RESUMO
BACKGROUND: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug. METHODS: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred. CONCLUSIONS: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma , Proteínas Recombinantes de Fusão , Neoplasias Uveais , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos HLA-A , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/secundário , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/mortalidade , Neoplasias Uveais/secundário , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
BACKGROUND: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. METHODS: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
Assuntos
Antineoplásicos/uso terapêutico , Melanoma/secundário , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Síndrome da Liberação de Citocina/induzido quimicamente , Dacarbazina/uso terapêutico , Exantema/induzido quimicamente , Feminino , Humanos , Ipilimumab/uso terapêutico , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Análise de Sobrevida , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/mortalidadeRESUMO
BACKGROUND: Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. METHODS: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). RESULTS: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). CONCLUSIONS: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Docetaxel/administração & dosagem , Indazóis/administração & dosagem , Pirimidinas/administração & dosagem , Neoplasias de Tecidos Moles/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Docetaxel/efeitos adversos , Feminino , Humanos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Neoplasias de Tecidos Moles/mortalidade , Sulfonamidas/efeitos adversos , Adulto Jovem , GencitabinaRESUMO
BACKGROUND: Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma. METHODS: This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort. RESULTS: 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients. CONCLUSIONS: In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Indazóis/administração & dosagem , Osteossarcoma/tratamento farmacológico , Pirimidinas/administração & dosagem , Sarcoma/tratamento farmacológico , Sulfonamidas/administração & dosagem , Topotecan/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Humanos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Topotecan/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).
Assuntos
Antineoplásicos/uso terapêutico , Fibromatose Agressiva/tratamento farmacológico , Sorafenibe/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Feminino , Fibromatose Agressiva/mortalidade , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sorafenibe/efeitos adversos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Translation of basic discoveries to clinical care for patients with cancer is a difficult process greatly enabled by physician-trained researchers. Three categories of physicians, with responsibilities spanning from laboratory and preclinical research to direct patient care, are involved in the translational research continuum: physician-scientist (PS), clinician investigator (CI), and academic clinician (AC). METHODS: To define how protected time for research efforts is supported, the Association of American Cancer Institutes (AACI) conducted a survey of their member institutions, obtaining 56 responses documenting time spent in research and clinical activities across multiple cancer disciplines, and providing information about funding streams for the different categories of cancer physicians. RESULTS: Responses showed that PSs and ACs are minimally involved in clinical research activities; the driver or clinical research in academic cancer centers is the CI. A significant concern was a lack of stable funding streams for nonbillable clinical research activities, putting the sustainability of the CI in jeopardy. Limited funding was derived from hospital sources, with most support derived from cancer center sources. CONCLUSIONS: This study highlights the importance of the CI in translational cancer medicine and represents a call to action for institutions and research funding agencies to develop new programs targeted toward CI support to ensure continued progress against cancer.
Assuntos
Neoplasias , Médicos , Pesquisadores , Pesquisa Translacional Biomédica , Pessoal de Saúde , Humanos , Neoplasias/terapia , Assistência ao PacienteRESUMO
BACKGROUND: This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. METHODS: Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). RESULTS: Forty-seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%-58%), which was superior to the null hypothesis rate of 30%, but the 2-sided P value (exact test) was .09 (1-sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3-35.0 months), and the median progression-free survival was 7.9 months (95% CI, 3.7-12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. CONCLUSIONS: This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Condrossarcoma/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Condrossarcoma/patologia , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Estudos Prospectivos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversosRESUMO
Developing tumors continuously release nano-sized vesicles that represent circulating "fingerprints" of the tumor's identity. In gastrointestinal stromal tumor (GIST), we have previously reported that these tumors release "oncosomes" carrying the constitutively activated tyrosine kinase (TK) receptor KIT. Despite the clinical utility of TK inhibitors, such as imatinib mesylate (IM), recurrence and metastasis are clinical problems that urge the need to identify new tumor-derived molecules. To this aim, we performed the first high quality proteomic study of GIST-derived exosomes (GDEs) and identified 1,060 proteins composing the core GDE proteome (cGDEp). The cGDEp was enriched in diagnostic markers (e.g. KIT, CD34, ANO1, PROM1, PRKCQ, and ENG), as well as proteins encoded by genes previously reported expressed in GIST (e.g. DPP4, FHL1, CDH11, and KCTD12). Many of these proteins were validated using cell lines, patient-derived KIT+ exosomes, and GIST tissues. We further show that in vitro and in vivo-derived GDE, carry proteins associated with IM response, such as Sprouty homolog 4 (SPRY4), surfeit 4 (SURF4), ALIX, and the cGMP-dependent 3',5'-cyclic phosphodiesterase 2A (PDE2A). Additionally, we report that the total exosome levels and exosome-associated KIT and SPRY4 protein levels have therapeutic values. In fact, molecular characterization of in vivo-derived KIT+ exosomes indicate significant sorting of p-KITTyr719, total KIT, and SPRY4 after IM-treatment of metastatic patients as compared with the pre-IM levels. Our data suggest that analysis of circulating exosomes levels and molecular markers of IM response in GIST patients with primary and metastatic disease is suitable to develop liquid based biopsies for the diagnosis, prognosis, and monitoring of response to treatment of these tumors. In summary, these findings provide the first insight into the proteome of GIST-derived oncosomes and offers a unique opportunity to further understand their oncogenic elements which contribute to tumorigenesis and drug resistance. Data are available via ProteomeXchange with identifier PXD007997.
Assuntos
Biomarcadores Tumorais/sangue , Exossomos/metabolismo , Neoplasias Gastrointestinais/sangue , Tumores do Estroma Gastrointestinal/sangue , Proteínas de Neoplasias/sangue , Linhagem Celular Tumoral , Feminino , Neoplasias Gastrointestinais/diagnóstico , Tumores do Estroma Gastrointestinal/diagnóstico , Humanos , ProteomaRESUMO
Cancer treatment has changed dramatically with the development of oral targeted therapies. Pazopanib, an oral VEGF tyrosine kinase inhibitor, is currently approved for advanced renal cell carcinoma, advanced soft tissue sarcoma, and is being studied for various tumor types. Due to the potential of increased exposure to pazopanib when crushed, pazopanib should be given as an intact whole tablet. Thus, in patients with difficulty swallowing medications or feeding tubes, pazopanib is usually not considered to be an option. Here, we describe two cases which show the administration of crushed pazopanib was feasible and had apparent clinical activity.
Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Cordoma/tratamento farmacológico , Feminino , Humanos , Indazóis , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Neoplasias da Base do Crânio/tratamento farmacológico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversosRESUMO
Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB-IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors.Trial Registration NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Produtos Biológicos/administração & dosagem , Feminino , Herpesvirus Humano 1 , Humanos , Injeções Intralesionais , Ipilimumab/administração & dosagem , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Immune checkpoint inhibitors, single or in combination, have recently become a cornerstone for the treatment of many malignancies. Ipilimumab, a CTLA-4 inhibitor, was initially FDA approved for treatment of unresectable or metastatic melanoma and subsequently in combination therapy for other cancers. Ipilimumab-induced hypophysitis (IH) risk of development varies in different studies between 0 and 17%. Furthermore, little is known on how to predict which patients will develop IH and its impact on efficacy of Ipilimumab and survival for these patients. Here we reviewed IH and its impact on progression-free survival (PFS) and overall survival (OS). METHODS: Retrospective, IRB- approved review of consecutive 117 melanoma patients who received ipilimumab between 2011 and 2016 was undertaken. Demographic and clinical characteristics, treatment timing and doses, time to progression after therapy, and survival data were reviewed. Patients were predefined in two groups: patients with and without IH. Descriptive statistics were used to summarize the demographic and clinical characteristics of the study sample. All values are shown as means and standard deviation [mean (SD)] unless indicated otherwise. P < 0.05 was considered to be statistically significant. RESULTS: Of the 117 patients, 15 (12.8%) with a median age of 62.1 years developed IH. In the IH cohort, 10 (66.7%) were male and were significantly older than females (median 67.7 vs. 50.8; P = 0.009). This difference was not seen in non-IH group. Male patients with IH were significantly older than males without IH (67.7 vs. 56.4 years, P = 0.020), however this difference was not observed in females. No patient who received prior cancer systemic therapy (0/30) developed IH vs. 17.2% (15/72) without prior therapy developed IH (OR 0.00; 95% CI 0.00 to 0.73, P = 0.011). Between IH and non-IH patients, there was no difference in gender, race, ethnicity, BMI, diabetes or autoimmune disease at baseline, number of administered ipilimumab cycles, presence of primary melanoma lesion, or BRAF status. IH and non-IH patients had a similar median PFS (8.1 vs. 6.8 months, HR = 0.51, 95% CI 0.24 to 1.05 P = 0.062) and OS (53.3 vs. 29.5 months; HR 0.66, 95% CI 0.30 to 1.46; P = 0.307). CONCLUSION: In this study of melanoma patients treated with Ipilimumab, risk of developing IH was high (almost 13%). Older age in men and no prior cancer therapy were associated with IH higher risk. Development of IH was not associated with PFS or OS. Increased use of immune checkpoint inhibitors in the future will impact IH overall risk, thus awareness is needed. Given the lack of reliable identifiable risk factors, close monitoring of signs and symptoms after each therapy cycle is critical for early detection and treatment of hypophysitis.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Hipofisite/induzido quimicamente , Ipilimumab/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Hipofisite/diagnóstico , Ipilimumab/uso terapêutico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE/BACKGROUND: Discussion of treatment goals between oncologists and patients is challenging. Patients frequently misunderstand goals of therapy. There are several methods to document goals of chemotherapy, however, and are frequently not incorporated into patient charts. METHODS/DESIGN: Cancer patients receiving their first cycle of chemotherapy were interviewed. Patients' recall of discussions with their oncologist regarding therapy intent was assessed and compared to documentation. An adjusted McNemar's test was utilised. A one-sample proportion test was used to evaluate whether the overall observed rate of discordance was significantly different from the proposed 33% rate; a rate posited as a threshold too high in the clinical sense. RESULTS: Two hundred and seven eligible patients were interviewed. Oncologist identified treatment goals were not documented in 24.6% of cases and had to be excluded. There was not a significant difference in the directionality of discordance present. Inter-rater agreement between patient and oncologist was found to be adequate (κ = 0.64). The overall rate of discordance (17.29%) was found to be significantly less than the proposed acceptable level of 33% (p < 0.01). Upon univariable analysis, age, gender, marital and employment status were not found to be associated with discordance. CONCLUSIONS: Discordance between treatment goals documentation and their understanding exists, indicating continued miscommunication between the patient and oncologist.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Planejamento de Assistência ao Paciente , Adulto , Idoso , Compreensão , Feminino , Humanos , Intenção , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Oncologistas , Relações Médico-PacienteRESUMO
BACKGROUND: Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma. METHODS: We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0-1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797. FINDINGS: Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1-16] of 38 patients) in the nivolumab group and six (16% [7-30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths. INTERPRETATION: Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted. FUNDING: Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ipilimumab/uso terapêutico , Nivolumabe/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Ipilimumab/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Sarcoma/imunologia , Sarcoma/mortalidade , Sarcoma/secundário , Neoplasias de Tecidos Moles/imunologia , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
It has been highlighted that in the original manuscript [1] Table S3 'An example of the predictive computational modeling process. Specific details on an annexure section of the PD-L1 pathway show the step-by-step reactions, mechanisms, and reaction equations that occur. Such reactions also occurred in all of the other pathways' was omitted and did not appear in the Additional files and that the Additional files were miss-numbered thereafter. This Correction shows the correct and incorrect Additional files. The original article has been updated.
RESUMO
BACKGROUND: Programmed Death Ligand 1 (PD-L1) is a co-stimulatory and immune checkpoint protein. PD-L1 expression in non-small cell lung cancers (NSCLC) is a hallmark of adaptive resistance and its expression is often used to predict the outcome of Programmed Death 1 (PD-1) and PD-L1 immunotherapy treatments. However, clinical benefits do not occur in all patients and new approaches are needed to assist in selecting patients for PD-1 or PD-L1 immunotherapies. Here, we hypothesized that patient tumor cell genomics influenced cell signaling and expression of PD-L1, chemokines, and immunosuppressive molecules and these profiles could be used to predict patient clinical responses. METHODS: We used a recent dataset from NSCLC patients treated with pembrolizumab. Deleterious gene mutational profiles in patient exomes were identified and annotated into a cancer network to create NSCLC patient-specific predictive computational simulation models. Validation checks were performed on the cancer network, simulation model predictions, and PD-1 match rates between patient-specific predicted and clinical responses. RESULTS: Expression profiles of these 24 chemokines and immunosuppressive molecules were used to identify patients who would or would not respond to PD-1 immunotherapy. PD-L1 expression alone was not sufficient to predict which patients would or would not respond to PD-1 immunotherapy. Adding chemokine and immunosuppressive molecule expression profiles allowed patient models to achieve a greater than 85.0% predictive correlation among predicted and reported patient clinical responses. CONCLUSIONS: Our results suggested that chemokine and immunosuppressive molecule expression profiles can be used to accurately predict clinical responses thus differentiating among patients who would and would not benefit from PD-1 or PD-L1 immunotherapies.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Simulação por Computador , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quimiocinas/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Mutação , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: The purpose of this investigation was to determine the effect of hospital volume on treatment decisions, treatment results, and overall patient survival in extremity soft tissue sarcoma. METHODS: The National Cancer Database was used to identify patients ≥18 years of age with non-metastatic soft tissue sarcoma of the extremity treated with surgery. Patients in high- and low-volume centers were matched by propensity score and placed into two equal comparative groups of 2437 patients each. RESULTS: Chemotherapy was used at a higher rate in high-volume centers (22% vs 17%, P < 0.001) and external beam radiation usage was similar (55% vs 52%, P = 0.108). There was a lower incidence of positive margins in high-volume centers (12% vs 17%, P < 0.001). There was no significant difference in the rates of limb salvage surgery or readmissions at high-volume hospitals compared to low-volume. In a multivariate Cox proportional hazards model, low-volume facilities demonstrated diminished overall survival at all time points (hazard ratio at 5 years = 1.24, 95%CI 1.10-1.39). CONCLUSIONS: Treatment at high-volume hospitals was associated with fewer positive margins and increased overall survival at 2, 5, and 10 years. Continued efforts should focus on optimizing the balance between patient access to specialty care and experience of the treating center.
Assuntos
Extremidades/cirurgia , Hospitais com Alto Volume de Atendimentos/estatística & dados numéricos , Salvamento de Membro/mortalidade , Sarcoma/mortalidade , Estudos de Coortes , Bases de Dados Factuais , Extremidades/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Sarcoma/patologia , Sarcoma/cirurgia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma. METHODS: Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12). RESULTS: Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy. CONCLUSIONS: The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. © 2017 American Cancer Society.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Lipossarcoma/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Indazóis , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Condrossarcoma/tratamento farmacológico , Cordoma/tratamento farmacológico , Dasatinibe/uso terapêutico , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Tumores Fibrosos Solitários/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Neoplasias Ósseas/mortalidade , Condrossarcoma/mortalidade , Cordoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Sarcoma Alveolar de Partes Moles/mortalidade , Tumores Fibrosos Solitários/mortalidade , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: Trabectedin demonstrated significantly improved disease control in leiomyosarcoma and liposarcoma patients in a global phase 3 trial (NCT01343277). A post hoc analysis was conducted to assess the efficacy and safety of trabectedin or dacarbazine in women with uterine leiomyosarcoma (uLMS), the largest subgroup of enrolled patients (40%). METHODS: Of 577 patients randomized 2:1 to receive trabectedin 1.5mg/m2 by 24-hour IV infusion or dacarbazine 1g/m2 by 20-120-minute IV infusion once every three weeks, 232 had uLMS (trabectedin: 144; dacarbazine: 88). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR: complete responses+partial responses+stable disease [SD] for at least 18weeks), duration of response (DOR), and safety. RESULTS: PFS for trabectedin was 4.0months compared with 1.5months for dacarbazine (hazard ratio [HR]=0.57; 95% CI 0.41-0.81; P=0.0012). OS was similar (trabectedin 13.4months vs. dacarbazine 12.9months, HR=0.89; 95% CI 0.65-1.24; P=0.51) between groups. ORR was 11% with trabectedin vs. 9% with dacarbazine (P=0.82). CBR for trabectedin was 31% vs. 18% with dacarbazine (P=0.05); median DOR was 6.5months for trabectedin vs. 4.1months for dacarbazine (P=0.32). Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients in the trabectedin group included transient aminotransferase (aspartate/alanine) elevations, anemia, leukopenia, and thrombocytopenia. CONCLUSIONS: In this post hoc subset analysis of patients with uLMS who had received prior anthracycline therapy, trabectedin treatment resulted in significantly longer PFS versus dacarbazine, with an acceptable safety profile. There was no difference in OS.