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1.
Nature ; 600(7888): 319-323, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34819663

RESUMEN

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Transformación Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas Receptoras/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 15/genética , Humanos , Lactamas/farmacología , Lactamas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Desnudos , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Gastric Cancer ; 26(1): 123-131, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36066725

RESUMEN

BACKGROUND: Dual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB's end-of study analyses aimed to evaluate the long-term efficacy and safety of pertuzumab plus trastuzumab and chemotherapy for previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer. METHODS: Eligible patients were randomized 1:1 to pertuzumab/placebo plus trastuzumab and chemotherapy every 3 weeks. PRIMARY ENDPOINT: overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. RESULTS: The intention-to-treat population comprised 388 patients in the pertuzumab arm and 392 in the placebo arm. The safety population comprised 385 and 388 patients, respectively. Median follow-up was ≥ 44.4 months. Median OS was increased by 3.9 months (hazard ratio 0.85 [95% confidence intervals, 0.72-0.99]) and median PFS by 1.3 months (hazard ratio 0.73 [95% confidence intervals, 0.62-0.85]) in the pertuzumab vs. the placebo arm. ORR was numerically higher (57.0% vs. 48.6%) and median DoR 1.8 months longer with pertuzumab treatment. There was a trend for more favorable hazard ratios in certain subgroups related to HER2 amplification/overexpression. Safety was comparable between arms, except for serious and grade 3-5 adverse events, and any-grade diarrhea, which were more frequent with pertuzumab. CONCLUSIONS: JACOB did not meet its primary endpoint. Nonetheless, the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up. Trial registration NCT01774786; https://clinicaltrials.gov/ct2/show/NCT01774786 .


Asunto(s)
Neoplasias de la Mama , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Femenino , Trastuzumab , Receptor ErbB-2 , Neoplasias Gástricas/patología , Biomarcadores de Tumor , Neoplasias de la Mama/patología , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Protocolos de Quimioterapia Combinada Antineoplásica
3.
Int J Clin Oncol ; 28(5): 654-663, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36856908

RESUMEN

BACKGROUND: Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. METHODS: HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. RESULTS: The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. CONCLUSIONS: We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.


Asunto(s)
Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas c-akt , Humanos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Células HEK293 , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Mutación , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo
4.
Proc Jpn Acad Ser B Phys Biol Sci ; 99(8): 241-253, 2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37558430

RESUMEN

We launched SCRUM-Japan platform for the cancer genome profiling (CGP) test screening followed by the enrollment to genomically-matched clinical trials in 2015. More than 30,000 tissue-based and 10,000 liquid-based CGP tests have already been performed for enrolling to a total of 127 industry-/investigator-initiated registration trials, which resulted in regulatory approvals of 12 new agents with 14 indications in Japan. Using the clinical-genomic database, a new driver gene was recently discovered with dramatic response by genomically-matched agent. Our comparative study with tissue-based CGPs revealed more usefulness of liquid biopsy in terms of less invasive manner, shorter turn-round time, and higher enrollment rate for matched treatments than tissue-based in gastrointestinal cancers. For detecting minimal/molecular residual disease (MRD) after surgery, post-surgical monitoring with tumor-informed liquid biopsy assay in association with two randomized control trials have also started in 2020 (CIRCULATE-Japan). The observational cohort study showed obvious efficacy of the MRD monitoring for predicting recurrence, leading to change clinical practice in patient selection who should receive adjuvant therapy in the near future.


Asunto(s)
Neoplasias , Humanos , Japón , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Atención al Paciente , Genómica
5.
Gan To Kagaku Ryoho ; 50(10): 1021-1026, 2023 Oct.
Artículo en Japonés | MEDLINE | ID: mdl-38035827

RESUMEN

In Europe and the United States, the Foundation Aide et Recherche en Cancérologie Digestive(ARCAD)database project was initiated in 2006 and 43,488 patient data(IPD)for metastatic colorectal cancer from 59 trials have been collected and constructed as the integrated database. The ARCAD-Asia was launched in 2021 and has been actively collecting Asian clinical trials and converted IPD are stored into the integrated database. In addition, the ARCAD-Asian data are transferred to ARCAD and IPD are integrated to ARCAD global database. All the data are shared with 3 data centers of ARCAD-Asia and ARCAD, located in France, the United States and Japan. In the ARCAD database, there are 1,673 IPD treated with placebo in a salvage line setting. We are now planning to utilize placebo IPD as the synthetic control arms(SCAs)to compare the efficacies of active agents. Furthermore, we will continue to collect the Asian IPD and will expand the cancer type, leading to more comprehensive global database.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Asia , Neoplasias Colorrectales/patología , Bases de Datos Factuales , Ensayos Clínicos como Asunto
6.
Gastric Cancer ; 25(1): 197-206, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34468869

RESUMEN

BACKGROUND: In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019). METHODS: Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models. RESULTS: 366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%). CONCLUSION: In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02370498.


Asunto(s)
Paclitaxel , Neoplasias Gástricas , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1 , Unión Esofagogástrica , Humanos , Paclitaxel/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico
7.
Esophagus ; 19(4): 702-710, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35904643

RESUMEN

BACKGROUND: PI3K/AKT/mTOR pathway is frequently overactive in esophageal squamous cell carcinoma (ESCC), making it an attractive treatment target. BKM120 is an oral pan-class I PI3K inhibitor with promising activity in several cancers. We prospectively investigated efficacy, safety, and biomarkers of BKM120 in advanced ESCC. We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. METHODS: BKM120 (100 mg/day) was administered orally in a 28-day cycle. The primary end point was disease control rate (DCR). Tumor samples for all patients were collected for gene alteration analysis in a comprehensive genomic profiling assay. RESULTS: Of 42 patients enrolled, 20 had stable disease and two had confirmed partial response. One ineligible patient was excluded from the primary analysis, which met the primary end point (DCR 51.2%; 95% confidence interval [CI], 35.1-67.1). In the 42 patients, median progression-free survival and overall survival were 2.3 (95% CI 1.8-3.2) and 9.0 (95% CI 6.5-11.4) months, respectively. Common grade 3 or 4 adverse events were rash, anorexia, hyponatremia, and abnormal hepatic function; profiles of these events in this study were similar to those in previous studies of BKM120 monotherapy. No treatment-related deaths occurred. PI3K pathway activation was observed in patients with good clinical response. CONCLUSIONS: BKM120 monotherapy showed promising efficacy and a manageable toxicity profile even in patients with pretreated advanced ESCC. This study showed the potential target PI3K for ESCC, and further confirmatory trial will be necessary to confirm it. Unique ID issued by UMIN: UMIN 000011217.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Humanos , Morfolinas , Fosfatidilinositol 3-Quinasas/metabolismo
8.
Cancer Sci ; 112(11): 4425-4432, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34510657

RESUMEN

Comprehensive genomic profiling enables the detection of genomic biomarkers in advanced solid tumors. However, efficient patient screening for the success of precision oncology remains challenging due to substantial barriers, such as genotyping costs and accessibility to matched therapies. To address these challenges, we launched GI-SCREEN, a nationwide gastrointestinal cancer genomic screening project within the SCRUM-Japan network in 2015 with the specific purpose of matching patients with a diverse portfolio of affiliated interventional targeted therapy trials. Subsequently, we initiated the molecular profiling projects GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2, which incorporate tissue and plasma multiomics approaches to accurately identify patients with advanced solid tumors who would benefit from matched therapies. These projects have led to a significant increase in patient participation in targeted clinical trials and the approval of several therapeutics and companion diagnostics. Additionally, clinicogenomic analyses utilizing the SCRUM-Japan database have provided new insights into the molecular mechanisms of advanced solid tumors. In this review, we describe the path to the realization of cancer precision medicine for patients with advanced solid tumors based on the SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN platforms.


Asunto(s)
ADN Tumoral Circulante/genética , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/terapia , Oncología Médica/métodos , Medicina de Precisión/métodos , Bases de Datos Genéticas , Neoplasias Gastrointestinales/patología , Perfilación de la Expresión Génica/métodos , Marcadores Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Japón , Sistema de Registros
9.
Cancer Sci ; 112(6): 2454-2466, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33759313

RESUMEN

The use of patient-derived xenografts (PDXs) has recently attracted attention as a drug discovery platform with a high predictive clinical efficacy and a preserved tumor heterogeneity. Given the racial differences in genetic variations, it would be desirable to establish a PDX library from Japanese cancer patients on a large scale. We thus tried to construct the Japanese PDX (J-PDX) library with a detailed clinical information for further clinical utilization. Between August 2018 and May 2020, a total of 1126 cancer specimens from 1079 patients were obtained at the National Cancer Center Hospital and National Cancer Center Hospital East, Japan, and were immediately transplanted to immunodeficient mice at the National Cancer Center Research Institute. A total of 298 cross-cancer PDXs were successfully established. The time to engraftment varied greatly by cancer subtypes, especially in the first passage. The engraftment rate was strongly affected by the clinical stage and survival time of the original patients. Approximately 1 year was needed from tumor collection to the time when coclinical trials were conducted to test the clinical utility. The 1-year survival rates of the patients who were involved in establishing the PDX differed significantly, from 95.6% for colorectal cancer to 56.3% for lung cancer. The J-PDX library consisting of a wide range of cancer subtypes has been successfully established as a platform for drug discovery and development in Japan. When conducting coclinical trials, it is necessary to consider the target cancer type, stage, and engraftment rate in light of this report.


Asunto(s)
Neoplasias/mortalidad , Neoplasias/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Niño , Preescolar , Femenino , Humanos , Japón/etnología , Masculino , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Trasplante de Neoplasias , Especificidad de Órganos , Modelación Específica para el Paciente , Adulto Joven
10.
Cancer Sci ; 112(7): 2563-2577, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33990993

RESUMEN

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English.


Asunto(s)
Antineoplásicos/uso terapéutico , Estudios Clínicos como Asunto/normas , Antineoplásicos/farmacología , Desarrollo de Medicamentos/organización & administración , Desarrollo de Medicamentos/normas , Humanos , Japón , Neoplasias/tratamiento farmacológico , Enfermedades Raras/tratamiento farmacológico , Resultado del Tratamiento
11.
Oncologist ; 26(10): e1704-e1729, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34288262

RESUMEN

BACKGROUND: Platinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA. MATERIALS AND METHODS: We conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively. RESULTS: In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination. CONCLUSION: For advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity. IMPLICATIONS FOR PRACTICE: The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica , Humanos , Neoplasias Gástricas/tratamiento farmacológico
12.
Oncologist ; 26(3): e414-e424, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33274542

RESUMEN

BACKGROUND: In the intent-to-treat (ITT) population of the RAINBOW study, objective response rate (ORR) was 28% and 16% in the ramucirumab and control arms, respectively. To further characterize tumor response, we present details on timing and extent of tumor shrinkage, as well as associations with symptom palliation. MATERIALS AND METHODS: Tumor response was assessed with RECIST v1.1, and quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) v3.0. Prespecified and post hoc analyses were conducted in the ITT population, patients with measurable disease, or responders, and included best overall response (BOR), ORR, disease control rate (DCR), duration of response, time to response (TtR), change in tumor size, and associations of QoL with tumor shrinkage and BOR. RESULTS: In both treatment arms, median TtR was 1.5 months. Responses were more durable in the ramucirumab versus control arm (median 4.4 vs. 2.8 months). In patients with measurable disease (78% of ITT), ORR was 36% versus 20%; DCR was 81% versus 61% in the ramucirumab versus control arms. Waterfall plots demonstrated more tumor shrinkage in the ramucirumab versus control arm. Regardless of treatment, tumor response and stable disease were associated with improved or stable QoL, with more tumor shrinkage associated with greater symptom palliation. CONCLUSION: Treatment with ramucirumab plus paclitaxel yielded the highest ORR reported to date for patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma. Additional details demonstrate robustness of tumor response results. The extent of tumor shrinkage is directly associated with symptom palliation and should be considered when evaluating patient needs and treatment selection. Clinical trial identification number. NCT01170663. IMPLICATIONS FOR PRACTICE: Ramucirumab plus paclitaxel is a recognized standard of care as it improves survival for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have been previously treated with recommended first-line therapy. These additional data on tumor response demonstrate a positive association between tumor shrinkage and symptom palliation in a patient population that is often symptomatic. These observations included patients with nonmeasurable disease, a group of patients often underrepresented in clinical trials. This knowledge can inform treatment decisions, which align individual patient characteristics and needs with demonstrated benefits.


Asunto(s)
Neoplasias Gástricas , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Paclitaxel/uso terapéutico , Calidad de Vida , Neoplasias Gástricas/tratamiento farmacológico , Ramucirumab
13.
Jpn J Clin Oncol ; 51(6): 879-885, 2021 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-33561262

RESUMEN

OBJECTIVE: We evaluated the efficacy and safety of first-line S-1 plus cisplatin in combination with cetuximab for Japanese patients with advanced gastric cancer, including gastroesophageal junction adenocarcinoma. METHODS: This open-label, single arm, multicenter, phase 2 trial was conducted to assess first-line cetuximab plus S-1 plus cisplatin for advanced gastric cancer. A total of 40 patients from 10 centers were enrolled. Cetuximab was administered weekly, with the initial infusion at 400 mg/m2 and then 250 mg/m2 each subsequent week. S-1 plus cisplatin chemotherapy was concomitantly conducted in a 5-week cycle: S-1 (40-60 mg, adjusted for body surface area) was given twice daily for 3 consecutive weeks, followed by a 2-week rest period, and cisplatin (60 mg/m2) was given on day 8 of each cycle for a maximum of 8 cycles. Treatment continued until the occurrence of radiographically confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary endpoint was the best overall response. Secondary endpoints included progression-free survival and safety. RESULTS: A total of 40 patients were evaluable. One patient (2.5%) had a complete response; 15 patients (37.5%) had a partial response. The observed overall response rate according to the independent review committee was 40.0% (95% confidence interval, 24.9-56.7; P = 0.7043 [one-sided null hypothesis: overall response rate ≤ 43%]); median PFS was 5.6 months (95% confidence intervals, 4.2-8.3). No adverse events leading to death were reported during the study, and no specific safety concerns were observed. CONCLUSIONS: Overall, the addition of cetuximab to S-1 plus cisplatin was well tolerated in patients with advanced gastric cancer but provided no additional clinical benefit in this study. ClinicalTrials.gov identifier: NCT01388790.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cetuximab/administración & dosificación , Cisplatino/administración & dosificación , Ácido Oxónico/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Tegafur/administración & dosificación , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Cetuximab/efectos adversos , Cetuximab/uso terapéutico , Cisplatino/efectos adversos , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Ácido Oxónico/efectos adversos , Inducción de Remisión , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tegafur/efectos adversos , Resultado del Tratamiento
14.
Esophagus ; 18(4): 835-843, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33993388

RESUMEN

BACKGROUND: In the phase II ATTRACTION-1 study, nivolumab demonstrated a promising antitumor activity among Japanese patients with treatment-refractory advanced esophageal cancer. Here, we report the follow-up results of ATTRACTION-1 of > 5 years. METHODS: We enrolled patients with esophageal cancer that was refractory or intolerant to a standard chemotherapy. Then, nivolumab (3 mg/kg) was administered every 2 weeks. The primary endpoint was a centrally assessed objective response rate. RESULTS: Nivolumab was administered to 65 patients with esophageal squamous-cell carcinoma (ESCC). The centrally assessed objective response rate was 17.2%. The overall survival rates at 3 and 5 years were 10.9% and 6.3%, respectively. Three-year survivors tended to have more reduced target lesions. A total of 63.1% of the patients exhibited treatment-related adverse events, and no new safety signal was observed. Patients with select adverse events tended to have better overall survival than those without. No apparent chronological order was observed between the first response and the onset of select adverse events. CONCLUSION: Our follow-up analysis of more than 5 years is currently the longest and is the first to demonstrate that nivolumab has long-term efficacy and safety for advanced ESCC.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Esofágicas/patología , Estudios de Seguimiento , Humanos , Japón/epidemiología , Nivolumab/efectos adversos
15.
Cancer Sci ; 111(5): 1676-1684, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32160365

RESUMEN

The long-term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment-refractory advanced esophageal cancer who participated in an open-label, single-arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand-1 (PD-L1) and CD8+ status of tumors and tumor-infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end-points included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD-L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut-off 1%) and OS (11.33 vs 6.24 months, cut-off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long-term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD-L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Nivolumab/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/administración & dosificación , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Antígenos CD8/metabolismo , Resistencia a Antineoplásicos , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Estudios de Seguimiento , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Japón , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Nivolumab/administración & dosificación , Tasa de Supervivencia , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos
16.
Br J Cancer ; 122(3): 413-420, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31761900

RESUMEN

BACKGROUND: Tumour microenvironments can differ according to intratumoural locations. We investigated the immune status at different locations in primary tumours and its clinical significance in oesophageal squamous cell carcinoma (ESCC). METHODS: The number of CD8+ tumour-infiltrating immune cells (TIICs) and PD-1+ TIICs, and PD-L1 expression on tumour cells (PD-L1TC) were immunohistochemically examined in the surface (Surf), centre (Cent) and invasive front (Inv) of tumours surgically resected from 192 patients with ESCC. RESULTS: The PD-L1+ rate was lower in Inv than in Cent (12.0% vs. 18.2%, P = 0.012), although the numbers of CD8+ TIICs and PD-1+ TIICs were comparable among intratumoural locations. High numbers of CD8+ and PD-1+ TIICs and positive PD-L1TC were related to better overall survival (OS) only in Surf and Cent (CD8: P = 0.012 in Surf, 0.018 in Cent, and 0.165 in Inv; PD-1: P = 0.028 in Surf, 0.021 in Cent, and 0.208 in Inv; and PD-L1: 0.044 in Surf, 0.026 in Cent, and 0.718 in Inv). Positive PD-L1TC in Surf and/or Cent but not in Inv demonstrated a strong tendency toward better OS (P = 0.053). CONCLUSIONS: Immune microenvironments according to the intratumoural location have different effects on the survival of patients with ESCC.


Asunto(s)
Neoplasias Esofágicas/inmunología , Carcinoma de Células Escamosas de Esófago/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Modelos de Riesgos Proporcionales , Tasa de Supervivencia
17.
Invest New Drugs ; 38(5): 1390-1399, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-31907738

RESUMEN

Background Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3-6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Ácido Oxónico/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Tegafur/administración & dosificación , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/sangre , Inhibidores de la Angiogénesis/farmacocinética , Anticuerpos/sangre , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Pueblo Asiatico , Combinación de Medicamentos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/metabolismo , Ácido Oxónico/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/sangre , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/sangre , Proteínas Recombinantes de Fusión/farmacocinética , Tegafur/efectos adversos , Resultado del Tratamiento
18.
Lancet ; 392(10142): 123-133, 2018 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-29880231

RESUMEN

BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. METHODS: This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. INTERPRETATION: Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Unión Esofagogástrica , Paclitaxel/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Neoplasias Gástricas/patología , Tasa de Supervivencia , Resultado del Tratamiento
19.
BMC Cancer ; 19(1): 255, 2019 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-30898102

RESUMEN

BACKGROUND: In the era of genome-guided personalized cancer treatment, we must understand chemotherapy-induced genomic changes in tumors. This study evaluated whether adjuvant FOLFOX chemotherapy modifies the mutational profile of recurrent colorectal cancer (CRC). METHODS: Whole exome sequencing was performed on samples from primary CRC tumors, untreated metastatic tumors, and recurrent tumors following adjuvant FOLFOX chemotherapy. The samples were resected from four patients. RESULTS: The number of mutations or the mutation spectrum in individual patients was nearly identical. Copy number variants persisted regardless of FOLFOX therapy administration. The genomic signature of oxaliplatin exposure (G > T/C > A, T > A/A > T) was not enriched after FOLFOX chemotherapy. Overlapping single nucleotide variants (SNVs) and indels remained in 26-65% of the patient-matched tumor samples. One patient harbored an AKT1 E17K mutation in the recurrent tumor, whereas PIK3CA E542K and E88Q mutations were detected in the primary and untreated metastatic tumor samples. Genes related to intracellular Ca2+ homeostasis were enriched among the genes uniquely mutated after FOLFOX chemotherapy. CONCLUSIONS: We found that the mutation rates, mutation spectrum, and copy number variants were nearly identical regardless of the administration of FOLFOX therapy in the four CRC cases. The mutational discordance between the patient-matched tumor samples is likely caused by tumor heterogeneity and chemotherapy-induced clonal selection. These findings might be useful as pilot data for larger studies to clarify the changes in the mutational landscape induced by adjuvant FOLFOX chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Recurrencia Local de Neoplasia/genética , Anciano , Quimioterapia Adyuvante/métodos , Evolución Clonal/efectos de los fármacos , Colectomía , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Variaciones en el Número de Copia de ADN/genética , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Masculino , Mutación/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Compuestos Organoplatinos/uso terapéutico , Proyectos Piloto , Medicina de Precisión/métodos , Proctectomía , Secuenciación del Exoma
20.
Gastric Cancer ; 22(4): 803-816, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30706247

RESUMEN

BACKGROUND: Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. METHODS: Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. RESULTS: Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68-1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94-2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. CONCLUSIONS: Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. CLINICAL TRIALS REGISTRATION: NCT01641939 ( https://clinicaltrials.gov/ct2/show/NCT01641939 ).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Unión Esofagogástrica/metabolismo , Polimorfismo Genético , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Ado-Trastuzumab Emtansina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Docetaxel/administración & dosificación , Unión Esofagogástrica/efectos de los fármacos , Unión Esofagogástrica/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Pronóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Tasa de Supervivencia , Adulto Joven
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