RESUMO
BACKGROUND: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. METHODS: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. FINDINGS: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). INTERPRETATION: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. FUNDING: Bristol Myers Squibb.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Melanoma/tratamento farmacológico , Idoso , Neoplasias Encefálicas/secundário , Feminino , Seguimentos , Humanos , Ipilimumab/administração & dosagem , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Although superficial spreading melanomas (SSM) are diagnosed as thinner lesions, nodular melanomas (NM) have a more rapid growth rate and are biologically more aggressive compared with other histologic subtypes. OBJECTIVE: To determine the difference in 5-year relative survival in patients with NM and SSM at the same Breslow depth and TNM stage. METHODS: A population-based cross-sectional analysis compared the 5-year relative survival of patients with NM and SSM using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)∗Stat software (version 8.2.1-8.3.5). Chi-square tests compared the proportions, and Kaplan-Meier method with Z-score compared 5-year relative survival. RESULTS: For patients receiving a diagnosis between 2004 and 2009, 5-year relative survival was lower in NM compared with SSM (53.7% vs 87.3%; Z score, -41.35; P < .001). Similarly, for patients receiving a diagnosis between 2010 and 2015, 5-year relative survival was lower in NM compared with SSM (61.5% vs 89.7%; Z score, -2.7078; P < .01). Subgroup analyses showed inferior survival in NM in T1b, and survival differences remained significant after excluding patients with nodal or distant metastases. CONCLUSIONS: Five-year relative survival is worse in NM compared with SSM especially in T1b, T2a, and T2b melanomas. Melanoma subtype should be taken into consideration when making treatment recommendations.
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Melanoma/mortalidade , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/classificação , Melanoma/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Programa de SEER , Neoplasias Cutâneas/patologia , Úlcera Cutânea/epidemiologia , Úlcera Cutânea/etiologia , Estados Unidos/epidemiologia , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Sorafenib and sunitinib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) approved in 2005 and 2006, respectively, for the treatment of patients with renal cell carcinoma (RCC). A population-based, observational cohort study of the cardiovascular risk of VEGFR TKI therapy in elderly RCC patients was conducted. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, this study analyzed patients who were 66 years old or older and were diagnosed with RCC from 2000 to 2009. The incidence of cardiovascular adverse events, including congestive heart failure and cardiomyopathy (CHF/CM), acute myocardial infarction (AMI), stroke, and cardiovascular deaths, was examined through December 2010. A Cox proportional hazards model was created to calculate the hazard ratio (HR), and adjustments were made for age, sex, comorbidity, and the use of other systemic therapy. RESULTS: A total of 171 of 670 patients who received sunitinib or sorafenib had cardiovascular events. The incidence rates for CHF/CM, AMI, and stroke were 0.87, 0.14, and 0.14 per 1000 person-days, respectively. Sunitinib or sorafenib use was associated with an increased risk of cardiovascular events (HR, 1.38; 95% confidence interval [CI], 1.02-1.87) and especially stroke (HR, 2.84; 95% CI, 1.52-5.31) in comparison with 788 patients diagnosed with advanced RCC from 2007 to 2009 who were eligible for Part D but did not receive either agent. In subgroup analyses, patients who were 66 to 74 years old at diagnosis had the highest increased risk of stroke associated with the use of either or both drugs. CONCLUSIONS: Sunitinib and sorafenib might be associated with an increased risk of cardiovascular events and particularly stroke.
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Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Pirróis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/epidemiologia , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Incidência , Indóis/administração & dosagem , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/epidemiologia , Masculino , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Modelos de Riscos Proporcionais , Pirróis/administração & dosagem , Fatores de Risco , Programa de SEER , Sorafenibe , Sunitinibe , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
The discovery of the BRAFV600 mutation and the development of targeted therapies directed against this mutation as well as effective immunotherapies with durable benefits have revolutionized the treatment of patients with melanoma. Nonetheless, the frequent occurrence of brain metastases in patients with advanced melanoma represents a significant obstacle to long-term, high quality survival. The application of stereotactic radiation therapy has provided an opportunity to control brain metastases in the majority of patients with metastatic melanoma reducing the impact of these lesions on morbidity and mortality and enabling patients to receive and potentially benefit from these novel systemic treatments. Encouragingly, several of these novel new therapies have shown antitumor activity against CNS metastases that approach that seen against extracranial disease. As a consequence, several effective treatment options are now available for patients with melanoma brain metastases. With these tools in hand, it is anticipated that further investigation into the optimal sequence and/or combination of systemic therapies and local therapies along with multidisciplinary team practice will continue to improve the outcome of patients with this previously life-limiting disease complication.
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Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Melanoma/secundário , Melanoma/terapia , Humanos , Imunoterapia , RadiocirurgiaAssuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Rejeição de Enxerto/induzido quimicamente , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Aloenxertos , Carcinoma de Células Escamosas/secundário , Feminino , Humanos , Hospedeiro Imunocomprometido , Rim/metabolismo , Rim/patologia , Transplante de Rim , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/secundárioRESUMO
Patients with metastatic melanoma had few treatment options until 2011, when two drugs-ipilimumab and vemurafenib-were approved following advances in the understanding of melanoma biology and tumour immunology. Almost 50% of melanomas harbour mutations in BRAF, mainly at codon 600, which result in constitutive activation of the MAPK pathway. The selective inhibitors of mutant BRAF Val600, vemurafenib and dabrafenib, showed major tumour responses, resulting in improved progression-free and overall survival in patients with metastatic disease, compared with chemotherapy. Antitumour activity was also recorded in brain metastases. The growth of cutaneous squamous-cell carcinomas is a unique side-effect of BRAF inhibitor therapy that is induced by the paradoxical activation of the MAPK pathway in cells with RAS mutations. Trametinib, which targets MEK downstream of BRAF, also produced an overall survival benefit compared with chemotherapy, although tumour responses were less frequent than they were with BRAF inhibitors. Despite this robust antitumour activity, most responses to these drugs are partial and disease progression is typically seen at a median of 5-7 months. Multiple resistance mechanisms have been identified, including those that lead to reactivation of the MAPK pathway and other pathways, such as the PI3K-AKT-mTOR and VEGF pathways. Some patients with BRAF Val600 mutant melanoma seem to also benefit from immunotherapies such as high-dose interleukin 2 and ipilimumab, which, by contrast with BRAF inhibitors, can produce durable complete responses. We review the available data to best guide initial treatment choice and the sequence of treatments for patients with BRAF Val600 mutant melanoma.
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Melanoma/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Anticorpos Monoclonais/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Ipilimumab , Melanoma/genética , Oximas/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Sulfonamidas/uso terapêutico , VemurafenibRESUMO
Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.
Melanoma is a serious form of skin cancer that develops from melanocytes, which are pigment cells that give the skin, hair, and other tissues their color. At advanced stages of spread, melanoma can be life-threatening. However, immunotherapy, a type of therapy that helps the body's immune system to destroy cancer cells, allows some patients with advanced melanoma to live longer. The OPTIMIzE study looked at how well patients with advanced melanoma did when treated with different immunotherapies. These patients were treated in a real-world setting, such as a doctor's office, and were not participating in a clinical trial. Compared with clinical trials, real-world studies like the OPTIMIzE study may include a more varied group of patients because of the less selective study enrollment requirements. In the OPTIMIzE study, patients were treated with either a single immunotherapy (nivolumab or pembrolizumab alone) or a combination of two immunotherapies (nivolumab plus ipilimumab). Both single and combination immunotherapies were effective and tolerable. Patients receiving nivolumab plus ipilimumab had greater tumor shrinkage than patients receiving nivolumab or pembrolizumab alone, but with more side effects from their treatment. Despite the occurrence of side effects with both single and combination immunotherapies, patients reported that their quality of life remained stable while being treated. The OPTIMIzE study shows that immunotherapy is effective and tolerable for patients with advanced melanoma in the real-world setting. This information may help doctors with selecting treatments for their patients with advanced melanoma. Clinical Trial Registration: NCT02780089 (ClinicalTrials.gov).
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Melanoma , Humanos , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Ipilimumab/efeitos adversos , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistema de RegistrosRESUMO
PURPOSE: Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136). METHODS: Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review. RESULTS: A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count). CONCLUSION: Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
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Inibidores de Checkpoint Imunológico , Melanoma , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1 , Melanoma/tratamento farmacológico , Proteínas Reguladoras de Apoptose/uso terapêutico , Melanoma Maligno CutâneoRESUMO
PURPOSE: The COVID-19 pandemic has posed significant challenges in the care of patients with cancer, including how to manage outpatients who are COVID-positive but do not require hospitalization. We explored the use of a remote patient monitoring (RPM) program to care for such outpatients. METHODS: Consecutive patients who were tested for COVID-19 because of symptom onset but were clinically stable were offered enrollment into a pilot RPM program. Patients were provided equipment for vital sign measurements and a computer tablet to enter results three times per day. The results were monitored centrally by clinical staff. The goal was to closely monitor patients and escalate care as warranted. RESULTS: Between March and June of 2020, 29 patients were approached and 26 were enrolled. The mean age was 57 years old (range, 30-88), 14 were women, and patients remained in the program for an average of 16 days (range, 2-63). Twenty-four patients (83%) were on active anticancer therapy. During that time period, only one patient was admitted to the hospital for worsening respiratory symptoms. The percentage of days during which at least one set of data and all three sets of data were entered was 97.2% and 65.7%, respectively. There was no association between the demographic factors of age, sex, or the reason for being monitored with the level of engagement (P > .05). CONCLUSION: In this pilot study, patients with cancer were readily enrolled in a remote home monitoring program. Monitoring was feasible, and there was a high rate of engagement with the program. The role of RPM should be further tested as the COVID pandemic continues.
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COVID-19 , Neoplasias , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Pandemias , Projetos Piloto , SARS-CoV-2RESUMO
PURPOSE: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). EXPERIMENTAL DESIGN: Tumors from a cohort of patients with late-stage melanoma (n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. RESULTS: Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (P = 0.016) than TMB alone (P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (P = 0.002). CONCLUSIONS: NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma.
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Resistencia a Medicamentos Antineoplásicos/imunologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Modelos Imunológicos , Previsões , Humanos , Resultado do TratamentoRESUMO
PURPOSE: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. METHODS: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers. RESULTS: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response. CONCLUSION: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Polietilenoglicóis/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Interleucina-2/efeitos adversos , Interleucina-2/uso terapêutico , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Polietilenoglicóis/efeitos adversos , Intervalo Livre de Progressão , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Fatores de Tempo , Estados UnidosRESUMO
BACKGROUND: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. METHODS: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). RESULTS: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. CONCLUSIONS: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.
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Neoplasias Encefálicas , Melanoma , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Humanos , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversosRESUMO
BACKGROUND: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. METHODS: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. RESULTS: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). CONCLUSIONS: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. TRIAL REGISTRATION NUMBER: NCT01546571.
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Vacinas Anticâncer/uso terapêutico , Melanoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Vacinas Combinadas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vacinas Combinadas/farmacologia , Adulto JovemRESUMO
To determine whether authors conducting economic analyses of aromatase inhibitors in breast cancer are less likely to reach unfavorable conclusions if the economic study is sponsored by the manufacturer of the drug. Articles reporting the economic analyses of aromatase inhibitors in breast cancer were selected from PubMed in May 2009. Information was collected on the types of analysis, the qualitative conclusion, the quantitative results, and the funding sources. Fisher's exact test was conducted to compare the frequency of unfavorable conclusions based on study sponsorship. Thirty-two eligible articles were identified. Twenty-six were funded by pharmaceutical companies, and 4 were funded by non-pharmaceutical companies. Two studies did not report a funding source. Twenty-one studies evaluated aromatase inhibitors in the adjuvant setting, while 11 studies examined their use in advanced breast cancer. Twenty-two studies evaluated one type aromatase inhibitor, while 10 compared multiple types of aromatase inhibitors. Only one of the 26 (4%) pharmaceutical company-sponsored studies reported unfavorable cost-effectiveness of an aromatase inhibitor, which was a competitor's product, whereas two of four (50%) non-pharmaceutical company-sponsored studies concluded aromatase inhibitors are not cost-effective in certain clinical scenarios (P < 0.05). Seven pharmaceutical company-sponsored studies conducted a comparison among several aromatase inhibitors; all 7 studies reported favorable conclusions for the sponsoring company's products. The majority of economic analyses of aromatase inhibitors in breast cancer are sponsored by pharmaceuticals. Economic evaluations of aromatase inhibitors in breast cancer that are funded by a pharmaceutical company are less likely to reach unfavorable conclusions about the sponsor's product.
Assuntos
Antineoplásicos Hormonais/economia , Inibidores da Aromatase/economia , Neoplasias da Mama/economia , Conflito de Interesses/economia , Indústria Farmacêutica/ética , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Indústria Farmacêutica/economia , Ética Médica , Feminino , Humanos , Apoio à Pesquisa como Assunto/economiaRESUMO
INTRODUCTION: Real-world data on recurrence and economic burden in patients with resected early-stage melanoma are limited. The objective of this study was to assess real-world recurrence rates, risk factors for recurrence, and costs of recurrence in patients with resected stage IIB, IIC, or IIIA melanoma in the USA. METHODS: This retrospective analysis included patients with resected stage IIB, IIC, or IIIA melanoma (American Joint Committee on Cancer staging manual, seventh edition) in the Surveillance, Epidemiology, and End Results (SEER) program-Medicare database of the National Cancer Institute. Recurrence rates and healthcare costs (2018 USD) after recurrence were assessed. RESULTS: Two-year recurrence rates for stages IIB, IIC, and IIIA melanoma were 29, 44, and 46%, respectively. In patients with stage IIB or IIC disease, the odds of recurrence were significantly higher in those aged > 75 years [odds ratio (OR) 1.853, 95% confidence interval (CI) 1.416, 2.425], with ulceration (OR 1.771; 95% CI 1.293, 2.425), or with a higher Charlson Comorbidity Index (OR 1.244; 95% CI 1.129, 1.372); however, the odds of recurrence were significantly lower in those with T3 staging (OR 0.522; 95% CI 0.393, 0.695). In those with stage IIIA melanoma, superficial spreading was associated with significantly lower odds of recurrence (OR 0.178; 95% CI 0.053, 0.601). Following recurrence, mean healthcare costs at 1 year were $31,870 for patients with stage IIB or IIC melanoma and $29,224 for those with stage IIIA melanoma. CONCLUSION: The SEER data show that a substantial proportion of adults with early-stage melanoma experience a recurrence within 2 years following resection, resulting in a significant economic burden to the US healthcare system. Dermatologists can distinguish patients with resected early-stage melanoma who are at a high risk for recurrence and consider referrals to medical oncologists for approved adjuvant therapy or enrollment in clinical trials after surgical resection to reduce the recurrence of melanoma.
RESUMO
The presentation of the numbers of patients in Tables 1 and 3 was adjusted.