RESUMO
Importance: Combination immunotherapy with nivolumab and ipilimumab has markedly improved outcomes for patients with advanced melanoma. However, these therapies pose a considerable financial burden to both patients and the health care system. The ADAPT-IT trial demonstrated comparable progression-free and overall survival for patients with response-adapted ipilimumab discontinuation compared with standard of care (SOC). Objective: To determine the cost-effectiveness of ipilimumab discontinuation for patients with interim imaging-confirmed tumor response in the treatment of advanced melanoma. Design, Setting, and Participants: This cost-effectiveness analysis was performed using data from the ADAPT-IT (follow-up of 33 months) and CheckMate 067 (follow-up of 6.5 years) trials, as well as published literature over the ADAPT-IT trial duration of 33 months. The analysis was performed in a US setting from a US-payer perspective, and the willingness-to-pay (WTP) threshold was set at $100â¯000/quality-adjusted life-year (QALY). A total of 355 patients with previously untreated melanoma (unresectable stage III or IV metastatic melanoma) were included. Exposure: Response-adapted ipilimumab discontinuation compared with SOC therapy. Main Outcomes and Measures: The primary outcomes of the CheckMate trial were overall survival and progression-free survival, while that of ADAPT-IT was objective response. This informed a decision model to estimate lifetime costs and QALYs associated with both strategies. Incremental cost, effectiveness, and cost-effectiveness ratio were assessed. Sensitivity and scenario analyses were performed to account for variability in trials and input parameters. Results: Of the 355 patients included in the analysis, 41 patients were from the ADAPT-IT trial (median age, 65 years; 28 [68%] male) and 314 patients from the CheckMate 067 trial (median age, 61 years; 206 [66%] male). Response-adapted treatment was the cost-effective option in 94.0% of scenarios based on Monte Carlo simulations, with a dominant incremental cost-effectiveness ratio and an incremental net monetary benefit of $28â¯849 compared with SOC therapy. Cost savings were estimated at $19â¯891 per patient compared with SOC. In scenario analyses, current SOC was only considered as a cost-effective option under best survival assumptions and if the willingness-to-pay threshold exceeded $630â¯000/QALY. Conclusions and Relevance: This economic evaluation demonstrated that response-adapted treatment de-escalation in patients with advanced melanoma may lead to considerable savings in health care costs and could represent the most cost-effective strategy across various resource settings. Future trials should aim to provide further evidence on noninferiority.
Assuntos
Melanoma , Humanos , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Ipilimumab , Análise Custo-Benefício , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Imunoterapia , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Evolução Clonal/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.
Assuntos
Linfócitos B/imunologia , Senescência Celular , Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Neoplasias Experimentais/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Receptores de Antígenos de Linfócitos B/imunologia , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Processamento Alternativo , Animais , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Senescência Celular/efeitos dos fármacos , Dano ao DNA , Predisposição Genética para Doença , Instabilidade Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Fenótipo , Fosfoproteínas/metabolismo , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Fatores de Processamento de RNA/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Células Tumorais CultivadasRESUMO
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.