Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)

Schachter, Jacob; Ribas, Antoni; Long, Georgina V.; Arance, Ana; Grob, Jean Jacques; Mortier, Laurent; Daud, Adil; Carlino, Matteo S.; McNeil, Catriona M.; Lotem, Michal; Larkin, James; Lorigan, Paul; Neyns, Bart; Blank, Christian U.; Petrella, Teresa M.; Hamid, Omid; Zhou, Honghong; Ebbinghaus, Scot; Ibrahim, Nageatte; Robert, Caroline

doi:10.1016/s0140-6736(17)31601-x

Cited by 1,005 publications

(801 citation statements)

References 23 publications

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“…For patients with BRAF wild‐type melanoma, the first‐line treatment with immune checkpoint inhibitors is recommended by European Society for Medical Oncology due to the lack of effective targeted treatment available. However, for patients with BRAF mutated melanoma, because previous studies have revealed that nivolumab and pembrolizumab, two PD‐1 inhibitors approved by FDA, can improve the survival in patients with BRAF‐inhibitor‐refractory or BRAF‐mutant disease, the best therapy option is unclear. Accordingly, consideration of patient‐specific characteristics, such as biochemical and clinicopathological features, and patient tolerance of toxicity should be weighed as the highest priorities when determining frontline treatment for patients with BRAF mutated melanoma.…”

Section: Introductionmentioning

confidence: 99%

Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma

Zhao

2018

Intl Journal of Cancer

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Immune checkpoint inhibitors (ICIs) have unprecedented effects on the treatment of metastatic melanoma. However, little is known about the prognostic values of various clinicopathological characteristics. Here, PubMed, Embase and Cochrane database were searched from inception to April 2018 for random controlled trials (RCTs) that compared ICIs with controls. The hazard ratios (HRs) for overall survival (OS) according to gender, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), lactate dehydrogenase (LDH) level and metastasis stage were extracted. Four phase III RCTs involving 1,598 patients with metastatic melanoma were included in this study. Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50–0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42–0.84; p = 0.003) in men; 0.84 (95% CI, 0.69–1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41–0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55–1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60–0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38–1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long‐term benefits were independent of metastasis stage and LDH level. In summary, although immunotherapy significantly prolongs OS in metastatic melanoma, the long‐term benefits in women, younger patients (<65 years old) and patients with ECOG PS = 0 were marginal. These results may assist in treatment decision‐making, design and interpretation of clinical trials and economic analyses.

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Section: Introductionmentioning

confidence: 99%

Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma

Zhao

2018

Intl Journal of Cancer

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“…17-21 Targeting the PD-1/PD-L1 inhibitory pathway has resulted in objective responses in 17%-28% of advanced melanoma patients, 12%-27% of renal cell cancer patients, 10%-18% of non-small cell lung cancer patients and 20% of advanced hepatocellular carcinoma patients. 22-25 In contrast, CRC patients hardly respond to PD-1 and PD-L1 blocking antibodies, 23-26 except for the minority of patients who are with mismatch repair (MMR)-deficient CRC.…”

Section: Introductionmentioning

confidence: 99%

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

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Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

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“…Portanto, a dimensão dos resultados não deve ser interpretada em valores absolutos. Além disso, embora o pembrolizumabe tenha indicação ampla para tratamento de melanoma irressecável ou metastático, seu estudo pivotal não apresentou resultados de mediana de SLP para a subpopulação de pacientes com mutação BRAF V600 (Schachter, 2017), informação necessária para o cálculo do NNT e do COPE, sendo excluído dessa comparação. Entretanto, como mencionado anteriormente, na escassez de dados farmacoeconômicos de NNT e COPE, este estudo apresenta valor e peso como pioneiro para novas análises econômicas para o tratamento de pacientes com melanoma irressecável ou metastático com mutação BRAF V600, em primeira linha de tratamento.…”

Section: Discussionunclassified

Análise de custo por evento evitado (COPE) da associação de cobimetinibe e vemurafenibe e outras opções terapêuticas para o tratamento de melanoma metastático com mutação BRAF V600

Souza¹,

Bellan²,

Alves³

2018

JBES

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Análise de custo por evento evitado (COPE) da associação de cobimetinibe e vemurafenibe e outras opções terapêuticas para o tratamento de melanoma metastático com mutação BRAF V600 Cost of preventing an event (COPE) RESUMOObjetivo: O melanoma maligno é o tipo de neoplasia de pele com pior prognóstico devido ao seu elevado potencial de gerar metástases e a sua letalidade. Algumas diretrizes internacionais recomendam a combinação de inibidores da via das proteínas quinases BRAF e MEK para o tratamento de melanoma metastático ou irressecável com mutação positiva BRAF V600 em primeira linha. Um estudo demonstrou que, em termos de sobrevida livre de progressão (SLP), a associação de cobimetinibe + vemurafenibe foi a opção terapêutica que proporcionou menor valor de número necessário para tratar (NNT) para o tratamento de melanoma metastático com mutação BRAF V600 em primeira linha. O objetivo desta análise foi de avaliar o custo por evento evitado (COPE) de cobimetinibe em associação com vemurafenibe no tratamento do melanoma irressecável ou metastático, positivos para mutações BRAF V600. Métodos: A análise econômica adotou a perspectiva do Sistema de Saúde Suplementar brasileiro. Os comparadores avaliados foram vemurafenibe monoterapia, dabrafenibe + trametinibe, nivolumabe e ipilimumabe. O COPE foi obtido pelo produto do NNT, baseado na SLP em 12 meses, reportado por Ho et al. e do custo de tratamento considerando custos de aquisição dos medicamentos e manejo de eventos adversos. Resultados: A maior eficiência da associação de cobimetinibe e vemurafenibe foi capaz de proporcionar o menor COPE (R$ 1.204.229) entre todos os comparadores da análise, demonstrando que, com um menor número de pacientes tratados, se observa um caso de sucesso com a terapia combinada, mesmo que esta apresente um custo anual de tratamento superior (R$ 626.477). Conclusão: A associação de cobimetinibe e vemurafenibe foi a mais eficiente em termos de NNT e COPE no melanoma metastático não tratado previamente. ABSTRACTObjective: Melanoma is a type of skin cancer with poor prognosis due to its high potential for metastasis and lethality. Some international guidelines recommend the combination of BRAF and MEK protein kinase pathway inhibitors for the first line treatment of metastatic or unresectable melanoma with BRAF V600 positive mutation. One study demonstrated that in terms of PFS, the combination of cobimetinib + vemurafenib was the first line therapeutic option that provided the lowest

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Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)

Cited by 1,005 publications

References 23 publications

Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma

Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Análise de custo por evento evitado (COPE) da associação de cobimetinibe e vemurafenibe e outras opções terapêuticas para o tratamento de melanoma metastático com mutação BRAF V600

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