BJMO - volume 11, issue 9, february 2017
Tom Feys MBA, MSc
The progress that has been made in the last decades in the treatment of stage IV non-small cell lung cancer (NSCLC) has overall not been translated to the curative setting of stage I to III disease. In fact, the list of failed clinical trials aimed at improving the cure rates in this setting is long. The successes with immune checkpoint inhibition in stage IV NSCLC formed the basis to also study these agents in the curative NSCLC setting. Several studies are underway evaluating the potential of adjuvant immune checkpoint inhibition in stage II and IIIA disease and promising data have also been generated in the pre-operative setting. In addition to that, immune checkpoint inhibition is also being studied as consolidation treatment following chemoradiotherapy in locally advanced, unresectable NSCLC. The PACIFIC trial forms the first of these studies to yield results and showed that the PD-L1 inhibitor durvalumab significantly prolongs the progression-free survival (PFS) compared to placebo in patients with locally advanced, unresectable stage III NSCLC. More mature (overall survival, OS) results of this study are eagerly awaited as are the results of the other clinical studies evaluating immune checkpoint inhibitors in the curative NSCLC setting.
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D. Gullentops , E. Wauters MD, PhD, J. Vansteenkiste MD, PhD
Since its start in 2009, immunotherapy with immune checkpoint inhibitors has become a hot topic in respiratory oncology. Randomized controlled trials have proven the superiority of immune checkpoint inhibitor therapy versus standard chemotherapy in advanced non-small cell lung cancer (NSCLC). PD-L1 immunohistochemistry (IHC) is so far the most commonly implemented predictive biomarker in the selection of optimal candidates for immunotherapy. Immunotherapy with pembrolizumab is approved in first-line for advanced NSCLC with a PD-L1 expression on >50% of tumor cells, and after at least one prior chemotherapy regimen in case of PD-L1 expression of >1%. Treatment with nivolumab or with atezolizumab is approved for advanced NSCLC after prior chemotherapy, irrespective of the PD-L1 status. Since PD-L1 expression does not always correlate with treatment efficacy, other biomarkers are under investigation. Tumor mutational burden (which correlates clinically with smoking status) and CD8 tumor-infiltrating lymphocytes are associated with increased responsiveness to PD-L1 inhibition, and thus are other promising predictive biomarkers. NSCLC with molecular drivers on the contrary is preferably treated with tyrosine kinase inhibitors (TKIs) rather than immunotherapy due to lower response rates, even in case of high PD-L1 expression. Immunotherapy and other therapeutic modalities (chemotherapy, radiotherapy, TKIs) might work in synergy. The results of the first prospective trials with combination therapy were recently published, and many others are to be expected.
Read moreBJMO - volume 11, issue 9, february 2017
B. Neyns MD, PhD, G. Awada MD, A. Rogiers MD
Over the past 10 years, several effective new therapies have been developed for patients with advanced melanoma. Since 2010, the primary endpoint of every major phase III trial in this setting has been met, revolutionizing the treatment options and survival for patients with unresectable advanced melanoma. With increasing numbers of patients experiencing durable remissions with these agents, even without continuing therapy, the issue of melanoma survival care becomes of relevance to more patients than ever before.
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L. Brochez MD, PhD, I. Chevolet MD, PhD, A. Meireson , V. Kruse MD, PhD
Indoleamine 2,3-dioxygenase (IDO, also referred to as IDO1) has been demonstrated to be a normal endogenous mechanism of acquired peripheral immune tolerance in vivo. This manuscript reviews the currently available data on the role of IDO in cancer and the current results obtained with IDO inhibition in clinical trials in humans. Preliminary results with IDO inhibitors, usually combined with other anti-cancer drugs, seem encouraging. Further studies are needed to clarify the conditions in which IDO inhibitors can be of value as an anti-cancer strategy. In addition, further research should address whether the expression of IDO in tissue or blood can be a marker to select patients who can benefit most from IDO inhibition.
Read moreBJMO - volume 10, issue 3, october 2016
Tom Feys MBA, MSc
The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) / programmed death-ligand 1 (PD-L1) immune checkpoints are negative regulators of the T-cell immune function. Inhibition of these targets, resulting in an increased activation of the immune system, has led to new immunotherapies for melanoma, non–small cell lung cancer, and other cancers. To set the stage for the impressive clinical data that have been produced with these agents, this introductory article will describe the similarities and differences of both pathways and will touch upon the implications of their inhibition.
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P. Germonpré , J. Lamont
Cancer immunotherapy consists of a number of approaches that aim to utilize the power of the immune system to combat the cancer by producing activated tumour-specific cytoxic T-cells (CTL) that are able to eradicate the antigen-bearing tumor cells. Cancer immunotherapies can be divided in (i) active immunotherapies aiming to mount an immune response to one or more tumour-associated antigens (i.e. cancer vaccines), (ii) passive immunotherapies relying on the administration of exogenously produced tumor antigen-specific lymphocytes or antibodies and (iii) immunomodulatory approaches that try to amplify the anticancer immune response by blocking the down-regulation of the adaptive immune system (i.e. checkpoint inhibitors). This brief overview will focus on those cancer immunotherapies for which survival data in lung cancer are available from large randomized controlled trials.
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J-F. Baurain MD, PhD
Cutaneous melanoma has long been one of the most aggressive forms of cancer, with limited treatment options and a very dismal prognosis. However, in recent years new strategies for treating melanoma have been introduced that significantly improve the outlook for patients with this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other checkpoint inhibitors and investigating combinations of agents targeting different immune checkpoints.
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