clinical characteristics, treatment and survival of lung cancer patients in Singapore over the past decade. MATERIALS AND METHODS: We reviewed all primary lung cancer cases from January 2004 to December 2013. Basic demographic, clinical and treatment data were extracted from the database. Overall survival (OS) was calculated using Kaplan-Meier method; survival curves were compared using log-rank test. Linear regression trend lines were estimated using least squares approach, and Cox regression analyses were performed to identify prognostic factors. RESULTS: Among 6006 lung cancer patients, the median age was 68 years old, 65% were males, 88% were Chinese, 92% had non-small-cell lung cancer and 76% had advanced stage IIIB/IV. There were proportionally more adenocarcinomas diagnosed over the years, while that of squamous cell carcinoma (SCC) and small-cell-lung cancer (SCLC) have remained stable. The median OS of all patients increased from 9.2 months in 2004 to 11.5 months in 2013. This survival improvement was statistically significant among patients with stage IIIB/IV (6.7 to 8.7 months; P = 0.005) and adenocarcinoma (12.7 to 15.4 months; P = 0.041). There was no improvement in median OS for SCC or SCLC. The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) (hazard ratio [HR] 0.68; 95% CI, 0.63 to 0.73) and pemetrexed (HR, 0.69; 95% CI, 0.63 to 0.76) were significantly associated with improved OS. CONCLUSION: Survival of patients with advanced stage IIIB/IV lung adenocarcinoma has improved over the past decade, and is potentially associated with the use of EGFR TKI and pemetrexed.


Assuntos
Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares , Pemetrexede/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Singapura/epidemiologia , Análise de Sobrevida
13.
BMC Cell Biol ; 3: 17, 2002 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-12095420

RESUMO

BACKGROUND Alternative exons encode different isoforms of the human insulin-like growth factor-I (IGF-I) precursor without altering mature IGF-I. We hypothesized that the various IGF-I precursors may traffic IGF-I differently. Chimeric IGF-I precursors were made with green fluorescent protein (GFP) cloned between the signal and mature IGF-I domains. RESULTS Chimeras containing exons 1 or 2 were located in the cytoplasm, consistent with a secretory pathway, and suggesting that both exons encoded functional signal peptides. Exon 5-containing chimeras localized to the nucleus and strongly to the nucleolus, while chimeras containing exon 6 or the upstream portion of exon 5 did not. Nuclear and nucleolar localization also occurred when the mature IGF-I domain was deleted from the chimeras, or when signal peptides were deleted. CONCLUSIONS We have identified a nucleolar localization for an isoform of the human IGF-I precursor. The findings are consistent with the presence of a nuclear and nucleolar localization signal situated in the C-terminal part of the exon 5-encoded domain with similarities to signals in several other growth factors.


Assuntos
Nucléolo Celular/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Precursores de Proteínas/metabolismo , Nucléolo Celular/genética , Citoplasma/química , Citoplasma/genética , Éxons/genética , Proteínas de Fluorescência Verde , Células HeLa/química , Células HeLa/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/genética , Íntrons/genética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Precursores de Proteínas/genética , Sinais Direcionadores de Proteínas/genética , Estrutura Secundária de Proteína/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Células Tumorais Cultivadas
14.
Cancer Chemother Pharmacol ; 72(6): 1213-22, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24085260

RESUMO

PURPOSE: Afatinib is an irreversible ErbB family blocker currently under evaluation in late-stage clinical trials. This study primarily assessed the cardiac safety, pharmacokinetics and antitumor activity of afatinib in cancer patients. METHODS: In this multicenter, Phase II, open-label, single-arm trial, 60 patients with solid tumors who were expected to express epidermal growth factor receptor-1 and HER2 received oral afatinib 50 mg daily. QTcF intervals (QT interval corrected by the Fridericia formula) were evaluated based on electrocardiogram recordings time-matched with pharmacokinetic blood samples after single (Day 1) and continuous (Day 14; steady state) administration. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0; antitumor activity was assessed using RECIST 1.0. RESULTS: There was a nonsignificant decrease of 0.3 ms (90 % confidence interval -2.8, 2.3; N = 49) in the mean of the average time-matched QTcF interval from baseline to steady state. The maximum plasma concentration for afatinib was seen at median tmax 3 h after both single dose and at steady state. No relationship between afatinib plasma concentrations and time-matched QTcF, QT and heart rate change was found. The overall adverse event profile was consistent with the known safety profile of afatinib. One patient demonstrated a partial response (PR) and two patients unconfirmed PRs. CONCLUSIONS: Afatinib had no impact on cardiac repolarization, had a manageable safety profile and demonstrated antitumor activity in this uncontrolled study.


Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/metabolismo , Neoplasias/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Administração Oral , Afatinib , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Resultado do Tratamento
15.
Eur J Cancer ; 46(12): 2166-77, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20413300

RESUMO

Primary or acquired drug resistance remains a fundamental cause of therapeutic failure in cancer therapy. Post-hoc analyses of clinical trials have revealed the importance of selecting patients with the appropriate molecular phenotype for maximal therapeutic benefit, as well as the requirement to avoid exposure and potential harm for those who have drug resistant disease, particularly with respect to targeted agents. Unravelling drug resistance mechanisms not only facilitates rational treatment strategies to overcome existing limitations in therapeutic efficacy, but will enhance biomarker discovery and the development of companion diagnostics. Advances in genomics coupled with state-of-the-art biomarker platforms such as multi-parametric functional imaging and molecular characterisation of circulating tumour cells are expanding the scope of clinical trials - providing unprecedented opportunities for translational objectives that inform on both treatment response and disease biology. In this review, we propose a shift towards innovative trial designs, which are prospectively set up to answer key biological hypotheses in parallel with the RNA interference elucidation of drug resistance pathways in monotherapy pre-operative or 'window of opportunity' early phase trials. Systematic collection of paired clinical samples before and after treatment amenable to genomics analysis in such studies is mandated. With concurrent functional RNA interference analysis of drug response pathways, the identification of robust predictive biomarkers of response and clinically relevant resistance mechanisms may become feasible. This represents a rational approach to accelerate biomarker discovery, maximising the potential for therapeutic benefit and minimising the health economic cost of ineffective therapy.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Genômica , Neoplasias/tratamento farmacológico , Interferência de RNA/efeitos dos fármacos , Comunicação Celular/genética , Humanos , Neoplasias/genética , Células-Tronco Neoplásicas/fisiologia , Tecnologia Farmacêutica , Microambiente Tumoral/genética
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