Recent Results Cancer Res
· 2020 · PMID 31473853
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Treatment of patients with advanced metastatic melanoma has for decades been a story of very limited success. This dramatically changed when therapy with anti-PD-1 checkpoint blocking antibodies was approved in the USA a...Treatment of patients with advanced metastatic melanoma has for decades been a story of very limited success. This dramatically changed when therapy with anti-PD-1 checkpoint blocking antibodies was approved in the USA and Europe in 2014 and 2015, respectively. The therapy exploits the capacity of CD8 T cells to specifically kill tumor cells. Within the tumor microenvironment, CD8 T cell activity is blocked by suppressive signals received via PD-1, an inhibitory co-receptor and so-called checkpoint of T cell activation. PD-1 binds to its ligand PD-L1 on melanoma cells which dampens the T cell's activity. Antibodies blocking inhibitory PD-1/PD-L1 interaction release T cells from suppression. Treatment of late-stage disease melanoma patients with antibodies targeting the PD-1/PD-L1 axis, termed immune checkpoint blocking therapy (ICBT), yields clinical frequently long-lasting responses in 30-40% of cases. Despite this remarkable breakthrough, still the majority of patients resists ICBT or develops resistance after initial therapy response. Administration of anti-PD-1 antibodies in combination with antibodies targeting CTLA-4, another inhibitory immune checkpoint increased clinical responses rate up to 50% but at costs of higher treatment-related toxicities. Thus, strong efforts are now directed toward the understanding of therapy resistance, the identification of biomarkers predicting therapy response, and the development of alternative PD-1-based combination treatment to improve patient outcomes.
Vormehr M, Diken M, Türeci Ö
… +2 more, Sahin U, Kreiter S
Recent Results Cancer Res
· 2020 · PMID 31473852
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After more than a century of efforts to establish cancer immunotherapy in clinical practice, the advent of checkpoint inhibition (CPI) therapy was a critical breakthrough toward this direction (Hodi et al. in Cell Rep 13...After more than a century of efforts to establish cancer immunotherapy in clinical practice, the advent of checkpoint inhibition (CPI) therapy was a critical breakthrough toward this direction (Hodi et al. in Cell Rep 13(2):412-424, 2010; Wolchok et al. in N Engl J Med 369(2):122-133, 2013; Herbst et al. in Nature 515(7528):563-567, 2014; Tumeh et al. in Nature 515(7528):568-571, 2014). Further, CPIs shifted the focus from long studied shared tumor-associated antigens to mutated ones. As cancer is caused by mutations in somatic cells, the concept to utilize these correlates of 'foreignness' to enable recognition and lysis of the cancer cell by T cell immunity seems an obvious thing to do.
Recent Results Cancer Res
· 2020 · PMID 31473851
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The adoptive cell transfer (ACT) of genetically engineered T cell receptor (TCR) T cells is one of the burgeoning fields of immunotherapy, with promising results in current clinical trials. Presently, clinicaltrials.gov...The adoptive cell transfer (ACT) of genetically engineered T cell receptor (TCR) T cells is one of the burgeoning fields of immunotherapy, with promising results in current clinical trials. Presently, clinicaltrials.gov has over 200 active trials involving adoptive cell therapy. The ACT of genetically engineered T cells not only allows the ability to select for TCRs with desired properties such as high-affinity receptors and tumor reactivity but to further enhance those receptors allowing for better targeting and killing of cancer cells in patients. Moreover, the addition of genetic material, including cytokines and cytokine receptors, can increase the survival and persistence of the T cell allowing for complete and sustained remission of cancer targets. The potential for improvement in adoptive cell therapy is limitless, with genetic modifications targeting to improve weaknesses of ACT and to thus enhance receptor affinity and functional avidity of the genetically engineered T cells.
Recent Results Cancer Res
· 2020 · PMID 31473850
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As a specifically programmable, living immunotherapeutic drug, chimeric antigen receptor (CAR)-modified T cells are providing an alternative treatment option for a broad variety of diseases including so far refractory ca...As a specifically programmable, living immunotherapeutic drug, chimeric antigen receptor (CAR)-modified T cells are providing an alternative treatment option for a broad variety of diseases including so far refractory cancer. By recognizing a tumor-associated antigen, the CAR triggers an anti-tumor response of engineered patient's T cells achieving lasting remissions in the treatment of leukemia and lymphoma. During the last years, significant progress was made in optimizing the CAR design, in manufacturing CAR-engineered T cells, and in the clinical management of patients showing promise to establish adoptive CAR T cell therapy as an effective treatment option in the forefront.
Recent Results Cancer Res
· 2020 · PMID 31473849
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Bispecific T cell engagers are antibody constructs directed to a tumor-specific target on the one hand and to CD3-positive T cells on the other hand. Blinatumomab is a compound with specificity for the pan-B cell marker...Bispecific T cell engagers are antibody constructs directed to a tumor-specific target on the one hand and to CD3-positive T cells on the other hand. Blinatumomab is a compound with specificity for the pan-B cell marker CD19. Clinical activity was tested in relapsed and refractory (R/R) non-Hodgkin's Lymphoma (NHL), R/R acute lymphoblastic leukemia (ALL), and ALL patients with minimal residual disease. Trials have already been started in de novo ALL. The most clinically relevant toxicities are neurologic events and cytokine release syndrome as with other T cell-activating therapies. The mechanisms of resistance are not fully understood. Higher leukemia load and later stage disease represent unfavorable factors. Besides, an upregulation of regulatory T cells and inhibitory molecules like PD-1/PD-L1 may have a role as the loss of target by several mechanisms. The future will show whether the use of bispecifics in ALL can change the standard treatment algorithms and whether bispecific T cell engagers will also be successfully used in other malignant entities.
Recent Results Cancer Res
· 2020 · PMID 31473848
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Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Re...Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.
Recent Results Cancer Res
· 2019 · PMID 30543014
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Conditions of scarcity impact healthcare services for cancer patients. This is the unpleasant reality for nations, local governments, hospitals, and even individual doctors. This means that medical services judged by obj...Conditions of scarcity impact healthcare services for cancer patients. This is the unpleasant reality for nations, local governments, hospitals, and even individual doctors. This means that medical services judged by objective standards as potentially effective by medical professionals are limited because of financial or access scarcity. With this situation of scarcity as premise, one must raise the ethical question of how to deal with scarcity while respecting fundamental principles of human dignity and human rights. This chapter focuses on the German healthcare context where dignity and rights form the basis and framework for medical ethics. Accordingly, in Germany, rationing medical services for life-threatening diseases has been traditionally and appropriately criticized and prohibited. Granting a situation of scarcity, however, some prioritization becomes increasingly necessary. Thus, there is present need for careful ethical analysis of non-emergency regulatory prioritization principles and protocols. Above all, analysis and conclusions must preserve and foster society's deepest moral commitments.
Recent Results Cancer Res
· 2019 · PMID 30543013
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In this chapter, we describe the changing landscape of the EU pharmaceutical legislation concerning regulation and evidence requirements for marketing authorisation. First, we describe the legal requirements for marketin...In this chapter, we describe the changing landscape of the EU pharmaceutical legislation concerning regulation and evidence requirements for marketing authorisation. First, we describe the legal requirements for marketing authorisation and the development of EU pharmaceutical legislation and the concept of risk-benefit balance. Second, we describe special types of authorisation, such as conditional approval and approval under exceptional circumstances, and special provisions such as incentives for orphan medicinal products and paediatric investigational plans. Lastly, we describe the available methodological guidelines focussing on choice of endpoints.
Recent Results Cancer Res
· 2019 · PMID 30543012
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This paper first reviews the evidence on price levels, price growth, and value for cancer drugs. The available evidence suggests that prices for originator (brand-name) drugs are rising significantly more rapidly than ge...This paper first reviews the evidence on price levels, price growth, and value for cancer drugs. The available evidence suggests that prices for originator (brand-name) drugs are rising significantly more rapidly than general inflation, but the available data are inadequate for robust comparisons between cancer and other categories of specialty drugs. We then examine the factors contributing to high and rising prices for cancer drugs. This analysis focuses mainly on the USA, which accounts for 46% of global expenditures on cancer drugs. It is the country of first launch for most cancer and other specialty drugs and frequently has the highest prices for drugs.
Recent Results Cancer Res
· 2019 · PMID 30543011
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Arguably, the most common structure currently adopted for oncology modelling is the three-state partitioned survival model with the following states: stable disease, post-progression and dead. This design can, therefore,...Arguably, the most common structure currently adopted for oncology modelling is the three-state partitioned survival model with the following states: stable disease, post-progression and dead. This design can, therefore, be adopted to capture the progressive nature of cancer. This chapter outlines the three-state model approach as well as introducing several other key aspects of economic modelling in oncology.
Korchagina D, Jaroslawski S, Jadot G
… +1 more, Toumi M
Recent Results Cancer Res
· 2019 · PMID 30543010
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Rare diseases represent a group of conditions affecting a very limited number of patients. Low profitability resulting from the small size of target population coupled with difficulties in conducting the research causes...Rare diseases represent a group of conditions affecting a very limited number of patients. Low profitability resulting from the small size of target population coupled with difficulties in conducting the research causes the lack of interest from the pharmaceutical industry. In order to promote research and development of medicines for rare diseases, a special 'orphan' legislation was introduced in a number of regions. These measures led to a significant increase in the number of approved orphan molecules. The high per patient cost of orphan drugs, as well the rapid growth of orphan drug sector, raised concerns regarding the sustainable funding of therapies for rare diseases. Rare cancers represent the majority of the current orphan drug market and are often associated with very high revenues. This chapter provides a review of orphan legislations and health technology assessment framework, analyses the position of oncology drugs on the orphan drug market and discusses future perspectives.
Recent Results Cancer Res
· 2019 · PMID 30543009
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This article sets out to describe different value frameworks in the field of new developments in oncology. Since the costs of new oncological therapies follow a steep path, their implementation and financing demand a tho...This article sets out to describe different value frameworks in the field of new developments in oncology. Since the costs of new oncological therapies follow a steep path, their implementation and financing demand a thorough assessment. This is an ambitious task due to the complex nature of oncological treatments within overall health policy. Five value frameworks were reviewed: European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale, American Society of Clinical Oncology (ASCO) Value Framework (version 2.0), National Comprehensive Cancer Network (NCCN) Evidence Blocks, Memorial Sloan Kettering Cancer Center DrugAbacus, and the Institute for Clinical and Economic Review Value Assessment Framework. They are all based on a large set of criteria. However, all these frameworks differ considerably in their outcomes. Among the main differences one has to cite are the inclusion of costs and the use of different outcomes, as well as the fact that they address different target stakeholders, etc. Despite these shortcomings, the value frameworks serve the necessity to introduce more rationality in health decision making seen from the perspective of physicians, patients, and financing bodies.
Recent Results Cancer Res
· 2019 · PMID 30543008
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Cancer causes significant death and disability globally. However, costs of more personalized cancer care continue to climb, while access to basic cancer screening and treatment is not available to much of the world. This...Cancer causes significant death and disability globally. However, costs of more personalized cancer care continue to climb, while access to basic cancer screening and treatment is not available to much of the world. This chapter provides an overview of the status of patient-reported outcomes (PROs) in cancer clinical care and research. PROs are valuable for health care and health economic decision-making at institutional, regional, national, and international levels. PRO data should be considered along with cost and survival data when approving new therapies. PRO data can also be helpful when assessing existing treatment options for patients, particularly for drugs with minor outcome and toxicity differences. Finally, PROs can be useful in reimbursement algorithms to ensure delivery of quality cancer care in value-based financing environments. The authors advocate for reframing the concept of health value, aligning PRO measures with societal values, and broadening the definition of society to extend beyond national boundaries.
Toumi M, Jarosławski S, Chouhaid C
… +2 more, Fallissard B, Auquier P
Recent Results Cancer Res
· 2019 · PMID 30543007
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The goal of the treatment of a disease has moved from treating organs and diseases through symptoms, biological parameters and imaging towards treating a human being as a whole. The treatments should deliver benefits tha...The goal of the treatment of a disease has moved from treating organs and diseases through symptoms, biological parameters and imaging towards treating a human being as a whole. The treatments should deliver benefits that patients can personally perceive. However, the patient's perspective does not always match the one of those surrounding them. Illustratively, patients' symptom assessments are more predictable for daily health status, whereas clinicians' symptom measurements are more related to clinical outcomes. The term, patient-reported outcomes (PROs), includes any data that are reported directly by the patient without an intermediary, such as a family member or a healthcare professional. The use of PROs in oncology trials is increasing and the U.S. Food and Drug Administration has published guidelines on the review and evaluation of PROs. However, while PROs are increasingly used in clinical trials, they are rarely used in daily clinical practice. Further, healthcare payers are concerned with issues related to relevance, quality, and interpretability of these outcomes.
Jarosławski S, Hanna E, Dabbous M
… +2 more, Chachoua L, Toumi M
Recent Results Cancer Res
· 2019 · PMID 30543006
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Rising budget constraints and demands for healthcare services create additional complexity within the decision process for resource allocation. Innovations and scientific progress have been shown to be key drivers of the...Rising budget constraints and demands for healthcare services create additional complexity within the decision process for resource allocation. Innovations and scientific progress have been shown to be key drivers of the increase in healthcare expenditures (1). In the context of rising medical care costs and limited resources, Health Technology Assessment (HTA) was developed as a tool to inform decision-making and to provide the rationalization behind these decisions driving resource allocation and spending for health technology products. Furthermore, HTA agencies make the decision-making process more transparent. The HTA approach involves evaluating multiple aspects of a new product's value in order to maximize health gain provided within the setting of limited resources.
Francois C, Zhou J, Pochopien M
… +2 more, Achour L, Toumi M
Recent Results Cancer Res
· 2019 · PMID 30543005
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In this chapter, we will present and discuss the challenges of assessing oncology products from a health economic perspective. We will provide a brief introduction on the need for economic evaluation in health care and f...In this chapter, we will present and discuss the challenges of assessing oncology products from a health economic perspective. We will provide a brief introduction on the need for economic evaluation in health care and focus on cost-effectiveness and comparative aspects of the evaluation of oncology products, which are of paramount interest to HTA decision-making bodies using economic evaluation in their decision-making framework. As the burden of oncology is well-documented, we do not discuss it in detail here. Before we address the specific issue of oncology, we will briefly define the critical aspects of HTA assessment and also define what a cost-effectiveness analysis is and why economic modelling is the most appropriate tool to assess the cost-effectiveness of oncology products. We will touch upon the prices of oncology drugs and the questions that high prices raise regarding funding and availability. We then present an overview of the general structure of an oncology cost-effectiveness model. Usually, this is quite simple, representing response, progression, advanced-stage disease and death. Despite the relative simplicity of these models, some issues may render the evaluation more complex; we will touch upon these in this chapter: Issue with clinical inputs due to the design of randomised clinical trials (e.g. cross-over designs involving a treatment switch) Need for survival extrapolation and limitations of current parametric models Rare conditions with limited economic and comparative evidence available High pace of clinical development Finally, we will conclude with a discussion of the uncertainty around the evaluation of oncology products and the major evolution expected in health economics in oncology.
Recent Results Cancer Res
· 2019 · PMID 30543004
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Healthcare expenditures for cancer account for a low share of total healthcare expenditures, compared to the relative burden of the disease. The share has also not changed very much over the last decades. Cost for cancer...Healthcare expenditures for cancer account for a low share of total healthcare expenditures, compared to the relative burden of the disease. The share has also not changed very much over the last decades. Cost for cancer drugs has increased as a share of total expenditures, but this has been offset by a reduction of inpatient hospital care for cancer. Accounting for the cost of cancer should not be limited to healthcare expenditures. Resources are also used for public and private care of cancer patients outside the healthcare sector, for example for palliative care. Informal care by family and friends is an important complement to professional care, and estimates indicate that this amounts to between half and one-third of the costs of formal care. Indirect costs related to the loss of production for persons with cancer are estimated to be of the same magnitude as the direct healthcare expenditures. Indirect costs related to premature mortality dominate the estimate of indirect costs, but those costs have declined over time, despite increasing incomes, due to the reduction in mortality due to cancer in the economically active age groups. Estimates of indirect costs due to morbidity are uncertain and vary significantly between published studies. A full accounting of the costs of cancer should include an estimate of the health burden of cancer. Loss of quality-adjusted life expectancy (QALY) can be measured and valued based on the willingness to pay for a QALY. Such estimates are possible to derive from decisions about allocating resources for cancer. There are few estimates of these costs, but available studies indicate that the intangible costs of lost QALY are by far the dominating cost of cancer. The value for policy-making of costs of cancer estimates increases when results with consistent methods and data are available that allow comparisons between countries and over time. The evidence about the cost of cancer is still limited, but when current scientific progress produces an increasing number of new options for prevention, diagnosis and treatment, studies of the cost of cancer become increasingly important to inform decisions about resource allocation.
Recent Results Cancer Res
· 2019 · PMID 30543003
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The overall aim of this book is to set out the main changes needed in the field of economic and regulatory conditions as a consequence of these rapid developments in oncology. The traditional approaches of health economi...The overall aim of this book is to set out the main changes needed in the field of economic and regulatory conditions as a consequence of these rapid developments in oncology. The traditional approaches of health economics, like health economic evaluation, health technology assessment (HTA), modeling methods, assessing value, pricing techniques, are bound to be altered in the contributions to this book. It is understandable that with the life-threatening diagnosis of cancer the new treatment options need to be accompanied by the best available health economic tools. This pertains to well-implemented decision rules concerning willingness to pay, incremental cost-effectiveness ratio thresholds, equity, patient access, end of life criteria, etc. Their application differs with regard to the usual health economic analyzes implemented in other treatment areas. Overstating a bit one could ask whether we need a strongly modified concept of oncology economics?
Malapelle U, Ricciuti B, Baglivo S
… +9 more, Pepe F, Pisapia P, Anastasi P, Tazza M, Sidoni A, Liberati AM, Bellezza G, Chiari R, Metro G
Recent Results Cancer Res
· 2018 · PMID 30069773
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Epidermal growth factor receptor (EGFR)-mutated (exons 18-21) advanced non-small cell lung cancers (NSCLCs) are generally characterized by exquisite sensitivity to treatment with an EGFR-tyrosine kinase inhibitor (-TKI)....Epidermal growth factor receptor (EGFR)-mutated (exons 18-21) advanced non-small cell lung cancers (NSCLCs) are generally characterized by exquisite sensitivity to treatment with an EGFR-tyrosine kinase inhibitor (-TKI). First-generation or reversible EGFR-TKIs include gefitinib and erlotinib, while, more recently, second-generation or irreversible EGFR-TKIs have been developed, namely afatinib and dacomitinib, with the aim of overcoming/delaying acquired resistance to treatment. Nevertheless, clinical trials have shown that resistance eventually emerges after a median time of slightly less than one year, regardless of whether first- or second-generation EGFR-TKIs are used. In this context, a secondary EGFR mutation in exon 20, namely T790M, has been found to be responsible for approximately 60% of cases of acquired resistance. Alternatively, T790M resistance mutation can be found de novo, in which case it limits the antitumor activity of both first- or second-generation EGFR-TKIs. Osimertinb is an orally bioavailable, third-generation EGFR-TKI that acts by irreversibly binding both EGFR activating mutations and T790M, while sparing wild-type EGFR. On this basis, osimertinib has proven more efficacious than platinum-based chemotherapy in the setting of EGFR T790M-positive NSCLCs pretreated with a first- or second-generation EGFR-TKI. More recently, in another phase 3 trial, osimertinib outperformed gefitinib or erlotinib as first-line treatment of EGFR-mutated (ex19del or L858R) advanced NSCLCs, thus emerging as a new standard of care in this setting. In the present review, we will discuss the preclinical and clinical development of osimertinib, briefly touching upon its activity in special populations and biomarkers of sensitivity to treatment.
Recent Results Cancer Res
· 2018 · PMID 30069772
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Alectinib is an ATP-competitive small molecule and a second-generation inhibitor of ALK. EML4-ALK rearrangement is found in 3-5% of patients with NSCLC. The first-generation inhibitor crizotinib has changed the treatment...Alectinib is an ATP-competitive small molecule and a second-generation inhibitor of ALK. EML4-ALK rearrangement is found in 3-5% of patients with NSCLC. The first-generation inhibitor crizotinib has changed the treatment dramatically, though most of the patients show disease progression within one year. Extra-thoracic progress, i.e., CNS metastases is common. The second-generation inhibitor alectinib has shown significant improvement in PFS and a remarkable prolongation of time to CNS progression. Alectinib has received approval as first-line therapy as well as second-line therapy after crizotinib failure. The toxicity profile is favorable compared to crizotinib and chemotherapy.