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Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.
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OBJECTIVES: The main objective of this report was to detail the long-term follow-up data from the REMORA study, which investigated the safety and efficacy of lenvatinib in patients with thymic carcinoma. In addition, an exploratory analysis of the association between relative dose intensity (RDI) and the efficacy of lenvatinib is presented. MATERIALS AND METHODS: The single-arm, open-label, phase 2 REMORA study was conducted at eight Japanese institutions. Forty-two patients received oral lenvatinib 24 mg once daily in 4-week cycles until the occurrence of intolerable adverse events or disease progression. The REMORA long-term follow-up data were evaluated, including overall survival (OS). RDI was calculated by dividing the actual dose administered to the patient by the standard recommended dose. This trial is registered on JMACCT (JMA-IIA00285) and on UMIN-CTR (UMIN000026777). RESULTS: The updated median OS was 28.3 months (95 % confidence interval [CI]: 17.1-34.0 months), and the OS rate at 36 months was 35.7 % (95 % CI: 21.7 %-49.9 %). When grouped by RDI of lenvatinib, the median OS was 38.5 months (95 % CI: 31.2-not estimable) in patients with ≥ 75 % RDI and 17.3 months (95 % CI: 13.4-26.2 months) in patients with < 75 % RDI (hazard ratio 0.46 [95 % CI: 0.22-0.98]; P = 0.0406) at 8 weeks. Patients who maintained their lenvatinib dose over 8 weeks had a higher objective response rate than patients whose doses were reduced (75.0 % vs 29.4 %; P = 0.0379). No new safety concerns or treatment-related deaths were reported, and lenvatinib had a tolerable safety profile. CONCLUSION: This follow-up report updated OS in patients with metastatic or recurrent thymic carcinoma. A higher RDI of lenvatinib at 8 weeks could be associated with improved outcomes.
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Recidiva Local de Neoplasia , Compostos de Fenilureia , Quinolinas , Timoma , Humanos , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Seguimentos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Timoma/tratamento farmacológico , Timoma/mortalidade , Timoma/patologia , Adulto , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/patologia , Neoplasias do Timo/mortalidade , Metástase Neoplásica , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
BACKGROUND: E7130 is a novel anticancer agent created from a total synthetic study of norhalichondrin B. The authors report the E7130 dose-escalation part of a first-in-human study of patients with advanced solid tumors (NCT03444701). METHODS: Japanese patients ≥20 years of age were enrolled. E7130 was administered intravenously in two cycles: day 1 of a 21-day cycle (Q3W) or days 1 and 15 of a 28-day cycle (Q2W). Doses were escalated from 270 to 550 µg/m2 for the Q3W group or 25-400 µg/m2 for the Q2W group. The primary end point of the dose-escalation phase was safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs) and adverse events. Other end points included determination of the maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics. RESULTS: Forty-four patients were enrolled: 15 in the E7130 Q3W group and 29 in the Q2W group. Treatment-emergent adverse events (TEAEs) occurred in all patients; the most common TEAE overall was leukopenia (78.6%). Grade 3-4 TEAEs occurred in 93.3% of patients in the Q3W group and 86.2% of patients in the Q2W group. None had a TEAE resulting in study drug discontinuation, and no treatment-related deaths were reported. Per the DLT evaluation, the MTDs were determined as 480 µg/m2 Q3W and 300 µg/m2 Q2W. Significant changes in multiple plasma biomarkers, including vascular endothelial growth factor 3 and matrix metallopeptidase 9, were dose-dependent after initial doses of 350-480 µg/m2 . CONCLUSIONS: E7130 480 µg/m2 Q3W was chosen for the dose-expansion part over 300 µg/m2 Q2W primarily per dose-dependent biomarker results.
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Antineoplásicos , Neoplasias , Humanos , Fator A de Crescimento do Endotélio Vascular , Microambiente Tumoral , Neoplasias/patologia , Antineoplásicos/efeitos adversos , Biomarcadores , Microtúbulos/metabolismo , Microtúbulos/patologia , Dose Máxima TolerávelRESUMO
BACKGROUND: The phase 3 CLEAR study demonstrated statistically significantly improved efficacy with lenvatinib plus pembrolizumab versus sunitinib, including progression-free survival and overall survival, in patients with previously untreated advanced renal cell carcinoma. This subset analysis investigated efficacy and safety in Japanese patients randomized to lenvatinib plus pembrolizumab or sunitinib in the CLEAR study. METHODS: Progression-free survival, overall survival, tumor response, and safety were assessed in Japanese patients with previously untreated advanced renal cell carcinoma randomized to receive lenvatinib plus pembrolizumab (n = 42) or sunitinib (n = 31). Efficacy outcomes were analyzed by independent imaging review per Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 22.1 vs. 10.9 months; hazard ratio, 0.39; 95% CI, 0.20-0.74). Median overall survival was not estimable in the lenvatinib plus pembrolizumab arm and 30.6 months in the sunitinib arm (HR, 1.20; 95% CI, 0.39-3.66). Overall survival adjusted for the imbalance of Memorial Sloan-Kettering Cancer Center prognostic risk group favored lenvatinib plus pembrolizumab (hazard ratio, 0.67; 95% CI, 0.18-2.39). Objective response rate (69.0% vs. 45.2%; odds ratio, 2.71; 95% CI, 1.03-7.10) was higher and median duration of response (20.3 vs. 9.1 months) was longer with lenvatinib plus pembrolizumab versus sunitinib. Grade ≥ 3 treatment-emergent adverse events occurred in 95.2% versus 87.1% of patients in the lenvatinib plus pembrolizumab versus sunitinib arms. CONCLUSIONS: These findings support lenvatinib plus pembrolizumab as a potential first-line treatment for Japanese patients with advanced renal cell carcinoma.
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Carcinoma de Células Renais , Neoplasias Renais , Sunitinibe , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , População do Leste Asiático , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêuticoRESUMO
PURPOSE: Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors. METHODS: Patients received a starting dose of 20 mg oral lenvatinib per day plus 200 mg intravenous pembrolizumab every 3 weeks in 21-day cycles. Dose-limiting toxicities were evaluated during the first cycle. Tumor assessments were performed by investigators based on modified RECIST v1.1. Pharmacokinetic parameters and serum biomarkers were assessed. RESULTS: Among enrolled patients (N = 6), 3 had non-small cell lung cancer, and 3 had urothelial cancer. No patients experienced a dose-limiting toxicity. All patients experienced at least 1 treatment-related treatment-emergent adverse event. The objective response rate was 33.3% (95% confidence interval 4.3-77.7); both responses (1 complete, 1 partial) were observed in patients with urothelial cancer. Pharmacokinetics were consistent with previous studies. Serum angiopoietin-2 levels tended to decrease, and serum fibroblast growth factor-23 levels tended to increase from baseline to Cycle 2 Day 1. CONCLUSIONS: This study supports the tolerability of 20 mg lenvatinib/day plus 200 mg pembrolizumab every 3 weeks in Japanese patients, consistent with the results from a global study of lenvatinib plus pembrolizumab combination therapy in patients with selected solid tumors. Favorable antitumor activity was observed and there were no new safety signals identified. TRIAL REGISTRATION: Clinical Trials.gov number: NCT03006887.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células de Transição , Neoplasias Renais , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Viabilidade , Japão , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. PATIENTS AND METHODS: Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. RESULTS: Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9-not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9-5.6; hazard ratio = 0.16; 95% CI, 0.10-0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0-78.8) in the lenvatinib arm and 0% (95% CI, 0-0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). CONCLUSIONS: Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.
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Antineoplásicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Método Duplo-Cego , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tolerância a Radiação , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Adulto JovemRESUMO
PURPOSE: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. EXPERIMENTAL DESIGN: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. RESULTS: Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; P = 0.0253). CONCLUSIONS: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Sorafenibe/uso terapêutico , Biomarcadores Tumorais/farmacocinética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/química , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/química , Valor Preditivo dos Testes , Taxa de SobrevidaRESUMO
PURPOSE: MORAb-202, an antibody-drug conjugate containing farletuzumab and eribulin with a cathepsin-B cleavable linker, targets folate receptor α (FRα)-expressing tumor cells. The primary objective of this first-in-human study was to evaluate the safety and tolerability of MORAb-202 in patients with solid tumors. PATIENTS AND METHODS: Patients ≥20 years with adequate organ function and FRα-positive solid tumors who failed to respond to standard therapy were eligible. Patients received MORAb-202 intravenously at doses of 0.3 to 1.2 mg/kg once every three weeks. Endpoints included dose-limiting toxicities, safety, tumor responses, pharmacokinetics, and pharmacodynamics. TRIAL REGISTRATION NUMBER: NCT03386942 (ClinicalTrials.gov). RESULTS: Between November 28, 2017 and June 4, 2019, 22 patients (median age, 58.0 years) with advanced solid tumors were enrolled. Treatment-emergent adverse events occurred in 21 (95%) patients, with leukopenia and neutropenia in 10 (45%) patients each. One patient (0.9 mg/kg cohort) experienced two grade 3 dose-limiting toxicities: serum alanine aminotransferase and γ-glutamyl transferase increases. Following review by an independent adjudication committee, grade 1/2 interstitial lung disease thought to be related to MORAb-202 was identified in five (23%) patients. Complete response, partial response, and stable disease were observed in one, nine, and eight patients, respectively. The normalized predose serum FRα tended to be positively correlated with the maximum tumor shrinkage (R 2 = 0.2379; P = 0.0291). CONCLUSIONS: The MTD of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Receptor 1 de Folato/análise , Furanos/efeitos adversos , Humanos , Imunoconjugados/uso terapêutico , Cetonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/química , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: It was reported that eribulin regulates the tumor microenvironment, including the immune system, by inducing vascular remodeling. Lymphocyte counts are a critical index of immune response in patients. The non-Asian, global EMBRACE study has suggested that baseline absolute lymphocyte count (ALC) may be a predictor of the survival benefit of eribulin in breast cancer patients. We examined whether the baseline ALC is a potential predictor of overall survival (OS) in Japanese patients with HER2-negative advanced breast cancer treated with eribulin. METHODS: This was a post hoc analysis of data from a post-marketing observational study of eribulin in Japan. The OS by baseline ALC was estimated using the Kaplan-Meier method, with the cut-off value of 1500/µL for ALC. The OS by baseline neutrophil-to-lymphocyte ratio (NLR), a general prognostic index in breast cancer patients, was also estimated, with the cut-off value of 3. RESULTS: The median OS was longer in patients with an ALC of ≥ 1500/µL than in those with an ALC of < 1500/µL (19.4 vs. 14.3 months; hazard ratio [HR]: 0.628; 95% confidence interval [CI]: 0.492, 0.801). Patients with an NLR of ≥ 3 showed shorter OS than those with an NLR of < 3 (13.2 vs. 18.8 months; HR: 1.552; 95% CI 1.254, 1.921), and NLR also separated OS in patients with an ALC of < 1500/µL. CONCLUSIONS: Consistent with the findings of a previous study involving a non-Asian, Western population, our study suggested that baseline ALC may be a predictive factor for the survival benefit of eribulin in Japanese patients.
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Neoplasias da Mama/tratamento farmacológico , Furanos/administração & dosagem , Cetonas/administração & dosagem , Moduladores de Tubulina/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Contagem de Linfócitos , Pessoa de Meia-Idade , Neutrófilos , Modelos de Riscos Proporcionais , Receptor ErbB-2RESUMO
Aim: To assess the pharmacokinetics of once-daily oral lenvatinib 24 mg in Chinese patients. Material & methods: Patients had any solid tumor (except hepatocellular carcinoma) that was resistant to standard antitumor therapies or for which no appropriate treatment was available. Results: Twelve patients were enrolled. Maximum plasma concentrations of lenvatinib were observed at 2 and 4 h (median) after single and multiple doses (day 15), respectively. Steady state was achieved within 8 days. The geometric mean maximum observed concentration at steady state was 258 ng/ml (coefficient of variance: 49.2%); and the geometric mean area under the concentration-time curve from zero to 24 h at steady state was 3090 ngâ¢h/ml (coefficient of variance: 44.7%). No accumulation was seen after 15 days. Conclusion: Lenvatinib pharmacokinetic data in Chinese patients are consistent with data in multinational trials, supporting usage of the 24-mg dose. Clinical trial registration: NCT03009292 (ClinicalTrials.gov).
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Neoplasias/tratamento farmacológico , Compostos de Fenilureia/farmacocinética , Quinolinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Povo Asiático , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagemRESUMO
BACKGROUND: No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus. METHODS: Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0). RESULTS: PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus). CONCLUSIONS: The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT01136733.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Everolimo/administração & dosagem , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Intervalo Livre de Progressão , Quinolinas/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1-3, FGFRs 1-4, and PDGFR-α) was evaluated for second-line treatment of BTC. METHODS: In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles. RESULTS: Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2-27.2). Median PFS was 3.19 months (95% CI: 2.79-7.23) per investigator assessment and 1.64 months (95% CI: 1.41-3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50-11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related. CONCLUSIONS: Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.
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Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Neoplasias do Sistema Biliar/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Background Data on eribulin as the first- or second-line treatment in a clinical setting, especially the overall survival (OS) of patients, are scarce. Therefore, we assessed the effectiveness and safety of eribulin as the first-, second-, and third- or later-line treatments in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in Japan. Methods This multicenter, prospective, post-marketing, observational study enrolled patients from September 2014 to February 2016 in Japan and followed them for 2 years. Patients were categorized by eribulin use into the first-, second-, and third- or later-line treatment groups. Results Of 651 registered patients, 637 patients were included in the safety and effectiveness analysis. In all, first-, second-, and third or later-line treatment groups, median OS (95% confidence interval) were 15.6 (13.8-17.6), 22.8 (17.3-31.0), 16.3 (12.4-19.9), and 12.6 (11.2-15.1) months and time to treatment failure (TTF) (95% confidence interval) were 4.2 (3.7-4.4), 5.2 (3.7-5.9), 4.2 (3.7-5.1), and 3.8 (3.5-4.2) months, respectively. Prolonged TTF was associated with complications of diabetes and the development of peripheral neuropathy after eribulin treatment, according to multivariate Cox regression analysis. Grade ≥ 3 adverse drug reactions (ADRs) were reported in 61.7% of the patients. Neutropenia (49.5%) was the most common grade ≥ 3 ADR in all groups. Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Povo Asiático , Neoplasias da Mama/mortalidade , Feminino , Furanos/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Cetonas/efeitos adversos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/mortalidade , Vigilância de Produtos Comercializados , Receptor ErbB-2 , Resultado do TratamentoRESUMO
BACKGROUND: Although communication between patients with breast cancer and physicians is central to treatment decision-making for patients and the concept of shared decision-making has been increasingly advocated worldwide, little is known about decision-making and perceptions among the population in Japan. Therefore, this cross-sectional study aimed to clarify the status of pharmacotherapy decision-making among patients with breast cancer in Japan and assess factors associated with patient satisfaction with patient-physician communication. METHODS: Data for women previously treated with pharmacotherapy agents for breast cancer in Japan were collected in July 2017 using an online survey. Respondents were categorized by their decision-making role (active, shared, passive). Characteristics, decisional conflict level, and satisfaction with communication with their physician at the time of pharmacotherapy selection were stratified by decision-making roles. Stepwise multivariate logistic regression was performed to assess factors associated with satisfaction. RESULTS: Of 486 women that responded, nearly half played an active decision-making role (48.4%) and 26.0% played a shared role. The lowest decisional conflict and higher satisfaction were observed among those who played a shared role. The highest decisional conflict and lower satisfaction were observed in passive decision-makers. Shared decision-making, a longer consultation time with the physician, and multiple treatment options provided by the physician were significantly associated with satisfaction with communication with the physician. CONCLUSIONS: Our findings suggest that among patients with breast cancer, a shared role in treatment decision-making, longer consultation time at treatment selection, and having multiple treatment options are important for higher patient satisfaction with communication with their physician.
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Neoplasias da Mama/tratamento farmacológico , Tomada de Decisões , Preferência do Paciente/psicologia , Relações Médico-Paciente , Adulto , Idoso , Comunicação , Estudos Transversais , Feminino , Seguimentos , Humanos , Japão , Modelos Logísticos , Pessoa de Meia-Idade , Médicos/psicologia , Encaminhamento e Consulta , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
Background We conducted a first-in-Japanese, phase I study of ontuxizumab, a humanized, anti-endosialin monoclonal antibody, to confirm its tolerability, safety, and pharmacokinetics, and identify exploratory efficacy. Methods This was a multicenter, multiple-dose, open-label study in Japanese patients aged ≥20 years with solid tumors, including gastric cancer (GC) or advanced hepatocellular carcinoma (HCC), who had failed standard chemotherapy. The study comprised two parts: part 1 (dose-escalation; ontuxizumab 2-12 mg/kg weekly) and part 2 (cohort-expansion; 4 or 8 mg/kg weekly, or 12 mg/kg biweekly). Results Fifteen patients were treated in part 1, and 31 in part 2 (16 patients with GC and 15 with HCC). In part 1, the most common treatment-related, treatment-emergent adverse event (TEAE) was fatigue (20%); no patients had grade ≥ 3 treatment-related TEAEs. In part 2, the most common treatment-related TEAEs were constipation, malaise, hiccups, and increased bilirubin; treatment-related grade 3 TEAEs occurred in two patients with HCC. In part 1, no patients achieved a partial response, and 6/15 (40%) had stable disease (SD). In part 2, 2/15 patients (13.3%) with GC and 8/15 (53.3%) with HCC had SD. Tumor shrinkage was observed in 5/15 HCC patients (33.3%). Conclusions Ontuxizumab, up to a dosage of 12 mg/kg weekly, was generally safe and well tolerated in this population, with no dose-limiting toxicities. The maximum tolerated dose was not reached; 8 mg/kg weekly or 12 mg/kg biweekly were the recommended dosages. We observed long-term disease stabilization in GC and extraskeletal chondrosarcoma, and tumor shrinkage in gastrointestinal stromal tumor and HCC. Trial registration: NCT01773434 ( ClinicalTrials.gov ).
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD/química , Antígenos de Neoplasias/química , Antineoplásicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/farmacocinética , Estudos de Coortes , Feminino , Seguimentos , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Distribuição TecidualRESUMO
AIM: To investigate the safety and efficacy of lenvatinib in advanced thyroid cancer. PATIENTS/METHODS: In this Phase II study, 51 Japanese patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC), medullary thyroid cancer (MTC) or anaplastic thyroid cancer (ATC) received once-daily lenvatinib 24 mg. The primary end point was safety. RESULTS: All patients experienced ≥1 adverse event (AE); only one patient experienced an AE leading to discontinuation. The most common any-grade AEs were hypertension, decreased appetite, palmar-plantar erythrodysesthesia, fatigue and proteinuria. Response rates for RR-DTC: 68%; MTC: 22%; ATC: 24%. Median progression-free survival for RR-DTC: 25.8 months; MTC: 9.2 months; ATC: 7.4 months. CONCLUSION: Lenvatinib demonstrated a manageable safety profile, proven antitumor activity in RR-DTC and promising efficacy in MTC and ATC. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01728623.
Assuntos
Antineoplásicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Resistencia a Medicamentos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Radioisótopos do Iodo/farmacologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To assess the tolerability, safety, pharmacokinetics and antitumor activities of lenvatinib, an oral inhibitor of multiple receptor tyrosine kinases, in combination with everolimus, an inhibitor of mammalian target of rapamycin, in Japanese patients with advanced or metastatic renal cell carcinoma after disease progression with vascular endothelial growth factor-targeted therapy. METHODS: Lenvatinib 18 mg and everolimus 5 mg once daily were administered on 28-day continuous cycles until disease progression or unacceptable toxicity. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 4.03, and tumor response was assessed according to the Response Evaluation Criteria in Solid Tumor version 1.1. Pharmacokinetics sampling was carried out during the first cycle. RESULTS: Seven patients with clear cell renal cell carcinoma received this combination treatment. Dose-limiting toxicity was not observed. The most commonly observed adverse events were thrombocytopenia and decreased appetite (100%), followed by hypertriglyceridaemia and palmar-plantar erythrodysesthesia syndrome (86%). The most common grade 3 adverse event was lymphopenia (43%). No grade 4 or 5 adverse events occurred. The steady-state mean areas under the concentration-time curves of lenvatinib and everolimus were 3220 and 401 ng·h/mL, respectively. Five patients (71%) had partial response, and one (14%) had stable disease. CONCLUSIONS: Lenvatinib 18 mg and everolimus 5 mg once daily are well tolerated and manageable, and their combined administration has no significant effect on either drug's pharmacokinetics. Overall, this combination therapy shows encouraging antitumor activity in Japanese patients with renal cell carcinoma.