Metastatic Malignant Pleural Mesothelioma Research Articles

PD-L1 expression complements CALGB prognostic scoring system in malignant pleural mesothelioma.

Programmed death ligand-1 (PD-L1) expression is a predictive biomarker in patients with lung cancer, but its role in malignant pleural mesothelioma (MPM) remains unclear. Evidence suggests that higher PD-L1 expression is correlated with worse survival. CALGB is the main scoring system used to predict the benefit of chemotherapy treatment. This study aimed to determine the prognostic value of PD-L1 expression and its addition to CALGB scoring system in patients with MPM. In this retrospective analysis, we evaluated samples with confirmed locally advanced or metastatic MPM. PD-L1 Tumor Proportional Score (TPS) was determined by immunohistochemistry at diagnosis. 73 patients were included in this study. A cutoff value of 15 was set for a high or low PD-L1 TPS. In total, 71.2% (n=52) and 28.8% (n=21) of individuals harbored low or high PD-L1 expression, respectively. PD-L1High was associated with worse median progression-free Survival (mPFS) [4.9 vs. 10.8 months; HR 2.724, 95% CI (1.44-5.14); p = 0.002] and Overall Survival (OS) [6.0 vs. 20.9 months; HR 6.87, 95% CI (3.4-8.7); p<0.001] compared to patients with PD-L1Low. Multivariate analysis confirmed that PD-L1 expression was an independent factor for PFS and OS in patients with MPM and CALGB score of 5-6. PD-L1 addition to CALGB scale improves its prognostic estimation of MPM survival and should be considered in future research.

Transvertebral Cryoablation of a Paraesophageal Mass in a Patient with Metastatic Malignant Pleural Mesothelioma

Transvertebral Cryoablation of a Paraesophageal Mass in a Patient with Metastatic Malignant Pleural Mesothelioma

S2077 Metastatic Malignant Pleural Mesothelioma Presenting as Sigmoid Polyps

S2077 Metastatic Malignant Pleural Mesothelioma Presenting as Sigmoid Polyps

Cost-effectiveness of nivolumab plus ipilimumab as first-line treatment for American patients with unresectable malignant pleural mesothelioma.

BackgroundThe treatment paradigm of unresectable malignant pleural mesothelioma (MPM) has changed in recent years. Checkmate 743 demonstrate that nivolumab plus ipilimumab showed good clinical benefits compared with chemotherapy in the treatment of MPM. The study is aim to evaluate the cost-effectiveness of Nivolumab plus ipilimumab vs. platinum plus chemotherapy for the first-line treatment of unresectable MPM.MethodsA Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of nivolumab plus ipilimumab and chemotherapy over a 10-year time horizon. Clinical efficacy and safety data were extracted from the CheckMate 743 trials. Health state utilities were obtained from published literature. Costs were collected from an US payer perspective. One-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness's results.ResultsIn the base case analysis, the incremental healthcare costs and QALYs for Nivolumab plus Ipilimumab vs. chemotherapy are $196,604.22 and 0.53, respectively, resulting an incremental cost-effectiveness ratio (ICER) of $372,414.28/QALYs for the model cohort of patients with locally advanced or metastatic MPM. However, Probabilistic sensitivity analysis showed that there was no probability that Nivolumab plus ipilimumab was cost-effective within the fluctuation range of other model parameters in first-line in unresectable MPM. The results of one-way sensitivity analysis showed that the cost of Nivolumab was the most sensitive parameter.ConclusionsThe ICER of Nivolumab plus ipilimumab is above the theoretical willingness-to-pay threshold in the U.S, which suggests that first-line nivolumab plus ipilimumab for unresectable MPM may be not a cost-effective choice.

Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models

ObjectivesTumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields with antimitotic effects on cancerous cells. TTFields concomitant with pemetrexed and a platinum agent are approved in the US and EU as first line therapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma (MPM). The goal of the current study was to characterize the mechanism of action of TTFields in MPM cell lines and animal models. MethodsHuman MPM cell lines MSTO-211H and NCI-H2052 were treated with TTFields to determine the frequency that elicits maximal cytotoxicity. The effect of TTFields on DNA damage and repair, and the cytotoxic effect of TTFields in combination with cisplatin and/or pemetrexed were examined. Efficacy of TTFields concomitant with cisplatin and pemetrexed was evaluated in orthotopic IL-45 and subcutaneous RN5 murine models. ResultsTTFields at a frequency of 150 kHz demonstrated the highest cytotoxicity to MPM cells. Application of 150 kHz TTFields resulted in increased formation of DNA double strand breaks, elevated expression of DNA damage induced cell cycle arrest proteins, and reduced expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins. Co-treatment of TTFields with cisplatin or pemetrexed significantly increased treatment efficacy versus each modality alone, with additivity and synergy exhibited by the TTFields-pemetrexed and TTFields-cisplatin combinations, respectively. In animal models, tumor volume was significantly lower for the TTFields-cisplatin-pemetrexed combination compared to control, accompanied by increased DNA damage within the tumor. ConclusionThis research demonstrated that the efficacy of TTFields for the treatment of MPM is associated with reduced expression of FA-BRCA pathway proteins and increased DNA damage. This mechanism of action is consistent with the observed synergism for TTFields-cisplatin vs additivity for TTFields-pemetrexed, as cisplatin-induced DNA damage is repaired via the FA-BRCA pathway.

RRM1 and ERCC1 as biomarkers in patients with locally advanced and metastatic malignant pleural mesothelioma treated with continuous infusion of low-dose gemcitabine plus cisplatin

BackgroundMalignant Pleural Mesothelioma (MPM) is a rare but aggressive neoplasia that usually presents at advanced stages. Even though some advances have been achieved in the management of patients with MPM, this malignancy continuous to impose a deleterious prognosis for affected patients (12–18 months as median survival, and 5–10% 5-year survival rate), accordingly, the recognition of biomarkers that allow us to select the most appropriate therapy are necessary.MethodsImmunohistochemistry semi-quantitative analysis was performed to evaluate four different biomarkers (ERCC1, RRM1, RRM2, and hENT-1) with the intent to explore if any of them was useful to predict response to treatment with continuous infusion gemcitabine plus cisplatin. Tissue biopsies from patients with locally advanced or metastatic MPM were analyzed to quantitatively asses the aforementioned biomarkers. Every included patient received treatment with low-dose gemcitabine (250 mg/m2) in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks as first-line therapy.ResultsFrom the 70 eligible patients, the mean and standard deviation (SD) for ERCC1, RRM1, RRM2 and hENT-1 were 286,178.3 (± 219, 019.8); 104,647.1 (± 65, 773.4); 4536.5 (± 5, 521.3); and 2458.7 (± 4, 983.4), respectively. Patients with high expression of RRM1 had an increased median PFS compared with those with lower expression (9.5 vs 4.8 months, p = < 0.001). Furthermore, high expression of RRM1 and ERCC1 were associated with an increased median OS compared with their lower expression counterparts; [(23.1 vs 7.2 months for RRM1 p = < 0.001) and (17.4 vs 9.8 months for ERCC1 p = 0.018)].ConclusionsERCC1 and RRM1 are useful biomarkers that predict better survival outcomes in patients with advanced MPM treated with continuous infusion of gemcitabine plus cisplatin.

Abstract 1051: Targeting replication stress pathway provides an avenue for novel combination therapy options including TTfields plus chemo agents which increase replication stress

Abstract Tumor Treating Fields (TTFields) is a new physical therapeutic modality, which has been FDA approved for the treatment of recurrent glioblastoma (GBM) as monotherapy, for newly diagnosed GBM in combination with temozolomide, and for unresectable locally advanced or metastatic malignant pleural mesothelioma (MPM) in combination with pemetrexed and a platinum-based chemotherapy. Clinical trials are ongoing for other cancers, including lung, pancreatic, and ovarian cancers. TTFields are low-intensity, intermediate frequency, alternating electric fields which are loco-regionally applied to tumor sites using non-invasive arrays. The initial mechanism by which TTFields was thought to kill tumor cells was the disruption of mitosis. Using gene expression analysis and functional characterization studies, we discovered a novel role of TTFields in DNA damage repair and replication stress pathways. TTFields treatment decreases Fanconi Anemia (FA) pathway signaling proteins thereby impairs ionizing radiation (IR)-induced DNA damage repair processes. The length of newly replicated DNA slowed as a function of TTFields exposure time and that TTFields increased R-loop formation, which indicates that TTFields induced replication stress. Hence, we hypothesized TTFields increase sensitivity of chemotherapy agents that target and increase replication stress in novel combination therapy options. PARP1 protects DNA breaks, by recruiting DNA repair and checkpoint proteins to the sites of damage and recruiting MRE11 for DNA end processing (required for replication restart and enhanced Chk1 activation). Indeed, TTFields treatment concomitant with the PARP1 inhibitor olaparib followed by IR was found to be synergistic compared to IR or olaparib alone or in combination. However, the degree of sensitization and synergy varied across non-small cell lung cancer cell lines. TTFields increased cell killing efficacy of etoposide synergistically, which forms a ternary complex with topoisomerase II and prevents re-ligation of DNA strands to elicit DNA strand breaks and induce replication stress. The advantage of combining TTFields with AZD6738 (an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor) was tested. ATR is an essential kinase regulator of the replication checkpoint that plays a critical role in safeguarding genome integrity from replication stress. Another novel combination of TTFields together with irinotecan, which traps topoisomerase I- DNA in ternary cleavage complex and inhibits initial cleavage reaction and re-ligation steps to increase replication stress, is also tested. Taken together, our results suggest that different chemo agents that target replication stress pathways can be used in combination with TTFields for cancer therapy, which need to be tested in in-vivo studies and clinical trials. Citation Format: Narasimha Kumar Karanam, Michael Dean Story. Targeting replication stress pathway provides an avenue for novel combination therapy options including TTfields plus chemo agents which increase replication stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1051.

Cellular cannibalism and consequent thrombocytopenia in a patient with bone marrow metastasis of malignant pleural mesothelioma: A case report.

Cellular cannibalism is a tumor activity where a cell is engulfed by another cell. This process promotes tumor cell survival under unfavorable conditions. The current report describes an extremely rare case of thrombocytopenia resulting from cellular cannibalism in a patient with bone marrow metastasis due to malignant pleural mesothelioma (MPM). A 77-year-old male presented with hemothorax and thrombocytopenia. He was diagnosed with MPM of the sarcomatoid cell type. However, his disease progressed rapidly and he died 11 days after admission. Bone marrow aspiration revealed metastatic MPM cells that had engulfed other blood cells. Accordingly, the observed thrombocytopenia was attributed to cellular cannibalism by metastatic MPM tumor cells. To the best of our knowledge, this is the first reported case of thrombocytopenia due to cellular cannibalism in a patient with this type of malignancy (MPM). The results suggested that although MPM rarely metastasizes to the bone marrow, bone marrow aspiration could be useful in such cases.

Abstract 559: Proteomic analysis of lung cancer cells exposed to tumor treating fields identified the dysregulation of the E2F-Rb-CDK4/6 axis rendering tumor cells susceptible to novel combination therapies that target CDK4/6 and/or E2F

Abstract TTFields is a novel non-invasive physical modality of cancer therapy now approved for recurrent and newly diagnosed glioblastoma multiforme (GBM) in combination with temozolomide, and unresectable locally advanced or metastatic malignant pleural mesothelioma (MPM) in combination with platinum based chemotherapy. Clinical trials are ongoing for other cancers, including lung, pancreatic, and ovarian cancers. TTFields are low-intensity, intermediate frequency, alternating electric fields that are applied to tumor regions and cells using non-invasive arrays. One mechanism described for TTFields induced cell death has been via the disruption of mitosis while a more recent examination suggests that TTFields causes replication stress, and down-regulates DNA repair and cell cycle checkpoint genes. However, the exact cause of the downregulation of DNA repair and cell cycle checkpoint genes has been elusive. To that end, we employed relative quantitative proteomic analysis using tandem mass tags (TMT). All samples underwent trypsin digestion and labelling with different TMT reagents. They were then combined and the mixture was analyzed on an Orbitrap Fusion mass spectrometry device. Peptide quantitation was accomplished by comparing the intensities of the TMT reporter ions. STRING DB analysis of differentially expressed proteins revealed interaction networks that included cell cycle, DNA damage repair and replication, and transcriptional and translational regulation. Upstream analysis of key genes associated with cell cycle checkpoint and DNA repair identified reduced expression of the transcriptional activators E2F1 and E2F2 and increased expression of the transcriptional repressor E2F6, suggesting that TTFields affects the CDK-RB-E2F axis. For example, the downregulation of key DNA repair genes including RAD51, BRCA1 and BRCA2 could be explained through the upregulation of the transcriptional repressors E2F4 and E2F6 (a known repressor of BRCA1). These proteins are involved in homologous recombination repair and nucleotide excision repair, but also with replication fork maintenance, replication fork collapse and overall replication stress, the latter of which likely leads to cell death. Therefore, TTFields was combined with the E2F inhibitor HLM006474 with or without the CDK4/6 inhibitor abemaciclib. TTFields in combination with either inhibitor enhanced cell killing synergistically, as compared to TTFields alone, while the triple combination was found to be highly lethal (&amp;gt;90% by 72 h) as measured by clonogenic assay followed by the Highest Single Agent approach to determine synergy. Taken together our results identify the CDK-RB-E2F axis as a novel druggable target that can be used in combination with TTFields for cancer therapy. Citation Format: Narasimha Kumar Karanam, Sivaramakrishna Yadavalli, Michael Story. Proteomic analysis of lung cancer cells exposed to tumor treating fields identified the dysregulation of the E2F-Rb-CDK4/6 axis rendering tumor cells susceptible to novel combination therapies that target CDK4/6 and/or E2F [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 559.

Analysis of survival of patients with metastatic malignant pleural mesothelioma.

To report the outcomes and prognosis of patients with malignant pleural mesothelioma (MPM) who present with or develop metastases during treatment. This is a retrospective observational study of patients diagnosed with MPM over 7 years. Metastases at presentation or during follow-up were recorded. Multivariate Cox regression was used to evaluate the relationship of clinicopathologic variables and overall survival (OS). Logistic regression was used for propensity score matching of patients to assess chemotherapy treatment effect. There were 367 patients included with a median age of 71 years (range, 29-91). A total of 69 patients (18%) had metastases: 14 at presentation and 55 during follow-up. Patients presenting with metastases had significantly worse median and 2-year OS compared to those developing metastases during follow-up: 13.3 months (95% confidence interval [CI], 2-24.6 months) and 0% versus 20.2 months (95% CI, 16.7-23.3 months) and 33%, respectively (p = 0.029). Female sex, age >70 years, nonepithelioid histology, and not receiving chemotherapy were independent poor prognostic factors. There was no difference in OS of patients with locally advanced (T4) disease compared to metastatic disease (M1): median OS 10.7 months (95% CI, 5.9-15.6) versus 13.3 months (95% CI, 2-24.6) (p = 0.18), respectively. Following propensity matching, sarcomatoid histology (hazard ratio, 7.86 [95% CI, 3.64-16.95]; p < 0.001) and multiple lines of chemotherapy (hazard ratio, 0.38 [95% CI, 0.19-0.84]; p = 0.015) were significant independent prognostic factors for OS. T4 disease carries a similar OS as metastatic MPM. Female sex, advanced age, nonepithelioid histology, and not receiving chemotherapy were independent poor prognostic factors.

Clinical Efficacy and Safety of Nivolumab: Results of a Multicenter, Open-label, Single-arm, Japanese Phase II study in Malignant Pleural Mesothelioma (MERIT).

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM. Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated. Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs. Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity.See related commentary by Mansfield and Zauderer, p. 5438.

P2.06-10 Combination Chemotherapy with Cisplatin, Pemetrexed, and Nivolumab for Malignant Pleural Mesothelioma: A Trial in Progress

Combination chemotherapy with cisplatin and pemetrexed is the standard treatment regimen for malignant pleural mesothelioma (MPM); however, the median overall survival (OS) is just about 12 months. Additional treatment options are urgently needed. The aim of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable MPM. This is a single-arm, prospective, non-randomized, non-comparative, open label, multicenter, phase II trial. This study will assess the efficacy and safety of the first-line combination therapy of cisplatin, pemetrexed, and nivolumab for advanced or metastatic MPM. Key inclusion criteria includes 1) age older than 20 years, 2) pathologically-confirmed MPM, 3) measurable lesion designated by modified RECIST criteria, 4) tumor sample available to test for Programmed Death-Ligand 1 (PD-L1) expression, 5) Eastern Cooperative Oncology Group Performance Status is 0 or 1. Combination chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (360 mg/body) is administered every 3 weeks for a total of 4 to 6 cycles. Then, maintenance therapy with nivolumab will be administered until disease progression, unacceptable toxicities, or the patient’s condition meets the withdrawal criteria. The primary endpoint is the centrally-reviewed overall response rate. The secondary endpoints include the disease control rate, overall survival, progression-free survival. Safety and adverse events will also be evaluated. This phase II trial commenced in January 2018. A total of 18 patients will be enrolled from four Japanese institutions within 1 year. This is the first prospective trial to evaluate the effect of an anti-PD-1 antibody combined with cisplatin and pemetrexed for unresectable MPM. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000030892.

A single centre phase II trial to assess the immunological activity of TroVax® plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma – the SKOPOS trial

ABSTRACTVaccines in combination with chemotherapy have been shown to be safe in different tumor types. We investigated the immunological activity of the TroVax® vaccine in combination with pemetrexed-cisplatin chemotherapy in malignant pleural mesothelioma (MPM).In this first line, open-label, single-arm, phase 2 study, patients with locally advanced or metastatic MPM were enrolled. Eligible patients received up to 9 intramuscular injections of TroVax®, starting two weeks before chemotherapy and continuing at regular intervals during and after chemotherapy to 24 weeks. The primary endpoint was the induction of cellular or humoral anti-5T4 immune response (defined as a doubling of either response at any of six follow-up time points), with a target response rate of 64%.Of 27 patients, enrolled between Feb 2013-Dec 2014, 23 (85%) received at least three doses of TroVax® and one cycle of chemotherapy and were included in the per-protocol analysis (PPA). 22/23 patients (95.6%) developed humoral or cellular immune response to 5T4. Thus, the study reached its primary endpoint. Disease control was observed in 87% of patients (partial response: 17.4%, stable disease: 69.6%). The median progression-free survival was 6.8 months and median overall survival 10.9 months. Treatment-related adverse events were comparable to those observed in patients with chemotherapy alone. Translational immunology studies revealed a circulating baseline immune signature that was significantly associated with long-term (>20 months in n = 8/23, 34.8%) survival.In this phase 2 trial, TroVax® with pemetrexed-cisplatin chemotherapy showed robust immune activity, acceptable safety and tolerability to warrant further investigation in a phase 3 setting.

A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol

BackgroundThe purpose of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma (MPM). Patients and MethodsPatients with untreated, advanced, or metastatic MPM who meet the inclusion and exclusion criteria will be included. A total of 18 patients will be enrolled from 4 Japanese institutions within 1 year. Combination chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (360 mg/person) is administered every 3 weeks for a total of 4 to 6 cycles. Then, maintenance therapy with nivolumab will be administered until disease progression, unacceptable toxicities, or the patient’s condition meets the withdrawal criteria. The primary end point is the centrally reviewed overall response rate. The secondary end points include the disease control rate, overall survival, progression-free survival, and adverse events. ConclusionThis phase II trial evaluating first-line combination chemotherapy for unresectable MPM commenced in January 2018. This is the first prospective trial to evaluate the effect of an anti-programmed death-1 antibody combined with cisplatin and pemetrexed for unresectable MPM.

Abstract A095: Phase Ib study of anetumab ravtansine in combination with pemetrexed and cisplatin in patients with mesothelin-expressing epithelial mesothelioma or nonsquamous non-small cell lung cancer

Abstract Background: Phase I study with the antibody-drug conjugate anetumab ravtansine demonstrated promising safety and efficacy as monotherapy in mesothelin-expressing tumors, and in particular for patients with advanced metastatic malignant pleural mesothelioma. Pemetrexed in combination with cisplatin is standard for first-line treatment of patients with metastatic mesothelioma and NSCLC. We therefore conducted a phase Ib study to determine the safety, tolerability, and maximum tolerated dose (MTD) of anetumab ravtansine in combination with pemetrexed/cisplatin (Pem/Cis) in subjects with mesothelin-expressing predominantly epithelial mesothelioma or nonsquamous NSCLC. Methods: Patients with histologically confirmed, unresectable, locally advanced or metastatic, mesothelin-expressing predominantly epithelial pleural or peritoneal mesothelioma or nonsquamous NSCLC, who previously failed ≤3 prior lines of chemotherapy, were eligible. Patients were prescreened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. Anetumab ravtansine was administered by 1-hour IV infusion on day 1 of every 21-day treatment cycle (Q3W). Pem (500 mg/m2) and Cis (75 mg/m2) were administered as IV infusions Q3W. Serial plasma samples were collected and analyzed for anetumab ravtansine and its components, pemetrexed, total and free platinum. Response to therapy was assessed by RECIST 1.1 and modified RECIST criteria for mesothelioma. Results: As of June 12, 2017, 17 patients had been treated and had received ≥2 cycles of treatment, including 7 patients with pleural mesothelioma, 9 with peritoneal mesothelioma, and 1 with NSCLC. Three patients were treated with anetumab ravtansine 5.5 mg/kg in combination with Pem/Cis with no dose-limiting toxicity (DLT). Six patients were then treated with anetumab ravtansine 6.5 mg/kg in combination with Pem/Cis, again without DLTs. This dose in combination was deemed as the MTD. An additional 8 patients were enrolled in an MTD expansion cohort. Anetumab ravtansine-related adverse events were mainly grade (G)1 and G2. G1/G2 eye toxicities were possibly more frequent with the combination than in historical data. There was one G3 corneal microcystic event and one G3 hypertension. There was a 50% overall response rate (all partial responses) from 16 evaluable patients. Of 13 patients treated at the 6.5 mg/kg MTD dose of anetumab ravtansine in combination with Pem/Cis, the overall response rate was 46%. Based on comparisons to historical data and within-subject comparisons in small number of subjects, clinically relevant PK interaction was not observed. Conclusions: Anetumab ravtansine at 6.5 mg/kg dosed Q3W in combination with standard dosing of Pem/Cis had a manageable toxicity profile without evidence of PK interaction and with early signs of clinical efficacy. Anetumab ravtansine at 6.5 mg/kg in combination with Pem 500 mg/m2 and Cis 75 mg/m2, all administered in a Q3W regimen, is thus feasible and the recommended dose for future study. Citation Format: Raffit Hassan, Ding Wang, John Wrangle, Anish Thomas, Angus Byars, Lianne Asschert, Rolando Atienza, Prabhu Rajagopalan, Annette Walter, Jun Zhang, Nenad Sarapa, Hedy Kindler. Phase Ib study of anetumab ravtansine in combination with pemetrexed and cisplatin in patients with mesothelin-expressing epithelial mesothelioma or nonsquamous non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A095.

Abstract CT083: A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140)

Abstract Background: Mesothelioma is a rare but aggressive cancer with a 5-year survival rate less than 10%. Mesothelin is a protein normally present on mesothelial cells and overexpressed in the majority of mesotheliomas. Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to ravtansine, an antitubulin cytotoxic agent. In a phase I study, anetumab ravtansine at 6.5 mg/kg on a q3w IV schedule was well tolerated and showed encouraging durable tumor responses in patients with previously treated mesothelioma. Design: A randomized, open-label, active-controlled, 2-arm, multicenter, phase II trial to evaluate the efficacy and safety of anetumab ravtansine at 6.5 mg Q3W versus vinorelbine 30 mg/m2 QW in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin and who have progressed on first-line platinum/pemetrexed-based chemotherapy. Objectives: The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS). The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Methods: Biomarker sampling will be performed on all patients to measure tumor mesothelin expression levels at prescreening. Biomarker-positive patients with moderate (2+) and/or strong (3+) level in at least 30% of tumor cells will be randomized and start study treatment following progression after 1st line treatment of platinum/pemetrexed (with or without bevacizumab). Approximately 183 patients meeting eligibility criteria will berandomized in a 2:1 ratio to receive anetumab ravtansine or vinorelbine. Randomization will be stratified by geographic region (Rest of World v. Asia) and time to progression on 1st line treatment (? 6 months vs &amp;lt; 6 months). The primary endpoint, PFS per modified RECIST criteria for metastatic pleural mesothelioma per central review, will be tested using a log-rank test stratified by randomization strata, with 1-sided significance level 0.0125. The primary analysis will occur after approximately 117 PFS events. Assuming true median PFS of 3.6 months under vinorelbine treatment, the primary hypothesis test is designed to detect a 100% prolongation of true PFS (median 7.2 months) with 90% power. Novel study methods include a grading system for AEs of special interest and the PRO instrument. Results: This trial is open and currently accruing patients. Citation Format: Raffit Hassan, John J. Nemunaitis, Jan P. van Meerbeeck, Ross Jennens, George R. Blumenschein, Jr, Dean A. Fennell, Hedy L. Kindler, Silvia Novello, Cem Elbi, Annette Walter, Danila Serpico, Emma Fountain, Sandra Vingerhoedt, Christine Brown, Jonathan Siegel, Barrett H. Childs. A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT083.

Metastatic malignant pleural mesothelioma masquerading as a case of acute abdomen secondary to small bowel perforation

Metastatic pleural mesothelioma is a rare disease. The present study aimed to report a rare presentation of metastatic malignant mesothelioma (MM). The patient was an elderly man who presented with small bowel (jejunal) perforation secondary to metastatic pleural mesothelioma deposits. This was a rare presentation of a rare disease and the first reported case in the published studies in which MM masqueraded as bowel perforation prior to the primary diagnosis.

Clinical and pathologic predictors of clinical outcome of malignant pleural mesothelioma.

Although worldwide use of asbestos has decreased, the incidence of malignant pleural mesothelioma (MPM) is expected to increase over the next few decades. A number of scoring systems has been proposed to assess clinicopathologic features and to predict the prognosis. We assessed the relationship between patients' features and disease evolution in order to choose the best treatment able to prolong overall survival (OS) and progression-free survival (PFS). We retrospectively analyzed patients with locally advanced or metastatic MPM, treated at the Department of Medical Oncology, Università Politecnica Marche, Italy, from January 2003 to September 2013. Data on age, sex, smoking history, asbestos exposure, performance status, tumor stage, histology, type of treatment, and routine laboratory tests including complete blood count panel, date of death, or censored status were collected. The OS and PFS were estimated using Kaplan-Meier method and Cox analysis was performed to analyze the prognostic relevance of clinical parameters. We enrolled a total of 62 patients. Univariate analysis showed that histologic type, performance status, response to first-line therapy, pretreatment hemoglobin levels, and plasmatic Ca125 were significant prognostic factors. Conversely, no significant correlation was found between age, sex, smoking history, reported exposure to asbestos, stages at diagnosis, treatments, and OS and PFS. Our results showed that anemia and increased Ca125 might be considered negative prognostic parameters in MPM patients and confirmed the prognostic role of histotype, performance status, and response to first-line chemotherapy.

Epithelioid pleural mesothelioma concurrently associated with miliary pulmonary metastases and minimal change nephrotic syndrome – A hitherto undescribed case

Malignant pleural mesothelioma (MPM) is the aggressive disease typically spreading along the pleural surface and encasing the lung, leading to respiratory failure or cachexia. Rare cases with atypical clinical manifestation or presentation have been reported in MPM. We experienced a unique case of MPM concurrently associated with miliary pulmonary metastases and nephrotic syndrome. A 73-year-old Japanese man with past history of asbestos exposure was referred to our hospital for the investigation of the left pleural effusion. Chest computed tomography showed thickening of the left parietal pleura. Biopsy specimen of the pleura showed proliferating epithelioid tumor cells, leading to the pathological diagnosis of epithelioid MPM with the aid of immunohistochemistry. After the diagnosis of MPM, chemotherapy was performed without effect. Soon after the clinical diagnosis of progressive disease with skull metastasis, edema and weight gain appeared. Laboratory data met the criteria of nephrotic syndrome, and renal biopsy with electron microscopic examination revealed the minimal change disease. Steroid therapy was started but showed no effect. Around the same time of onset of nephrotic syndrome, multiple miliary lung nodules appeared on chest CT. Transbronchial biopsy specimen of the nodules showed the metastatic MPM in the lung. The patient died because of the worsening of the general condition. To our knowledge, this is the first case of MPM concurrently associated with multiple miliary pulmonary metastases and nephrotic syndrome.

Role of Mesothelin Measurement in Patients With Cytology-Negative Pleural Effusion Undergoing Medical Thoracoscopy

Background: Malignant pleural mesothelioma (MPM) is a rapidly fatal tumor of increasing worldwide incidence. Diagnosis of MPM may be difficult and is an area of academic and clinical interest. Diagnosis by effusion cytology is controversial, and the clinical utility of soluble biomarkers, particularly mesothelin, remains unexplored in the difficult to diagnose patient. Objectives: We studied the diagnostic value of measuring mesothelin in patients with cytology-negative pleural effusion undergoing medical thoracoscopy. Methods: Patients were enrolled prospectively and underwent medical thoracoscopy. Biopsy samples were reviewed following standard care guidelines. Soluble mesothelin was quantitated by commercial enzyme-linked immunosorbent assay in effusion and serum samples collected at the time of thoracoscopy. Patients were followed up until death or for a median of 28 (interquartile range 18-43) months. Results: Biopsy for thoracoscopy was definitive for malignancy in 17 of the 36 cases (16 MPM and 1 lung adenocarcinoma) and suspicious of malignancy in 6 cases. A final diagnosis of malignancy was made for 27 cases (24 MPM, 2 lung adenocarcinoma, and 1 primary pleural T-cell lymphoma). At thoracoscopy, soluble mesothelin was elevated in the effusion of 13 cases all of which were MPM. Serum mesothelin was elevated in 6 cases with MPM. One case with elevated mesothelin on whom thoracoscopic biopsy demonstrated a pleural plaque was diagnosed with metastatic MPM 9 months later. Conclusion: Elevated effusion mesothelin had a positive predictive value of 100% for a final diagnosis of MPM. Elevated mesothelin, in effusion or serum, should raise the index of suspicion of malignancy and warrants continued clinical follow-up.