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1.
Eur J Cancer ; 207: 114146, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38838446

RESUMEN

BACKGROUND: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials. METHODS: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year. Adverse events (AEs) were summarized for patients who received ≥ 1 dose of treatment. RESULTS: Data were pooled from 4125 patients treated with pembrolizumab (n = 2060) or placebo (n = 2065). Median (range) duration of treatment was 11.1 months (0.0-18.9) with pembrolizumab and 11.2 months (0.0-18.1) with placebo. Treatment-related AEs occurred in 78.6 % (1620/2060) of patients in the pembrolizumab group (grade 3-5, 16.3 % [336/2060]) and 58.7 % (1212/2065) in the placebo group (grade 3-5, 3.5 % [72/2065]). Immune-mediated AEs (e.g. adrenal insufficiency, hypophysitis, and thyroiditis) occurred in 36.2 % (746/2060) of patients in the pembrolizumab group (grade 3-5, 8.6 % [177/2060]) and 8.4 % (174/2065) in the placebo group (grade 3-5, 1.1 % [23/2065]). Of patients with ≥ 1 immune-mediated AE or infusion reaction, systemic corticosteroids were required for 35.2 % (268/761) and 20.2 % (39/193) of patients in the pembrolizumab and placebo groups, respectively. CONCLUSIONS: Adjuvant pembrolizumab demonstrated a manageable safety profile that was comparable to prior reports in advanced disease.

2.
Melanoma Res ; 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38814728

RESUMEN

Long follow-up time is needed for overall survival (OS) data to mature for early-stage melanoma. This retrospective study aimed to describe the relationships between OS and two intermediate endpoints - real-world recurrence-free survival (rwRFS) and real-world distant metastasis-free survival (rwDMFS) - for patients with stage IIB or IIC melanoma that was completely resected from 1 January 2008 to 31 December 2017, with follow-up to 31 December 2020. We used three different approaches to describe the relationships: estimates of correlation using Kendall τ rank correlation; comparisons of all-cause survival with/without recurrence or distant metastasis using adjusted Cox proportional hazard models; and landmark analyses of all-cause survival stratified by recurrence status at 1-5 years. During a 39-month median follow-up from surgical resection, 223/567 patients (39%) experienced recurrence, among whom 171/567 patients (30%) developed distant metastasis. Median OS from surgical resection was 117.6 months [95% confidence interval (CI), 104.7-not reached], median rwRFS was 49.8 months (95% CI, 39.6-61.0), and median rwDMFS was 70.9 months (95% CI, 58.4-89.1). We observed strong correlations between rwRFS and OS, and between rwDMFS and OS (Kendall τ of 0.73 and 0.82, respectively). Risk of death was significantly greater after recurrence (all-cause survival adjusted hazard ratio [HR], 7.48; 95% CI, 4.55-12.29) or distant metastasis (adjusted HR, 11.00; 95% CI, 6.92-17.49). Risk of death remained significantly elevated with recurrence or distant metastasis by landmark years 1, 3, and 5 after surgical resection. These findings support the use of recurrence/rwRFS and distant metastasis/rwDMFS as surrogate endpoints for OS after complete resection of stage IIB or IIC melanoma.

3.
J Immunother Cancer ; 12(3)2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38485189

RESUMEN

BACKGROUND: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. METHODS: Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm2 (median) vs ≥5 per mm2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). RESULTS: Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm2 and 0.57 (0.40 to 0.80) for ≥5 per mm2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. CONCLUSIONS: In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03553836.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Adyuvantes Inmunológicos/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Terapia Combinada , Melanoma/patología , Neoplasias Cutáneas/patología , Adolescente , Adulto
4.
J Clin Oncol ; 42(14): 1619-1624, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38452313

RESUMEN

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Melanoma , Estadificación de Neoplasias , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Melanoma/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Quimioterapia Adyuvante , Anciano , Método Doble Ciego , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Antineoplásicos Inmunológicos/uso terapéutico , Adulto , Supervivencia sin Enfermedad , Anciano de 80 o más Años
5.
J Clin Oncol ; 41(24): 3998-4003, 2023 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-37348035

RESUMEN

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Immune checkpoint inhibitors have led to unprecedented prolongation of overall survival (OS) for patients with advanced melanoma. Five-year follow-up of KEYNOTE-006 showed pembrolizumab prolonged survival versus ipilimumab. Efficacy results with 7-year follow-up are presented. At data cutoff (April 19, 2021), median follow-up was 85.3 months (range, 0.03-90.8 months). Median OS was 32.7 months for pembrolizumab versus 15.9 months for ipilimumab (hazard ratio [HR], 0.70; 95% CI, 0.58 to 0.83); 7-year OS was 37.8% and 25.3%, respectively. OS HRs favored pembrolizumab regardless of BRAF status or prior BRAF/MEK-inhibitor treatment and prognostic characteristics (elevated lactate dehydrogenase, large tumor size, and brain metastasis). Median modified progression-free survival (mPFS) was 9.4 months for pembrolizumab versus 3.8 months for ipilimumab; 7-year mPFS was 23.8% and 13.3%, respectively. In patients who completed ≥94 weeks of pembrolizumab, the 5-year OS was 92.9% and the 5-year mPFS was 70.1%. The objective response rate with second-course pembrolizumab (n = 16) was 56% (95% CI, 30 to 80) and the 2-year mPFS was 62.5%. These findings confirm that pembrolizumab provides long-term survival benefit in advanced melanoma.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Ipilimumab , Melanoma , Proteínas Proto-Oncogénicas B-raf , Humanos , Estudios de Seguimiento , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico
6.
Adv Ther ; 40(7): 3038-3055, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37191852

RESUMEN

INTRODUCTION: Pembrolizumab was approved in the US as adjuvant treatment of patients with stage IIB or IIC melanoma post-complete resection, based on prolonged recurrence-free survival vs. placebo in the Phase 3 KEYNOTE-716 trial. This study aimed to evaluate the cost-effectiveness of pembrolizumab vs. observation as adjuvant treatment of stage IIB or IIC melanoma from a US health sector perspective. METHODS: A Markov cohort model was constructed to simulate patient transitions among recurrence-free, locoregional recurrence, distant metastasis, and death. Transition probabilities from recurrence-free and locoregional recurrence were estimated via multistate parametric modeling based on patient-level data from an interim analysis (data cutoff date: 04-Jan-2022). Transition probabilities from distant metastasis were based on KEYNOTE-006 data and network meta-analysis. Costs were estimated in 2022 US dollars. Utilities were based on applying US value set to EQ-5D-5L data collected in trial and literature. RESULTS: Compared to observation, pembrolizumab increased total costs by $80,423 and provided gains of 1.17 quality-adjusted life years (QALYs) and 1.24 life years (LYs) over lifetime, resulting in incremental cost-effectiveness ratios of $68,736/QALY and $65,059/LY. The higher upfront costs of adjuvant treatment were largely offset by reductions in costs of subsequent treatment, downstream disease management, and terminal care, reflecting the lower risk of recurrence with pembrolizumab. Results were robust in one-way sensitivity and scenario analyses. At a $150,000/QALY threshold, pembrolizumab was cost-effective vs. observation in 73.9% of probabilistic simulations that considered parameter uncertainty. CONCLUSION: As an adjuvant treatment of stage IIB or IIC melanoma, pembrolizumab was estimated to reduce recurrence, extend patients' life and QALYs, and be cost-effective versus observation at a US willingness-to-pay threshold.


Asunto(s)
Análisis de Costo-Efectividad , Melanoma , Humanos , Estados Unidos , Análisis Costo-Beneficio , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Melanoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Años de Vida Ajustados por Calidad de Vida
7.
Neuro Oncol ; 25(4): 674-686, 2023 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-36054930

RESUMEN

BACKGROUND: Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood. METHODS: We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo. RESULTS: Brain-specific genetic alterations were not detected; however, MBM cells in vitro displayed lower proliferation rates and MBM-specific protein expression patterns associated with proliferation, DNA damage, adhesion, and migration. MBM lines displayed higher levels of RAC1 expression, involving a distinct RAC1-PAK1-JNK1 signaling network. RAC1 knockdown or treatment with small molecule inhibitors contributed to a less aggressive MBM phenotype in vitro, while RAC1 knockdown in vivo led to reduced tumor volumes and delayed tumor appearance. Proliferation, adhesion, and migration were higher in MBM vs nonMBM lines in the presence of insulin or brain-derived factors and were affected by RAC1 levels. CONCLUSIONS: Our findings indicate that despite their genetic variability, MBM engage specific molecular processes such as RAC1 signaling to adapt to the brain microenvironment and this can be used for the molecular characterization and treatment of brain metastases.


Asunto(s)
Neoplasias Encefálicas , Melanoma , Neoplasias Cutáneas , Humanos , Pronóstico , Melanoma/patología , Neoplasias Encefálicas/genética , Biomarcadores , Microambiente Tumoral , Proteína de Unión al GTP rac1/metabolismo
8.
J Clin Oncol ; 41(1): 75-85, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-35867951

RESUMEN

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.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Melanoma , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1 , Melanoma/tratamiento farmacológico , Proteínas Reguladoras de la Apoptosis/uso terapéutico , Melanoma Cutáneo Maligno
9.
Future Oncol ; 18(33): 3755-3767, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36346064

RESUMEN

Aim: To describe clinical outcomes after complete surgical resection of stage IIB and IIC melanoma. Methods: Adult patients (n = 567) with stage IIB or IIC cutaneous melanoma initially diagnosed and completely resected from 2008-2017 were identified using data from a US community-based oncology network. Results: Median patient follow-up was 38.8 months from melanoma resection to death, last visit or data cut-off (31 December 2020). For stage IIB (n = 375; 66%), Kaplan-Meier median real-world recurrence-free survival (rwRFS) was 58.6 months (95% CI, 48.6-69.5). For stage IIC (n = 192; 34%), median rwRFS was 29.9 months (24.9-45.5). Overall, 44% of patients had melanoma recurrence or died; 30% developed distant metastases. Conclusion: Melanoma recurrence was common, highlighting the need for effective adjuvant therapy for stage IIB and IIC melanoma.


New treatments are now available that decrease tumor recurrence when administered after surgery to remove melanoma skin tumors that are graded as stage IIB or IIC (i.e., with no cancer spread to the local lymph nodes). We studied 567 'real-world' patients at clinics in the USA who had stage IIB or IIC melanoma tumors removed in 2008­2017, before these new postsurgical treatments were widely available, to evaluate their survival and tumor recurrence. We found that almost half of these patients (44%) had melanoma recurrence or had died, and a third (30%) had tumor spread beyond the original site, by the end of 2020. These findings highlight the need for more effective treatments after surgical removal of stage IIB and IIC melanoma.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Adulto , Humanos , Melanoma/terapia , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Terapia Combinada , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/patología , Melanoma Cutáneo Maligno
10.
Eur J Cancer ; 176: 207-217, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36202690

RESUMEN

BACKGROUND: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported. METHODS: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to <18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment. RESULTS: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms. CONCLUSIONS: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.


Asunto(s)
Melanoma , Calidad de Vida , Humanos , Recurrencia Local de Neoplasia , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Adyuvantes Inmunológicos/uso terapéutico , Melanoma Cutáneo Maligno
11.
Lancet Oncol ; 23(11): 1378-1388, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36265502

RESUMEN

BACKGROUND: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up. METHODS: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Neoplasias Testiculares , Masculino , Humanos , Niño , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía , Recurrencia Local de Neoplasia/patología , Anticuerpos Monoclonales Humanizados/efectos adversos , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
12.
J Immunother Cancer ; 10(7)2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35793874

RESUMEN

BACKGROUND: Immunotherapies targeting programmed cell death-1 (PD-1) and its ligands have improved clinical outcomes for advanced melanoma. However, many tumors exhibit primary resistance or acquire secondary resistance after an initial positive response. The mechanisms of resistance are not well understood, and no validated predictive biomarkers are available. This exploratory study aimed to characterize baseline differences and molecular changes arising during treatment in acral and mucosal melanomas that exhibited primary or secondary resistance to anti-PD-1 monotherapy. METHODS: This was an observational retrospective study of 124 patients who had been treated for metastatic acral or mucosal melanoma with anti-PD-1 monotherapy. Tumor samples were collected at baseline (all patients) and post-treatment (resistant tumors only) and were assayed by immunohistochemistry, whole-exome sequencing, and RNA sequencing. RESULTS: At baseline, more non-progressor than resistant tumors exhibited expression of PD-L1, immune cell infiltration, and high tumor mutational burden (TMB); baseline PD-L1 expression was also more common in secondary-resistant than in primary-resistant tumors as well as in late versus early secondary-resistant tumors. Non-progressor tumors also had higher median baseline expression of an 18-gene T cell-inflamed gene expression profile (TcellinfGEP). Among resistant tumors, the proportion of PD-L1-positive melanomas and the expression of the TcellinfGEP mRNA signature increased during treatment, while the expression of mRNA signatures related to WNT and INFA1 signaling decreased. There was evidence for greater changes from baseline in secondary-resistant versus primary-resistant tumors for some markers, including expression of RAS-related and WNT-related mRNA signatures and density of CD11c+ and FOXP3+ T cells. Greater changes in CD11c+ cell density were observed in early compared with late secondary-resistant tumors. CONCLUSIONS: Our findings suggest that TcellinfGEP and PD-L1 expression, TMB, immune cell infiltration, and RAS and WNT signaling warrant further investigation as potential mechanisms and/or biomarkers of anti-PD-1 therapy resistance in acral and mucosal melanomas. Confirmation of these findings in larger populations is needed.


Asunto(s)
Melanoma , Receptor de Muerte Celular Programada 1 , Biomarcadores/análisis , Humanos , Melanoma/inmunología , Melanoma/patología , Melanoma/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , ARN Mensajero/biosíntesis , Estudios Retrospectivos
13.
Nat Commun ; 13(1): 3055, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35650266

RESUMEN

Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific elimination.


Asunto(s)
Melanoma , Monofenol Monooxigenasa , Línea Celular Tumoral , Proliferación Celular/genética , Humanos , Melanocitos/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología
14.
Cancers (Basel) ; 14(7)2022 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-35406577

RESUMEN

Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman's rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0-35.4) months, the rwPFS was 3.9 months (95%CI 3.5-4.9), the rwTtNT was 10.7 months (95%CI 9.0-12.9), and the rwToT was 6.2 months (95%CI 5.1-6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.

15.
NEJM Evid ; 1(11): EVIDoa2200214, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38319852

RESUMEN

BACKGROUND: In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence- and distant metastasis-free survival than placebo in patients with resected high-risk stage III melanoma. To confirm the stability of these benefits, longer-term data were needed. METHODS: We randomly assigned 1019 patients to receive 200 mg of pembrolizumab or placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year) and had previously reported data with a 15-, 36-, and 42-month median follow-up. We now report data at a median follow-up of 4.9 years. We report a number of outcomes, including recurrence-free survival in the overall population and in the subgroup of patients with cancer who were positive for the programmed death-ligand 1 (PD-L1). Distant metastasis-free survival was a secondary end point. RESULTS: In the overall intention-to-treat population, pembrolizumab was still associated with longer recurrence-free survival than placebo (5-year rate of recurrence-free survival, 55.4% [95% confidence interval (CI), 50.8 to 59.8] vs. 38.3% [95% CI, 33.9 to 42.7]; hazard ratio for recurrence or death, 0.61 [95% CI, 0.51 to 0.72]) and a longer distant metastasis-free survival (5-year rate of distant metastasis-free survival, 60.6% [95% CI, 56.0 to 64.9] vs. 44.5% [95% CI, 39.9 to 48.9]; hazard ratio for distant metastasis or death, 0.62 [95% CI, 0.52 to 0.75]). Similar findings were obtained in the subgroup of 853 patients with PD-L1­positive tumors. CONCLUSIONS: The 5-year analysis of adjuvant therapy with pembrolizumab resulted in a sustained improvement in the long-term recurrence- and distant metastasis-free survival compared with placebo in patients with resected stage III melanoma. (Funded by Merck & Co., Inc.; ClinicalTrials.gov number, NCT02362594, and EudraCT number, 2014-004944-37.)


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Adyuvantes Inmunológicos/uso terapéutico , Adyuvantes Farmacéuticos/uso terapéutico , Anticuerpos Monoclonales Humanizados , Melanoma/tratamiento farmacológico , Estadificación de Neoplasias , Neoplasias Cutáneas/tratamiento farmacológico
16.
Eur J Cancer ; 158: 156-168, 2021 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-34678677

RESUMEN

BACKGROUND: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. METHODS: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. RESULTS: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. CONCLUSIONS: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.

17.
Cancer Res ; 81(20): 5230-5241, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34462276

RESUMEN

Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells. SIGNIFICANCE: This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Melanoma/patología , Cresta Neural/patología , Células-Madre Neurales/patología , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Cresta Neural/efectos de los fármacos , Cresta Neural/metabolismo , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Pronóstico , Receptores del Ácido Lisofosfatídico/genética , Transcriptoma , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Lancet Oncol ; 22(5): 643-654, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33857412

RESUMEN

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results. METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]). INTERPRETATION: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma. FUNDING: Merck Sharp & Dohme.


Asunto(s)
Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Femenino , Humanos , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología
19.
Lancet Oncol ; 22(5): 655-664, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33857414

RESUMEN

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint. METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing. FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant. INTERPRETATION: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. FUNDING: Merck Sharp & Dohme.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Melanoma/tratamiento farmacológico , Calidad de Vida , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Humanos , Masculino , Melanoma/mortalidad , Melanoma/patología , Melanoma/psicología , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/psicología
20.
J Immunother ; 44(6): 224-233, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33734142

RESUMEN

Favorable outcomes have been observed with pembrolizumab among patients with advanced melanoma in clinical trials; however, limited evidence exists on the long-term efficacy in the real-world setting. This was an updated, retrospective observational study of adult patients with advanced (unresectable or metastatic) melanoma who initiated pembrolizumab (in any line of therapy) between January 1, 2014, and December 31, 2016, in The US Oncology Network and were followed through December 31, 2019 [median follow-up: 18.2 mo (range: 0.1-63.1 mo)]. Study data were sourced from electronic health records. Patient demographic, clinical, and treatment characteristics were assessed descriptively. Kaplan-Meier methods were used to evaluate overall survival (OS), time to treatment discontinuation, time to next treatment, physician-assessed time to tumor progression, and physician-assessed progression-free survival (rwPFS). Independent risk factors for OS and rwPFS were identified with multivariable Cox regression models. Of the 303 study-eligible patients, 119, 131, and 53 received pembrolizumab in the first-line, second-line, and third-line or beyond setting, respectively. Median OS across the study population was 29.3 months [95% confidence interval (CI): 20.3-49.7] and was the longest among those who received first-line pembrolizumab [42.8 mo (95% CI: 24.8-not reached)]. Median rwPFS across the study population was 5.1 months (95% CI: 4.0-7.6) and 8.1 months (95% CI: 4.6-14.4) among those who received first-line pembrolizumab. In the multivariable analyses for OS, increased age, worsening performance status, elevated lactate dehydrogenase, brain metastases, and pembrolizumab use in later lines were significantly associated a worse prognosis.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/epidemiología , Terapia Molecular Dirigida , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Ensayos Clínicos como Asunto , Terapia Combinada , Bases de Datos Factuales , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Encuestas de Atención de la Salud , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estimación de Kaplan-Meier , Masculino , Melanoma/diagnóstico , Melanoma/etiología , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del Tratamiento , Estados Unidos/epidemiología
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