RESUMO
BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).
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Antineoplásicos Imunológicos , Melanoma , Terapia Neoadjuvante , Neoplasias Cutâneas , Humanos , Adjuvantes Imunológicos , Progressão da Doença , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/cirurgia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Quimioterapia AdjuvanteRESUMO
Although genome-wide hypomethylation is a hallmark of many cancers, roles for active DNA demethylation during tumorigenesis are unknown. Here, loss of the APC tumor suppressor gene causes upregulation of a DNA demethylase system and the concomitant hypomethylation of key intestinal cell fating genes. Notably, this hypomethylation maintained zebrafish intestinal cells in an undifferentiated state that was released upon knockdown of demethylase components. Mechanistically, the demethylase genes are directly activated by Pou5f1 and Cebpß and are indirectly repressed by retinoic acid, which antagonizes Pou5f1 and Cebpß. Apc mutants lack retinoic acid as a result of the transcriptional repression of retinol dehydrogenase l1 via a complex that includes Lef1, Groucho2, Ctbp1, Lsd1, and Corest. Our findings imply a model wherein APC controls intestinal cell fating through a switch in DNA methylation dynamics. Wild-type APC and retinoic acid downregulate demethylase components, thereby promoting DNA methylation of key genes and helping progenitors commit to differentiation.
Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/metabolismo , Metilação de DNA , Intestinos/embriologia , Peixe-Zebra/embriologia , Polipose Adenomatosa do Colo/patologia , Oxirredutases do Álcool/metabolismo , Animais , Encéfalo/citologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Correpressoras/metabolismo , Neoplasias do Colo/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Tretinoína/metabolismoRESUMO
Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.
Assuntos
Melanoma , Neoplasias Cutâneas , Neoplasias Encefálicas/secundário , Humanos , Excisão de Linfonodo , Melanoma/diagnóstico , Melanoma/cirurgia , Melanoma/terapia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/terapiaRESUMO
INTRODUCTION: Anti-PD-1 antibodies are commonly used as frontline therapy for patients with metastatic melanoma. Although these medications can cause long term responses, a significant number of patients will not respond or will lose response. Optimal second-line therapy after losing response to anti-PD-1 antibodies is not well established. Therefore, we retrospectively compared the overall survival of patients who lost response to anti-PD1 antibodies between patients treated with single agent ipilimumab or ipilimumab and nivolumab. METHODS: A de-identified U.S. nationwide electronic health record-derived database was reviewed for patients with advanced melanoma treated with single agent anti-PD1 antibodies in the frontline setting and who subsequently received second-line ipilimumab or combination ipilimumab and nivolumab. Overall survival from initiation of second-line therapy was compared using Kaplan Meier curves and log-rank analysis. Other known prognostic markers for melanoma were analyzed for correlation with survival in a similar fashion. Disease characteristics between the two groups were compared using chi-square analysis. RESULTS: A total of 842 patients with advanced melanoma who received frontline anti-PD-1 antibodies were included for analysis. Of these, 57 received either ipilimumab (n = 22) or ipilimumab in combination with nivolumab (n = 35) in the second-line setting. Median survival from second-line therapy initiation for those treated with ipilimumab alone was 6 months and was 5.6 months for those treated with combination ipilimumab and anti-PD-1 antibodies, p = 0.81. CONCLUSIONS: In this small, retrospective analysis, for patients who lost response to frontline anti-PD-1 therapy, patients treated with ipilimumab had similar survival to those who received ipilimumab in combination with anti-PD-1 antibodies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Ipilimumab/administração & dosagem , Ipilimumab/uso terapêutico , Melanoma/terapia , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Idoso , Terapia Combinada , Bases de Dados Factuais , Registros Eletrônicos de Saúde , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Background: Pembrolizumab (P) and nivolumab (N) are commonly used therapies for advanced melanoma. However, their effectiveness has never been directly compared, leaving little guidance for clinicians to select the best therapy. Therefore, we sought to retrospectively compare the overall survival of patients with metastatic melanoma treated with front line P or N in the real-world setting.Material and methods: This study included patients with advanced melanoma, diagnosed between 1 January 2011 and 31 July 2018, treated with frontline P or N who were included in a nationwide, longitudinal de-identified electronic health record (EHR)-derived database. Overall survival (OS) was estimated for each treatment group using Kaplan-Meier curves with a log-rank test. Comparison of OS was estimated using an inverse probability weighting model to reduce bias between the groups. The model was adjusted using age, sex, ECOG, LDH (elevated or not), BRAF (mutated or not), Kit (mutated or not), NRAS (mutated or not), PD-L1 expression (0% or greater), Body Mass Index, and primary site.Results: 888 patients with advanced disease who received treatment with frontline P (n = 486) or N (n = 402) were identified. Median OS for all patients treated with P was 22.6 months (m) and was 23.9 m for those treated with N (p = 0.91). In the inverse probability weight analysis there was no difference in survival between patients treated with P or N 1.06 (95% CI 0.84-1.33).Concluding Statement: In our retrospective, real-world analysis of patients with advanced melanoma, no statistical difference in OS was noted between patients treated with frontline P compared to N. This supports the current practice of choosing either P or N based on patient and provider preference.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma. METHODS: In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. RESULTS: Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication. CONCLUSIONS: The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Ipilimumab , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Nivolumabe , Proteínas Proto-Oncogênicas B-raf/genética , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Ipilimumab , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Nivolumabe , Neoplasias Cutâneas/patologia , Carga Tumoral/efeitos dos fármacosRESUMO
AIMS: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS: Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. RESULTS: Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, -1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg Cmax and AUC(0-∞) were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC(0-τ) with 300 mg BID was ≈ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was <5 msec (upper 90% CI, <10 msec). No unexpected toxicities occurred with supratherapeutic dosing. CONCLUSION: Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen.
Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Simulação por Computador , Relação Dose-Resposta a Droga , Eletrocardiografia Ambulatorial/métodos , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Neoplasias/genética , Neoplasias/patologia , Oximas/efeitos adversos , Oximas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidoresRESUMO
BACKGROUND: Survival data are mixed comparing patients with multiple primary melanomas (MPM) to those with single primary melanomas (SPM). OBJECTIVES: We compared MPM versus SPM patient survival using a matching method that avoids potential biases associated with other analytic approaches. METHODS: Records of 14,138 individuals obtained from the Surveillance, Epidemiology, and End Results registry of all melanomas diagnosed or treated in Utah between 1973 and 2011 were reviewed. A single matched control patient was selected randomly from the SPM cohort for each MPM patient, with the restriction that they survived at least as long as the interval between the first and second diagnoses for the matched MPM patient. RESULTS: Survival curves (n = 887 for both MPM and SPM groups) without covariates showed a significant survival disadvantage for MPM patients (chi-squared 39.29, P < .001). However, a multivariate Cox proportional hazards model showed no significant survival difference (hazard ratio 1.07, P = .55). Restricting the multivariate analysis to invasive melanomas also showed no significant survival difference (hazard ratio 0.99, P = .96). LIMITATIONS: Breslow depth, ulceration status, and specific cause of death were not available for all patients. CONCLUSIONS: Patients with MPM had similar survival times as patients with SPM.
Assuntos
Melanoma/mortalidade , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Causas de Morte , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise por Pareamento , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Modelos de Riscos Proporcionais , Programa de SEER , Neoplasias Cutâneas/patologia , Úlcera Cutânea/patologia , Utah/epidemiologia , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING: Bristol-Myers Squibb.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Método Duplo-Cego , Humanos , Ipilimumab , Melanoma/genética , Melanoma/mortalidade , Mutação , Nivolumabe , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
BACKGROUND: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor ß superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN. METHODS: Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS: Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016;122:3641-9. © 2016 American Cancer Society.
Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Inibidores da Angiogênese/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
PURPOSE: In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16-20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment. MATERIALS AND METHODS: All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months. RESULTS: 391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48-1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39-1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09-0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23-0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable. CONCLUSIONS: Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses.
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Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Estudos de Coortes , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/farmacologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. INTERPRETATION: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING: Bristol-Myers Squibb.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/uso terapêutico , Carboplatina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Ipilimumab , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe , Paclitaxel/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
BACKGROUND: Patients with melanoma of the scalp may have higher failure (recurrence) rates than melanoma of other body sites. OBJECTIVE: We sought to characterize survival and patterns of failure for patients with scalp melanoma. METHODS: Between 1998 and 2010, 250 nonmetastatic patients underwent wide local excision of a primary scalp melanoma. Kaplan-Meier analyses were performed to evaluate overall survival, scalp control, regional neck control, distant metastases-free survival, and disease-free survival. RESULTS: Five-year overall survival was 86%, 57%, and 45% for stages I, II, and III, respectively, and 5-year scalp control rates were 92%, 75%, and 63%, respectively. Five-year distant metastases-free survival for these stages were 92%, 65%, and 45%, respectively. Of the 74 patients who recurred, the site of first recurrence included distant disease in 47%, although 31% recurred in the scalp alone. LIMITATIONS: This is a retrospective review. CONCLUSION: Distant metastases-free survival and overall survival for stage II and III patients with scalp melanoma are poor, and stage III patients experience relatively high rates of scalp failure suggesting that these patients may benefit from additional adjuvant systemic and local therapy. Further research is needed to characterize the environmental, microenvironmental, and genetic causes of the increased aggressiveness of scalp melanoma and to identify more effective treatment and surveillance methods.
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Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Melanoma/mortalidade , Recidiva Local de Neoplasia/mortalidade , Couro Cabeludo , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Análise de Variância , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Análise de SobrevidaRESUMO
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
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Antibacterianos , Microbioma Gastrointestinal , Melanoma , Humanos , Melanoma/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Biomarcadores Tumorais , Vancomicina/uso terapêutico , Adulto , COVID-19/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologiaRESUMO
BACKGROUND: The incidence of melanoma is rising in young women of childbearing age. Melanoma diagnosed during pregnancy presents unique challenges. This study was conducted to determine the effect of sentinel lymph node biopsy (SLNB) for melanoma on maternal and fetal outcomes in pregnant women. METHODS: A prospective melanoma database was retrospectively queried for women diagnosed with melanoma during or immediately before pregnancy as well as SLNB in pregnant women. The outcomes of SLNB for the mothers and fetuses were evaluated. RESULTS: Fifteen pregnant women underwent wide local excision (WLE) and SLNB for melanoma from 1997 to 2012. The median gestational age was 20 weeks. More than half of the women noticed changes in the primary melanoma lesion during the pregnancy. The median Breslow thickness was 1.00 mm. Lymphatic mapping and SLNB were performed with some combination of radiocolloid or vital blue dye without adverse effects. Three patients had micrometastatic disease and underwent a completion lymphadenectomy. Sixteen children were born at a median gestational age of 39 weeks. The median 1- and 5-minute Apgar scores were 8 and 9, respectively. At a median follow-up of 54.4, months none of the patients had experienced recurrence, and all children were healthy and free of melanoma. CONCLUSIONS: In this series of pregnant women with melanoma, SLNB was performed safely during pregnancy without adverse effects to the mothers and fetuses. We recommend that clinicians explain the risks and benefits of the SLNB procedure to pregnant women so an informed decision can be made about the procedure.
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Feto/patologia , Melanoma/cirurgia , Complicações Pós-Operatórias , Complicações Neoplásicas na Gravidez/cirurgia , Biópsia de Linfonodo Sentinela/efeitos adversos , Neoplasias Cutâneas/cirurgia , Adulto , Feminino , Seguimentos , Idade Gestacional , Humanos , Melanoma/patologia , Estadiamento de Neoplasias , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Resultado da Gravidez , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
The objective of this study was to evaluate the feasibility of developing personalized, tumor-informed assays for patients with high-risk resectable melanoma and examine circulating tumor DNA (ctDNA) levels in relation to clinical status. Pilot prospective study of clinical stage IIB/C and resectable stage III melanoma patients. Tumor tissue was used to design bespoke somatic assays for interrogating ctDNA in patients' plasma using a multiplex PCR (mPCR) next-generation sequencing (NGS)-based approach. Plasma samples for ctDNA analysis were collected pre-/post-surgery and during surveillance. Out of 28 patients (mean 65â years, 50% male), 13 (46%) had detectable ctDNA prior to definitive surgery and 96% (27/28) tested ctDNA-negative within 4â weeks post-surgery. Pre-surgical detection of ctDNA was significantly associated with the later-stage ( P â =â 0.02) and clinically evident stage III disease ( P â =â 0.007). Twenty patients continue in surveillance with serial ctDNA testing every 3-6â months. With a median follow-up of 443â days, six out of 20 (30%) patients developed detectable ctDNA levels during surveillance. All six of these patients recurred with a mean time to recurrence of 280â days. Detection of ctDNA in surveillance preceded the diagnosis of clinical recurrence in three patients, was detected concurrent with clinical recurrence in two patients and followed clinical recurrence in one patient. One additional patient developed brain metastases without detection of ctDNA during surveillance but had positive pre-surgical ctDNA. Our results demonstrate the feasibility of obtaining a personalized, tumor-informed mPCR NGS-based ctDNA assay for patients with melanoma, particularly in resectable stage III disease.
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DNA Tumoral Circulante , Melanoma , Neoplasias Cutâneas , Humanos , Masculino , Feminino , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Estudos Prospectivos , Estudos de Viabilidade , Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , MutaçãoRESUMO
BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) has been linked to granulomatous and sarcoid-like lesions (GSLs) affecting different organs. This study sought to evaluate GSL incidence in patients with high-risk melanoma treated with cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD1) blockade adjuvant therapy in two clinical trials: ECOG-ACRIN E1609 and SWOG S1404. Descriptions and GSL severity ratings were recorded. METHODS: Data were collected from ECOG-ACRIN E1609 and SWOG S1404. Descriptive statistics along with GSL severity grades were reported. Additionally, a literature review for such cases was summarized. RESULTS: A total of 11 GSL cases were reported among 2878 patients treated with either ICI or with High-Dose Interferon Alfa-2b (HDI) in ECOG-ACRIN E1609 and SWOG S1404 trials. Cases were numerically more commonly reported with ipi10, followed by pembrolizumab, ipi3, and HDI, respectively. Most of the cases were grade III. Further, organs involved included lung, mediastinal lymph nodes, skin and subcutaneous tissue, and eye. Furthermore, a summary of 62 reports in the literature was described. CONCLUSIONS: GSLs following anti-CTLA4 and anti-PD1 antibody therapy in patients with melanoma were reported unusually. Reported cases ranged in grade from I to III and appeared manageable. Careful attention to these events and their reporting will be essential to better guide practice and management guidelines.
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Importance: A key issue for the adjuvant treatment of patients with melanoma is the assessment of the effect of treatment on relapse, survival, and quality of life (QOL). Objective: To compare QOL in patients with resected melanoma at high risk for relapse who were treated with adjuvant pembrolizumab vs standard of care with either ipilimumab or high-dose interferon α 2b (HDI). Design, Setting, and Participants: The S1404 phase 3 randomized clinical trial was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the US, Canada, and Ireland. Patients were enrolled from December 2015 to October 2017. Data analysis for this QOL substudy was completed in March 2022. Overall, 832 patients were evaluable for the primary QOL end point. Interventions: Patients were randomized (1:1) to treatment with adjuvant pembrolizumab vs standard of care with ipilimumab/HDI. Main Outcomes and Measures: Quality of life was assessed for patients at baseline and cycles 1, 3, 5, 7, and 9 after randomization using the Functional Assessment of Cancer Therapy (FACT) Biological Response Modifiers (FACT-BRM), FACT-General, Functional Assessment of Chronic Illness Therapy-Diarrhea, and European QOL 5-Dimension 3-Level scales. The primary end point was the comparison by arm of cycle 3 FACT-BRM trial outcome index (TOI) scores using linear regression. Linear-mixed models were used to evaluate QOL scores over time. Regression analyses included adjustments for the baseline score, disease stage, and programmed cell death ligand 1 status. A clinically meaningful difference of 5 points was targeted. Results: Among 1303 eligible patients (median [range] age, 56.7 [18.3-86.0] years; 524 women [40.2%]; 779 men [59.8%]; 10 Asian [0.8%], 7 Black [0.5%], 44 Hispanic [3.4%], and 1243 White [95.4%] individuals), 1188 (91.1%) had baseline FACT-BRM TOI scores, and 832 were evaluable at cycle 3 (ipilimumab/HDI = 267 [32.1%]; pembrolizumab = 565 [67.9%]). Evaluable patients were predominantly younger than 65 years (623 [74.9%]) and male (779 [58.9%]). Estimates of FACT-BRM TOI cycle 3 compliance did not differ by arm (ipilimumab/HDI, 96.0% vs pembrolizumab, 98.3%; P = .25). The adjusted cycle 3 FACT-BRM TOI score was 9.6 points (95% CI, 7.9-11.3; P < .001) higher (better QOL) for pembrolizumab compared with ipilimumab/HDI, exceeding the prespecified clinically meaningful difference. In linear-mixed models, differences by arm exceeded 5 points in favor of pembrolizumab through cycle 7. In post hoc analyses, FACT-BRM TOI scores favored the pembrolizumab arm compared with the subset of patients receiving ipilimumab (difference, 6.0 points; 95% CI, 4.1-7.8; P < .001) or HDI (difference, 17.0 points; 95% CI, 14.6-19.4; P < .001). Conclusions and Relevance: This secondary analysis of a phase 3 randomized clinical trial found that adjuvant pembrolizumab improved QOL vs treatment with adjuvant ipilimumab or HDI in patients with high-risk resected melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT02506153.
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Melanoma , Qualidade de Vida , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Ipilimumab/efeitos adversos , Recidiva Local de Neoplasia , Melanoma/tratamento farmacológico , Melanoma/cirurgiaRESUMO
In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .