JTO Clinical and Research Reports

Our medical research library holds 39 studies published in JTO Clinical and Research Reports (2020–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 37 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Elsevier Inc
• Published: 2020 to the present, United States
• Language: English
• ISSN: 2666-3643 (electronic)
• Its record in the NLM Catalog

2020s

• BAP1 Loss in Pleural Mesothelioma Is Associated With Reduced Soluble CCL2 in Patient Effusion, Abrogated CCL2-Mediated Monocyte Recruitment In Vitro. A. Nash, E. Rouse, T. Firth, et al. 2026;7(10):101049. PubMed · Publisher · Free full text

  Abstract

  Objectives: Pleural mesothelioma is an incurable cancer of the cell layer lining the chest wall and lung. Patients frequently present with pleural effusion, which is often drained for symptom relief and enables minimally invasive sampling of the tumour environment, including immune cells and related soluble factors. Most of the mesothelioma tumours exhibit loss of BRCA1-associated protein 1 (BAP1), a multifunctional tumour suppressor protein. Here, we aim to elucidate the effect of BAP1 loss on the mesothelioma microenvironment through profiling soluble factors within pleural effusion.

  Methods: A custom panel of 22 soluble factors was measured by Luminex assay and enzyme-linked immunosorbent assay in an initial cohort of 40 patients with known BAP1 status. Validation was performed by enzyme-linked immunosorbent assay in an independent cohort of 100 cases. Secretion of soluble factors and chemoattraction of monocytes were characterised using a CRISPR-mediated BAP1 deletion model in a mesothelioma and a lung cancer cell line. Immune cell infiltration, estimated by CIBERSORT, was further explored in the Cancer Genome Atlas -MESO cohort.

  Results: Soluble C-C motif chemokine ligand 2 (CCL2) was approximately 55% to 60% lower in pleural effusion from BAP1-loss cases in both independent cohorts. Deletion of BAP1 reduced CCL2 secretion in vitro and abolished CCL2-mediated chemoattraction of monocytes in both mesothelioma and lung cancer cell lines. In the Cancer Genome Atlas -MESO cohort, BAP1-mutant tumours exhibited a reduction in estimated macrophage content.

  Conclusion: Loss of BAP1 impairs CCL2 secretion into pleural effusions, potentially influencing monocyte recruitment into the tumour microenvironment.

  © 2026 The Authors.

• Brain Metastases in Diffuse Pleural Mesothelioma: Clinical, Histologic, and Molecular Correlates. A. Ocejo, C. Wilhem, F.M. Bodd, et al. 2026;7(4):100968. PubMed · Publisher · Free full text

  Abstract

  Introduction: Brain metastases (BrMs) are poorly studied and likely underreported in diffuse pleural mesothelioma (DPM), limiting understanding of risk factors associated with their development. We evaluated the genomic, histologic, and clinical landscapes of patients with DPM and BrMs.

  Methods: We retrospectively reviewed all patients with a mesothelioma diagnosis treated at the Memorial Sloan Kettering Cancer Center between January 1, 2010, and May 1, 2025, with cross-sectional brain imaging. Clinicopathologic data and treatment outcomes were annotated for patients with BrMs.

  Results: Among 194 patients with mesothelioma and brain imaging, 16 (8%) had BrMs. Half (n = 8) had tumors of epithelioid histology, 44% (n = 7) biphasic, and 6% (n = 1) sarcomatoid. Compared with our DPM cohort regardless of BrMs (n = 194) or a DPM cohort from The Cancer Genome Atlas (n = 74), patients with DPM and BrMs had a higher prevalence of LATS2 alterations (46% versus 7% versus 12%, respectively [p < 0.00001]). BrMs were typically (88%, n = 14) diagnosed after neurologic symptoms prompting imaging. Among patients with BrMs, the median overall survival from initial mesothelioma diagnosis was 35.4 (95% confidence interval, 19.3-not reached) months and 3.7 (95% confidence interval, 3.5-not reached) months from BrM diagnosis.

  Conclusions: Our findings suggest that BrM develops relatively late in DPM, is more common than previously reported, and may be enriched in patients with LATS2 alterations. Prospective, multi-institutional studies with standardized brain imaging are needed to further characterize the incidence of BrMs in DPM and associated risk factors. Routine brain surveillance at diagnosis and with symptoms should be considered for patients with DPM.

  © 2026 The Authors.

• First Central Asian Forum on Lung Cancer. J. Amankulov, D.F. Yankelevitz, A. Mukhamejan, et al. 2026;7(1):100898. Editorial PubMed · Publisher · Free full text

  Abstract

  The First Central Asian Forum on Lung Cancer was held at the National Academy of Sciences of the Republic of Kazakhstan on April 8 and 9, 2025. Organized by the Kazakhstan Cancer Society, KazIOR, and the I-ELCAP/IELCART consortia, the forum brought together regional and international experts to address the urgent challenge of late-stage lung cancer diagnosis in Central Asia. National data show that fewer than one-third of patients are diagnosed at stages I and II, while over 70% present with advanced disease. High smoking prevalence, environmental exposures such as radon, asbestos, and industrial pollution, and strong geographic variation in risk highlight the need for tailored screening programs. Kazakhstan is well-positioned to scale up low-dose CT (LDCT) screening given its CT scanner capacity, mobile units for underserved regions, and prior pilot screening successes. Conference sessions emphasized risk modeling, cost-effectiveness, artificial intelligence applications, and the added value of LDCT for detecting cardiovascular disease and emphysema. Plans are underway for collaborative projects and future conferences to strengthen regional capacity for early detection and treatment.

  © 2025 The Authors.

• Organized Lung Cancer Screening of Subjects Occupationally Exposed to Lung Carcinogens: The LUng Cancer Screening Occupational exposure Study Entry Findings. F. Delva, S. Gendarme, L. Boudet, et al. 2026;7(6):100995. PubMed · Publisher · Free full text

  Abstract

  Introduction: The LUng Cancer Screening Occupational exposure (LUCSO) program was designed as a feasibility study of organized screening for lung cancer in subjects with occupational exposure to lung carcinogens in France. Herein, we report the program's entry-level (baseline) findings.

  Methods: The inclusion criteria were subjects aged 55 to 74 years, with sufficient exposure to International Agency for Research on Cancer group 1 occupational carcinogens and smoker or ex-smoker for less than 15 years. The first phase of the study addressed subjects aged 65 to 74 years in two French regional counties to test feasibility. Lung cancer screening was based on a low-dose computed tomography (CT) scan at baseline and spirometry, followed by an annual CT scan for 2 years and telephone follow-up at 3 years.

  Results: Letters were sent to 247,152 subjects from the Regional Cancer Screening Coordination Center inviting them to participate, allowing eligibility screening by letter. Among the 21,502 respondents (8.7%), 311 (1.4%) were included. Asbestos exposure predominated (92%), but co-exposures were also frequent (73% crystalline silica and 48% welding fumes); 45% were active smokers at inclusion, and 37% of them agreed to consult a smoking-cessation specialist. Baseline CT scans revealed anomalies in 19 (6.1%); seven (2.4%) were diagnosed with the following stages of lung cancer: three stage IA, three stage IIA, and one stage IIB; the false-positive rate was 4.2%.

  Conclusion: Before considering nationwide implementation, this feasibility study provided new real-life insights finding that the selected population was indeed at high risk of lung cancer and that screening effectively detected early stages.

  © 2026 The Authors.

• Outcomes of Platinum plus /Pemetrexed Rechallenge in Pleural Mesothelioma: The Role of Platinum-Free Interval in a Multicenter Real-World Analysis. R. Shah, M. Reck, C. Grohé, et al. 2026;7(11):101073. PubMed · Publisher · Free full text

  Abstract

  Introduction: Real-world (rw) practice of rechallenge with platinum plus pemetrexed (PP) in pleural mesothelioma (PM) has been recommended in international guidelines, but the evidence is scarce and based on a few very small retrospective studies.

  Methods: In total, 612 patients with PM treated with first-line PP between 2010 and 2023 across 12 centers were retrospectively identified. Outcomes and treatment patterns were analyzed across second-line regimens, with a particular focus on PP rechallenge. The platinum-free interval (PFI) was evaluated using a two-tier classification (platinum-sensitive ≥6 mo and platinum-resistant <6 mo) as a selection criterion.

  Results: Among 375 patients (61%) receiving second-line therapy, the rw median overall survival (rw-mOS) and rw median progression-free survival (rw-mPFS) were 11.6 months and 4.7 months, respectively. Patients with PP rechallenge (n = 78) had a median OS of 20.5 months, a median rwPFS of 6.8 months, and a disease control rate of 88%. Patients with platinum sensitivity derived greater benefit from rechallenge, with rw-mOS differing across PFI categories (platinum-sensitive: 21.4 mo versus platinum-resistant: 11.9 mo; p = 0.007). Outcomes with nivolumab plus ipilimumab (n = 29) were comparable to those observed with PP rechallenge (rw-mOS = 22.8 mo, rw-mPFS = 8.0 mo), with treatment-free interval (TFI) associated with improved median OS in the platinum-sensitive group compared with the platinum-resistant group (32 mo versus 18.1 mo, p = 0.03). Single-agent pemetrexed (n = 32) and single-agent chemotherapy were associated with substantially shorter rw-mOS of 11.6 and 8.0 months, respectively.

  Conclusion: In conclusion, PP rechallenge has favorable outcomes and remains a viable alternative in patients with platinum sensitivity with PM, whereas nivolumab plus ipilimumab may be considered in both TFI categories, particularly in platinum-resistant disease, in which PP rechallenge offers limited benefit. A PFI or TFI-guided approach to second-line treatment selection is supported, although prospective validation is warranted.

  © 2026 The Authors.

• Paraneoplastic Brachial Amyotrophic Diplegia and Encephalitis With Ma2-IgG During Immune Checkpoint Inhibitor Use for Mesothelioma: A Case Report. S.P. Uysal, S. Badihian, K. Toljan, et al. 2026;7(5):100980. Case report PubMed · Publisher · Free full text

  Abstract

  Background: Immune checkpoint inhibitors (ICIs) improve cancer survival but can cause neurologic immune-related adverse events. Ma2-IgG-associated paraneoplastic neurologic syndrome typically presents with central nervous system involvement in patients with testicular or lung cancers. We present a case of paraneoplastic brachial amyotrophic diplegia (BAD) associated with Ma2-IgG which developed after ICI.

  Case Report: This is a case report of an 86-year-old man with pleural mesothelioma treated with nivolumab and ipilimumab, who presented with progressive, asymmetric weakness of his upper extremities after 5 cycles of ICI. Examination did not reveal associated sensory deficits. Blood creatine kinase level was normal and acetylcholine receptor antibody testing result was negative. Magnetic resonance imaging revealed findings consistent with bilateral frontal temporal lobe encephalitis, but without concurrent cervical cord lesions. Cerebrospinal fluid analysis revealed mild pleocytosis and oligoclonal bands. Ma2-IgG was present in the cerebrospinal fluid (>1:32) and serum (>1:3200). Electrodiagnostic testing revealed diffuse chronic innervation and active denervation changes involving the upper extremities raising concern for a motor neuron disorder. He was diagnosed with having paraneoplastic BAD and encephalitis. A progressive course ensued, despite initial transient improvement with escalation of immunosuppression.

  Conclusion: Paraneoplastic BAD is an uncommon paraneoplastic phenomenon that can occur with Ma2-IgG in the setting of ICI use and atypical tumors.

  © 2026 The Authors.

• Pre-treatment Tumor Volume Growth Rate and Baseline Volume Measured by an Artificial Intelligence Program Predict Overall Survival in Patients With Pleural Mesothelioma Undergoing Deferred Systemic Therapy. I. Smesseim, V. Pugliese, J. Burgers, et al. 2026;7(9):101040. PubMed · Publisher · Free full text

  Abstract

  Introduction: The optimal timing of systemic therapy in pleural mesothelioma remains debated, particularly for asymptomatic patients with a limited disease burden. Prior studies suggest that deferred treatment may not compromise overall survival (OS) in selected patients. Reliable prognostic markers to guide treatment timing are lacking. We investigated whether baseline tumor volume and pretreatment tumor growth rate, quantified using an artificial intelligence (AI)-based model, predict OS in patients deferring systemic therapy.

  Methods: We conducted a single-center retrospective study including patients with pleural mesothelioma diagnosed between 2010 and 2025 who deferred systemic therapy for more than or equal to 3 months and had at least two pretreatment computed tomography scans. Total tumor volume and tumor growth rate (mL/mo) were automatically measured using the AI-based ARTIMES model. Optimal cutoffs were determined using receiver operating characteristic analysis. OS was analyzed using Kaplan-Meier estimates and Cox proportional hazards models.

  Results: A total of 71 patients were included (median age 66.8 y; 80.3% male; Eastern Cooperative Oncology Group 0-1). The median deferral time was 8.0 months. Optimal cutoffs were 56.5 mL for baseline tumor volume and 67.8 mL/mo for tumor growth rate. Patients with a low baseline tumor volume had a significantly longer median OS compared with those with a high volume (30.95 versus 16.89 mo; p = 0.0066). Similarly, a low tumor growth rate was associated with improved OS (29.40 versus 14.59 mo; p = 0.00057). In multivariable analysis, sarcomatoid histology remained independently associated with worse OS (hazard ratio = 3.28, 95% confidence interval: 1.38-7.75, p = 0.007).

  Conclusions: AI-derived baseline tumor volume and tumor growth rate are strong prognostic factors for OS in patients with pleural mesothelioma deferring systemic therapy. Patients with low baseline tumor volume and those with low tumor growth rate were significantly associated with a longer OS.

  © 2026 by the International Association for the Study of Lung Cancer.

• Combining a WT1 Vaccine (Galinpepimut-S) With Checkpoint Inhibition (Nivolumab) in Patients With WT1-Expressing Diffuse Pleural Mesothelioma: A Phase 1 Study. P. Agrawal, M. Offin, V. Lai, et al. 2025;6(1):100756. PubMed · Publisher · Free full text

  Abstract

  Introduction: WT1 often presents on the surface of diffuse pleural mesotheliomas (DPMs) and is an ideal therapeutic target. Galinpepimut-S (GPS), a tetravalent, non-human leukocyte antigen-restricted, heteroclitic WT1-specific peptide vaccine was safe and effective in early phase clinical trials and upregulates T-cell suppressive programmed death-ligand 1 in the tumor microenvironment of other malignancies. A randomized phase 2 study of adjuvant GPS in patients with DPM trended toward improved median overall survival.

  Methods: To further enhance immunogenicity, we combined GPS with nivolumab, an anti-PD1 monoclonal antibody, in an open-label, single-center phase 1 study, examining tolerability and immunogenicity in patients with previously treated DPM. We enrolled patients with progressive or recurrent DPM treated with at least one course of pemetrexed-based chemotherapy. Patients received two doses of GPS followed by six doses of GPS with intravenous nivolumab every 2 weeks, and up to six additional cycles until disease progression or unacceptable toxicity.

  Results: Ten patients were treated; 70% experienced mostly mild treatment-related adverse events; two experienced a grade 3 or higher adverse event. Three of the 10 patients (30%) reported vaccine-specific T-cell responses. There were no partial responses; three patients had prolonged stable disease with up to 17% decrease in tumor volume. Median progression-free survival was 3.9 months and the median overall survival was 7.4 months.

  Conclusions: Coadministration of GPS and nivolumab reported a tolerable toxicity profile and induced immune responses in a subset of patients, but initial response and survival benefit were limited possibly owing to the small sample size.

  © 2024 The Authors.

• Discordant Response to Nivolumab Plus Ipilimumab and Identification of BRAF V600E Mutation in Biphasic Malignant Pleural Mesothelioma: Case Report. O. Wilkins, A. Omogbehin, P.J. Bergquist, et al. 2025;6(5):100820. Case report PubMed · Publisher · Free full text

  Abstract

  Therapeutic advancement for malignant pleural mesothelioma (MPM) has been limited. Combination immunotherapy with nivolumab plus ipilimumab is a frontline treatment option for advanced MPM that is typically deployed for patients with sarcomatoid or biphasic MPM. Here, we present a case of biphasic MPM that exhibited a unique response pattern to first-line treatment with nivolumab plus ipilimumab, with brisk response in pleural and mediastinal sites of disease, but rapid progression in osseous/soft tissue sites of disease complicated by pathologic spinal cord compression. Pathologic findings from bony metastasis at progression found pure epithelioid histology without any evidence of sarcomatoid differentiation. Next-generation sequencing of this specimen revealed a BRAF V600E mutation, and the patient was subsequently treated with dabrafenib plus trametinib, achieving ongoing clinical and imaging response in all sites of the disease, including bones. This case supports the use of next-generation sequencing profiling in MPM, particularly in circumstances in which novel discordant response patterns are observed.

  © 2025 The Authors.

• Durvalumab Combined With Pemetrexed-Based Chemotherapy in Trial-Ineligible Patients With Mesothelioma: A Brief Report. I. Dagogo-Jack, A. Lasko, E.A. Krueger, et al. 2025;6(5):100775. PubMed · Publisher · Free full text

  Abstract

  Introduction: Chemoimmunotherapy is associated with promising activity in mesothelioma in phase II to III trials. Studies exploring this approach in patients ineligible for clinical trials are lacking. We assembled a cohort of patients receiving pemetrexed-based chemotherapy with durvalumab outside of clinical trials.

  Methods: Patients with pleural mesothelioma received pemetrexed plus durvalumab or carboplatin plus pemetrexed plus durvalumab via off-label authorization at Massachusetts General Hospital. Response to chemoimmunotherapy was assessed per modified Response Evaluation Criteria in Solid Tumors version 1.1. A retrospective chart review was conducted to assess safety per Common Terminology Criteria for Adverse Events version 5.0.

  Results: Twelve patients were included in the series. Nine patients were treated with triplet chemoimmunotherapy. Three patients received doublet chemoimmunotherapy because of platinum ineligibility. Concurrent active malignancies and symptomatic cardiac disease were present in three patients (25%) and two patients (17%), respectively. Ten patients had measurable disease at baseline. With the triplet regimen, partial responses were observed in four of the seven (57%) patients with measurable disease. All three patients receiving pemetrexed plus durvalumab had measurable disease and experienced a partial response. Primary progression was not observed with either regimen. Overall, eight patients (75%) remained on treatment for more than 6 months without progression. Five patients developed immune-related adverse events (n = 1 each pyrexia, arthritis, neutropenia, Raynaud's disease, stomatitis). Three patients discontinued treatment because of toxicity or symptomatic comorbid conditions (n = 1 grade 3 heart failure, n = 1 grade 2 fever + progressive kidney cancer, n = 1 grade 2 fatigue).

  Conclusions: Antitumor activity of chemoimmunotherapy reported in phase II to III clinical trials is generalizable to the broader patient population with mesothelioma. However, the tolerability of chemoimmunotherapy is impacted by comorbid conditions in real-world patients.

  © 2024 The Authors.

• Health Utility and Symptom Scores in Patients With Advanced Malignant Pleural Mesothelioma Treated in a Real-World Setting. A. Mittal, L. Everest, D. Patel, et al. 2025;6(6):100802. PubMed · Publisher · Free full text

  Abstract

  Introduction: There is a paucity of real-world associations between EQ-5D-generated health utility scores (HUS), symptoms as measured by the Edmonton Symptom Assessment System (ESAS), and the patient-reported outcomes version of the common terminology criteria for adverse events (pro-CTCAE), and survival in patients with advanced Malignant Pleural Mesothelioma (aMPM).

  Methods: Clinico-demographic variables and treatment information were captured retrospectively in patients diagnosed with aMPM between January 2004 and February 2021 at Princess Margaret Cancer Centre. Quality of life outcomes were measured using HUS, ESAS, and pro-CTCAE scales, by stable versus progressive disease and line-of-treatment states. Survival by mean ESAS scores were analyzed using the Kaplan-Meier method.

  Results: Of the 262 patients, the median age was 69 years (interquartile range: 62-74), 77% were male individuals, 52% were ever-smokers, 67% were the epithelioid-subtype, and 62% received first-line systemic therapy for advanced disease. The mean baseline HUS at diagnosis was 0.68 (95% confidence interval: 0.62-0.74) with most symptoms consisting of pain, dyspnea, and fatigue. Pooled ESAS physical and psychological scores changed significantly with disease state: the mean scores were worst at baseline, improved with stable or responding disease (physical, p < 0.001; psychological, p < 0.001), and worsened at progressive disease (physical: p < 0.001; psychological, p < 0.001). Similar trends were seen in HUS and pro-CTCAE symptom severity/frequency. Patients with high baseline ESAS physical symptom burden had inferior overall survival (median = 8.9 [high] versus 12.6 months [low], p = 0.022). Weak-to-moderate correlations were observed between most ESAS domains and HU and between pro-CTCAE domains and HU. The strongest domain correlations were with well-being, shortness of breath, tiredness, and depression domains.

  Conclusions: Baseline quality of life burden is high in patients with aMPM and is well captured by both EQ-5D and ESAS Individual ESAS and pro-CTCAE domains reported low/moderate correlations with HUS, reflecting the inability of one symptom to predict the entire disease state, thus paving the way for future mapping studies. The baseline physical symptom burden (ESAS) was prognostic of survival.

  © 2025 by the International Association for the Study of Lung Cancer.

• Incidence and Outcomes of Brain Metastasis in Pleural Mesothelioma in the Era of Immunotherapy. M. Stalker, S.L. Walker, E. Lebow, et al. 2025;6(5):100823. PubMed · Publisher · Free full text

  Abstract

  Introduction: Immunotherapy (IO) has reported efficacy in pleural mesothelioma (PM). Brain metastases (BMs) in PM are rare; thus, surveillance brain imaging is not included in the guidelines. We evaluated the incidence of BM by treatment type.

  Methods: In this retrospective analysis, patients with PM treated at the University of Pennsylvania between January 1, 2015, and August 31, 2023, were included. Demographic and clinical data were extracted from the medical records. The treatment categories included chemotherapy, single-agent IO, and dual-agent IO. A two-tailed Z score was used to determine a difference in the proportion of BM. Overall survival (OS) was analyzed using the Kaplan-Meier method. Of those with BM, available brain tissue was further analyzed.

  Results: In total, 251 patients were included; the median age of the participants was 73 years (range: 35-92 y), 79% were male individuals, 91% were white, and 73% had epithelioid histology. In the study, 102 (40.6%) were treated with chemotherapy, 100 (39.8%) with single-agent IO, and 49 (19.5%) with dual-agent IO. The median OS (mOS) was 21.6 months (95% confidence interval: 17.7-25.5) and did not differ between treatment groups (p = 0.774). A higher proportion of patients treated with IO developed BM than those treated with chemotherapy (6/149 [4%] versus 0/102 [0%]; Z score p = 0.04). The mOS from BM diagnosis was 95 days (range: 16-1025 d). The histomorphology of three patients with available brain tissue were similar to the primary site and reported substantial edema and hemorrhage.

  Conclusions: In this retrospective study, clinically significant BM was most prevalent in those exposed to IO and not seen in those receiving chemotherapy despite similar mOS between the groups. Brain imaging should be considered before starting IO in patients with PM.

  © 2025 The Authors.

• Retreatment With Nivolumab and Ipilimumab in Pleural Mesothelioma Following Disease Progression After a Durable Response: Case Series. I. Smesseim, P. Baas, J.A. Burgers. 2025;6(7):100835. Case report PubMed · Publisher · Free full text

  Abstract

  The CheckMate 743 trial established nivolumab and ipilimumab as the standard first-line treatment for unresectable pleural mesothelioma. However, optimal management following disease progression after a durable response to dual immunotherapy remains unclear. We report two cases of patients with pleural mesothelioma (epithelioid subtype) initially treated with nivolumab-ipilimumab, achieving prolonged disease control. Both patients experienced disease progression several years after treatment discontinuation and were subsequently retreated with nivolumab-ipilimumab on regulatory approval. In both cases, retreatment resulted in stable disease for at least 12 months. However, immune-related toxicities occurred, with one patient developing recurrent colitis and the other experiencing nephrotic syndrome, ultimately leading to treatment discontinuation. These cases suggest that retreatment with dual immunotherapy may be a viable strategy for selected patients with previous durable responses, although the risk of immune-related toxicity remains significant. Given the lack of prospective data, further research is needed to determine whether rechallenge with nivolumab-ipilimumab offers superior outcomes compared with chemotherapy or best supportive care in this setting. Rechallenging patients with pleural mesothelioma with nivolumab-ipilimumab after a durable response is feasible but associated with immune-related toxicity.

  © 2025 The Authors.

• Trends in Mesothelioma Mortality in the United States Between 1999 and 2020. A.J. Didier, M. Li, J. Gheeya, et al. 2025;6(5):100804. PubMed · Publisher · Free full text

  Abstract

  Introduction: Mesothelioma is a rare but aggressive cancer primarily caused by asbestos exposure. In March 2024, the Environmental Protection Agency banned asbestos in the United States, but its use will take years to phase out. Therefore, asbestos remains a threat, and incidence may remain stable or slowly decrease due to the long latency between exposure and diagnosis. This study investigates mesothelioma mortality trends in the United States from 1999 to 2020, focusing on demographic and geographic variations.

  Methods: Data on mesothelioma-related deaths from 1999 to 2020 were extracted from the Centers for Disease Control and Prevention database. Variables including race/ethnicity, sex, geographic density, and mesothelioma subtype were assessed. Age-adjusted mortality rates were calculated per 1 million individuals and standardized to the 2000 United States population. Joinpoint regression identified statistically significant changes in mortality trends over time.

  Results: From 1999 to 2020, there were 54,905 mesothelioma-related deaths in the United States (age-adjusted mortality rate = 7.5). Pleural mesothelioma accounted for 8.1% of deaths, peritoneal for 4.6%, pericardial for 0.01%, other sites for 10.9%, and unspecified sites for 76.3%. Most deaths (81.3%) occurred in individuals aged over 65 years. Overall mortality decreased from 8.5 in 1999 to 5.7 in 2020 at -1.9% annually. Non-Hispanic Whites had the highest mortality, and male individuals experienced higher mortality than female individuals. Suburban and rural populations had the highest mortality rates.

  Conclusions: The study highlights significant declines in mesothelioma mortality in the United States from 1999 to 2020, with variations across demographic and geographic groups. Continued monitoring and targeted interventions are necessary to address disparities and further reduce mesothelioma mortality.

  © 2025 The Authors.

• BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma. D. Xu, Y. Gao, H. Yang, et al. 2024;5(5):100672. PubMed · Publisher · Free full text

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive.

  Methods: We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry.

  Results: We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis).

  Conclusion: Our results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.

  © 2024 The Authors.

• Individualized Cell-Free DNA Monitoring With Chromosomal Junctions for Mesothelioma. K. Parikh, F.R. Harris, G. Karagouga, et al. 2024;5(12):100692. PubMed · Publisher · Free full text

  Abstract

  Introduction: The spatially complex nature of mesothelioma and interventions like pleurodesis, surgery, and radiation often complicate imaging-based assessment. Further, cell-free DNA (cfDNA) based monitoring strategies are inadequate for mesothelioma, given the presence of a few recurring nonsynonymous somatic variants. However, patient-specific chromosomal rearrangements are commonly found in mesothelioma. Our study objective was to develop an individualized cfDNA assay to enable blood-based monitoring using circulating tumor DNA (ctDNA) in mesothelioma. We hypothesized that the unique chromosomal rearrangement junctions found in mesothelioma could be employed for individualized ctDNA detection and disease monitoring.

  Methods: DNA was extracted from tumor specimens for whole genome sequencing. Chromosomal junctions, prioritized by highest allele frequency and low homology to the rest of the genome, were selected for detection. Primers and Taqman probes were designed to span the junctions, forming personalized junction panels. Patient plasma obtained before therapy and at response assessment was tested for the presence of personalized junctions via quantitative polymerase chain reaction.

  Results: Our study included nine patients, four with peritoneal and five with pleural mesothelioma. 763 chromosomal junctions were identified in the tumors of all cases. We selected three to five junctions per sample for quantitative polymerase chain reaction. We detected 25/30 (83%) of selected junctions in the plasma of seven out of nine patients (78%). Cell-free junction detection at follow-up was concordant with disease status: cfDNA junctions were detected in three patients with persistent disease, and not detected in a patient with no evidence of disease after surgery.

  Conclusions: With further validation, individualized ctDNA junction assays could supplement imaging for disease monitoring in mesothelioma.

  © 2024 The Authors.

• Real-World Outcomes of Patients With Malignant Pleural Mesothelioma Receiving a Combination of Ipilimumab and Nivolumab as First- or Later-Line Treatment. S. Schmid, L. Holer, K. Gysel, et al. 2024;5(12):100735. PubMed · Publisher · Free full text

  Abstract

  Objectives: On the basis of the positive results of CheckMate-743, first-line (1L) treatment of malignant pleural mesothelioma (MPM) with the combination of ipilimumab and nivolumab (ipi-nivo) has become a standard-of-care. Furthermore, patients who received 1L platinum/pemetrexed chemotherapy are often considered for second or further-line (2L+) ipi-nivo on the basis of MAPS2 results. Here we report on real-world survival and safety outcomes of ipi-nivo for patients with MPM in Switzerland.

  Methods: Twelve cancer centers contributed data to this retrospective cohort. Baseline characteristics including age, sex, histology, programmed death-ligand 1 expression, Eastern Cooperative Oncology Group performance status (ECOG PS), and previous/subsequent therapies were collected. The efficacy and safety outcomes were assessed by local investigators.

  Results: Of the 109 patients with MPM treated with ipi-nivo between November 2017 and March 2023 (median follow-up of 16.6 months) 75% had epithelioid, 9% biphasic, and 16% sarcomatoid histology. The median age was 72 years; 91% were males, and 83% had an ECOG PS of 0 to 1. Ipilimumab in combination with nivolumab was given as 1L in 43% and as 2L+ treatment in 57% of patients. The objective response rate was 21% in 1L and 15% in 2L+. Median progression-free survival was 6.5 and 2.8 months, respectively. Median overall survival (OS) from the start of ipi-nivo was 12.6 months for 1L and 6.9 months for 2L+. No differences in OS were observed depending on age and programmed death-ligand 1 expression. Nevertheless, the median OS was significantly worse in patients with an ECOG PS of 2 or higher than those with an ECOG PS of 0 to 1 (2.4 versus 11.9 months, p < 0.001). Treatment-related adverse events (TRAEs) of any grade related to ipi-nivo treatment occurred in 65 patients (62%). The highest-grade TRAE was 1 to 2 in 58% of these patients and 3 or higher in 42% Treatment discontinuation due to a TRAE occurred in 22% of patients.

  Conclusion: In this real-world cohort of patients with MPM treated with ipi-nivo survival outcomes were inferior to those reported in the CheckMate-743 and MAPS2 trials, whereas safety outcomes were similar.

  © 2024 The Authors.

• A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma. A. Rimner, P.S. Adusumilli, M.D. Offin, et al. 2023;4(1):100440. PubMed · Publisher · Free full text

  Abstract

  Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma.

  Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT.

  Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2).

  Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

  © 2022 The Authors.

• Extrathoracic Metastases in Pleural Mesothelioma. I. Dagogo-Jack, B.Y. Yeap, M. Mino-Kenudson, et al. 2023;4(9):100557. PubMed · Publisher · Free full text

  Abstract

  Introduction: Guidelines recommend obtaining a computed tomography scan of the chest for the staging of pleural mesothelioma and for assessing response to treatment. Consensus is lacking regarding the necessity of serial imaging of distant extrathoracic sites. In this study, we determined the prevalence of extrathoracic metastases in patients with pleural mesothelioma.

  Methods: We conducted a retrospective review of patients with pleural mesothelioma treated at Massachusetts General Hospital between 1999 and 2022 who were referred for extrathoracic imaging during their disease course. Imaging reports were reviewed to determine sites of metastasis and calculate the time to development of extrathoracic metastasis. Overall survival and prevalence of extrathoracic metastasis were compared for patients with epithelioid versus nonepithelioid mesothelioma.

  Results: The study included 148 patients, 69 (47%) of whom had undergone cytoreductive surgery. Histologic types included epithelioid (n = 82, 55%), biphasic (n = 49, 33%), and sarcomatoid (n = 10, 7%) mesothelioma. The median overall survival for the cohort was 24.0 months, specifically 34.7 months and 16.7 months for patients with epithelioid and nonepithelioid tumors, respectively (p < 0.001). There were 65 (44%) patients who developed extrathoracic metastases, with a median time to extrathoracic metastasis of 11.5 months. The most common sites of involvement were extrathoracic nodes (22%), peritoneum (20%), bone (11%), and liver (11%). Of the 76 patients referred for brain imaging, seven (9%) had brain metastases. The frequency of extrathoracic metastasis was identical for epithelioid and nonepithelioid mesothelioma (44%). Overall survival was shorter for patients who developed extrathoracic metastases (hazard ratio 5.9, p < 0.001).

  Conclusions: Patients with pleural mesothelioma often develop extrathoracic metastases, providing a rationale for routinely obtaining imaging that encompasses sites outside of the thoracic cavity.

  © 2023 The Authors.

• Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299. A.Z. Dudek, M.X. Xi, K.A. Scilla, et al. 2023;4(12):100584. PubMed · Publisher · Free full text

  Abstract

  Introduction: We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of unresectable mesothelioma.

  Methods: This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen. Ramucirumab and nivolumab were given intravenously every 14 days for up to 24 months. The primary end point was ORR; secondary end points were progression-free survival (PFS) rate at 24 weeks and overall survival (OS).

  Results: Between April 2018 and October 2021, 34 patients were recruited. Median age was 72 (range: 40-89) years, 12% were women, and 79% of tumors had epithelial histology. Median follow-up was 10.2 months (interquartile range 19.6 mo [4.3-23.8]). ORR was 22.6% (95% confidence interval [CI]: 9.6%-41.1%) in all population and 43% (95% CI: 10%-82%) in patients with nonepithelioid histology. Of all patients, 45.2% (95% CI: 27.3%-64.0%) had stable disease. PFS rate at 24 weeks was 32% (95% CI: 17%-51%). Median PFS was 4.2 months (95% CI: 1.9-6.4 mo). Median OS was 12.5 months (95% CI: 6.3-23.5 mo). There was no grade greater than or equal to four toxicity. Programmed death-ligand 1 expression in the tumor did not correlate with benefit from treatment. Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS.

  Conclusions: Nivolumab and ramucirumab combination was safe and generated PFS and OS rates and ORR that compare favorably with single-agent nivolumab in a similar patient population. The primary end point of 40% ORR was not reached. Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746.

  © 2023 The Authors.

• A Real-World Analysis of the Use of Systemic Therapy in Malignant Pleural Mesothelioma and the Differential Impacts on Overall Survival by Practice Pattern. K. Kerrigan, Y. Jo, J. Chipman, et al. 2022;3(3):100280. PubMed · Publisher · Free full text

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is an aggressive malignancy that affects older adults with frequent comorbidities, making real-world treatment decisions challenging. This study compares the overall survival (OS) of patients with MPM by physician's choice of first-line (1L) platinum chemotherapy (PC), second-line (2L) immunotherapy versus chemotherapy, and by receipt of maintenance therapy (MT).

  Methods: The study included patients diagnosed with advanced MPM in the Flatiron Health electronic health record-derived database who initiated PC with pemetrexed in the 1L setting between 2011 and 2019. Patients in the 2L therapy analysis received single-agent chemotherapy versus immunotherapy after the progression of disease from our 1L cohort. Patients in the MT cohort were identified on the basis of continued receipt of pemetrexed with or without bevacizumab after dropping PC at prespecified intervals. The OS of patients by choice of 1L PC, 2L immunotherapy versus chemotherapy, and receipt of MT was summarized by means of Kaplan-Meier survival estimates and compared in the context of propensity score matching weighted analyses.

  Results: In propensity score matching weighting analysis from 2065 patients with MPM, there was no evidence of an OS difference by choice of 1L PC (hazard ratio [HR] = 1.08, 95% confidence interval [CI]: 0.89-1.31, p = 0.43), suggestive evidence of an OS difference by choice of 2L immunotherapy versus chemotherapy (HR = 0.68, 95% CI: 0.42-1.08; p = 0.10), and no evidence of an OS difference by receipt of MT (HR = 0.92, 95% CI: 0.72-1.16, p = 0.46).

  Conclusions: Using real-world, propensity score-matched weighted analysis of MPM, we found there was no difference in OS by choice of 1L PC, 2L immunotherapy or chemotherapy, or by receipt of MT.

  © 2022 The Authors.

• Bilateral Pleural Mesothelioma In Situ and Peritoneal Mesothelioma In Situ Associated With BAP1 Germline Mutation: A Case Report. A. MacLean, A. Churg, S.T. Johnson. 2022;3(8):100356. Case report PubMed · Publisher · Free full text

  Abstract

  Mesothelioma in situ is a recently described precursor to invasive mesothelioma. Thus far, all cases in the literature have involved one pleural cavity or the peritoneal cavity. We describe a patient with biopsy-proven mesothelioma in situ involving both pleural cavities and the peritoneal cavity. Genetic analysis results revealed that the patient had a BAP1 germline mutation. This is the first report of mesothelioma in situ involving multiple body cavities and raises a question of whether such patients will all have BAP1 germline mutations.

  © 2022 The Authors.

• Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase. T.A. Szyszko, J.T. Dunn, M.M. Phillips, et al. 2022;3(9):100382. PubMed · Publisher · Free full text

  Abstract

  Introduction: Pegargiminase (ADI-PEG 20I) degrades arginine in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma (MPM) and NSCLC. Imaging with proliferation biomarker 3'-deoxy-3'-[18F] fluorothymidine (18F-FLT) positron emission tomography (PET)-computed tomography (CT) was performed in a phase 1 study of pegargiminase with pemetrexed and cisplatin (ADIPemCis). The aim was to determine whether FLT PET-CT predicts treatment response earlier than CT.

  Methods: A total of 18 patients with thoracic malignancies (10 MPM; eight NSCLC) underwent imaging. FLT PET-CT was performed at baseline (PET1), 24 hours post-pegargiminase monotherapy (PET2), post one cycle of ADIPemCis (PET3), and at end of treatment (EOT, PET4). CT was performed at baseline (CT1) and EOT (CT4). CT4 (modified) Response Evaluation Criteria in Solid Tumors (RECIST) response was compared with treatment response on PET (changes in maximum standardized uptake value [SUVmax] on European Organisation for Research and Treatment of Cancer-based criteria). Categorical responses (progression, partial response, and stable disease) for PET2, PET3, and PET4 were compared against CT using Cohen's kappa.

  Results: ADIPemCis treatment response resulted in 22% mean decrease in size between CT1 and CT4 and 37% mean decrease in SUVmax between PET1 and PET4. PET2 agreed with CT4 response in 62% (8 of 13) of patients (p = 0.043), although decrease in proliferation (SUVmax) did not precede decrease in size (RECIST). Partial responses on FLT PET-CT were detected in 20% (3 of 15) of participants at PET2 and 69% (9 of 13) at PET4 with good agreement between modalities in MPM at EOT.

  Conclusions: Early FLT imaging (PET2) agrees with EOT CT results in nearly two-thirds of patients. Both early and late FLT PET-CT provide evidence of response to ADIPemCis therapy in MPM and NSCLC. We provide first-in-human FLT PET-CT data in MPM, indicating it is comparable with modified RECIST.

  © 2022 The Authors.

• The Predictive and Prognostic Nature of Programmed Death-Ligand 1 in Malignant Pleural Mesothelioma: A Systematic Literature Review. A.S. Mansfield, R.J. Brown, C. Sammon, et al. 2022;3(5):100315. Review PubMed · Publisher · Free full text

  Abstract

  Introduction: Given the emergence of combination of programmed cell death protein-1 and CTLA4 pathway blockade as effective treatment options in malignant pleural mesothelioma (MPM), there is interest in the extent to which programmed death-ligand 1 (PD-L1) expression may be prognostic of clinical outcomes and predictive of response to anti-programmed death (ligand) 1 (PD-[L]1) therapies.

  Methods: MEDLINE and EMBASE electronic databases were searched until November 4, 2020. English-language randomized trials and observational studies that reported clinical outcomes and PD-L1 expression in adult patients (>18 or >20 y) with MPM were included. Forest plots were used to descriptively summarize clinical outcome data across studies.

  Results: A total of 29 publications were identified providing data on the research question. Among the studies in which anti-PD-(L)1 therapies were not specified to have been used, 63% (10 of 16) found patients with tumors expressing PD-L1 (typically >1%) to have poorer survival than those with tumors expressing lower levels of PD-L1. Among the studies in which anti-PD-(L)1 therapies were used, 83% (five of six) did not reveal an association between survival and PD-L1 tumor expression. The single study directly comparing outcomes between those treated and untreated with anti-PD-(L)1 therapies across different PD-L1 cutoffs did not identify any differences between the groups.

  Conclusions: The quality and consistency of the existing evidence base are currently insufficient to draw conclusions regarding a prognostic or predictive role of PD-L1 in MPM. Furthermore, high-quality studies on this topic are required to support the use of PD-L1 as a biomarker in MPM.

  © 2022 The Authors.

• The Role of Real-World Evidence to Support Treatment Choices in Malignant Pleural Mesothelioma. P. Wheatley-Price, S. Moore, C.W. Lee. 2022;3(4):100300. Editorial · Comment PubMed · Publisher · Free full text

• Thrombocytopenia as an Immune-Related Adverse Event in Malignant Pleural Mesothelioma: A Case Report. T. Tanaka, S. Asakura, K. Hisamatsu, et al. 2022;3(7):100351. Case report PubMed · Publisher · Free full text

  Abstract

  A 69-year-old man presented with a pulmonary opacity at a regular medical check-up. He had been exposed to asbestos in a chemical fiber manufacturing setting. Result of positron emission tomography with computed tomography (CT) revealed fluorodeoxyglucose accumulations along the right pleura in areas with multiple nodules and irregular pleural thickening. On the basis of analysis of a CT-guided needle biopsy result, he had been diagnosed with having epithelioid malignant pleural mesothelioma. He received neoadjuvant chemotherapy, and subsequently, a pleurectomy and decortication. After 6 months, malignant pleural mesothelioma recurred with multiple tumors in the pleural cavity. Nivolumab was administered as salvage immunotherapy. A CT scan result revealed marked tumor reduction; however, his platelet count was low (8000/μL), and he was diagnosed with having nivolumab-induced immune thrombocytopenia. Oral prednisone and thrombopoietin receptor agonist were delivered, and the platelet count improved; therefore, a sustained cycle of nivolumab was resumed. This case revealed that nivolumab could be readministered for continued antitumor effects, with careful management of immune-related adverse events.

  © 2022 The Authors.

• Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma. S. Sun, W. Qi, H. Rehrauer, et al. 2022;3(12):100430. PubMed · Publisher · Free full text

  Abstract

  Introduction: The aim of this study was to investigate endogenous retrovirus (ERV) expression and type I interferon (IFN) activation in human pleural mesothelioma (PM) and their association with clinical outcome.

  Methods: The expression of ERV was determined from PM cohorts and mesothelial precursor RNA sequencing data. The expression of ERV was confirmed by quantitative polymerase chain reaction (qPCR). Methylation of genomic DNA was assessed by quantitative methylation-specific PCR. DNA demethylation was induced in cells by demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) treatment. To block type I IFN signaling, the cells were treated with ruxolitinib or MAVS silencing. The expression of IFN-stimulated genes (ISGs) was determined by qPCR and Western blot. Circulating ERVs were detected by qPCR.

  Results: Long terminal repeats (LTRs) represent the most abundant transposable elements up-regulated in PM. Within the LTR, ERVmap_1248 and LTR7Y, which are specifically enriched in PM, were further analyzed. The 5-Aza-CdR treatment increased the levels of ERVmap_1248 expression and induced ERVmap_1248 promoter demethylation in mesothelial cells. In addition, ERVmap_1248 promoter was more demethylated in the mesothelioma tissue compared with nontumor tissue. The 5-Aza-CdR treatment of the mesothelial cells also increased the levels of ISGs. Basal ISG expression was higher in the mesothelioma cells compared with the mesothelial cells, and it was significantly decreased by ruxolitinib treatment or MAVS silencing. Furthermore, ISG expression was higher in the tumor tissue with high expression levels of ERVmap_1248. High expression of ERVmap_1248 was associated with longer overall survival and BAP1 mutations. ERVmap_1248 and LTR7Y can be detected in the PM plasma.

  Conclusions: We provide clues for patient stratification especially for immunotherapy where best clinical responses are associated with an activated basal immune response.

  © 2022 The Authors.

• Clinical Efficacy and Safety of Nivolumab in Japanese Patients With Malignant Pleural Mesothelioma: 3-Year Results of the MERIT Study. N. Fujimoto, M. Okada, T. Kijima, et al. 2021;2(3):100135. PubMed · Publisher · Free full text

  Abstract

  Introduction: We examined the long-term efficacy and safety of nivolumab, a human monoclonal antibody that inhibits interactions between the programmed cell death protein-1 receptor and its ligands (programmed death-ligand 1 and programmed death-ligand 2), in Japanese patients with malignant pleural mesothelioma (MPM).

  Methods: Japanese patients with previously treated MPM (one or two regimens) were enrolled in a single-arm, phase 2 study and received nivolumab intravenously 240 mg every 2 weeks until progressive disease or unacceptable toxicity. The primary end point was the centrally assessed objective response rate. Other end points included overall survival (OS), progression-free survival (PFS), treatment-related adverse events, and patient-reported outcomes (Lung Cancer Symptom Scale for mesothelioma and EuroQOL visual analog scale). Patient enrollment started on June 16, 2016. Here, we report 3-year follow-up data (cutoff date: November 12, 2019).

  Results: Thirty-four patients were enrolled. The centrally assessed objective response rate was previously reported (29.4%). The 2- and 3-year OS rates were 35.3% and 23.5%, respectively, and the corresponding PFS rates were 17.0% and 12.7%. Median OS and PFS were 17.3 and 5.9 months, respectively. Eight patients were alive at 3 years of follow-up. Nivolumab was well tolerated and no new safety signals were found. The patient-reported outcomes were maintained without marked deteriorations during the study.

  Conclusions: Our results reveal clinically relevant long-term efficacy and safety of nivolumab for the treatment of MPM.

  © 2021 The Authors.

• Current Landscape of Immunotherapy Trials Involving the Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Axis in Intrathoracic Tumors. S.A. Kareff, S. Samtani, M. Burotto, et al. 2021;2(4):100149. PubMed · Publisher · Free full text

  Abstract

  Introduction: The clinical successes seen with anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-[L]1) agents have galvanized the field of immuno-oncology. We evaluated the landscape and trends in immunotherapy trials involving the PD-(L)1 axis in intrathoracic tumors.

  Methods: We identified clinical trials involving anti-PD-(L)1 agents on the ClinicalTrials.gov registry through November 13, 2020 for NSCLC, SCLC, mesothelioma, and thymic epithelial tumor. Clinical trials were indexed according to monotherapy versus combination approaches, PD-(L)1 agents under investigation, clinical settings, trial start date, and partner drug(s). We assessed redundancy among the clinical trials.

  Results: We found 686 clinical trials investigating anti-PD-(L)1 agents for intrathoracic tumors (540 trials in NSCLC, 96 in SCLC, 38 in mesothelioma, and 12 in thymic epithelial tumor). A total of 23 PD-(L)1 inhibitors are undergoing clinical development. A total of 81% of trials assess combination treatment. The number of clinical trials has been growing exponentially in the past decade. PD-(L)1 blockade was frequently combined with chemotherapy or immunomodulatory therapy. Various strategies are in development to overcome resistance to PD-(L)1 blockade in metastatic NSCLC. PD-(L)1 blockade is also increasingly evaluated in neoadjuvant and adjuvant settings. After the U.S. Food and Drug Administration's approval of an anti-PD-(L)1 agent for a specific indication, 14 trials were launched thereafter, which continued to randomize patients to treatments that were inferior to the best available therapy.

  Conclusions: The number of clinical trials investigating anti-PD-(L)1 agents in intrathoracic tumors has experienced a steep increase over the past decade with a notable upward trend for combination trials. To reduce duplicative research efforts and accelerate the development of effective immunotherapeutics, improved coordination among key stakeholders and the adoption of innovative trial designs will be vital.

  © 2021 The Authors.

• Early Response to Chemotherapy in Malignant Pleural Mesothelioma Evaluated Using Diffusion-Weighted Magnetic Resonance Imaging: Initial Observations. S. Curcean, L. Cheng, S. Picchia, et al. 2021;2(12):100253. PubMed · Publisher · Free full text

  Abstract

  Introduction: We compared the magnetic resonance imaging total tumor volume (TTV) and median apparent diffusion coefficient (ADC) of malignant pleural mesothelioma (MPM) before and at 4 weeks after chemotherapy, to evaluate whether these are potential early markers of treatment response.

  Methods: Diffusion-weighted magnetic resonance imaging was performed in 23 patients with MPM before and after 4 weeks of chemotherapy. The TTV was measured by semiautomatic segmentation (GrowCut) and transferred onto ADC maps to record the median ADC. Test-retest repeatability of TTV and ADC was evaluated in eight patients. TTV and median ADC changes were compared between responders and nonresponders, defined using modified Response Evaluation Criteria In Solid Tumors on computed tomography (CT) at 12 weeks after treatment. TTV and median ADC were also correlated with CT size measurement and disease survival.

  Results: The test-retest 95% limits of agreement for TTV were -13.9% to 16.2% and for median ADC -1.2% to 3.3%. A significant increase in median ADC in responders was observed at 4 weeks after treatment (p = 0.02). Correlation was found between CT tumor size change at 12 weeks and median ADC changes at 4 weeks post-treatment (r = -0.560, p = 0.006). An increase in median ADC greater than 5.1% at 4 weeks has 100% sensitivity and 90% specificity for responders (area under the curve = 0.933, p < 0.001). There was also moderate correlation between median tumor ADC at baseline and overall survival (r = 0.45, p = 0.03).

  Conclusions: Diffusion-weighted magnetic resonance imaging measurements of TTV and median ADC in MPM have good measurement repeatability. Increase in ADC at 4 weeks post-treatment has the potential to be an early response biomarker.

  © 2021 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.

• Immune Checkpoint Inhibitor Uptake in Real-World Patients With Malignant Pleural Mesothelioma. R.Y. Kim, N. Mitra, S.J. Bagley, et al. 2021;2(6):100188. PubMed · Publisher · Free full text

  Abstract

  Introduction: Since the July 2017 National Comprehensive Cancer Network (NCCN) malignant pleural mesothelioma (MPM) guideline revision recommended second-line immune checkpoint inhibitors (ICIs), studies have suggested a greater response to ICI among patients with nonepithelioid MPM. Nevertheless, little is known regarding adoption of ICI in routine practice and if uptake differs by histologic subtype. Our objectives were to evaluate the real-world uptake of second-line ICI among patients with MPM and to reveal its association with histologic subtype.

  Methods: This was a multicenter, retrospective cohort study of real-world patients with MPM receiving at least two lines of systemic therapy between 2011 and 2019. We found the uptake of second-line ICI over time and evaluated the association between histologic subtype and ICI use, adjusting for relevant patient demographic and clinical factors.

  Results: Among the 426 patients with MPM in our cohort, 310 had epithelioid and 116 nonepithelioid histologic subtype. The median age was 73 years (interquartile range: 67-78). Overall, 144 patients (33.8%) received second-line ICI and 282 (66.2%) traditional chemotherapy. ICI uptake began in early 2015 before the NCCN guideline revision and increased rapidly to 2019. After the 2017 NCCN guideline revision, patients with nonepithelioid MPM histologic subtypes had more than 3 times the odds of receiving second-line ICI (OR = 3.26; 95% confidence interval: 1.41-7.54).

  Conclusions: Among real-world patients with MPM, second-line ICI uptake began over two years before the 2017 NCCN guideline recommendations and was associated with nonepithelioid histologic subtype after contemporary studies suggested increased clinical benefit in this population, reflecting prompt integration of scientific discovery into clinical practice.

  © 2021 The Authors.

• Ki67 (MIB-1) as a Prognostic Marker for Clinical Decision Making Before Extended Pleurectomy Decortication in Malignant Pleural Mesothelioma. R.A. Belderbos, A.P.W.M. Maat, S.J. Baart, et al. 2021;2(4):100155. PubMed · Publisher · Free full text

  Abstract

  Introduction: The role of surgery for early stage malignant pleural mesothelioma (MPM) remains controversial. Current expert opinion is only to treat patients surgically as part of multimodality therapy. It is still challenging to identify patients who will not benefit from surgery. We specifically evaluated tumor-related parameters in combination with clinical parameters to identify prognostic markers for survival.

  Methods: Clinical data of 27 consecutive patients with MPM treated with extended pleurectomy and decortication within a multimodality approach were collected and analyzed. Several tumor (immuno-)histopathologic characteristics were determined on resected tumor material, among which MTAP and Ki67 (MIB-1). Univariable and multivariable analyses served to correlate clinical and tumor-related parameters to overall survival (OS) and progression-free survival (PFS).

  Results: The median PFS (mPFS) was 15.3, and the median OS (mOS) was 26.5 months. Patients with a Ki67 score greater than 10% had a significantly shorter PFS (mPFS = 8.81 versus 25.35 mo, p = 0.001) and OS (mOS 19.7 versus 44.5 mo, p = 0.002) than those with a Ki67 score less than or equal to 10. Receiver operating characteristic curve analysis for Ki67 revealed an area under the curve of 0.756 with a sensitivity of 90% and specificity of 71% for a cutoff of 10% for Ki67. Patients with loss of MTAP had a significantly shorter mPFS (9 versus 21.1 mo, p = 0.014) and mOS (19.7 versus 42.6 mo, p = 0.047) than those without MTAP loss.

  Conclusions: In our study, Ki67 was prognostic for OS and PFS in patients with MPM treated with extended pleurectomy/decortication in a multimodality approach. Determination of Ki67 before surgery combined with specific clinical parameters could assist in clinical decision making by identifying patients, with high Ki67, who are unlikely to benefit from surgery.

  © 2021 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.

• Malignant Peritoneal Mesothelioma With EWSR1-ATF1 Fusion: A Case Report. H. Ke, A.J. Gill, C. McKenzie, et al. 2021;2(11):100236. Case report PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma with EWSR1-ATF1 fusion is a rare malignancy described in young adults without asbestos exposure. To the best of our knowledge, outcomes to local and systemic therapies for this subtype of malignant mesothelioma have not been described. This case report describes the clinical course of a 19-year-old man diagnosed with malignant peritoneal mesothelioma with EWSR1-ATF1 fusion localized to the abdomen. His disease followed an aggressive course and resulted in limited survival (18 mo). There was treatment resistance to several lines of conventional local and systemic treatments for peritoneal mesothelioma and biologically targeted MET inhibition with crizotinib. More research is required in this rare subtype of peritoneal mesothelioma.

  © 2021 The Authors.

• Malignant Pleural Mesothelioma-Does Ki67 Make the Grade?. O.W.J. Prall. 2021;2(5):100170. Editorial PubMed · Publisher · Free full text

• Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene. A. Ghafoor, I. Mian, C. Wagner, et al. 2021;2(10):100231. PubMed · Publisher · Free full text

  Abstract

  Introduction: PARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality.

  Methods: A single-center, nonrandomized, phase 2 trial was conducted, in which patients with refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor.

  Results: A total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n = 4; germline MRE11A, n = 1; somatic BAP1, n = 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval [CI]: 2.7-4.2 mo) and 8.7 months (95% CI: 4.7 mo-not estimable), respectively. The median PFS of germline BAP1 mutants (n = 4) was 2.3 months (95% CI: 1.3-3.6 mo) versus 4.1 months (95% CI: 2.7-5.5 mo) for wild-type (n = 19; p = 0.019). The median OS was 4.6 months (95% CI: 3.1-4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo-not estimable) in no germline mutation (p = 0.0040). Olaparib was safe with no new safety concerns.

  Conclusions: Olaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.

• Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma. K. Nakagawa, T. Kijima, M. Okada, et al. 2021;2(6):100178. PubMed · Publisher · Free full text

  Abstract

  Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study.

  Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest).

  Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab-groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths.

  Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.

  © 2021 The Authors.

• Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms. P.W. Szlosarek, M.M. Phillips, I. Pavlyk, et al. 2020;1(4):100093. PubMed · Publisher · Free full text

  Abstract

  Introduction: Pegargiminase (ADI-PEG 20; ADI) degrades arginine and potentiates pemetrexed (Pem) cytotoxicity in argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). We conducted a phase 1 dose-expansion study at the recommended phase 2 dose of ADI-PEG 20 with Pem and cisplatin (ADIPemCis), to further evaluate arginine-lowering therapy in ASS1-deficient MPM and explore the mechanisms of resistance.

  Methods: A total of 32 patients with ASS1-deficient MPM (11 epithelioid; 10 biphasic;11 sarcomatoid) who were chemonaive received weekly intramuscular pegargiminase (36 mg/m2) with Pem (500 mg/m2) and cisplatin (75 mg/m2) intravenously, every 3 weeks (six cycles maximum). Maintenance pegargiminase was permitted until disease progression or withdrawal. Safety, pharmacodynamics, immunogenicity, and efficacy were determined. Biopsies were performed in progressing patients to explore the mechanisms of resistance to pegargiminase.

  Results: The treatment was well tolerated. Most adverse events were of grade 1/2, whereas four nonhematologic grade 3/4 adverse events related to pegargiminase were reversible. Plasma arginine decreased whereas citrulline increased; this was maintained by 18 weeks of ADIPemCis therapy. The disease control rate in 31 assessed patients was 93.5% (n = 29 of 31; 95% confidence interval [CI]: 78.6%-99.2%), with a partial response rate of 35.5% (n = 11 of 31; 95% CI: 19.2%-54.6%). The median progression-free and overall survivals were 5.6 (95% CI: 4.0-6.0) and 10.1 (95% CI: 6.1-11.1) months, respectively. Progression biopsies on pegargiminase revealed a statistically significant influx of macrophages (n = 6; p = 0.0255) and patchy tumoral ASS1 reexpression (n = 2 of 6). In addition, we observed increased tumoral programmed death-ligand 1-an ADI-PEG 20 inducible gene-and the formation of CD3-positive T lymphocyte aggregates on disease progression (n = 2 of 5).

  Conclusions: The dose expansion of ADIPemCis confirmed the high clinical activity and good tolerability in ASS1-deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (ClinicalTrials.govNCT02709512). Notably, resistance to pegargiminase correlated with marked macrophage recruitment and-along with the tumor immune microenvironment-warrants further study to optimize arginine deprivation for the treatment of mesothelioma.

  © 2020 The Authors.

• Retrospective Evaluation of the Use of Pembrolizumab in Malignant Mesothelioma in a Real-World Australian Population. T. Ahmadzada, W.A. Cooper, M. Holmes, et al. 2020;1(4):100075. PubMed · Publisher · Free full text

  Abstract

  Introduction: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab.

  Method: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples.

  Results: A total of 98 patients were included with a median age of 70 years (range, 46-91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6-6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6-13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate.

  Conclusions: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.

  © 2020 The Authors.

• Veterans Affairs Insurance Disparities for Metastatic Lung Cancer in the Hawaiian Islands. J.Q. Lin, S.Q. Li, T.A. Pezzi, et al. 2020;1(1):100003. PubMed · Publisher · Free full text

  Abstract

  Introduction: The highest concentration of military personnel in the United States is located in Hawaii where occupational exposures, such as to asbestos in the Pacific Fleet shipyards, predispose them to thoracic malignancies. For this reason, Veterans Affairs (VA) insurance outcomes for lung cancer in Hawaii are of interest.

  Methods: All cases of lung cancer in the Hawaii Tumor Registry from 2000 to 2015 were evaluated. The selection criterion included evidence of extensive-stage SCLC (ES-SCLC) or metastatic NSCLC. Overall survival was compared using the Kaplan-Meier log-rank method. Univariate analysis and multivariable analysis (MVA) were carried out to understand the variables associated with overall survival.

  Results: There were 434 cases of ES-SCLC and 2139 cases of metastatic NSCLC identified. VA insurance (median survival [MS], 2 mo), Medicaid (MS, 4 mo), and Medicare (MS, 4 mo) had worse survival (log-rank p < 0.001) than private insurance (MS, 8 mo). In ES-SCLC, VA insurance (hazard ratio [HR], 2.74; 95% confidence interval [CI]: 1.50-5.01; p = 0.001) and Medicaid (HR, 1.46; 95% CI: 1.04-2.03; p = 0.027) had significantly worse survival compared with private insurance on MVA. VA insurance (HR, 1.84; 95% CI: 1.34-2.53; p < 0.001) and Medicaid (HR, 1.40; 95% CI: 1.20-1.63; p < 0.001) also had worse survival compared with private insurance in metastatic NSCLC on MVA.

  Conclusions: VA insurance coverage was associated with dismal survival for metastatic lung cancer that was effectively similar to hospice or supportive care, compelling further investigation to identify reasons for this disparity.

  © 2020 The Authors.

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