New Era for Malignant Pleural Mesothelioma: Updates on Therapeutic Options

2022 ◽  
Author(s):  
Anne S. Tsao ◽  
Harvey I. Pass ◽  
Andreas Rimner ◽  
Aaron S. Mansfield
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Checkpoint Inhibitors ◽  
Treatment Plan ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Pleural Mesothelioma ◽  
Frontline Treatment ◽  
Rare Malignancy

Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes in the standard of care with a novel biomedical device approved for use with platinum-pemetrexed, and also for immunotherapy agents to be included as a frontline treatment option in unresectable disease. Although predictive biomarkers for systemic therapy are not currently in use in clinical practice, it is essential to correctly identify the MPM histology to determine an optimal treatment plan. Patients with nonepithelioid MPM may have a greater magnitude of benefit to dual immunotherapy checkpoint inhibitors and this regimen should be preferred in the frontline setting for these patients. However, all patients with MPM can derive benefit from immunotherapy treatments, and these agents should ultimately be used at some point during their treatment journey. There are ongoing studies in the frontline unresectable setting that may further define the frontline therapy space, but a critical area of research will need to focus on the immunotherapy refractory population. This review article will describe the new developments in the areas of biology with genomics and chromothripsis, and also focus on updates in treatment strategies in radiology, surgery, radiation, and medical oncology with cellular therapies. These recent innovations are generating momentum to find better therapies for this disease.

scholarly journals Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3932
Author(s):  
Dannel Yeo ◽  
Laura Castelletti ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Pleural Mesothelioma ◽  
Normal Tissues ◽  
Drug Conjugates ◽  
Aggressive Cancer ◽  
Immunotherapy Target ◽  
Bull's Eye

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

scholarly journals Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma

2020 ◽  
Vol 12 ◽  
pp. 175883592097142
Author(s):  
Haitang Yang ◽  
Duo Xu ◽  
Ralph A. Schmid ◽  
Ren-Wang Peng
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Tumor Suppressor Genes ◽  
Treatment Options ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Pleural Mesothelioma ◽  
Precision Oncology ◽  
Tremendous Progress ◽  
High Degree

Malignant pleural mesothelioma (MPM) is a lethal thoracic malignancy whose incidence is still increasing worldwide. MPM is characterized by frequent inactivation of tumor-suppressor genes (TSGs), e.g., the homozygous deletion of CDKN2A/2B and various genetic alterations that inactivate BAP1, NF2, LATS1/2, and TP53. The leading cause for the poor prognosis of patients with MPM is the lack of effective treatment options, with conventional chemotherapy being the standard of care in the clinic, which has remained unchanged for almost 20 years. Precision oncology, a burgeoning effort to provide precise cancer treatment tailored to unique molecular changes in individual patients, has made tremendous progress in the last decade in several cancers, but not in MPM. Recent studies indicate a high degree of tumor heterogeneity in MPM and the importance to optimize histological and molecular classifications for improved treatment. In this review, we provide an up-to-date overview of recent advances in MPM by focusing on new stratifications of tumor subgroups, specific vulnerabilities associated with functional loss of TSGs and other biomarkers, and potential clinical implications. The molecularly based subdivisions not only deepen our understanding of MPM pathobiology, but more importantly, they may raise unprecedented new hopes for personalized treatment of MPM patients with biomarker-guided targeted and immunotherapies.

scholarly journals Oncological Frontiers in the Treatment of Malignant Pleural Mesothelioma

2021 ◽  
Vol 10 (11) ◽  
pp. 2290
Author(s):  
Emanuele Vita ◽  
Alessio Stefani ◽  
Mariantonietta Di Di Salvatore ◽  
Marco Chiappetta ◽  
Filippo Lococo ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Genomic Sequencing ◽  
Pleural Mesothelioma ◽  
Targeted Drugs ◽  
Treatment Algorithms ◽  
Rare Malignancy ◽  
New Generation ◽  
The Way

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by very poor prognosis and lack of treatment options. Immunotherapy has rapidly emerged as an effective tool for MPM, particularly for tumors of non-epithelioid histology. At the same time, comprehensive genomic sequencing may open the way to new-generation targeted-drugs able to hit specific MPM molecular vulnerabilities. These innovations will possibly enrich, but also dramatically complicate, the elucidation of treatment algorithms. Multidisciplinary integration is urgently needed.

scholarly journals Newly Diagnosed Myeloma in 2020

2020 ◽  
pp. e144-e158 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Touzeau ◽  
Ravi Vij ◽  
Scott R. Goldsmith ◽  
Ashley E. Rosko
Keyword(s):  
Older Adults ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Newly Diagnosed ◽  
New Agents ◽  
Specific Patient ◽  
Clinical Endpoints ◽  
Frontline Treatment ◽  
Treatment Tolerance

Over the last few years, there has been great progress in the treatment of multiple myeloma (MM), with many new agents and combinations having been approved and being now routinely incorporated into treatment strategies for newly diagnosed patients. As a result, patients are experiencing benefits in terms of survival and better tolerance. However, the multitude of treatment options also presents a challenge to select the best options tailored to the specific patient situation. Frontline autologous stem cell transplantation (ASCT) is the standard of care for fit patients younger than age 71 who are newly diagnosed with MM, and triplet combinations are the backbone of induction therapy before ASCT. Post-transplant consolidation and prolonged lower-intensity maintenance are two strategies that have been used to deepen responses and delay progression. For older patients not eligible for ASCT, lenalidomide (len) is increasingly being used as part of frontline therapy, and current approaches are now targeting combinations of anti-CD38 antibodies. Strategies for selecting therapeutic regimens for older adults newly diagnosed with MM can be augmented with use of predictive tools to better capture physiologic age and estimate treatment tolerance. Here we review a decade of trials identifying clinical endpoints and toxicities relevant for the frontline treatment of younger patients and older adults.

scholarly journals Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy in Hepatocellular Carcinoma: Where Do We Stand?

2021 ◽  
Vol 11 ◽  
Author(s):  
Alessandro Rizzo ◽  
Angela Dalia Ricci ◽  
Alessandro Di Federico ◽  
Giorgio Frega ◽  
Andrea Palloni ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Phase Iii ◽  
Cochrane Library ◽  
Advanced Hcc ◽  
Treatment Naïve

Hepatocellular carcinoma (HCC) remains the sixth most commonly diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Over the next few years, novel systemic treatment options have emerged. Among these, immune checkpoint inhibitors (ICIs) have been widely evaluated and are under assessment, as monotherapy or in combination with other anticancer agents in treatment-naïve and previously treated patients. In particular, the approval of the PD-L1 inhibitor atezolizumab plus the antiangiogenic agent bevacizumab as front-line treatment for advanced HCC has led to the adoption of this combination in this setting, and the IMbrave 150 phase III trial has established a novel standard of care. However, several questions remain unanswered, including the identification of reliable predictors of response to ICIs in HCC patients. In the current paper, we will provide an updated overview of potentially useful predictive biomarkers of response to immunotherapy in advanced HCC. A literature search was conducted in September 2021 of Pubmed/Medline, Cochrane library and Scopus databases.

Molecular profiling of appendix-derived pseudomyxoma peritonei (PMP).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 571-571 ◽  
Author(s):  
Elizabeth Gleeson ◽  
Rebecca Feldman ◽  
Sherri Z. Millis ◽  
Beth Mapow ◽  
Lynn Mackovick ◽  
...  
Keyword(s):  
Protein Expression ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Tumor Infiltrating Lymphocytes ◽  
Molecular Profiling ◽  
Low Frequencies ◽  
Rare Malignancy

571 Background: PMP is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. Cytoreductive surgery and intraperitoneal chemotherapy offers optimal outcomes for most patients; however, for patients that progress, there are few treatment options. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy. Methods: 54 patients with appendix-derived PMP were included in the study and tested centrally at Caris Life Sciences (Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: Targeted sequencing of 47 genes detected variants in KRAS (79%), GNAS (73%) and SMAD4 (18%). Mutations were found at low frequencies (n = 1-2) in APC, ATM, BRAF, PIK3CA, MLH1 and TP53. GNAS and KRAS co-occurrence was found in 38%. High rates of protein overexpression were found in EGFR (83%), cMET (59%), cKIT (58%) and PDGFRA (58%), respectively. Immune checkpoint expression was found in 36% (PD1-positive tumor infiltrating lymphocytes) and 9% (PDL1 tumor expression). Expression of surrogate markers of cell proliferation were found at low rates (TLE3 27%, TOP2A 22%), consistent with the slow-growing biology of PMP. PTEN was intact (wild type [100%] and positive IHC [80%]) in the majority of PMP. Patients exhibit stable microsatellite status and mismatch repair proficiency in 93% of patients. Importantly, multidrug resistance protein expression was found at high levels (100% BCRP, 94% MRP1, 88% PGP). Markers for gemcitabine (RRM1), fluorouracil (TS), oxaliplatin (ERCC1) and irinotecan (TOPO1) chemo-sensitivities were found to be favorable in 93%, 87%, 77% and 65%, respectively. Conclusions: Molecular profiling by multiple platforms identified potential therapy options in the non-targetable setting of a KRAS-mutated population. The role of cMET-targeted therapies and immune checkpoint inhibitors merit further investigation. Biomarker-guided selection of cytotoxic chemotherapies may facilitate responses to systemic treatment.

Survival meta-analysis from fifteen years of a standard systemic therapy in malignant pleural mesothelioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20066-e20066
Author(s):  
Joseph S. Friedberg ◽  
Melissa Culligan
Keyword(s):  
Overall Survival ◽  
Malignant Pleural Mesothelioma ◽  
Meta Analysis ◽  
Weighted Average ◽  
Standard Of Care ◽  
Pleural Mesothelioma ◽  
Platinum Drug ◽  
Average Survival ◽  
Pubmed Search ◽  
Rare Malignancy

e20066 Background: Malignant pleural mesothelioma is a rare malignancy with an annual incidence of 3,000 cases in the US and is still considered incurable. The standard of care for this cancer, a combination of pemetrexed and a platinum drug, was established in 2003 as the result of a landmark study that reported a median overall survival of 12.1 months for this combination in patients not eligible for surgery. The aim of the current analysis was to determine if there has been a change in the outcome for this population in the past 15 years. Methods: A PubMed search was performed and 9 prospective, randomized or single arm (minimum n = 50), trials were selected. All studies included patients treated using pemetrexed in combination with platimun as front line therapy in unresectable mesothelioma patients. Average and weighted average OS were calculated and also corrected per the reported odds ratio for survival between the epithelioid and non-epithelioid histologies. Results: The average OS was 12.9 months and the weighted average OS was 13.3 months (range: 8.5 – 16.1 months). The two studies showing the highest median OS (MAPS and LUME-meso) had a higher percentage of tumors with epithelioid histology, which could explain their favorable outcome. Adjusting the average OS using the reported odds ratios for survival between epithelioid and non-epithelioid histologies eliminated the superior outcome in these studies. Furthermore, correcting average survival per the original ratio between tumor histologies for all studies included in the meta-analysis showed an average and weighted average OS lower than 13 months. Conclusions: This analysis strongly supports the contention that survival results for nonoperative patients with mesothelioma should be stratified by histology, epithelioid versus nonepithelioid, similar to the trend in the surgical mesothelioma literature. When factoring in histology, it appears that overall advances in patient care and additional treatments have not significantly changed the overall survival for nonoperative mesothelioma patients in the last 15 years. This meta-analysis underscores the desperate need for new and innovative treatments for this cancer.

scholarly journals Angiogenesis and Immunity in Renal Carcinoma: Can We Turn an Unhappy Relationship into a Happy Marriage?

2020 ◽  
Vol 9 (4) ◽  
pp. 930 ◽  
Author(s):  
Alessia Mennitto ◽  
Veronica Huber ◽  
Raffaele Ratta ◽  
Pierangela Sepe ◽  
Filippo de Braud ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Suppressor Cells ◽  
European Medicines Agency ◽  
Frontline Treatment ◽  
Happy Marriage ◽  
And Function

The frontline treatment options for patients with metastatic renal cell carcinoma (mRCC) are evolving rapidly since the approval of combination immunotherapies by the U.S. Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). In particular, in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) have significantly improved the outcome of patients with mRCC compared to TKI monotherapy. Here, we review the preclinical data supporting the combination of ICIs with VEGFR TKIs. The VEGF-signaling inhibition could ideally sustain immunotherapy through a positive modulation of the tumor microenvironment (TME). Antiangiogenetics, in fact, with their inhibitory activity on myelopoiesis that indirectly reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells’ (Tregs) frequency and function, could have a role in determining an effective anti-tumor immune response. These findings are relevant for the challenges posed to clinicians concerning the clinical impact on treatment strategies for mRCC.

scholarly journals Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma

2020 ◽  
Vol 8 (1) ◽  
pp. e000461 ◽  
Author(s):  
Katsuyuki Hotta ◽  
Nobukazu Fujimoto
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Relevant Literature ◽  
Predictive Biomarkers ◽  
Current Evidence ◽  
Pleural Mesothelioma ◽  
First Line ◽  
Platinum Based Chemotherapy

Platinum-based chemotherapy is commonly used as the standard first-line treatment for unresectable malignant pleural mesothelioma (MPM). However, in recent times, immune-checkpoint inhibitors (ICIs) have led to a paradigm shift. Herein, we review relevant literature and ongoing trials of ICIs used as both first-line and salvage therapies. Specifically, in the Japanese single-arm, phase II trial, the MERIT trial, nivolumab, an antiprogrammed cell death 1 (PD-1) antibody showed favorable efficacy when used as a salvage therapy. Currently, multiple ICI monotherapy or combination therapy trials have been conducted, which could provide further evidence. Among available ICIs, the anti-PD-1 antibody is promising for unresectable MPM, despite the limited efficacy of anti-CTLA4 monotherapy. Ongoing studies will further confirm the potential efficacy of ICIs for MPM, as observed across other malignancies. It is also crucial to identify any clinically useful predictive biomarkers that could reveal ICIs with maximal effects in MPM.

Malignant Mesothelioma: Has Anything Changed?

2019 ◽  
Vol 40 (03) ◽  
pp. 347-360 ◽  
Author(s):  
Roger Y. Kim ◽  
Daniel H. Sterman ◽  
Andrew R. Haas
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Multimodal Therapy ◽  
Asbestos Exposure ◽  
Treatment Options ◽  
Standard Of Care ◽  
Turn Of The Century ◽  
Clinical Approach ◽  
Pleural Mesothelioma ◽  
Dismal Prognosis ◽  
Near Future

AbstractMalignant pleural mesothelioma is a rare cancer associated with asbestos exposure and portends a dismal prognosis. Its worldwide incidence has been increasing, and treatment options are currently suboptimal and noncurative. However, since the turn of the century, several encouraging steps have been made toward improving outcomes for mesothelioma patients. An increased understanding of disease pathophysiology has led to more accurate diagnosis and staging, and the establishment of the standard of care first-line pemetrexed/platin doublet chemotherapy regimen in 2003 initially revolutionized treatment. While significant debate remains regarding the preferred approach to surgical and radiation therapy in the context of multimodal therapy, recent breakthroughs in immunotherapy offer hope for another paradigm shift in the near future. This review will summarize the current clinical approach to diagnosis, staging, and treatment of malignant pleural mesothelioma.

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