Malignant Pleural Mesothelioma Patients Research Articles

Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

e20062 Background: The increasing incidence and poor outcome associated with MPM demand identification of effective treatment options. Promising results have been reported with immunotherapy (IO) in a small proportion of MPM patients (p). MMR deficiency (dMMR) has been well described in several malignancies and was recently approved as a tumor biomarker for IO with anti-PD-1 checkpoint inhibitor. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM p. Methods: Tumors of 159 MPM p from Vall d´Hebron University Hospital and October 12th University Hospital diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR when any MMR protein expression was negative and MMR intact when all MMR proteins were positively expressed. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: P characteristics: median age: 69 years (29-88 years), males: 71%, performance status (PS) 1:69%, asbestos exposure: 52%, stage III at diagnosis: 42%, epithelial subtype: 65%, systemic treatment 81% (57% chemotherapy with cisplatin plus pemetrexed in first line), 50% received second line and 28% third line. MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8m). In a multivariate model factors associated to improved mOS were PS 0 vs PS2 (13 v 2 m, HR 12.8, p < 0.01), neutrophil-lymphocyte ratio (NLR) < 5 (18 v 9 m in NLR ≥5,HR 1.5, p < 0.05) and epitheliod vs sarcomatoid histology (18 vs 4 m HR 4.7, p < 0.01). Thirteen p received IO with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1m). Conclusions: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate novel predictive biomarkers benefit from IO in MPM.

Oral vinorelbine as a second-line chemotherapy option in advanced malignant pleural mesothelioma.

e20073 Background: Malignant pleural mesothelioma (MPM) is an infrequent entity with a poor prognosis. Standard first line chemotherapy therapy is based on pemetrexed and cisplatin, however, there is no established standard second-line therapy. We report our experience with patients treated at a third-level referral center in Mexico, making emphasis in the use of oral vinorelbine. Methods: We conducted a retrospective cohort study of MPM patients treated between 2012 and 2018 at the Centro Médico Nacional Siglo XXI, a third-level referral center in Mexico City. Our objective was to evaluate the effectiveness of different second-line chemotherapy schemes in MPM patients. Results: A total of 143 patients were included. There were 47 women (32.8%) and 96 men (67.1%). Median age was 64 (range 39 - 86). The histological subtypes comprised of 73.4 % epitheloid, 9 % with a sarcomatoid component and 17.4% not otherwise specified. The majority of patients presented with advanced disease 32.1 stage III and 63.6 stage IV. 72% of patients had performance status 0-1, however 9.7% of patients had performance status 3-4 at diagnosis, and received only palliative care as treatment. A total of 125 patients received first-line chemotherapy, and 40 patients underwent second-line therapy. Usual schemes were based on pemetrexed, paclitaxel, gemcitabine and oral vinolrebine. Overall, partial response rate was 5% and stable disease was 35%. There were no statistical differences in response rates between schemes (p = 0.75). The most usual second-line scheme was oral vinolrebine. Progression-free survival was 4 months in vinolrebine-treated patients vs 2 months (HR 1.04, 95% CI 0.86 – 1.25, p = 0.63) as compared with patients treated with other schemes. Conclusions: Our results are comparable with similar series in the second-line scenario. Oral-vinolrebine treatment progression-free survival was similar to other, more toxic drugs. However, we included few patients. More work is needed to identify the characteristics of benefitting patients.

Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent.

2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.

Randomized phase 2 study of maintenance pemetrexed (Pem) versus observation (Obs) for patients (pts) with malignant pleural mesothelioma (MPM) without progression after first-line chemotherapy: Cancer and Leukemia Group B (CALGB) 30901 (Alliance).

8517 Background: Standard front-line chemotherapy for advanced MPM is (Pem and a platinum; optimal treatment duration is unknown. We performed a randomized phase 2 trial (NCT01085630) to determine if continuation of single-agent Pem after 4-6 cycles of Pem-platinum would improve progression-free survival (PFS). Methods: Eligible pts had histologically confirmed unresectable MPM, and performance status (PS) 0-1. Pts with at least stable disease following 4-6 cycles of Pem-platinum were stratified by first-line regimen (cis- or carboplatin) and histology (epithelioid versus other) and randomized 1:1 to Obs or continuation of Pem until progression. The primary endpoint was PFS. We assumed that Obs produced a median (m) PFS of 3 months (mo) and Pem would yield a 100% improvement in mPFS to 6 mo; 60 eligible pts (30 per arm) were to be randomized. Results: 72 pts from 30 sites registered 12/10-6/16. The study closed early due to slow accrual once 53 pts were randomized; 49 eligible pts (22 Obs, 27 Pem) are included in the efficacy analysis. Pt characteristics (Obs/Pem): age: median (range) 70 (39-85)/70 (52-87); male 68%/78%; PS 0 27%/33%; epithelioid histology 77%/70%; first-line cisplatin 27%/26%. A median of 4 cycles of Pem (range 1-33) was delivered; 22% of pts required dose modification. mPFS was 3 mo on Obs and 3.4 mo on Pem (hazard ratio (HR) 0.99; 95% CI: 0.51-1.90; p=0.9733). Median overall survival (mOS) was 11.8 mo for Obs, and 16.3 mo for Pem (HR 0.86; 95% CI 0.44-1.71; p=0.6737). Toxicities ≥ grade 3 on Pem included anemia 8%, lymphopenia 8%, neutropenia 4%, and fatigue 4%; there were no grade 5 toxicities. A higher baseline level of serum mesothelin related peptide (SMRP) was associated with worse PFS (HR 1.861, p=0.049). Baseline osteopontin did not significantly affect PFS (p=0.3630). Conclusions: Although it was well tolerated, maintenance Pem following initial Pem/platinum doublet chemotherapy does not improve PFS in MPM patients. High baseline SMRP was associated with shorter PFS. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01085630.

Outcome of neo-adjuvant chemotherapy in 225 surgical candidates with malignant pleural mesothelioma.

8548 Background: Since any surgery for malignant pleural mesothelioma (MPM) are cytoreductive, effective chemotherapy is a prerequisite for surgery. In this context, we give neo-adjuvant chemotherapy (NAC) to all surgical candidates. Methods: Hyogo College of Medicine MPM Surgery Program mandates all surgical candidates to receive NAC, and only patients with stable disease (SD) or better response proceeds to surgery. The program comprised NAC followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation until 2012, and NAC followed by pleurectomy/decortication (P/D) and postoperative chemotherapy thereafter. Eligibility criteria are histologically confirmed non-sarcomatoid MPM, clinically resectable stage (T1-3N0-1M0), performance status 0–1, and no major comorbidity. Results: From December 2006 to December 2018, 225 patients were enrolled. Of 225, 24 patients (10.7%, Group A) did not proceed to surgery because of progressive disease (n=23) or serious adverse events (n=2). Of the remaining 201 patients with partial response (n=38, 16.9%) or stable disease (n=163, 72.4%), 19 refused surgery (Group B), 16 received exploratory thoracotomy (Group C), and 165 completed surgery (Group D, EPP58, P/D107). Surgical mortality rates at 30 and 90 days were 1.1% (n=2) and 2.8% (n=5), and surgical morbidity (≧grade 3) was 26.0% (n=47). Median survival time and survival rates of each group were shown in the table. Briefly, 2-yr survival competed among Group B,C and D, whereas 5-yr survival rapidly dropped in Group B and C. Conclusions: Approximately 90% of MPM patients with surgical intent successfully underwent either of EPP or P/D after effective chemotherapy with acceptable surgical mortality and morbidity. Comparison of patients who refused or accepted surgery suggested that surgery contributed to long-term survival. [Table: see text]

Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort

BackgroundAnticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456). Patients and MethodsTumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables. ResultsPD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1–expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1–stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1–positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047). ConclusionAlthough high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

IntroductionA comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified. MethodsWe enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients’ outcome. ResultsThe cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule–positive (CD4+) programmed death 1–positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3–positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3–positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival. ConclusionsA clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients’ outcome.

ENVIRONMENTAL AND OCCUPATIONAL RISK FACTORS AND PREDICTORS OF SURVIVAL AMONG MALIGNANT PLEURAL MESOTHELIOMA PATIENTS

AbstractIntroduction: Malignant pleural mesothelioma (MPM) remains a serious health problem due to the poor outcome of different therapies. In Egypt, it is mainly attributed to an environmental origin with a high incidence in women and young adults. Aim of work: To identify risk factors of malignant pleural mesothelioma and to carry out survival analysis for malignant pleural mesothelioma patients attending outpatient clinic of Clinical Oncology department at Ain Shams University hospital. Materials and methods: Ninety cases with pathologically confirmed MPM attending the outpatient clinic of clinical oncology department at Ain Shams University hospital were interviewed. Patients in critical conditions who needed hospitalization or palliative treatment were excluded. Included patients were then followed up for two years starting from the date of diagnosis. Results: Logistic regression analysis revealed that living in industrial areas, household exposure to asbestos and history of smoking were significant risk factors of MPM. The mean survival duration of all cases was 24.49 months. Cox regression analysis revealed that factors predicting survival were age and gender. The difference in survival between patients treated with different treatment modalities was not statistically significant. Conclusion: Environmental and householdexposure to asbestos as well as smoking play an important role in occurrence of MPM. Age and gender were significant predictors of survival of patients. Strict measures to reduce pollution and thus rates of MPM should be adopted in addition to communityawareness of the possible risk factors and preventive measures. Moreover, development of a national record system is required to determine the true size and scope of this environmental problem in Egypt.

Management of Malignant Pleural Mesothelioma in the Elderly Population.

The median age at diagnosis for malignant pleural mesothelioma (MPM) is approximately 72years. Elderly patients pose unique management challenges because of the increased risk of therapy-related toxicities and mortality. Because there are no high-volume retrospective studies, prospective trials, or dedicated treatment recommendations for this population, this investigation addresses a major knowledge gap by examining national practice patterns and postoperative/survival outcomes in elderly MPM patients. The National Cancer Database was queried for patients aged ≥ 80years with newly diagnosed nonmetastatic MPM. Multivariable logistic regression ascertained factors associated with observation and surgery. Kaplan-Meier analysis assessed overall survival (OS), and multivariable Cox proportional hazards modeling examined factors associated with OS. Survival was also calculated following propensity matching. Additionally, postoperative outcomes were evaluated in surgical patients. Of 4526 patients, 2% received surgery and chemotherapy, 22% underwent chemotherapy alone, and 63% were observed. Respective median OS was 12.2, 9.5, and 4.1 months (p<0.001). Differences between all groups persisted following propensity matching (all comparisons p<0.05). For the 8% of patients who underwent specified definitive surgery (95% of whom received pleurectomy/decortication), 30- and 90-day mortality rates were 11.0% and 28.5%, respectively. The median length of postoperative hospitalization was 6days, with 30-day readmission occurring in 7.5% of patients. The majority of elderly MPM patients in the US are observed, which was associated with poorer OS than chemotherapy and/or surgery. Although highly selected surgery/chemotherapy patients were associated with the longest OS, given the high biases in database studies and high perioperative mortality rates, careful patient selection for combined modality approaches in this population is imperative.

Extra-pleural pneumonectomy in the era of image-guided intensity-modulated radiotherapy.

To assess the outcome of malignant pleural mesothelioma patients treated with extra-pleural pneumonectomy (EPP) and adjuvant radiotherapy (RT), using the most advanced radiotherapeutic techniques, namely image-guided intensity-modulated RT (IG-IMRT). Fifty-four patients were analyzed. Minimum radiation dose was 50Gy (2Gy/fr). Planning target volume encompassed the entire hemithorax, including the ipsilateral mediastinum if interested by disease, the pericardium and diaphragm, and any drain sites. The study endpoints included loco-regional control (LRC), distant metastases free survival (DMFS), and overall survival (OS), as well as radiation-related toxicity. Major patients and treatment characteristics were the following: median age 62years, epithelioid histology in 51 (94%) cases, locally advanced disease in 41 (90%) cases, and metastatic mediastinal lymph nodes in 27 patients (50%). Only 7 patients (13%) had gross residual disease after surgery. Chemotherapy was administered in 38 patients (70%). Median follow-up was 16months (range 0-73months). Median and 2-year OS were 21months and was 43.8%, respectively. The predominant pattern of failure was distant: 34 patients (62.9%) developed some component of distant failure, and only 5 patients (9.2%) developed an isolated loco-regional recurrence. The estimates of LRC and DMFS at 2years were 63.4% and 43.4%, respectively. Three fatal pneumonitis were documented. Other major toxicities included: Grade 2 and 3 pneumonitis in 1 and 2 cases, respectively, 1 case of bronchial fistula, pleural empyema, and Grade 3 esophagitis, respectively. Although executed in the era of high-technology radiotherapy (IG-IMRT), EPP should not be routinely performed.

Survival analysis via nomogram of surgical patients with malignant pleural mesothelioma in the Surveillance, Epidemiology, and End Results database.

BackgroundMalignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates from the pleura and has a poor prognosis. Eligible patients can benefit from surgery, but their survival is affected by many factors. Therefore, we created a graphic model that could predict the prognosis of surgically treated patients.MethodsWe retrospectively analyzed data from the Surveillance, Epidemiology, and End Results database from 2004 to 2014 to identify the key factors affecting the prognosis of surgically treated MPM patients. On this basis we built a nomogram to predict survival. We then evaluated the performance of the nomogram in a validation cohort.ResultsIn a training cohort of 828 cases, independent prognostic factors, including age, gender, histological type, differentiation, N stage, chemotherapy, type of surgery, and lymph node dissection, were identified. We then developed a nomogram to evaluate individual patient survival. In Kaplan–Meier analysis, a higher score in the nomogram was associated with a worse prognosis. We also used a validation cohort consisting of 312 patients to evaluate the performance of the nomogram, which was well calibrated and had good discrimination ability, with concordance indices of 0.715 and 0.656 for the training and validation cohorts, respectively.ConclusionThis study has improved our understanding of resected MPM and shown that key factors, including age and histological type, are associated with overall survival. The nomogram is a reliable tool that can help clinicians turn individualized prediction into reality and maximize patient benefit by identifying the most beneficial treatment approach.

A survey of patient and caregiver experience with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare cancer with poor prognosis. As there is little information on the lived experience of MPM, our aim was to document the experience of MPM patients and their caregivers. Surveys for MPM patients and caregivers were developed from previous interviews with patients, caregivers, and health professionals, about treatments and decision-making. Participants were recruited from two hospitals, government compensation body, and support groups. Survey responses were received from 78 MPM patients and 106 caregivers from January to September 2014. 85% male, median age 69years, median time since diagnosis 15months. Caregivers: median age 68, 91% female, 90% spouse of MPM patient, 95% bereaved. Most participants felt informed about treatment options but only 69% thought all treatment options were discussed. Chemotherapy was discussed most frequently (92-95%); ~80% had sufficient information for decision-making. Decision regarding chemotherapy was made by patient considering doctor's opinion (24%), doctor and patient equally (18%), and doctor (17%). Participants 'agreed'/'strongly agreed' that they made the right decision about chemotherapy (patients 81%, caregivers 60%), but 5% and 16%, respectively, regretted the decision. Most participants received 'sufficient' support (71%). A quarter reported seeing cancer nurse specialists. Palliative care referral: 31% patients, 85% caregivers. Caregivers would have liked to talk to someone by themselves (41%), more time with doctors (30%), psychological support (29%), and clearer information (31%). Bereaved caregivers requested grief counselling (39%) and post-death consultation with specialists (23-25%). Satisfaction with treatment was high, but participants identified need for improved communication and quality information, discussion about all treatments, end-of-life assistance, and caregiver support after the patient's death.

198P - Efficacy of 150 kHz tumor treating fields (TTFields) and cisplatin or pemetrexed for the treatment of mesothelioma cells in vitro

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic cancer that has been strongly linked to asbestos exposure. The standard of care treatment for unresectable mesothelioma is cisplatin plus pemetrexed chemotherapy, which offers modest outcomes. Thus, there is an urgent need to identify more effective treatments for mesothelioma patients. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. We explored the potential use of TTFields alone and in combination with cisplatin or pemetrexed as a treatment for mesothelioma. Methods: NCI-H2052 and MSTO-211H cells were treated at various TTFields frequencies for 72 hours using the inovitro system. Results: The optimal TTFields frequency leading to the highest reduction in cell counts was 150 kHz for both NCI-H2052 and MSTO-211H cells. TTFields application (1.1 V/cm, 72 hours) at 150 kHz led to 45%, 51% reduction in cell counts and 64%, 46% reduction in clonogenic potential in NCI-H2052 and MSTO-211H cells, respectively. Efficacy of the combined treatment of TTFields and cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency together with various drug concentrations. The combined treatment of TTFields and cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis and reduced clonogenic potential as compared to either modality alone (2-way ANOVA, p < 0.0001(. Safety studies did not reveal any adverse event associated with 150 kHz TTFields application to the rat torso. Conclusions: These results demonstrate that TTFields can be an effective treatment against mesothelioma cells and that the combination with cisplatin or pemetrexed may further enhance treatment efficacy. These results are supported by a recent phase 2 study, which reported that MPM patients treated with the combination of TTFields with pemetrexed and platinum experienced improved overall survival as compared to historical control with no increase in systemic toxicity. Legal entity responsible for the study: Novocure Israel. Funding: Novocure Israel. Disclosure: U. Weinberg, M. Munster, R.S. Schneiderman, Y. Porat, T. Voloshin Sela, A. Shteingauz, E. Zeevi, M. Giladi, A. Kinzel, Y. Palti: Full time employee, stock options, stock ownership: Novocure Israel. K. Gotlib, S. Davidi, N. Kaynan: Full time employee, stock options: Novocure Israel. E. Kirson: Full time employee stock options, stock ownership: Novocure Israel; Holds senior leadership position: Novocure Israel.

Patterns of care and survival of older patients with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a cancer that primarily affects older adults. However this patient population is frequently under-represented in clinical studies. Therefore, we studied the impact of advancing age on treatment utilisation and clinical outcomes in an extensive series of minimally selected MPM patients. Patients with MPM receiving compensation from the New South Wales (NSW) Dust Diseases Authority (2002-2009) were assessed. They were categorised by age (<70 years, 70-80 years or > 80 years) and chi-square testing was used to assess the relationship between clinical and demographic variables, age, treatment and overall survival (OS). We identified 910 patients; 41% were aged <70 years, 40% were aged 70-80 years, and 19% were aged >80 years old. Median OS decreased with increasing age: 13.5 months in <70 years, 9.5 months in 70-80 years and 7.1 months in >80 years as did chemotherapy use (66%, 35% and 8% respectively). Radical surgical intervention, adjuvant, and palliative radiotherapy were less frequently used with advanced age. A Kaplan Meier analysis revealed that there was a significant survival advantage (p < .001) for patients <70 and 70-80 years receiving chemotherapy (16.8 vs 7.0 months; 13.9 vs 5.8 months respectively), but not for patients >80 years. Advancing age group of NSW patients with MPM was associated with reduced treatment utilisation and a decline in OS. Prospective studies are warranted to verify if current treatment guidelines are relevant for the older adults with MPM.

A phase II single-arm study of CRS-207 with pembrolizumab (pembro) in previously treated malignant pleural mesothelioma (MPM).

29 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) engineered to stimulate immune response to mesothelin. In a phase I trial of 60 MPM patients, 34% of subjects had tumor reduction (range -1 to -47%) following 2 doses of CRS-207 alone. In KEYNOTE-028 pembro showed activity in PDL1+ (≥1% by IHC) MPM, with an objective response rate (ORR) of 20% (5/25) and stable disease in 52% of subjects who had failed or did not receive chemotherapy. Subsequent studies of pembro have shown similar results in MPM. Results from a pre-clinical murine lung tumor model (CT26hMeso) showed anti-PD-1 enhanced LADD-induced tumor response. The study described here evaluated the efficacy of combination therapy of CRS-207/pembro. Methods: Adults with epithelial/biphasic MPM, ≤2 prior lines, progression on pemetrexed and platinum-based therapy, and no prior immunotherapies were enrolled. CRS-207/pembro were administered IV Q3W for 4 cycles, after which pembro continued Q3W and CRS-207 changed to Q6W. Response was assessed Q6W by modified RECIST for MPM (Byrne and Nowak, 2004). The primary endpoint was ORR; secondary endpoints included DOR, disease control rate (DCR), progression-free survival (PFS) and overall survival. Pre- and on-treatment blood and tumor samples were collected. Shedding and blood clearance of CRS-207 were evaluated. Results: 9/10 subjects were evaluable for response. No responses were observed; DCR was 11% (1/9 with SD) and PFS ranged from 3.4 to 8.9 weeks. Most common treatment related adverse events were chills, pyrexia and nausea. 3/10 subjects evaluated were PDL-1 negative by IHC. Of 6 subjects who underwent clearance and shedding evaluation, CRS-207 was detected in blood in 1 at 18-24 hrs after the first CRS-207 dose and cleared by the next evaluation at Day 4; shedding samples (urine, fecal, and saliva) tested negative. Conclusions: The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone. No evidence of clinical activity was observed. Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued. (NCT01675765) (NCT02054806). Clinical trial information: NCT03175172.

Diagnostic performance of glucose transporter-1 immunohistochemistry in malignant pleural mesothelioma: a meta-analysis

Background: Malignant pleural mesothelioma (MPM) is a rare neoplasm with indolent course and worse prognosis. Notwithstanding improvements in histologic and cytologic characterization, a generalized lack of consensus about diagnostic criteria still claims debate, though several new immunohistochemical markers have been introduced. Aim of this study is to evaluate current role and accuracy of glucose transporter-1 (GLUT-1) assay in the evaluation of malignant mesothelial proliferations. Methods: A PubMed Embase, Google Scholar research was carried out by identifying eight eligible articles fulfilling inclusion criteria. Quality assessment was conducted according to QUADAS-2 test. Data were extracted to evaluate true positive (TP), false positive (FP), true negative (TN) and false negative (FN) rates. Results: Enrolling 728 patients (297 MPM vs. 431 reactive pleural diseases), TP, FP, TN and FN cases were 215, 33, 398 and 82, respectively. A proportion of 74.25% of MPM patients showed immunoreactivity for GLUT-1. The pooled sensitivity (Se), specificity (Spe), positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy (DA) and disease prevalence (DP) were 0.74 [95% confidence interval (CI): 0.57–0.85], 0.91 (95% CI: 0.79–0.96), 0.87 (95% CI: 0.82–0.90), 0.83 (95% CI: 0.80–0.85), 0.84 (95% CI: 0.81–0.97) and 0.41 (95% CI: 0.37–0.44). Conclusions: In conclusions, GLUT-1 immunohistochemistry for MPM is characterized both by high Se and Spe rates. However, according to DP rates, its properties should be considered in the setting of a panel of markers rather than alone.

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.

Physical function and health-related quality of life in the convalescent phase in surgically treated patients with malignant pleural mesothelioma.

According to reports, patients with lung cancer have decreased pulmonary function and exercise capacity after surgery. However, to date, physical function and health-related quality of life (HRQOL) after surgery for malignant pleural mesothelioma (MPM) have not been evaluated in detail in the convalescent phase. This study aimed to assess physical function and HRQOL of MPM patients following pleurectomy/decortication (P/D) in the convalescent phase. The study included 16 male MPM patients who underwent P/D between September 2014 and August 2016. Physical function was assessed based on handgrip and knee extensor strengths, the six-minute walk distance (6MWD), and pulmonary function, including forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). HRQOL was assessed using the Medical Outcome Study 36-item Short Form Health Survey (SF-36). The assessment was performed preoperatively, postoperatively, and 1-year after surgery. The 6MWD, FVC, and FEV1 values 1-year postoperatively improved significantly compared with baseline (P< 0.05 all). Additionally, the scores of six of the eight SF-36 domains were significantly improved 1year after P/D: physical functioning, body pain, general health, vitality, social functioning, and mental health (all P< 0.05). 6MWD, FVC, and FEV1 were correlated with vitality, mental health, and physical functioning (P< 0.05 all). Patients with MPM who underwent P/D showed improved physical function and HRQOL compared with postoperative values in the convalescent phase. Physicians, nurses, and rehabilitation staff should note these findings, which may provide insight into the development of customized rehabilitation strategies in the convalescent phase for such patients.

Development and Validation of a Prognostic Signature for Malignant Pleural Mesothelioma.

Introduction: Dysregulated genes play a critical role in the development and progression of cancer, suggesting their potential as novel independent biomarkers for cancer diagnosis and prognosis. Prognostic model-based gene expression profiles are not widely utilized in clinical medicine. We investigated the prognostic significance of an expression profile-based gene signature for outcome prediction in patients with malignant pleural mesothelioma (MPM).Methods: The gene expression profiles of a large cohort of patients with MPM were obtained and analyzed by repurposing publicly available microarray data. A gene-based risk score model was developed with the training dataset and then validated with the TCGA-MESO (mesothelioma) dataset. The time-dependent receiver operating characteristic (ROC) curve was used to evaluate the prognostic performance of survival prediction. The biological function of the prognostic genes was predicted using bioinformatics analysis.Results: Three genes in the training dataset (GSE2549) were identified as significantly associated with the overall survival (OS) of patients with MPM and were combined to develop a three-gene prognostic signature to stratify patients into low-risk and high-risk groups. The MPM patients of the training dataset in the low-risk group exhibited longer OS than those in the high-risk group (HR = 0.25, 95% CI = 0.11–0.56, P < 0.001). Similar prognostic values for the three-gene signature were observed in the validated TCGA-MESO cohort (HR = 0.53 95% CI = 0.33–0.85, P = 0.008). ROC analysis also demonstrated the good performance in predicting 3-year OS in the GEO and TCGA cohorts (KM-AUC for GEO = 0.989, KM-AUC for TCGA = 0.618). The C-statistic for the 3-gene model was 0.761. Validation with TCGA-MESO confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic: 0.68). Functional enrichment analysis suggested that these three genes may be involved in genetic and epigenetic events with known links to MPM.Conclusions: This study has identified and validated a novel 3-gene model to reliably discriminate patients at high and low risk of death in unselected populations of patients with MPM. Further larger, prospective multi-institutional cohort studies are necessary to validate this model.

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial

BackgroundThe Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed–cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.MethodsPromoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.ResultsSTK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09–2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.ConclusionsMST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.