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1.
Liver Cancer ; 10(5): 500-509, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34721511

RESUMO

Introduction: In a multicenter, open-label, parallel-group, randomized, phase 2 study for pretreated advanced hepatocellular carcinoma (HCC), camrelizumab showed potent antitumor activity and acceptable safety profile. The aim of this report was to provide long-term data and evaluate potential benefit of treatment with camrelizumab beyond progression. Methods: From November 15, 2016, to November 16, 2017, 217 patients received camrelizumab 3 mg/kg intravenously every 2 or 3 weeks. Treatment beyond first Response Evaluation Criteria in Solid Tumors (RECIST)-defined progression (TBP) with camrelizumab was allowed. Results: At data cutoff of December 16, 2019 (>2 years after the last patient enrollment; median duration of follow-up, 13.2 months [IQR 5.7-25.8]), 14 (43.8%) of the 32 responses per blinded independent central review were ongoing. The median duration of response was not reached (range 2.5-30.5 + months). The ongoing response rates at 12, 18, and 24 months were 68.3% (95% confidence interval [CI] 47.7-82.2), 59.8% (95% CI 38.8-75.6), and 53.1% (95% CI 31.0-71.0), respectively. The median overall survival (OS) was 14.2 months (95% CI 11.5-16.3). The 18- and 24-month OS rates were 41.3% (95% CI 34.6-47.9) and 33.7% (95% CI 27.3-40.2), respectively. Of the 172 patients who experienced RECIST-defined progression per investigator, 102 received TBP, while 70 did not (non-TBP). The median OS was 16.9 months (95% CI 13.3-22.6) in the TBP group versus 9.4 months (95% CI 5.8-14.8) in the non-TBP group, and the 18- and 24-month OS rates were 47.5% (95% CI 37.3-56.9) versus 33.1% (95% CI 22.3-44.3) and 38.8% (95% CI 29.2-48.4) versus 23.2% (95% CI 13.8-34.1), respectively. No new safety signals of camrelizumab were observed. Conclusions: With prolonged follow-up, camrelizumab continues to demonstrate the durable response and long survival in pretreated advanced HCC patients with manageable toxicities, especially in those who continued the treatment beyond first RECIST-defined progression.

3.
BMC Gastroenterol ; 21(1): 398, 2021 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-34688250

RESUMO

BACKGROUND: Larotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend an appropriate dose for its further study. METHODS: Patients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8 weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC). RESULTS: 81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI 4.9-10.2) months and 3.4 (95% CI 2.4-3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs. CONCLUSIONS: Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression. TRIAL REGISTRATION: This trial was retrospectively registered on 25/03/2019, NCT03888092. https://clinicaltrials.gov/ct2/show/NCT03888092 .


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias Pulmonares , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/efeitos adversos
4.
JAMA ; 326(10): 916-925, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34519801

RESUMO

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.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Método Duplo-Cego , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Placebos , Intervalo Livre de Progressão , Qualidade de Vida , Análise de Sobrevida
5.
Liver Cancer ; 10(4): 296-308, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34414118

RESUMO

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported. Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population. Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25-0.76) and for PFS was 0.60 (95% CI, 0.40-0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2-8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6-4.8) with sorafenib. Grade 3-4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3-4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent. Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.

6.
Onco Targets Ther ; 14: 4439-4450, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408440

RESUMO

Objective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy. Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups. Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45-0.77, P<0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17-0.30; P<0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group. Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM. ClinicalTrialsgov Identifier: NCT02314819.

7.
Cancer ; 127(21): 3975-3984, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34355801

RESUMO

BACKGROUND: Several clinical studies of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) therapy as a second-line treatment for biliary tract cancer (BTC) have shown modest efficacy. In this study, surufatinib was evaluated as a second-line VEGFR therapy in patients with BTC. METHODS: This was a single-arm, multicenter, open-label phase 2 study conducted in China. The study enrolled eligible patients with BTC, who had received surufatinib monotherapy as second-line treatment, at a dose of 300 mg, once daily, in 28-day cycles. Tumor assessments were performed every 8 weeks (±7 days) according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: As of November 30, 2018, 39 patients with BTC, including 29 (74.4%) with intrahepatic cholangiocarcinoma, 5 (12.8%) with extrahepatic cholangiocarcinoma, and 5 (12.8%) with gallbladder cancer, were enrolled and treated with surufatinib. The 16-week progression-free survival rate was 46.33% (95% CI, 24.38-65.73), with median progression-free survival of 3.7 months and median overall survival of 6.9 months. In addition, results from subgroup and post hoc analyses revealed that patients with the proper tumor locations or appropriate levels of serum biomarkers might receive greater clinical benefits. The top 3 treatment-related adverse events with severity of grade ≥3 included blood bilirubin increased (20.5%), hypertension (17.9%), and proteinuria (12.8%). CONCLUSIONS: When applied in the treatment of patients with BTC, surufatinib monotherapy has offered moderate clinical efficacy and shown expected tolerability and safety profiles.

8.
Front Oncol ; 11: 684867, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327136

RESUMO

Objective: This study aims to assess the efficacy and safety of penpulimab (a humanized anti-PD-1 IgG1 antibody) with anlotinib in the first-line treatment of Chinese patients with uHCC. Methods: In this open-label multicenter phase Ib/II trial, patients with histologically or cytologically confirmed uHCC, without previous systemic treatment, aged 18-75 years old, classified as BCLC stage B (not amenable for locoregional therapy) or C, with Child-Pugh score ≤7 and ECOG performance status ≤1 were enrolled. Patients received penpulimab [200 mg intravenous (i.v.) Q3W] and oral anlotinib (8 mg/day, 2 weeks on/1 week off). The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), duration of response (DoR), and overall survival (OS). This trial is registered with ClinicalTrials.gov (NCT04172571). Results: At the data cutoff (December 30, 2020), 31 eligible patients had been enrolled and treated with a median follow-up of 14.7 months (range, 1.4-22.1). The ORR was 31.0% (95% CI, 15.3-50.8%), and the DCR was 82.8% (95% CI, 64.2-94.2%). The median PFS and TTP for 31 patients were 8.8 months (95% CI, 4.0-12.3) and 8.8 months (95% CI, 4.0-12.9) respectively. The median OS was not reached; the 12-month OS rate was 69.0% (95% CI, 48.9-82.5%). Only 19.4% (6/31) of patients had grade 3/4 treatment-related adverse events (TRAEs). Conclusion: Penpulimab plus anlotinib showed promising anti-tumor activity and a favorable safety profile as first-line treatment of patients with uHCC.

9.
Lancet Oncol ; 22(8): 1081-1092, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34252374

RESUMO

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Capecitabina/administração & dosagem , Quimioterapia Adjuvante/métodos , Combinação de Medicamentos , Neoplasias Esofágicas/cirurgia , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/cirurgia , Tegafur/administração & dosagem
10.
Cancer Sci ; 112(10): 3979-3994, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34252266

RESUMO

Pyroptosis refers to the process of gasdermin (GSDM)-mediated programmed cell death (PCD). Our understanding of pyroptosis has expanded beyond cells and is known to involve extracellular responses. Recently, there has been an increasing interest in pyroptosis due to its emerging role in activating the immune system. In the meantime, pyroptosis-mediated therapies, which use the immune response to kill cancer cells, have also achieved notable success in a clinical setting. In this review, we discuss that the immune response induced by pyroptosis activation is a double-edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome-mediated pyroptosis and the release of pyroptosis-produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis-produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies. Pyroptosis is also related to some immune checkpoints, especially programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1). In this review, we mainly focus on our current understanding of the interplay between the immune system and tumors that process through pyroptosis, and debate their use as potential therapeutic targets.


Assuntos
Sistema Imunitário/imunologia , Neoplasias/imunologia , Piroptose/fisiologia , Microambiente Tumoral/imunologia , Antígeno B7-H1/imunologia , Citocinas/metabolismo , Progressão da Doença , Humanos , Evasão da Resposta Imune , Imunoterapia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Neoplasias/etiologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Piroptose/imunologia , Vesículas Secretórias/fisiologia , Evasão Tumoral/imunologia
11.
Cancer Lett ; 520: 143-159, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256094

RESUMO

Photodynamic therapy (PDT) uses a photosensitizer (PS) and visible light to induce cancer cell death. Pyroptosis is a new type of programmed cell death that is associated with the gasdermin protein family. However, the precise mechanism of pyroptosis in PDT-induced suppression of esophageal cancer remains unknown. We demonstrate that PDT can induce gasdermin E (GSDME)-mediated pyroptosis, which is characterized by the formation of pyroptotic blebs in esophageal squamous cell carcinoma (ESCC), which burst and release intracellular contents and pro-inflammatory mediators. Mechanistically, PDT may inhibit pyruvate kinase M2 (PKM2) and consequently, activate caspase-8 and caspase-3, which ultimately releases N-GSDME and triggers pyroptosis in ESCC. Moreover, PDT decreased the efficiency of pyroptosis in the presence of a glycolytic inhibitor. Overall, our results show that PDT induces pyroptosis in ESCC by targeting the PKM2/caspase-8/caspase-3/GSDME axis. This is the first in-depth study of the specific mechanism underlying PKM2-mediated pyroptosis under PDT in ESCC, and potentially has great implications for the clinical application of PDT in ESCC.

12.
Lancet Oncol ; 22(7): 977-990, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143971

RESUMO

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , China , Progressão da Doença , Feminino , Hepatite B/virologia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sorafenibe/efeitos adversos , Fatores de Tempo , Adulto Jovem
13.
Oncologist ; 26(10): e1693-e1703, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34105207

RESUMO

BACKGROUND: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. MATERIALS AND METHODS: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. RESULTS: A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). CONCLUSION: Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. IMPLICATIONS FOR PRACTICE: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.


Assuntos
Neoplasias Colorretais , Quinolinas , Neoplasias Colorretais/tratamento farmacológico , Método Duplo-Cego , Humanos , Indóis , Qualidade de Vida
14.
J Clin Oncol ; 39(27): 3002-3011, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34185551

RESUMO

PURPOSE: Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS: This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS: Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months (P = .0570). The objective response rate was 4.6% v 2.7% (P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION: Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Piridinas/uso terapêutico , Sorafenibe/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Piridinas/farmacologia , Sorafenibe/farmacologia
15.
BioDrugs ; 35(4): 445-458, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34014555

RESUMO

BACKGROUND: HLX04 is a proposed biosimilar of bevacizumab. OBJECTIVE: This phase III study aimed to evaluate the efficacy, safety, and immunogenicity of HLX04 compared with reference bevacizumab in combination with XELOX or mFOLFOX6 as first-line treatment for recurrent/metastatic colorectal cancer (CRC). METHODS: In this double-blind, parallel-group study, patients were randomized 1:1 to receive HLX04 or bevacizumab (7.5 mg/kg every 3 weeks when combined with XELOX; 5 mg/kg every 2 weeks when combined with mFOLFOX6). The primary endpoint was progression-free survival rate at week 36 (PFSR36w) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Prespecified equivalence margins of PFSR36w were set as - 11 to 15% (rate difference) and 0.8 to 1.25 (rate ratio). Secondary endpoints included efficacy, safety, immunogenicity, and pharmacokinetics. RESULTS: A total of 677 patients were randomized (HLX04 n = 340; bevacizumab n = 337) between April 2018 and April 2020. PFSR36w was 46.4% (95% confidence interval [CI] 41.1-51.8) with HLX04 and 50.7% (95% CI 45.4-56.1) with bevacizumab. The rate difference (- 4.2%; 90% CI - 10.6 to 2.1) and rate ratio (0.92; 90% CI 0.80-1.05) both fell within the prespecified equivalence margins. No notable differences were observed between treatment groups in any efficacy endpoints or their subgroup analyses. Safety, immunogenicity, and pharmacokinetic profiles were comparable between the two treatment groups. CONCLUSIONS: HLX04 demonstrated equivalent efficacy with similar safety and immunogenicity profiles to reference bevacizumab among patients with recurrent/metastatic CRC, thus offering an alternative treatment option to patients. TRIAL REGISTRATION: Chinadrugtrials.org.cn, CTR20171503 (18 March 2018); ClinicalTrials.gov, NCT03511963 (30 April 2018).


Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Capecitabina , Neoplasias Colorretais/tratamento farmacológico , Método Duplo-Cego , Humanos , Oxaloacetatos
16.
Lancet Gastroenterol Hepatol ; 6(7): 559-568, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33971141

RESUMO

BACKGROUND: Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma. METHODS: AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov, NCT02329860. FINDINGS: Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in the placebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand-foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators. INTERPRETATION: Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile. FUNDING: Jiangsu Hengrui Medicine.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Estadiamento de Neoplasias , Piridinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Gastric Cancer ; 24(4): 913-925, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33945049

RESUMO

PURPOSE: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. PATIENTS AND METHODS: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. RESULTS: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). CONCLUSION: RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status. CLINICAL TRIAL INFORMATION: NCT02881190.

18.
Cancer Biol Med ; 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33724741

RESUMO

OBJECTIVE: In this post-hoc analysis, we evaluated anlotinib treatment-induced hypertension as a potential predictive factor of efficacy in esophageal squamous cell carcinoma (ESCC) patients. METHODS: A total of 109 patients enrolled in the anlotinib group in a phase 2 trial were included. The tumor response was assessed by computed tomography at week 3, week 6, and then every 6 weeks until progressive disease was observed. The primary endpoint of the study was progression free survival (PFS). The secondary endpoints included overall survival (OS) and objective response rate (ORR). RESULTS: In all patients, the median PFS was 3.02 months [95% confidence interval (CI): 2.63-3.65 months] and the OS was 6.11 months (95% CI: 4.40-7.79 months). The ORR was 7.34% (95% CI: 3.22%-13.95%). A total of 59 (54%) patients were diagnosed with treatment-induced hypertension (Group A), and the remaining patients (n = 50, 46%) were in Group B. Baseline prognostic factors were similar between the 2 groups. Patients in Group A had a longer PFS and OS and higher ORR. When stratifying patients using a previously known history of hypertension, treatment-induced hypertension was a predictor only for patients without previous hypertension, who had longer PFS [hazard ratio (HR): 0.40, 95% CI: 0.24-0.68] and OS (HR: 0.37, 95% CI: 0.21-0.67). CONCLUSIONS: We showed, for the first time, a correlation between treatment-induced hypertension and better prognoses in recurrent or metastatic ESCC patients treated with anlotinib, without a previously known history of hypertension. Treatment-induced hypertension may be a simple and low cost predictor for anlotinib antitumor efficacy in these patients, which may also reflect the intended target inhibition.

19.
Eur J Cancer ; 148: 1-13, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33691262

RESUMO

BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Imunoglobulina G/imunologia , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Linfoma/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Adulto Jovem
20.
Cancer Med ; 10(5): 1681-1689, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33586360

RESUMO

BACKGROUND: Currently, there are no randomized trials on the effect of antiangiogenic therapy in patients with esophageal squamous cell carcinoma (ESCC). The following study investigated the efficacy and safety of anlotinib in patients with advanced ESCC who were previously treated with chemotherapy. METHODS: This randomized, placebo-controlled, double-blind phase 2 trial (NCT02649361) was conducted in 13 Chinese hospitals. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC who were previously treated with chemotherapy, and were randomly assigned (2:1) to receive oral anlotinib 12 mg or placebo on days 1-14 (repeated every 21 days). The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and sixty-five patients were randomly assigned to the anlotinib (n = 110) or the placebo (n = 55) arm. Median PFS was 3.02 months (95% CI 2.63-3.65) in the anlotinib group and 1.41 months (95% CI 1.38-1.41) in the placebo group (hazard ratio 0.46 [95% CI 0.32-0.66]; p < 0.001). The most common treatment-related adverse events of grade 3 or 4 were hypertension (17 [16%] patients), decreased appetite (6 [6%] patients), and hyponatremia (4 [4%] patients) in the anlotinib group and decreased appetite (2 [4%] patients) in the placebo group. Three (3%) deaths in the anlotinib group were considered as drug related, while there were no treatment-related deaths in the placebo group. CONCLUSIONS: The use of anlotinib in previously treated, recurrent, or metastatic ESCC patients significantly improved PFS compared with placebo. Our findings suggest that antiangiogenesis might be an important therapeutic target in advanced ESCC. CLINICAL TRIALS REGISTRATION: Study of Anlotinib in Patients With Esophageal Squamous Cell Carcinoma (ALTER1102), NCT02649361.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Indóis/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Quinolinas/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Método Duplo-Cego , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/secundário , Transtornos da Alimentação e da Ingestão de Alimentos/induzido quimicamente , Feminino , Humanos , Hipertensão/induzido quimicamente , Hiponatremia/induzido quimicamente , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico , Intervalo Livre de Progressão , Quinolinas/efeitos adversos
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