RESUMEN
BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.
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Neoplasias , Trombocitopenia , Humanos , China , Estudios Transversales , Interleucina-11/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Trombopoyetina/uso terapéutico , Adulto Joven , AdultoRESUMEN
BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Adolescente , Adulto , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Tirosina Quinasas/uso terapéutico , Quinasa de Linfoma Anaplásico/uso terapéutico , Proteínas Proto-Oncogénicas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.
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Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Unión Esofagogástrica , Neoplasias Gástricas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoglobulina G/inmunología , Método Doble Ciego , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Oxaloacetatos/administración & dosificación , Oxaloacetatos/efectos adversosRESUMEN
BACKGROUND: KEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer. METHODS: This randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety. RESULTS: Between February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively. CONCLUSIONS: Definitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.
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Anticuerpos Monoclonales Humanizados , Neoplasias Esofágicas , Paclitaxel , Neoplasias Gástricas , Anticuerpos Monoclonales Humanizados/efectos adversos , China , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Humanos , Paclitaxel/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patologíaRESUMEN
Importance: Standard first-line therapy for advanced or metastatic esophageal carcinoma is chemotherapy, but the prognosis remains poor. Camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) showed antitumor activity in previously treated advanced or metastatic esophageal squamous cell carcinoma. Objective: To evaluate the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as a first-line treatment in advanced or metastatic esophageal squamous cell carcinoma. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (ESCORT-1st study) enrolled patients from 60 hospitals in China between December 3, 2018, and May 12, 2020 (final follow-up, October 30, 2020). A total of 751 patients were screened and 596 eligible patients with untreated advanced or metastatic esophageal squamous cell carcinoma were randomized. Interventions: Patients were randomized 1:1 to receive either camrelizumab 200 mg (n = 298) or placebo (n = 298), combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were given intravenously every 3 weeks. Main Outcomes and Measures: Coprimary end points were overall survival (significance threshold, 1-sided P < .02) and progression-free survival (significance threshold, 1-sided P < .005). Results: Of the 596 patients randomized (median age, 62 years [interquartile range, 56-67 years]; 523 men [87.8%]), 1 patient in the placebo-chemotherapy group did not receive planned treatment. A total of 490 patients (82.2%) had discontinued the study treatment. The median follow-up was 10.8 months. The overall survival for the camrelizumab-chemotherapy group was a median of 15.3 months (95% CI, 12.8-17.3; 135 deaths) vs a median of 12.0 months (95% CI, 11.0-13.3; 174 deaths) for the placebo-chemotherapy group (hazard ratio [HR] for death, 0.70 [95% CI, 0.56-0.88]; 1-sided P = .001). Progression-free survival for camrelizumab plus chemotherapy was a median of 6.9 months (95% CI, 5.8-7.4; 199 progression or deaths) vs 5.6 months (95% CI, 5.5-5.7; 229 progression or deaths) for the placebo-chemotherapy group (HR for progression or death, 0.56 [95% CI, 0.46-0.68]; 1-sided P < .001). Treatment-related adverse events of grade 3 or higher occurred in 189 patients (63.4%) in the camrelizumab-chemotherapy group and 201 (67.7%) in the placebo-chemotherapy group, including treatment-related deaths among 9 patients (3.0%) and 11 patients (3.7%), respectively. Conclusions and Relevance: Among patients with advanced or metastatic esophageal squamous cell carcinoma, the addition of camrelizumab to chemotherapy, compared with placebo and chemotherapy, significantly improved overall survival and progression-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03691090.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Método Doble Ciego , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/secundario , Femenino , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Placebos , Supervivencia sin Progresión , Calidad de Vida , Análisis de SupervivenciaRESUMEN
BACKGROUND: Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients. METHODS: ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants. FINDINGS: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage). INTERPRETATION: Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China. FUNDING: Jiangsu Hengrui Medicine.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Irinotecán/administración & dosificación , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , China , Progresión de la Enfermedad , Docetaxel/efectos adversos , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/secundario , Femenino , Humanos , Irinotecán/efectos adversos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Transducción de Señal , Factores de Tiempo , Adulto JovenRESUMEN
To investigate the effect of Fibrillin 2 (FBN2) expression on the invasion and migration of lung cancer cells, and the underlying mechanism. Protein and mRNA expressions of FBN2 were assayed. The relationship between FBN2 protein expression and clinical characteristics of lung cancer patients was analyzed. Correlation between FBN2 expression level and patient survival time was analyzed. Moreover, the mRNA and protein expression of FBN2 in lung cancer cells and human normal lung epithelial cells were assayed. After constructing low-expressing FBN2 cells, the cell proliferation, clone formation, migration and invasion capabilities were tested. Lung cancer cells proliferation with low FBN2 expression in nude mice was measured with a nude mouse tumorigenic experiment. The mRNA and protein expressions of FBN2 in lung cancer tissues were significantly higher than those in para-cancerous tissues (p<0.05). FBN2 protein expression was significantly correlated with TNM stage, lymph node metastasis and histological type (p<0.05). Survival time was markedly reduced in patients with high FBN2 expression (p<0.001). The expressions of FBN2 mRNA and protein were markedly higher in lung cancer cells than in human normal lung epithelial cells. The proliferation, migration and invasion of lung cancer cells were significantly inhibited by FBN2 knockdown. The FBN2 knockdown significantly inhibited the protein expressions of p-FAK, p-MEK and p-ERK. FBN2 is highly expressed in lung cancer tissues, and as an oncogene, it affects the pathogenesis of lung cancer. The knockdown of the expression of FBN2 significantly inhibits the proliferation, invasion and migration abilities of lung cancer cells.
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Movimiento Celular/genética , Fibrilina-2/genética , Técnicas de Silenciamiento del Gen , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Anciano , Línea Celular Tumoral , Proliferación Celular/genética , Células Clonales , Transición Epitelial-Mesenquimal/genética , Femenino , Fibrilina-2/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Persona de Mediana Edad , Mutación/genética , Invasividad Neoplásica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de SupervivenciaRESUMEN
BACKGROUND: Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase inhibitor. In an exploratory study, the combination of tucidinostat with exemestane showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone receptor-positive breast cancer. To build on these findings, we aimed to assess the efficacy and safety of this combination in a randomised trial in a larger population of postmenopausal patients with advanced, hormone receptor-positive breast cancer. METHODS: We did the randomised, double-blind, placebo-controlled, phase 3 ACE trial at 22 specialist cancer centres in China. Eligible patients were postmenopausal women (aged ≥60 years or aged <60 years if their serum follicle-stimulating hormone and oestradiol concentrations were within postmenopausal ranges) with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate haematological and biochemical parameters. Endocrine therapy did not have to be the most recent therapy before randomisation, but recurrence or progression after the most recent therapy was a prerequisite. Patients were randomly assigned (2:1) by a dynamic randomisation scheme via an interactive web-response system to receive 30 mg oral tucidinostat or placebo twice weekly. All patients in both groups also received 25 mg oral exemestane daily. Randomisation was stratified according to the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy analyses were done in the full analysis set population, comprising all patients who received at least one dose of any study treatment, and safety analyses were done in all patients who received at least one dose of any study treatment and for whom at least one safety case report form was available. This study is registered with ClinicalTrials.gov, number NCT02482753. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. FINDINGS: Between July 20, 2015, and June 26, 2017, 365 patients were enrolled and randomly assigned, 244 to the tucidinostat group and 121 to the placebo group. The median duration of follow-up was 13·9 months (IQR 9·8-17·5). Investigator-assessed median progression-free survival was 7·4 months (95% CI 5·5-9·2) in the tucidinostat group and 3·8 months (3·7-5·5) in the placebo group (HR 0·75 [95% CI 0·58-0·98]; p=0·033). The most common grade 3 or 4 adverse events in either group were neutropenia (124 [51%] of 244 patients in the tucidinostat group vs three [2%] of 121 patients in the placebo group), thrombocytopenia (67 [27%] vs three [2%]), and leucopenia (46 [19%] vs three [2%]). Serious adverse events of any cause occurred in 51 (21%) of 244 patients in the tucidinostat group and seven (6%) of 121 patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3-4 haematological adverse events were more common in the tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients. FUNDING: Chipscreen Biosciences.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Recuperativa , Aminopiridinas/administración & dosificación , Androstadienos/administración & dosificación , Benzamidas/administración & dosificación , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Posmenopausia , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins upon alcohol induction. In total, high expression of BRF1 (P = 0.010) and positive cell infiltration of MPO (P = 0.004) in tumor tissues as well as positive expression of BRCA1 (P < 0.001) in para-tumor tissues were more frequent in GC patients with hazardous or harmful alcohol consumption habits. BRF1 (P = 0.021), BRCA2 (P < 0.001), and MPO (P = 0.039) were independent prognostic factors for disease-free survival. BRCA1 (P = 0.005) and BRCA2 (P < 0.001) also were identified as independent prognostic factors for overall survival. Furthermore, BRCA2 was an independent unfavorable prognostic factor for disease-free survival and overall survival (P < 0.001) in GC patients who underwent platinum-based adjuvant chemotherapy. BRF1, BRCA1/2, and MPO are DNA repair-related biomarkers, induced by alcohol with prognostic value in GC patients.
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Adenocarcinoma/diagnóstico , Alcoholismo/complicaciones , Biomarcadores de Tumor/metabolismo , Reparación del ADN , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/etiología , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Proteína BRCA2/metabolismo , Biopsia , Quimioterapia Adyuvante , ADN de Neoplasias/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Peroxidasa/metabolismo , Pronóstico , Neoplasias Gástricas/etiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Resultado del Tratamiento , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. The clinical prognostic implications of tumor-associated macrophages (TAMs) in DLBCL remain controversial and the correlation between TAMs and peripheral absolute monocyte count (AMC) has not yet been elucidated. METHODS: In 221 untreated, newly diagnosed patients with DLBCL, we evaluated the prognostic value of TAMs using immunohistochemical analysis, as well as the association of TAMs and AMC. RESULTS: We found that high CD68 or high CD163 expression was correlated with clinicopathological characteristics, high CD163 expression was an adverse predictor for both overall survival (OS) [hazard ratio (HR) = 2.265, P = 0.005] and progression- free survival (PFS) (HR = 1.925, P = 0.017) in patients with DLBCL. Patients with high CD68 or high CD163 expression had significantly poorer OS and PFS than those with low CD68 or low CD163 expression, respectively (CD68: OS: P<0.001, PFS: P<0.001; CD163: OS: P<0.001, PFS: P<0.001), even in the rituximab era. Moreover, high-risk patients could be further identified by the expression of CD68 or CD163, especially in those classified as low/intermediate risk by International Prognostic Index (IPI). Furthermore, the significant positive correlation was also detected between CD68 expression or CD163 expression and AMC (r = 0.256, P<0.001; r = 0.303, P<0.001). CONCLUSIONS: Patients with high expression of TAMs tend to have poorer OS and PFS, even in the rituximab era, and have positive correlation with AMC. Therefore, the peripheral AMC is a useful prognostic marker reflecting the status of the tumor microenvironment (TME) in DLBCL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Macrófagos/metabolismo , Monocitos/metabolismo , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Recuento de Leucocitos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad , Monocitos/patología , Pronóstico , Receptores de Superficie Celular/metabolismo , Rituximab/administración & dosificaciónRESUMEN
BACKGROUND: DNA aneuploidy has attracted growing interest in clinical practice. Nevertheless, its prognostic value in gastric cancer patients remains controversial. This meta-analysis aims to explore the impact of DNA ploidy status on the survival of gastric cancer patients. METHODS: We used PubMed and Web of Science databases to retrieve relevant articles. The correlation between DNA aneuploidy and the clinicopathological features of gastric cancer, such as stage, depth of invasion (T), lymph node metastasis (N), distant metastasis (M), differentiation (G), tumor types (Lauren classification) and overall survival (OS) were evaluated. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were collected carefully from each article OS was presented with HRs. The relationships between DNA aneuploidy and each characteristic were analyzed using risk ratios (RR) and a 95% confidence interval (CI). Significance was established using P < 0.05. Funnel plot was conducted to detect the publication bias. RESULTS: After careful selection, 25 studies involving 3449 cases were eligible for further analyses. Patients with DNA aneuploidy were considered at risk of more advanced stages (stage III-IV vs. stages I-II, RR = 1.23; 95% CI, 1.07 to 1.42; P = 0.003), lymph node metastasis (N+ vs. N-: RR = 1.43; 95% CI, 1.12 to 1.82, P = 0.004), and intestinal tumor type (intestinal vs. diffuse: RR = 1.45; 95% CI, 1.02 to 2.06; P = 0.04). And an adverse relation was observed between DNA aneuploidy and tumor differentiation. While no association was found between DNA aneuploidy and distant metastasis (P = 0.42) nor depth of tumor invasion (P = 0.86). Regarding overall survival, aneuploid tumors were associated with worse survival in all patients (P < 0.00001). CONCLUSIONS: We found that DNA aneuploidy was an important predictor for gastric cancer patients, and should be used as a potential biomarker for further classification in gastric cancer.
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Aneuploidia , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Intervalos de Confianza , ADN de Neoplasias , Humanos , Metástasis Linfática , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Gástricas/patologíaRESUMEN
Aberrant monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) expression in malignant tissues have been reported; however, their role in hematological malignancies prognosis remains little known. The aim of this study was to investigate the prognostic value of MCP-1 and CCR2 expression in patients with diffuse large B cell lymphoma (DLBCL). The study included 221 patients with DLBCL. MCP-1 and CCR2 expression was analyzed by immunohistochemical staining and its correlations with clinicopathologic features and prognosis were evaluated. High expression of MCP-1 or CCR2 was correlated with clinicopathological characteristics, and an adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) of DLBCL patients. Also, significant positive correlation between MCP-1 and CCR2 expression was revealed (r = 0.545, P < 0.001). Patients with high MCP-1 or high CCR2 expression had significantly poorer OS and PFS than those with low MCP-1 or low CCR2 expression (OS: P < 0.001, P < 0.001; PFS: P < 0.001, P < 0.001), respectively, even in the rituximab era, and MCP-1 or CCR2 expression could further identify high-risk patients otherwise classified as low/intermediate risk by the International Prognostic Index (IPI) alone. Furthermore, incorporation of MCP-1 or CCR2 expression into the IPI score could improve prognostic value for OS. This is the first report describing the clinicopathological features and survival outcome according to expression of MCP-1 and CCR2 in DLBCL.
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Quimiocina CCL2/sangre , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso , Proteínas de Neoplasias/sangre , Receptores CCR2/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
BACKGROUND: Despite the use of modern immunochemotherapy regimens, a significant proportion of diffuse large B-cell lymphoma (DLBCL) patients will relapse. We proposed absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) as a new prognostic factor in relapsed or primary refractory DLBCL. METHODS: We retrospectively analyzed 163 patients who have been diagnosed with relapsed or primary refractory DLBCL. The overall survival (OS) and progression-free survival (PFS) were measured from the time of first relapse. The Cox proportional hazards model was used to evaluate ALC/AMC ratio as prognostic factors for OS and PFS. RESULTS: On univariate and multivariate analysis performed with factors included in the saaIPI, early relapse, prior exposure to rituximab and autologous stem-cell transplantation (ASCT), the ALC/AMC ratio at the time of first relapse remained an independent predictor of PFS and OS (PFS: P < 0.001; OS: P < 0.001). Patients with lower ALC/AMC ratio (<2.0) had lower overall response rate, 1-year PFS and 2-year OS rate compared with those with higher ALC/AMC ratio (≥2.0). Moreover, the ALC/AMC ratio can provide additional prognostic information when superimposed on the saaIPI. CONCLUSIONS: Lower ALC/AMC ratio at the time of first relapse is a adverse prognostic factor for OS and PFS in relapsed or primary refractory DLBCL, and leads to the identification of high-risk patients otherwise classified as low/intermediate risk by the saaIPI alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos/inmunología , Linfoma de Células B Grandes Difuso/terapia , Monocitos/inmunología , Trasplante de Células Madre , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Recuento de Linfocitos , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/mortalidad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Endostatin is a potent endogenous angiogenic inhibitor with implicated antitumor activity. However, efficacy of recombinant human endostatin (rhES) in clinical trials is controversial, and application of rhES in treatment of metastatic melanoma awaits further investigations. This phase II trial evaluated the efficacy and safety of a soluble and stable rhES (Endostar) plus dacarbazine in patients with metastatic melanomas that contains no mutations in c-kit and BRAF genes. A total of 110 patients received placebo plus dacarbazine (250 mg/m², n = 54) or Endostar (7.5 mg/m²) plus dacarbazine (250 mg/m², n = 56). The primary end points were progression-free survival (PFS) and overall survival (OS). Median PFS in the Endostar plus dacarbazine arm was 4.5 months versus 1.5 months in the placebo plus dacarbazine arm (hazard ratio (HR) = 0.578; P = 0.013). There were statistically significant improvements in OS (median, 12.0 months versus 8.0 months; HR, 0.522; P = 0.005) in favor of the Endostar plus dacarbazine arm. The regimen was generally well tolerated and had a manageable toxicity profile. Our trial suggests that Endostar plus dacarbazine is well tolerated in patients with metastatic melanoma harboring no genetic mutations popular for targeted therapy and yields a significant improvement in PFS and OS.
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Antineoplásicos/uso terapéutico , Endostatinas/uso terapéutico , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Splicing factor B subunit 4 (SF3B4) has been confirmed to participate in the progression of many cancers and is considered to be a potential target for non-small cell lung cancer (NSCLC). Thus, the role and molecular mechanism of SF3B4 in NSCLC progression deserves further study. METHODS: Quantitative real-time PCR and western blot were employed to detect the mRNA and protein levels of SF3B4, Sm-like protein 4 (LSM4) and methyltransferase-like 3 (METTL3). Cell proliferation, apoptosis, invasion, migration and stemness were tested by cell counting kit-8, colony formation, flow cytometry, transwell, wound healing, and sphere formation assays. The interaction between SF3B4 and METTL3 or LSM4 was confirmed by MeRIP, RIP and Co-IP assays. Mice xenograft models were constructed to assess the effects of METTL3 and SF3B4 on NSCLC tumorigenesis. RESULTS: SF3B4 had high expression in NSCLC tissues and was associated with the shorter overall survival of NSCLC patients. Knockdown of SF3B4 suppressed NSCLC cell proliferation, invasion, migration and stemness, while inducing apoptosis. METTL3 promoted SF3B4 mRNA stability by m6A modification, and its knockdown inhibited NSCLC cell growth, metastasis and stemness by downregulating SF3B4. SF3B4 could interact with LSM4, and sh-SF3B4-mediated the inhibition on NSCLC cell functions could be reversed by LSM4 overexpression. In addition, reduced METTL3 expression restrained NSCLC tumor growth, and this effect was reversed by SF3B4 overexpression. CONCLUSION: METTL3-stablized SF3B4 promoted NSCLC cell growth, metastasis and stemness via positively regulating LSM4.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Humanos , Ratones , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Pulmonares/genética , Metiltransferasas/genética , Ribonucleoproteínas Nucleares Pequeñas , Factores de Empalme de ARN/genéticaRESUMEN
BACKGROUND: There is a need to determine lenvatinib-associated real-world adverse events (AEs) as its adverse effects may result in its discontinuation. RESEARCH DESIGN AND METHODS: Lenvatinib-associated AEs were analyzed and quantified and risk signals from the first quarter of 2015 to the fourth quarter of 2023 were detected through data mining. Potential targets for lenvatinib-associated cholecystitis, cholangitis, and hepatic encephalopathy were identified by data mining. RESULT: 68 Preferred Terms (PTs) with an important imbalance were kept. Unexpected AEs, such as immune-mediated hepatitis, portal vein thrombosis and adrenal insufficiency were associated with the use of lenvatinib use. lenvatinib alone was more strongly associated with adrenal insufficiency than lenvatinib and pembrolizumab combination. Hepatic encephalopathy was more strongly correlated with drug use when Lenvatinib was administered to male patients with hepatocellular carcinoma. Most AEs occurred during the first month after treatment, with a median onset time of 41 days. FGFR4, PDGFRA, and KIT (Lenvatinib targets) are potentially linked to cholecystitis, cholangitis, and hepatic encephalopathy. CONCLUSIONS: We identified Lenvatinib-associated AEs and discovered new AEs that will be useful for clinical monitoring and risk assessment.
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To investigate immune checkpoint inhibitors (ICIs) induced pancreatic injury (ICIPI), the prognostic effect of COVID-19 vaccine on cancer patients, and whether COVID-19 vaccine increases the incidence of ICIPI. We conducted a retrospective study of 256 stage IV cancer patients treated with ICIs at The First Affiliated Hospital of Anhui Medical University from January 2020 to November 2022. Data collected included pancreatic enzyme levels, treatment outcomes, and vaccination status. Statistical significance was determined using the χ2 test and Kaplan-Meier method (p < .05). Compared to the control group, the vaccinated group (p < .0001) and the group with elevated pancreatic enzyme levels (p = .044) demonstrated higher disease control rates, indicating a direct benefit of vaccination and enzyme monitoring on treatment outcomes. Additionally, vaccinated patients demonstrated longer overall survival versus unvaccinated patients (23.9 months [95% CI, 22.3-25.5] vs 23.6 months [95% CI, 21.1-26.2], HR = 0.45 [95% CI, 0.24-0.86], p = .015) and progression-free survival (17.2 months [95% CI, 14.3-20.1] vs 13.7 months [95% CI, 11.3-16.1], HR = 0.54 [95% CI, 0.36-0.82], p = .004). Importantly, the analysis revealed no significant association between vaccination and pancreatic injury (p = .46). Monitoring pancreatic enzymes can effectively evaluate the therapeutic impact in patients using ICIs. Patients vaccinated against COVID-19 experience better immunotherapy outcomes without an increased risk of ICIPI.
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Vacunas contra la COVID-19 , COVID-19 , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , COVID-19/prevención & control , COVID-19/mortalidad , Vacunas contra la COVID-19/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Páncreas/patología , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Cancer is characterized by unlimited proliferation and metastasis, and traditional therapeutic strategies usually result in the acquisition of drug resistance, thus highlighting the need for more personalized treatment. mRNA vaccines transfer the gene sequences of exogenous target antigens into human cells through transcription and translation to stimulate the body to produce specific immune responses against the encoded proteins, so as to enable the body to obtain immune protection against said antigens; this approach may be adopted for personalized cancer therapy. Since the recent coronavirus pandemic, the development of mRNA vaccines has seen substantial progress and widespread adoption. In the present review, the development of mRNA vaccines, their mechanisms of action, factors influencing their function and the current clinical applications of the vaccine are discussed. A focus is placed on the application of mRNA vaccines in cancer, with the aim of highlighting unique advances and the remaining challenges of this novel and promising therapeutic approach.
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Vacunas contra el Cáncer , Neoplasias , Desarrollo de Vacunas , Vacunas de ARNm , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , COVID-19/prevención & control , COVID-19/inmunología , ARN Mensajero/genética , ARN Mensajero/inmunología , Medicina de Precisión/métodos , Inmunoterapia/métodosRESUMEN
OBJECTIVE: To explore the efficacy of serplulimab plus chemotherapy in esophageal squamous cell carcinoma (ESCC) patients with liver metastases. METHODS: A post hoc exploratory analysis of ASTRUM-007 study was performed, focusing on the association between the liver metastases status and the clinical outcomes. A systematic literature search of electronic databases was conducted to identify eligible randomized controlled trials for the meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for PFS according to liver metastases were performed. RESULTS: The post hoc analysis of ASTRUM-007 showed that although patients with liver metastases had a worse prognosis comparing with the non-liver metastases patients in both treatment arms (serplulimab plus chemotherapy arm: median PFS, 5.7 vs. 6.6 months, HR 1.57 [95% CI, 1.15-2.13]; median OS, 13.7 vs. 15.3 months, HR 1.48 [95% CI, 1.09-1.98]; placebo plus chemotherapy arm: median PFS, 4.3 vs. 5.5 months, HR 1.58 [95% CI, 1.01-2.39]; median OS, 10.3 vs. 11.2 months, HR 1.32 [95% CI, 0.84-2.00]), OS and PFS benefits derived from serplulimab plus chemotherapy versus placebo plus chemotherapy in this study were observed in both patients with liver metastases (HR of PFS: 0.60; 95% CI, 0.37-0.97; HR of OS: 0.68; 95% CI, 0.43-1.11) and the non-liver metastases patients (HR of PFS: 0.62; 95% CI, 0.49-0.80; HR of OS: 0.69; 95% CI, 0.55-0.87) with similar magnitude. Three randomized controlled trials were included in the meta-analysis. Pooled HRs demonstrated that the addition of anti-PD-1 antibodies significantly improved PFS compared to chemotherapy alone regardless of liver metastases status. CONCLUSIONS: This study reveals that the presence of liver metastases is a poor prognostic factor but does not affect the improvements in both PFS and OS brought by adding PD-1 blockade to chemotherapy in ESCC patients. Predictive biomarkers for survival in these patients warrant further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/secundario , Carcinoma de Células Escamosas de Esófago/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Anciano , Resultado del Tratamiento , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificaciónRESUMEN
BACKGROUND: The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. METHODS: Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo, both in combination with up to six cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were administered intravenously every 3 weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. FINDINGS: As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6 months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p < 0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. CONCLUSIONS: The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.