Pleural Mesothelioma Patients Research Articles

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients.

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.

VEGFR2 and CD34 expression associated with longer survival in patients with pleural mesothelioma in the IFCT-GFPC-0701 MAPS phase 3 trial

ObjectivesVEGF/VEGFR autocrine loop is a hallmark of pleural mesothelioma (PM). We thus assayed the prognostic and predictive values of VEGFR-2 [vascular endothelial growth factor receptor 2 or Flk-1] and CD34, a marker of endothelial cells, in samples from patients accrued in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456). Materials and MethodsVEGFR2 and CD34 expression were assayed using immunohistochemistry in 333 MAPS patients (74.3%), and their prognostic value was evaluated in terms of overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses, before validation by bootstrap methodology. ResultsPositive VEGFR2 or CD34 staining was observed in 234/333 (70.2%) and 322/323 (99.6%) of tested specimens, respectively. VEGFR2 and CD34 staining correlated weakly, yet significantly, with each other (r = 0.36, p < 0.001). High VEGFR2 expression or high CD34 levels were associated with longer OS in PM patients in multivariate analysis (VEGFR2: adjusted [adj.] hazard ratio [HR]: 0.91, 95% confidence interval [CI] [0.88; 0.95], p < 0.001; CD34: adj. HR: 0.86, 95 %CI [0.76; 0.96], p = 0.010), with only high VEGFR2 expression resulting in significantly longer PFS (VEGFR2: adj. HR: 0.96, 95 %CI [0.92; 0.996], p = 0.032). Stability of these results was confirmed using bootstrap procedure. Nevertheless, VEGFR2 expression failed to specifically predict longer survival in bevacizumab-chemotherapy combination trial arm, regardless of whether the VEGFR2 score was combined or not with serum VEGF concentrations. ConclusionVEGFR2 overexpression independently correlated with longer OS or PFS in PM patients, such biomarker deserving prospective evaluation as stratification variable in future clinical trials.

Circulating FGF18 is decreased in pleural mesothelioma but not correlated with disease prognosis.

Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker. FGF18 mRNA expression was analyzed by real-time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters. FGF18 showed high mRNA expression in PM and PM-derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed. FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation.

Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) for patients with pleural metastases from thymic malignancies.

TPS8616 Background: Pleural metastases are common sites for recurrence and progression in patients with thymic malignancies. The management of pleural metastases typically involves surgical resection with or without neoadjuvant or adjuvant systemic therapy. After surgical resection of pleural metastases, the 5-year progression-free survival (PFS) rate is about 29-45%. While radiation therapy (RT) is standardly used in the management of locally-advanced thymic malignancies, the role of RT in patients with pleural metastases in unclear. Intensity-modulated pleural radiation therapy (IMPRINT) is a RT technique currently being used to treat malignant pleural mesothelioma (MPM) patients with 2 intact lungs at centers that specialize in MPM treatment. This IMPRINT technique can potentially be extrapolated to thymic patients with pleural metastases. Because the risk of toxicity is of greater concern for thymic patients given their overall relatively favorable prognosis, the rate of toxicity, particularly radiation pneumonitis, needs to be established in the thymic patient population. Methods: This is a single-arm, single institution Phase II study of hemithoracic IMPRINT for patients with pleural metastases from thymic malignancies. The primary endpoint of this study is grade 3 or higher radiation pneumonitis within 4 months of completing RT. Secondary endpoints include any toxicity, progression-free survival, patterns of failure and overall survival. Patients must have a pathologically confirmed diagnosis of a thymic malignancy with radiologic or pathologic evidence of pleural metastases. Thymoma or thymic carcinoma are allowed. Patients may have de novo stage IVA disease or recurrent disease in the pleura. There must be no evidence of extrathoracic metastatic disease or contralateral pleural/pericardial disease. Surgical resection of the pleural nodules (ex: pleurectomy/decortication, debulking/metastasectomy) are allowed. Extrapleural pneumonectomy is not allowed. Patients are excluded if they have undergone prior thoracic radiation therapy preventing hemithoracic pleural IMRT, whereas prior thymic bed radiation and/or prior pleural SBRT are allowed. RT will be administered to the ipsilateral pleura to 50.4 Gy in 28 fractions. An optional dose-painting boost to gross disease up to 60 Gy while respecting normal tissue constraints is allowed. Patients can be treated with photon or proton therapy. Simulation, contouring and RT planning guidelines have been developed. Patients will be followed per protocol at regular intervals for at least 12 months following RT. The expected accrual is 36 patients over 4 years. Further information can be found on clinicaltrials.gov (NCT05354570). Clinical trial information: NCT05354570 .

High density and proximity of CD8+ T cells to tumor cells are correlated with better response to nivolumab treatment in metastatic pleural mesothelioma.

The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer. A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD-L1 positive cells, cell density, and cell-to-cell distance were analyzed by multiplex immunofluorescence. PD-L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group. High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma.

Epigenetic investigation into circulating microRNA 197-3p in sera from patients affected by malignant pleural mesothelioma and workers ex-exposed to asbestos

The epigenetic role of microRNAs is established at both physiological and pathological levels. Dysregulated miRNAs and their targets appear to be a promising approach for innovative anticancer therapies. In our previous study, circulating miR-197-3p tested dysregulated in workers ex-exposed to asbestos (WEA). Herein, an epigenetic investigation on this circulating miRNA was carried out in sera from malignant pleural mesothelioma (MPM) patients. MiR-197-3p was quantified in MPM (n = 75) sera and comparatively analyzed to WEA (n = 75) and healthy subject (n = 75) sera, using ddPCR and RT-qPCR techniques. Clinicopathological characteristics, occupational, non-occupational information and overall survival (OS) were evaluated in correlation studies. MiR-197-3p levels, analyzed by ddPCR, were significantly higher in MPM than in WEA cohort, with a mean copies/µl of 981.7 and 525.01, respectively. Consistently, RT-qPCR showed higher miR-197-3p levels in sera from MPM with a mean copies/µl of 603.7, compared to WEA with 336.1 copies/µl. OS data were significantly associated with histologic subtype and pleurectomy. Circulating miR-197-3p is proposed as a new potential biomarker for an early diagnosis of the MPM onset. Indeed, miR-197-3p epigenetic investigations along with chest X-ray, computed tomography scan and spirometry could provide relevant information useful to reach an early and effective diagnosis for MPM.

Establishment and validation of nomograms to predict survival probability of advanced malignant pleural mesothelioma based on the SEER database and a Chinese medical institution.

The purpose of this study was to build nomograms for predicting the survival of individual advanced pleural mesothelioma (MPM) patients using the Surveillance, Epidemiology, and End Results (SEER) database. The 1251 patients enrolled from the SEER database were randomized (in a 7:3 ratio) to a training cohort and an internal validation cohort. Eighty patients were enrolled from the Harbin Medical University Cancer Hospital as the external validation cohort. Nomograms were constructed from variables screened by univariate or multivariate Cox regression analyses and evaluated by consistency indices (C-index), calibration plots, and receiver operating characteristic (ROC) curves. Patients from the SEER database who received chemotherapy alone and chemoradiotherapy were statistically paired using propensity score matching of the two groups and performed subgroup analysis in the screened variables. The nomograms are well-structured and well-validated prognostic maps constructed from four variables: gender, histology, AJCC stage, and treatment. All individuals were allocated into high-risk versus low-risk groups based on the median risk score of the training cohort, with the high-risk group having worse OS and CSS in all three cohorts (P<0.05). The outcomes of the subgroup analysis indicated that the advanced MPM patients receiving chemotherapy with or without local radiotherapy do not affect OS or CSS. The accurate nomograms to predict the survival of patients with advanced MPM were built and validated based on an analysis of the SEER database with an external validation cohort. The study suggests that the additional local radiotherapy to chemotherapy does not increase the survival benefit of patients.

Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli-Responsive Nanocages.

Platinum-based chemotherapy is the first-line treatment for different cancer types, and in particular, for malignant pleural mesothelioma patients (a tumor histotype with urgent medical needs). Herein, a strategy is presented to stabilize, transport, and intracellularly release a platinumIV (PtIV ) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as an anticancer drug, is promoted by the presence of glutathione in neoplastic cells that also causes the destruction of the carrier. The nanocage presents a single internal cavity in which the hydrophobic complex (Pt(dach)Cl2 (OH)2 ), (dach = R,R-diaminocyclohexane) is encapsulated. The in vitro uptake and the internalization kinetics in cancer model cells are evaluated and, using flow cytometry analysis, the successful release and activation of the Pt-based drug inside cancer cells are demonstrated. The in vitro findings are confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patient-derived malignant pleural mesothelioma. MPM487 confirms the well-known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth is observed when mice are treated with the PtIV , entrapped in the nanocages, at an equivalent dose of the platinum complex.

Second Primary Cancers in a Population-Based Mesothelioma Registry.

The presence of a second primary cancer (SPC) in patients with pleural mesothelioma (PM) may impact overall survival and suggest a common mechanism of carcinogenesis or an underlying germline genetic alteration. We evaluated the occurrence of SPCs within PM cases collected from 2000 to 2018 by the Lombardy Mesothelioma Registry and their prognostic implications. Kaplan-Meier analysis was performed to estimate median survival times, together with univariate and multivariate Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) of death. The median overall survival (OS) of the entire study population (N = 6646) was 10.9 months (95% CI: 10.4-11.2); patient age and histotype were the strongest prognostic factors. No substantial survival difference was observed by the presence of an SPC (10.5 months in 1000 patients with an SPC vs. 10.9 months in 5646 patients in the non-SPC group, HR 1.03, p = 0.40). Shorter OS in the SPC group was only observed in 150 patients with the non-epithelioid subtype (median OS of 5.4 vs. 7.1 months, HR 1.21, p = 0.03). The diagnosis of an SPC did not influence the outcome of PM patients in the overall study population but was associated with shorter OS in non-epithelioid cases. Further studies are needed to clarify the role of SPCs as markers of genetic susceptibility in mesothelioma.

Platin desensitizations in thoracic malignancies and risk factors for breakthrough reactions.

Although platin desensitization is a safe and effective alternative for patients with hypersensitivity reactions (HSRs), sometimes breakthrough reactions (BTRs) can be encountered. However, data about the risk factors for BTRs are limited. The aim of this study is to define the outcomes of desensitization, the characteristics of BTRs, and to identify the risk factors for BTRs with platins in thoracic malignancies. This is a retrospective report of patients with thoracic malignancies who underwent platin desensitization. Patients' demographics, initial HSR characteristics, skin test results, desensitization outcomes, and BTR characteristics were recorded. Thirty-three lung cancer and 14 malignant pleural mesothelioma (MPM) patients were included in the study. The culprit drug was cisplatin in 29 and was carboplatin in 18 patients. Skin test positivity was 43.5% with cisplatin, 50% with carboplatin, and it was found to be higher if the interval between the initial HSR and skin testing (ST) was ˃20 days (p = 0.027). One hundred and five desensitization courses were performed. Twenty-two patients had 33 BTRs. Skin test positivity was higher in the BTR-positive group (p = 0.025). BTRs (18.2%; n = 6) were more severe than initial HSR. In the case of epinephrine administration during initial HSR, epinephrine administration during the first BTR was found to be more (p = 0.036). The target dose was achieved in 92.4% of desensitization courses. The number of previous platin infusions ≥10 was found to be an independent risk factor for BTR development (p = 0.036 OR:17.641, 95% CI: 1.211-256.971). Identification of risk factors for BTR will guide appropriate management and desensitization approaches for platin HSRs.

YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations.

The Hippo signalling pathway is dysregulated across a wide range of cancer types and, although driver mutations that directly affect the core Hippo components are rare, a handful is found within pleural mesothelioma (PM). PM is a deadly disease of the lining of the lung caused by asbestos exposure. By pooling the largest-scale clinical datasets publicly available, we here interrogate associations between the most prevalent driver mutations within PM and Hippo pathway disruption in patients, while assessing correlations with a variety of clinical markers. This analysis reveals a consistent worse outcome in patients exhibiting transcriptional markers of YAP/TAZ activation, pointing to the potential of leveraging Hippo pathway transcriptional activation status as a metric by which patients may be meaningfully stratified. Preclinical models recapitulating disease are transformative in order to develop new therapeutic strategies. We here establish an isogenic cell-line model of PM, which represents the most frequently mutated genes and which faithfully recapitulates the molecular features of clinical PM. This preclinical model is developed to probe the molecular basis by which the Hippo pathway and key driver mutations affect cancer initiation and progression. Implementing this approach, we reveal the role of NF2 as a mechanosensory component of the Hippo pathway in mesothelial cells. Cellular NF2 loss upon physiological stiffnesses analogous to the tumour niche drive YAP/TAZ-dependent anchorage-independent growth. Consequently, the development and characterisation of this cellular model provide a unique resource to obtain molecular insights into the disease and progress new drug discovery programs together with future stratification of PM patients.

Alvopem® (pemetrexed) safety assessment in patients with non-small cell lung cancer or malignant pleural mesothelioma: a post-marketing surveillance

BackgroundLung cancer is the leading cause of cancer deaths worldwide in both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority (~ 85%) of lung cancers. This post-marketing surveillance (PMS) study aimed to evaluate the safety of Pemetrexed (Alvopem®, NanoAlvand, Iran) in Iranian patients with lung cancer or mesothelioma.MethodsThe present study is an observational, single-center, open-label, and post-authorization study. All eligible non-squamous NSCLC and malignant pleural mesothelioma (MPM) patients who received pemetrexed based on the physicians’ decision, were enrolled.ResultsA total of 199 patients with non-squamous NSCLC [186 patients (93.47%) or MPM (12 patients (6.03%)] were enrolled from March 2016 to February 2020. The most common reported adverse event (AE) was anemia (89.39%), followed by neutropenia (28.79%) and leukopenia (24.75%). The most important grade 3 AEs were anemia and neutropenia, with the incidence rate of 3.54% and 7.58%, respectively. No grade 4 AEs were reported. Moreover, the results of our study showed negative statistically significant correlations between patients’ age and mean neutrophil count (r = − 0.17; P = 0.0156) and hemoglobin (r = − 0.16; P = 0.0201) in all six visits.ConclusionsThe results of this open-label, observational PMS showed that Pemetrexed (Alvopem®) is safe in patients with non-squamous NSCLC patients receiving pemetrexed-containing regimens.Trial registration: The trial was registered at ClinicalTrials.gov (NCT04843007) in April 13th, 2021.

The Predictive Value of ERCC1, RRM1, and Thymidylate Synthase in Advanced Malignant Pleural Mesothelioma Patients Treated with Platinum-Based Chemotherapy.

A rare yet severe neoplasia called malignant pleural mesothelioma (MPM) typically manifests itself in advanced stages. Despite some improvements in the treatment of patients with MPM, this malignancy continues to have a detrimental prognosis . The primary goal of the present study was to assess the associatin between ERCC1, RRM1, and thymidylate synthase (TS) expression and disease outcome in patients with malignant pleural mesothelioma (MPM) treated with either pemetrexed plus cisplatin or gemcitabine plus cisplatin. This prospective cohort study was done on ninety-one advanced MPM patients. The patients received either pemetrexed plus platinum (55 of 91) or gemcitabine plus platinum chemotherapy (36 of 91). Tissue biopsy was taken at time of diagnosis. Immunohistochemistry was used to assess the levels of ERCC1, RRM1, and TS transcription in tissue biopsies (paraffin embedded). Based on the findings, 70% of patients with low expression of TS had low expression of ERCC1, and 68% of patients with high expression of TS had high expression of ERCC1, suggesting a significat association between ERCC1 expression and TS expression (p=0.005). However, there was no relation between ERCC1 and RRM1 expression patterns (p= 0.296). In patients underwen platinum-based theraphy (n 91), a significant correlation was detected between low ERCC1 median High-scoring and longer progression time (TTP;9.6 v 5.3 months;P< .001) or overall survival (OS) (OS;18.1 v 9.1 months; P<0.001). A significant correlation was found between low TS protein expression and longer time progression (TTP; 11.8 v 5.4 months; P< .001) or OS (OS; 19.8 v 8.5 months; P <0.001) in patients undergoing pemetrexed plus platinum chemotherapy (n 55). Low RRM1 expression was accompanied by high progression free survival (TTP; 10.6 v 3.8 months) and OS (OS; 20.6 v 8.6 months) in patients receiving gemcitabine plus platinum chemotherapy. Based on the multivariate test results, the independent variables significantly affecting OS were tumor stage (HR: 2.3; 95% CI: 1.1-4.9; p= 0.021) and ERCC1 (HR: 2.7; 95% CI: 1.7-4.3; p < 0.001). Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

Patient-Level Omics Data Analysis Identifies Gene-Specific Survival Associations for a PD-1/PD-L1 Network in Pleural Mesothelioma

Immune checkpoint blockade targeting PDCD1 (PD-1) or CD274 (PD-L1) has demonstrated efficacy and interest across multiple cancers. However, the exact determinants of the response and cancer-specific molecular features remain unclear. A recent pan-cancer study identified a PDCD1/CD274-related immunotherapy network of 40 genes that had differential patient survival associations across multiple cancers. However, the survival relevance of this network in mesothelioma could not be assessed due to a lack of available survival data for the mesothelioma study included. Mesothelioma, a rare cancer that most commonly arises in the pleural membranes around the lung, does have immune checkpoint blockade as an approved treatment strategy, yet questions over its efficacy remain. RNA-seq data from 87 pleural mesothelioma patients were interrogated on cBioPortal to assess the role of the PDCD1/CD274 network identified in a previous study, in addition to identifying repurposed drugs that may have therapeutic efficacy. Extensive literature searches were conducted to identify known information from the literature around the genes shown to impact patient survival (CCR5, GATD3A/GATD3, CXCR6, GZMA, and TBC1D10C). The same literature validation was performed for putative repurposed drugs that were identified as potential immunotherapeutic adjuvants in the context of mesothelioma (disulfiram, terfenadine, maraviroc, clioquinol, chloroxine, and oxyphenbutazone). Only disulfiram returned a specifically focused research article based on the literature search. This article demonstrated cytotoxicity in a panel of five human MPM cell lines of mixed histology (epithelioid, biphasic, and sarcomatoid). There was little information on the remaining five drugs, yet the clear preclinical efficacy of disulfiram validates the methodology used herein and prompts further exploration of the remaining drugs in mesothelioma. This study ultimately sheds light on novel preclinical information of genes related to PDCD1/CD274 in mesothelioma, as well as identifying putative drugs that may have therapeutic efficacy either independently or as an immunotherapeutic adjuvant.

The Rocky Road from Preclinical Findings to Successful Targeted Therapy in Pleural Mesothelioma.

Pleural mesothelioma (PM) is a rare and aggressive disease that arises from the mesothelial cells lining the pleural cavity. Approximately 80% of PM patients have a history of asbestos exposure. The long latency period of 20-40 years from the time of asbestos exposure to diagnosis, suggests that multiple somatic genetic alterations are required for the tumorigenesis of PM. The genomic landscape of PM has been characterized by inter- and intratumor heterogeneity associated with the impairment of tumor suppressor genes such as CDKN2A, NF2, and BAP1. Current systemic therapies have shown only limited efficacy, and none is approved for patients with relapsed PM. Advances in understanding of the molecular landscape of PM has facilitated several biomarker-driven clinical trials but so far, no predictive biomarkers for targeted therapies are in clinical use. Recent advances in the PM genetics have provided optimism for successful molecular strategies in the future. Here, we summarize the molecular mechanism underlying PM pathogenesis and review potential therapeutic targets.

Comparison of Survival by Multimodal Treatment Regimen Among Malignant Pleural Mesothelioma Patients in an Integrated Health System

BackgroundOptimal therapy for malignant pleural mesothelioma (MPM) remains unclear. We compared overall survival in patients with MPM after various multimodal treatment regimens including combinations of immunotherapy, chemotherapy, and surgery. Patients and MethodsWe examined MPM patients treated within our integrated health system from January 1, 2009 to December 31, 2020. Patients were grouped based on treatment regimen: chemotherapy alone (CT), immunotherapy with or without chemotherapy (iCT), surgery with chemotherapy (sCT), and surgery with immunotherapy and chemotherapy (siCT). We analyzed baseline characteristics and overall patient survival among these groups and several subgroups. ResultsOne hundred seventy-nine patients were included. Among the study groups, there was no difference in age, sex, race/ethnicity, Charlson Comorbidity Index, or Eastern Cooperative Oncology Group performance status. Patients treated with CT (N = 109), iCT (N = 35), sCT (N = 26), and siCT (N = 9) had median (95% confidence interval) survivals of 11.7 (9.9-16.3), 18.2 (14.5-29.8), 20.7 (11.6-37.2), and 22.6 (19.7-37.8) months, respectively (P < .001). Median survival among patients with and without immunotherapy was 19.7 (17.4-29.8) and 12.3 (10.6-17.3) months, respectively (P = .023). Median survival among patients with and without surgery was 21.7 (17.6-34.8) and 13.6 (11.5-17.3) months, respectively (P = .007). Patients with biphasic/sarcomatoid subtypes who received immunotherapy experienced 76.2% (55.8%-100.0%) 12 month survival vs. 13.6% (4.8%-39.0%) among those who did not (P < .001). ConclusionMPM patients receiving surgery and immunotherapy as part of multimodal treatment regimens experienced the longest survival. Surgery and immunotherapy are each associated with survival. Further investigations are warranted to assess the benefit of immunotherapy within multimodal treatment regimens for MPM.

1632P Analysis of penpulimab plus anlotinib in pleural mesothelioma or thymic carcinoma patients who have received at least one line of chemotherapy

Pleural mesothelioma and thymic carcinoma have low morbidity and few treatment options available. Penpulimab is an IgG1 PD-1 antibody, which features point mutations in the antibody Fc region to eliminate all Fc gamma receptor binding and associated effector function. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit，Preclinical research has confirmed that penpulimab and anlotinib can significantly reduce the proportion of TIM3+PD1+CD8+ T cells，improving anti-tumor efficacy. This study aimed to evaluate the efficacy and safety of anlotinib in combination with penpulimab in patients with pleural mesothelioma or thymic carcinoma who have received at least one line of chemotherapy. This study is a single-arm phase II study. Eligible patients had recurrent/metastatic pleural mesothelioma and thymic carcinoma who were inoperable or intolerant to radical radiotherapy and had failed at least first-line chemotherapy, were over 18 years old, with ECOG PS of 0-1. The primary endpoint was ORR, and secondary endpoints were DCR, PFS, DOR, OS and safety. Patients received anlotinib (12mg QD from day 1 to 14 of a 21-day cycle) plus penpulimab (200mg Q3W) until disease progression or intolerance. Between Nov 13, 2020, and May 12,2021, 12 patients were enrolled and treated, including 5 cases of thymic carcinoma and 7 cases of pleural mesothelioma. The data cutoff date was on Apr 19, 2022. There were 10 males and 2 females. All patients had ECOG PS of 1. Four patients received only one prior line of chemotherapy. 11 patients were available for tumor assessment, ORR was 18.2%, and DCR was 81.8%. The data on PFS and OS were not mature. The common TEAE were hypoalbuminemia (75%), hypertension (75%), anemia (75%), and hypertriglyceridemia(62.5%). The incidence of grade 3 or higher treatment-related AEs was 62.5%, and there was one immune-related AE of grade 3 or higher which was hypocalcemia. Penpulimab plus annlotinib demonstrated preliminary antitumor efficacy and acceptable toxicity in pleural mesothelioma or thymic carcinoma patients who have received at least one line of chemotherapy.

EP07.01-022 Analysis of Second Surgery for Recurrence in Malignant Pleural Mesothelioma (MPM) Patients (P)

MPM is a highly aggressive pleural tumor associated with asbestos exposure and with limited survival despite systemic therapy. Recently immunotherapy have demonstrated survival benefit in first line. Currently there is no universally accepted surgical therapy for MPM and it remains unclear whether cytoreductive surgery prolongs survival. Some reports on selected patients demonstrated that, at the progressive disease, second round surgery is an effective strategy with minimal morbidity and promising survival rates.

EP07.01-004 Long Survivor Epithelioid Pleural Mesotheliomas Are Characterized by Tertiary Lymphoid Structures: An Update to the MATCH Study

In a previous poster presentation at the EACR 2021 (poster n. EACR21v0229), we presented transcriptomic data showing that long survivor epithelioids pleural mesothelioma (PM) patients had a higher B lymphocytes fraction in comparison to shorter survivors. Here we present an update focusing on long survivors in this study.