Systematic Review of Pharmacoeconomic Studies on Immuno-Oncology: Assessment of the cost-effectiveness of Immuno-oncology medicines used in the treatment of Advanced Melanoma

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019A imunoterapia para o cancro mudou o paradigma de tratamento para todas as pessoas diagnosticadas com Melanoma Metastático. Estas imunoterapias quando comparadas com a quimioterapia, proporcionam aos doentes não só um aumento na sua esperança de vida mas também uma melhoria muito significativa na sua qualidade de vida. No entanto, esta nova abordagem acarreta um aumento nos custos relacionados com o tratamento e tem particularidades no que concerne à avaliação da sua eficácia clínica. Num ambiente definido pela escassez de recursos é crucial definir quais as formas mais eficazes de tratar as doenças. Por essa razão, os decisores devem suportar as suas decisões nos estudos económicos, porque ao considerarem todo o impacto económico causado por novos tratamentos podem assegurar a sustentabilidade dos sistemas de saúde. O objetivo deste estudo é rever, sistematizar e avaliar os estudos de custo-efetividade relevantes relacionados com o uso de imunoterapia para o tratamento do Melanoma Metastático produzidos desde 2013. Foi realizada um revisão sistemática da literatura para estudos de custo-efetividade e custo-utilidade de imunoterapias para o cancro. No total 480 estudos foram triados, desses estudos, 9 reuniam todos os critérios de inclusão. A avaliação da qualidade dos estudos incluídos foi realizada com recurso a uma ferramenta validada, “Quality of Health Economic Studies” ou QHES. Dois dos estudos incluídos avaliaram a relação de custo-efetividade do Pembrolizumab comparada com o Ipilimumab. Outros dois estudos avaliaram a relação de custo-efetividade do Nivolumab comparada com a do Ipilimumab. Dois estudos avaliaram a relação de custoefetividade de diferentes abordagem sequenciais no tratamento de doentes sem mutações BRAF. Dois estudos estudaram a relção de custo-efetividade de diferentes combinações terapêuticas. Um desses estudos avaliou a relação de custo-efetividade da combinação de Talimogene Laherparepvec com Ipilimumab em comparação com Ipilimumab em monoterapia. Outro estudo avaliou a relação de custo-efetividade da combinação de Nivolumab com Ipilimumab em comparação com Ipilimumab em monoterapia. Por fim, um estudo avaliou a relação de custo-efetividade de Vemurafenib seguido de Ipilimumab como segunda linha de tratamento em comparação com Vemurafenib em monoterapia. O questionário QHES revelou que seis dos noves estudos incluídos eram de alta qualidade e que os restantes três, apesar de terem uma qualidade aceitável, ficaram perto do limiar de alta qualidade.Cancer immunotherapies have given new hopes to patients with Metastatic Melanoma by improving the overall survival and the quality of life of the patients when compared with conventional chemotherapy. However, these new therapies increase the costs of treatment and present new challenges regarding their clinical efficacy assessment. In an environment defined by the scarcity of resources, it is crucial to define the most effective ways of managing diseases. Therefore, decision-makers must support their decisions on economic analysis in order to consider the economic impact of new treatments and in this way, ensure the sustainability of health care systems. The purpose of this study is to review, systematize and assess the relevant costeffectiveness studies produced since 2013 regarding cancer immunotherapies for Metastatic Melanoma. A systematic literature review was conducted for cost-effectiveness and cost-utility, analysis of cancer immunotherapy drugs. A total of 480 studies were screened and, of those, nine studies met all the inclusion criteria. The quality of the included studies was evaluated with the Quality of Health Economic Studies (QHES) assessment tool. Two studies assessed the cost-effectiveness (CE) of Pembrolizumab against Ipilimumab. Another two studies analysed the CE of Nivolumab against Ipilimumab. Two studies assessed the cost-effectiveness of different sequential approaches for the treatment of BRAF wild-type patients. Two studies measured the CE of different combination strategies. One study compared the CE of the combination of Talimogene Laherparepvec and Ipilimumab against Ipilimumab monotherapy. Another one, analysed the cost-effectiveness of Nivolumab combined with Ipilimumab against Ipilimumab or Nivolumab monotherapy. Lastly, one study assessed the cost-effectiveness of Ipilimumab in the second-line of treatment following Vemurafenib against Vemurafenib alone. The QHES assessment tool revealed that the quality of six out of the nine studies included was high, and the other three despite being fair in quality, had their scores near the high-quality threshold.Faculty of Pharmacy of the University of Ljubljan

Next Generation of Advanced Non-Small Cell Lung Cancer Therapy: Targeted and Immuno-Therapies

Lung cancer is one of the deadliest cancers in the world. Current clinical trials are focused on developing the next generation of therapies that target novel anti-cancer mechanisms. One approach is to prime the immune system, as the cancer has been known to suppress immune cells in the tumour microenvironment. Using pharmacotherapy, the immune system can be unleashed and suppress the cancer’s growth. Another pathway is targeting known oncogenic genes that are important for the cancer’s growth and survival. In lung cancer, the epidermal growth factor receptor and several other mutated proteins are targets of small-molecule inhibitors that have been shown to drastically improve patient survival and quality of life. Discussed in this review are broad highlights of the different immunotherapies and small molecule targeted therapies that have been studied in the latest clinical trials for lung cancer

Pharmacoeconomic aspects of the use of immunotherapeutic combinations in oncology: immunomodulatory options for lung cancer

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.Ainda subsiste muita incerteza sobre a melhor maneira de utilizar novas terapias imunomoduladoras em doentes oncológicos, especialmente em doentes com cancro do pulmão. A prevalência global desta doença, a mortalidade e o mau prognóstico a ela associados justificam a necessidade de um rápido desenvolvimento e aplicação de novas terapias, capazes de mudar o atual paradigma complicado da doença. Dado que as imunoterapias, nomeadamente os inibidores de pontos de controlo imunitário (ICI), têm produzido resultados melhorados em doentes com cancro do pulmão, mas exigem despesas elevadas para as suas aquisições, este estudo procura sistematizar os dados atualmente publicados sobre ICIs para doentes com cancro do pulmão, de modo a ajudar a clarificar os métodos atuais mais custo-efetivo para as aplicar e a evidência que ainda falta ser gerada. As combinações com estas terapias possuem o potencial de melhorar a eficácia dos regimes, através do uso de mecanismos de ação sinérgicos, mas também representam riscos de eventos adversos agravados e custos elevados, sendo o foco do presente estudo. Foi construída uma revisão sistemática de estudos disponíveis que analisavam a eficácia, a relação custo-eficácia ou o custo-utilidade dos ICI no cancro do pulmão. Foram analisados 175 estudos através do respetivo resumo, tendo sido selecionados 85 para análise integral e, dos quais, 43 foram selecionados para inclusão no presente trabalho. Os estudos incluídos analisaram regimes variados com ICIs em monoterapia ou em combinação, quer entre ICIs quer com outras opções como a quimioterapia ou o bevacizumab. Embora a maioria dos regimes tenha apresentado resultados significativamente melhores em comparação com a quimioterapia clássica, apenas o Pembrolizumab e o Atezolizumab em monoterapia foram considerados custo-efetivos, em grupos de doentes selecionados por biomarcadores. Os preços elevados com que estes medicamentos entram no mercado foram considerados como a maior barreira à utilização generalizada dos ICI. Este estudo sugere a investigação de uma melhor utilização dos biomarcadores atuais ou estratégias de partilha de custos e riscos para contrariar esta dificuldade, permitindo, potencialmente, que os sistemas de cuidados de saúde possam adquirir de forma sustentável estas novas opções terapêuticas e utilizá-las nos subgrupos de doentes oncológicos que mais beneficiam com as mesmas, ao mesmo tempo que apoiam e incentivam a inovação.Much uncertainty remains on how to best use novel immunomodulatory therapies in oncologic patients, especially lung cancer patients. This disease’s global prevalence, mortality and poor prognosis warrant fast development and application of novel therapies, capable of changing the current disease’s grave paradigm. As immunotherapies, namely immune checkpoint inhibitors (ICIs), have yielded improved outcomes for lung cancer patients, but demand high expenditures for their purchases, this study looks to systemize currently published data on ICIs for lung cancer patients, to help clarify the evidence that’s still lacking and the current most cost-effective methods to apply such therapies. As combinations with these options hold the potential of improving effectiveness, through the enhanced benefits of synergistic mechanisms of action, but also aggravated adverse events and high costs, these regimens were the focus of the present study. A systematic literature review of studies analysing effectiveness, cost-effectiveness or cost-utility of ICIs in lung cancer was constructed. 175 studies were abstract screened, with 85 being selected for integral analysis and, from those, 43 being selected for inclusion in the present review. Varied regimens with ICIs in monotherapy or in combination, either between ICIs or with other options like chemotherapy or bevacizumab, were analysed in the included studies. Although most regimens presented significantly improved outcomes in comparison to classical chemotherapy, only Pembrolizumab and Atezolizumab in monotherapy were found to be costeffective, in biomarker-selected groups of patients. The high prices at which these medicines enter the market were found to be the biggest barrier to ICI’s generalized use in lung cancer patients. Investigation of new ways to use current biomarkers for ICIs or cost-sharing and risksharing strategies were suggested to balance this issue, potentially allowing healthcare systems to sustainably imburse the use of these novel options in oncologic patients’ subgroups that most benefit from them, while still supporting and incentivising innovation

Regulatory and valuation challenges of immune checkpoint inhibitors in lung cancer

Advances in innovative drug development translated into tangible improvements in clinical outcomes for patients with non-small cell lung cancer (NSCLC). Immunotherapy, specifically immune checkpoint inhibitors (ICIs), has transformed the standard of care for NSCLC patients. Although ICIs have brought meaningful opportunities in NSCLC care and transformed the treatment landscape, their regulatory decisions and economic value assessments pose important challenges. In this research, regulatory and valuation challenges of ICIs in NSCLC were explored to help support the future use of ICIs in health systems

A systematic review of economic evaluations assessing the cost-effectiveness of licensed drugs used for previously treated epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) negative advanced/metastatic non-small cell lung cancer

Background Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers. There are many published studies of cost-effectiveness analyses of licensed treatments, but no study has compared these studies or their approaches simultaneously. Objective To investigate the methodology used in published economic analyses of licensed interventions for previously treated advanced/metastatic NSCLC in patients without anaplastic lymphoma kinase or epidermal growth factor receptor expression. Methods A systematic review was performed, including a systematic search of key databases (e.g. MEDLINE, EMBASE, Web of Knowledge, Cost-effectiveness Registry) limited to the period from 01 January 2001 to 26 July 2019. Two reviewers independently screened, extracted data and quality appraised identified studies. The reporting quality of the studies was assessed by using the Consolidated Health Economic Evaluation Reporting Standards and the Philips’ checklists. Results Thirty-one published records met the inclusion criteria, which corresponded to 30 individual cost-effectiveness analyses. Analytical approaches included partitioned survival models (n = 14), state-transition models (n = 7) and retrospective analyses of new or published data (n = 8). Model structure was generally consistent, with pre-progression, post-progression and death health states used most commonly. Other characteristics varied more widely, including the perspective of analysis, discounting, time horizon, usually to align with the country that the analysis was set in. Conclusions There are a wide range of approaches in the modelling of treatments for advanced NSCLC; however, the model structures are consistent. There is variation in the exploration of sensitivity analyses, with considerable uncertainty remaining in most evaluations. Improved reporting is necessary to ensure transparency in future analyses

Current and future aspects of TIM-3 as biomarker or as potential targeted in non-small cell lung cancer scope: is there a role in clinical practice?

Lung cancer is an aggressive disease with a high rate of mortality (1). Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all histology types (2). In the 1990’s, chemotherapy was the standard of care for the treatment of metastatic NSCLC (3). Since 2005, targeted therapies have emerged as a new cornerstone in the treatment of NSCLC. These include epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKI) such as gefitinib, erlotinib, afatinib, osimertinib, and dacomitinib (4) as well as the anaplastic lymphoma kinase (ALK) inhibitors crizotinib, alectinib, ceritinib, brigatinib and lorlatinib (5,6). Improving our understanding of tumor biology has therefore become a fundamental issue among oncologists to optimize these novel treatment strategies (7). In 2018, James P. Allison and Tasuku Honjo (8) won the Nobel prize for their research on the mechanisms of the tumor immune escape, which led to the first immunotherapy drugs to be utilized in clinical practice: nivolumab and ipilimumab (3,9). The Karolinska Institute Nobel Prize Committee declared that Allison and Honjo’s findings constituted the fourth cornerstone of cancer treatment, alongside surgery, radiotherapy and chemotherapy (1,9).National Council for Scientific and Technological Development (CNPq) 402621/2016-6info:eu-repo/semantics/publishedVersio

Economic evaluation of five first-line PD-(L)1 inhibitors for treating non-squamous non-small cell lung cancer in China: A cost-effectiveness analysis based on network meta-analysis

Background and objective: Non-small cell lung cancer (NSCLC) is one of the most malignant cancer types that causes substantial economic burden in China. This study aimed to evaluate the cost-effectiveness of five first-line anti-PD-(L)1 treatments, including sintilimab, camrelizumab, atezolizumab, pembrolizumab and sugemalimab with each combined with chemotherapy, for treating advanced non-squamous NSCLC (nsq-NSCLC) from Chinese healthcare system perspective.Methods: Clinical data were obtained from the following clinical trials, namely, ORIENT-11, CameL, IMpower132, KEYNOTE-189 and GEMSTONE-302. A network meta-analysis was performed based on fractional polynomial models. We constructed a partitioned survival model with a three-week cycle length and a lifetime horizon to derive the incremental cost-effectiveness ratio (ICER). We performed one-way sensitivity analysis and probablistic sensitivity analysis to test the robustness. Additionally, two scenario analyses were undertaken to investigate the impact of Patient Assistant Program on the economic conclusion and to explore potential uncertainty associated with population representativeness of the global trial.Results: Compared with camrelizumab + chemotherapy, sugemalimab + chemotherapy and atezolizumab + chemotherapy were dominated, and the ICERs generated from sintilimab + chemotherapy and pembrolizumab + chemotherapy were $15,280.83/QALY and$159,784.76/QALY, respectively. Deterministic sensitivity analysis showed that uncertainty around ICERs was mainly driven by HR related parameters derived from NMA and drug price. The probablistic sensitivity analysis suggested that camrelizumab treatment was cost-effective at a willingness-to-pay threshold of 1-time GDP per capita. When the threshold was set as 3-time GDP per capita, sintilimab strategy demonstrated the excellent cost-effective advantage. Sensitivity analysis proved the reliability of base-case results. Results from two scenario analyses indicated that the primary finding was robust.Conclusion: In current context of Chinese healthcare system, sintilimab + chemotherapy appeared to be cost-effective for the treatment of nsq-NSCLC compared with sugemalimab, camrelizumab, pembrolizumab as well as atezolizumab combined with chemotherapy

Emerging role of circulating tumor cells in immunotherapy.

Over the last few years, immunotherapy, in particular, immune checkpoint inhibitor therapy, has revolutionized the treatment of several types of cancer. At the same time, the uptake in clinical oncology has been slow owing to the high cost of treatment, associated toxicity profiles and variability of the response to treatment between patients. In response, personalized approaches based on predictive biomarkers have emerged as new tools for patient stratification to achieve effective immunotherapy. Recently, the enumeration and molecular analysis of circulating tumor cells (CTCs) have been highlighted as prognostic biomarkers for the management of cancer patients during chemotherapy and for targeted therapy in a personalized manner. The expression of immune checkpoints on CTCs has been reported in a number of solid tumor types and has provided new insight into cancer immunotherapy management. In this review, we discuss recent advances in the identification of immune checkpoints using CTCs and shed light on the potential applications of CTCs towards the identification of predictive biomarkers for immunotherapy