Malignant Pleural Mesothelioma Pts Research Articles

Statin treatment improves response to anti-PD1 agents in patients with malignant pleural mesothelioma and non-small cell lung cancer.

3074 Background: After progression to standard chemotherapy, only a small proportion of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) patients (pts) benefit from anti-programmed cell death (PD-1) treatment. Combination strategies might improve response. In pre-clinical models, statins showed vaccine adjuvant activities and synergized with anti-PD1 agents. In this multi-center study, we evaluated the impact of baseline statin treatment in MPM and NSCLC pts. Methods: We separately examined MPM and NSCLC pts treated with anti-PD1 monotherapy after progression to standard chemotherapy at two European academic institutions. As control cohort, MPM pts treated with first-line chemotherapy were also examined. Pts receiving statins at start of treatment were compared with those who did not. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 287 patients were examined. Twenty-seven out of 80 (34%) MPM and 36 out of 130 (20%) NSCLC pts received statins at start of anti-PD1 treatment. The most common statins were simvastatin, atorvastatin and rosuvastatin. In MPM pts, statin use was associated with improved ORR (22% versus 5%, P = 0.05), longer PFS (median 6.7 versus 2.4 months, hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.23–0.77, P < 0.01), and longer OS (median not reached versus 6.0 months, HR 0.43, 95% CI 0.21–0.85, P = 0.01). In NSCLC pts, statin use was associated with improved ORR (40% versus 22%, P = 0.04), longer PFS (median 7.8 versus 3.6 months, HR 0.59, 95% CI 0.37–0.97.2, P = 0.03) but similar OS (median 13.1 versus 10.1 months, HR 0.79, 95% CI 0.49–1.28, P = 0.30). At multivariate analyses, after adjusting for ECOG performance status (PS) and histological subtype, the impact of statins remained significant for ORR, PFS and OS in MPM and for PFS in NSCLC. Conversely, no association between statin use and outcomes was found in 77 MPM pts treated with first-line chemotherapy. Conclusions: This study shows that statin use at start of anti-PD1 treatment improves response to anti-PD1 agents in MPM and NSCLC pts who progressed to standard chemotherapy in routine clinical practice. This association could not be found in MPM pts treated with first-line chemotherapy, thus suggesting a synergy between statins and anti-PD1 agents. Prospective studies are needed to confirm whether the combination of statin and anti-PD1 therapy could improve outcome in pts with poorly immunogenic thoracic malignancies.

Randomized phase II study on gemcitabine with or without ramucirumab as second-line treatment for advanced malignant pleural mesothelioma (MPM): Results of Italian Rames Study.

9004 Background. The RAMES Study (EudraCT Number 2016-001132-36) is a multicenter, double-blind, randomized phase II trial exploring the efficacy and the safety of the addition of ramucirumab to gemcitabine as the second-line treatment in MPM patients (pts) after platinum/pemetrexed regimens. Methods. The pts were assigned (1:1) to receive Gemcitabine 1000 mg/m2 i v on days 1 and 8 every 21 days with Placebo (Arm A) or Ramucirumab 10 mg/kg i v on day 1, of a 21-day cycle (Arm B), until tolerability or progressive disease. Pts was stratified by ECOG/PS (0-1 vs 2), age (≤ 70 vs > 70 yrs), histology (epithelioid vs non-epithelioid) and time to progression (TTP) after first-line therapy. The primary endpoint was overall survival (OS). Assuming a proportion of OS equal to 40% at 1 year in arm A, a 12% absolute improvement in OS at 1 yrs was expected in Arm B (hazard ratio = 0.70).114 events (156 subjects) are required for a one-sided log-rank test with α = 0.15 to have 80% power. Results. From December 2016 to July 2018, 164 pts were randomized, 81 pts in Arm A and 80 Arm B; 3 pts were randomized but not treated. Characteristics of pts were: median age 69 yrs (44-81), males 119 (73.9%), females 42 (26.1%); ECOG/PS0 96 (59.6%) ECOG/PS1-2 65 (40.4%); histotype epithelioid 132 (81.9%), non-epithelioid 29 (18.1%); stage III 98 (60.7%), stage IV 60 (37.3%), 3 (2.0%) missing; asbestos exposure assessed 80 (49.7%). Median of courses was 3.50 in Arm A and 7.50 in Arm B. OS was significantly longer in Arm B with median 13.8 mths (70% CI 12.7-14.4) vs Arm A with 7.5 mths (70% CI 6.9-8.9), HR 0.71 (70% CI 0.59-0.85, p = 0.057). OS at 6 and 12 mths was in Arm A 63.9% and 33.9%, and in Arm B 74.7% and 56.5%, respectively. In Arm B OS was not correlated to TTP at first-line therapy (13.6 mths in TTP ≤6 mths and 13.9 mths in TTP > 6 mths) and histotypes (13.8 months in the epithelioid and 13.0 months in non-epithelioid). No significant differences in thromboembolism G3-4 events were observed in Arm A vs Arm B (p= 0.64). None hypertension G3-4 was reported in Arm A vs 5 pts (6.3%) in Arm B (p= 0.022). No significant differences in G3-4 haematological toxicities between the two arms were reported. Conclusion: In the RAMES Study the addition of Ramucirumab to Gemcitabine significantly improved OS regardless of age of pts, tumor histotype and TTP at the first-line treatment. Gemcitabine plus Ramucirumab can be considered a manageable regimen in second-line treatment of advanced MPM pts. Clinical trial information: NTC03560973.

1854P - Pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment for Egyptian patients with malignant pleural mesothelioma

BackgroundThe combination of cisplatin and pemetrexed is considered the standard of care front line regimen for malignant pleural mesothelioma (MPM). Several phase II trials demonstrated comparable response and survival rates with the use of gemcitabine and cisplatin. Few retrospective studies have compared the two regimens and with conflicting results. However, no prospective clinical trial has compared them directly. MethodsBetween June 2015 and September 2017, 51 chemotherapy-naïve MPM Pts were randomized 1:1 to receive either pemetrexed (500mg/m2) and cisplatin (75mg/m2) (PC) or gemcitabine 1000mg/m2 on days 1 and 8 combined with cisplatin (75mg/m2) on day 1 (GC). Chemotherapy was repeated every 3 weeks for a maximum of six cycles unless there was earlier evidence of disease progression or unacceptable toxicity. We used modified RECIST criteria for mesothelioma to evaluate treatment response and CTCAE v4.0 to assess toxicity. ResultsThe mean age was 52.5 years with males representing 51% of Pts. The ECOG PS was 0, I, and II in 3.9, 86.3, and 9.8% of cases, respectively. Epithelial histology was the most common (88.2%) followed by biphasic (9.8%) and sarcomatoid (2%). 6 pts had stage II disease, whereas 45 had stage III or IV. The baseline characteristics of the PC arm (N=26) and GC arm (N=25) were well-balanced in the age, gender, ECOG, pathology, and stage. RR with PC was 53.8% compared with 36% for GC (p value= 0.132). Significant superiorities in PFS and OS were observed with PC therapy. For the PC pts, the median PFS was 10.45 vs. 8.4 months for the GC Pts (log-rank p-Value < 0.001, HR=3.23, CI (95%) = 1.693 − 6.175). The median OS was 16.15 months for the PC arm and 13.1 months for the GC arm (log-rank p-Value = 0.020, HR=1.91, CI (95%) = 1.042 − 3.496). In general, hematological toxicities were more frequent in both arms in comparison to other types of toxicities. Neutropenia tended to be more severe with GC, whereas nausea was more frequent with PC. However, these differences in toxicity were statistically insignificant. ConclusionsFirst-line treatment of MPM with PC resulted in statistically significant improvement in PFS and OS compared to GC, therefore it should remain the standard of care for this group of pts. Legal entity responsible for the studyAin Shams Faculty of Medicine IRB. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

1843O - SAKK 17/16 - Lurbinectedin as second or third line palliative chemotherapy in malignant pleural mesothelioma (MPM): A multi-center, single-arm phase II trial

BackgroundAvailable systemic 2nd or 3rd line options for MPM show a median progression-free survival (mPFS) of less than 2 months (mo) and median overall-survival (mOS) of 6-9mo. Lurbinectedin (PharmaMar) is a novel compound with a dual role of binding to the DNA minor groove and inhibiting cytokine transcription of tumor-associated macrophages. Single MPM pts treated with lurbinectedin in early clinical trials showed encouraging outcome. The aim of current trial was to provide further data on safety and efficacy of lurbinectedin in progressive MPM. MethodsMPM pts (all histologies) not amenable for local treatment and progressing after first-line platinum-pemetrexed chemotherapy +/- immunotherapy (IO) received 2nd or respectively 3rd line lurbinectedin. Lurbinectedin 3.2mg/m2 every 3 weeks was given i.v. until progression or unacceptable toxicity. Primary endpoint was PFS at 12 weeks (PFS12wks) and would be met if achieved by at least 21 pts (p0 ≤ 35%; mPFS 2mo). Secondary endpoints were mPFS, mOS and adverse events (AEs). Results6 Swiss and 3 Italian centers recruited 42 pts (33 epithelioid, 4 biphasic, 5 sarcomatoid). 10/42 (23.8%) pts also received prior IO. At cut-off date (31st January 2019) PFS12wks was met by 22/42 pts (52.4%; 95%CI [38.7%; 63.5%]; p=0.015) for mPFS of 4.1mo (95% CI [2.6; 5.5]) and mOS of 11.9mo (95% CI [9.2; 14.7]). 1pt had complete, 1pt partial response and 20 pts stable disease as best response. No significant difference in PFS12wks, mPFS and mOS was observed in epithelioid vs non-epithelioid MPM and prior-IO vs non-prior IO pts. All pts experienced AEs. Grade 3-4 toxicity was seen in 33 pts with most common being leuco-/lymphopenia (60.6%) and fatigue (24.2%). Febrile neutropenia was 9.1%. No pt discontinued treatment due to toxicity. ConclusionsThe primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity compared to historical data. Neither histology nor prior IO seems to affect efficacy of lurbinectedin, but respective pts numbers are small for definitive conclusions. Further evaluation of lurbinectedin in a large randomized trial is warranted. Clinical trial identificationNCT03213301. Legal entity responsible for the studySwiss Group for Clinical Cancer Research. FundingPharmaMar; State Secretariat for Education, Research and Innovation (SERI). DisclosureY. Metaxas: Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: PharmaMar; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol Meyer Squibb; Honoraria (institution), Advisory / Consultancy: MSD; Research grant / Funding (institution): Krebsliga Graubünden; Research grant / Funding (institution): Suva Switzerland. M. Frueh: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Takeda. F. Grosso: Travel / Accommodation / Expenses: Novocure; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Boehringer Ingelheim; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Bristol-Meyer Squibb; Travel / Accommodation / Expenses: Amianto-Italia-Canada-Asbestos Committee; Honoraria (self): Merck; Honoraria (self): Italian Centro per la Prevenzione e Controllo delle Malattie; Research grant / Funding (self): Associazione Famigliari e Vittime Amianto. P.A. Zucali: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self): Pfizer; Honoraria (self): Ipsen; Honoraria (self): Tesaro. G.L. Ceresoli: Honoraria (self), Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self): Astellas; Honoraria (self): Pfizer; Travel / Accommodation / Expenses: Novocure. M.T. Mark: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Boehringer; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Takeda. M.R.A. Perrino: Honoraria (self): Astellas; Honoraria (self): Bristol Meyer Squibb; Honoraria (self): Novartis. S. Schmidt: Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Takeda. R. von Moos: Honoraria (institution), Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Elly Lilly; Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Bristol-Meyers ; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Vifor. All other authors have declared no conflicts of interest.

LBA91_PR - A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM): Results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial

LBA91_PR - A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM): Results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial

A phase II trial of nintedanib in recurrent malignant pleural mesothelioma (MPM).

e20061 Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGFR, FGFR, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy. Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and &gt; 4 pts had to have a PFS of ≥4 months to proceed to the second stage. Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS = 1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea. Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for &gt; 4 months thus potentially deriving some clinical benefit from treatment. Supported by Boehringer Ingelheim. Clinical trial information: NCT02568449.

Expansion study of ADI-PEG 20, pemetrexed and cisplatin in patients with ASS1-deficient malignant pleural mesothelioma (TRAP).

8553 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) cells are sensitive to arginine deprivation with pegylated arginine deiminase (ADI-PEG20), which also potentiates the cytotoxic effect of pemetrexed (PEM). In the phase I dose-escalation TRAP study (NCT02029690) we showed that ADI-PEG20 with first-line PEM and cisplatin (CIS) chemotherapy (ADIPEMCIS) produced a 100% disease control rate (DCR) in patients (pts; n = 9) with ASS1-deficient thoracic cancers, with no additional toxicity (Beddowes et al 2017). Here, we present the TRAP expansion cohort experience in MPM. Methods: Good performance (ECOG 0-1) MPM pts with non-resectable disease and measurable by modified RECIST, were enrolled in a phase I TRAP expansion cohort at the maximum tolerated dose (MTD) of ADIPEMCIS, using tumoral ASS1 loss as a selection biomarker. PEM (500mg/m2) and CIS (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for a maximum of 6 cycles with maintenance ADI-PEG20 in responding pts. Primary endpoint was tumor response rate (modified RECIST), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We measured plasma arginine and citrulline concentrations, ADI-PEG20 antibodies, and biopsied patients on progression to explore resistance mechanisms. Results: 31 ASS1-deficient MPM pts (median age 67) were enrolled (11 epithelioid, 10 biphasic and 10 sarcomatoid) out of 92 screened pts. Plasma arginine decreased with a reciprocal increase in plasma citrulline. The partial response rate was 35.5% (95% CI 19.2%-54.6%) with a DCR of 93.5% (95% CI 78.6%-99.2%). Median PFS was 5.6 months (95% CI 4-6) and median OS was 10.1 months (95% CI 6.7-17.7). 10/31 pts (32.3%) experienced grade 3/4 treatment-related toxicities, the most common being neutropenia (16.1%). Upregulation of ASS1 expression was observed in 2/3 biopsies on progression. Conclusions: The ADIPEMCIS regimen is active in ASS1-deficient MPM pts, including non-epithelioid disease. Based on these data the ATOMIC-meso phase 2/3 trial has opened comparing ADIPEMCIS versus PEMCISPlacebo, focusing on pts with non-epithelioid MPM. Clinical trial information: NCT02029690.

P3.03-042 Study Comparing Volume and TNM in Predicting Clinical Outcome in Malignant Pleural Mesothelioma: Topic: Mesothelioma Clinical

Malignant pleural mesothelioma (MPM) is a rare cancer with relatively poor outcome. Only stage (TNM) and histotype can be considered prognostic factors, but TNM still results inaccurate and difficult to be classified. Several studies investigated the use of tumor volume (TV) for response assessment, but its role as predictor of survival is unclear. A cut-off of 600 cm3 seemed to divide patients (pts) with different prognosis. Our objective is to assess the association between baseline TV, stage/TNM and overall survival (OS). We retrospectively selected 49 MPM pts treated from August 2002 to January 2012. All pts had a digitally available baseline chest computed tomography (CT), performed before any treatment and up to 3 months after histological diagnosis. CT staging was carried out by two thoracic radiologists according to TNM staging system (7th Edition). Pleural disease volume measurements were obtained by a computer system. Major prognostic variables (age, sex, histology, TV, stage/TNM, treatment) were collected. Pts were divided in 2 groups according to baseline TV (large volume >600cm3; small volume <=600cm3). Association of volume groups, stage, T, N, M separately and OS was tested using Cox models adjusted by age, sex, histology and surgery. Thirty-three pts were men, 16 women; median age was 62 years (range 25-78). Forty pts had epithelioid MPM, 7 mixed histology, 2 unknown histology. Four pts were diagnosed in early stage (I-II) and 45 in advanced stage (III-IV). The mean baseline TV was 494.15 cm3 (range 17.91- 2,329.03). Pts with small volume had a slight but not statistically significant tendency to survive longer than pts with large volume (3-year OS=32% vs 21%, respectively). The HR was 1.5 (95% CI=0.6-3.7) for large volume pts, 4.3 (p=0.08;95%CI=0.8-22.1) and 7.5 (p=0.02; 95% CI=1.4-39.9) for stage III and IV, 7.0 (p=0.001; 95% CI=2.3-21) and 5.4 (p=0.005; 95% CI=1.7-17.4) for T3 and T4, respectively. Regarding N and M, not statistically significant results were observed. Coherently with the available literature, we report an association between baseline TV and prognosis; however it seems weak and barely near to statistical significance. On the contrary, stage, in particular T3, showed a stronger association with prognosis. Considering the small sample and the wide 95% CI, our results should be interpreted with caution; nevertheless they open a critical question on the TV prognostic role and suggest a greater relevance of adjacent organs infiltration in predicting prognosis. Further collaborative studies are needed.

Detection of circulating tumour cells in peripheral blood of patients with malignant pleural mesothelioma.

The independent prognostic value of Circulating Tumour Cells (CTC) level has been demonstrated in several solid tumours. There is currently few data on Malignant Pleural Mesothelioma (MPM) and CTC. We investigated whether the presence of CTC was correlated with prognosis factors and treatment efficacy. MPM patients (pts) were enrolled in a prospective monocentric study. CTC detection was made using the "CellSearch" assay. The correlation between the presence of CTC and worse prognosis factors was assessed using the X(2) test. Comparison of Overall Survival (OS) and Progression Free Survival (PFS) according to CTC detection was performed using the log-rank test. Twenty-seven MPM pts with a median follow-up of 4.2 months were included. CTC were detected in 44% of pts with a median level of 1.5. No significant correlation was observed between the presence of CTC and worse prognosis factors. Moreover, CTC detection was not a significant predictor of OS or PFS (p=0.155 and p=0.32 respectively). CTC were detected in a small cohort of MPM patients. We couldn't demonstrate a significant prognostic value or a difference in OS/PFS between CTC levels. Further analyses, validation studies and detection techniques are needed to establish their real clinical value in MPM.

1534P - Efficacy and Toxicity Observed in Malignant Pleural Mesothelioma Patients Treated in Phase I Trials at a Single Institution

ABSTRACT Background Malignant Pleural Mesothelioma (MPM) is a locally aggressive disease with a poor prognosis. After failure of first line platinum-based chemotherapy, there is no widely approved salvage regimen. New strategies for treatment are needed and phase I trials appear as a rationale alternative. The results of such an approach have been evaluated.Materials and methods: MPM patients, were enrolled in 20 different phase I trials between March 2005 and January 2012, and their data analysed retrospectively. The primary endpoint was response rate and secondary endpoints were toxicity profile, Overall Survival (OS) and Progression Free Survival (PFS). Median follow-up of patients was estimated through Schemper's method. The cut-off date for the analysis was April 2012. Adverse events were assessed by NCI-CTC v.3.0 and response rate according to RECIST 1.1 criteria. Results Forty-six patients with a confirmed histology of MPM were included in the analysis with a median follow up of 20 months. The median age and the sex ratio (M/F) were 61 years old and 2.29 respectively. Radiological disease progression was observed in 50% of pts, clinical progression in 28%, and dose limiting toxicity in 22%. The best tumour response was as follows: 7% of pts had a RECIST partial response, 59% had stable disease for a median duration of 2.8 months and 24% had progressive disease. The median treatment duration in the phase I was 1.9 months. Median OS and PFS were 6 months (95% CI= [4.3-10.7]) and 2.1 months (95% CI= [1.3-2.8]), respectively. The most common grade 3/4 adverse events (41%) were haematological (11%), gastro-intestinal (4%), cutaneous (7%), renal (4%) and hepatic (4%). All adverse events were reversible and no death due to toxicity was reported. Conclusion Including MPM pts in phase I trials beyond first line of treatment can result in clinical benefits with an acceptable toxicity profile. Several molecular pathways involved in MPM have been identified and further novel biologic therapies might be tested in a phase I setting in a biology-oriented approach rather than a stochastical one. We are currently offering a tumour molecular profiling in our pts (MOSCATO trial) for a better selection of phase I trial. Disclosure All authors have declared no conflicts of interest.

244 - Detection of Circulating Tumour Cells in Peripheral Blood of Patients With Malignant Pleural Mesothelioma

ABSTRACT Background The independent prognostic value of Circulating Tumour Cells (CTC) level has been demonstrated in patients with advanced breast, prostate and colorectal cancers. There is currently few data on Malignant Pleural Mesothelioma (MPM) and CTC. We investigated whether the presence of CTC was correlated with prognosis factors and treatment efficacy in MPM patients. Methods Patients (pts) with MPM in progression were enrolled before any new line of treatment in a prospective monocentric study. CTC detection was made on peripheral blood samples (7.5ml) using the “CellSearch” assay according to the manufacturer's protocol. The correlation between the presence of CTC and known worse prognosis factors was assessed using the X2 test. Progression Free Survival (PFS) was defined as the time from diagnosis until first progression (PFS1) and as the time from CTC measure until progression or death (PFS2). Comparison of PFS according to CTC detection was performed using the log-rank test. The cut-off date of the analysis was May 2012. Results Twenty-five MPM pts with a median follow-up of 4.2 months were included. The median age and sex ratio (M/F) were 65 years old and 2.1 respectively. Eighty-four percent of pts had an epithelioid MPM, 64% had a stage 4 disease, 60% had an anemia, a thrombocytosis or a leucocytosis at the time of inclusion. All pts except one had an Eastern Cooperative Oncology Group performance status (ECOG) Conclusion Detection of CTC has been done in a small cohort of MPM patients. It could be an important tool though we were not able to demonstrate a significant prognostic value or a difference in PFS between CTC levels. The Cellsearch assay might not be the best technique to use in this setting. Further analyzes are in progress, and updated results will be presented in September. Disclosure All authors have declared no conflicts of interest.

Circulating tumor cell (CTC) as a significant clinical marker in epithelioid-type malignant pleural mesothelioma (MPM).

7080 Background: Circulating tumor cell (CTC) is a surrogate of distant metastasis, and our preliminary study suggested that CTC detected by an EpCAM-based immuno-magnetic separation system (“CellSearch”) was a useful clinical marker in the diagnosis of malignant pleural mesothelioma (MPM) (Tanaka F. et al ASCO 2008). Methods: Patients who presented at our institute to receive pleural biopsy with suspicion of MPM were prospectively enrolled. CTCs in 7.5mL of peripheral blood were quantitatively evaluated with the CellSearch system. Results: Among 136 eligible patients, 104 were finally diagnosed with MPM, and 32 were with non-malignant diseases (NM). CTC was positive (CTC≥1) in 32.7% (37/104) of MPM pts, and in 9.4% (3/32) of NM pts (p=0.011). CTC-count was significantly higher in MPM (range, 0-9) than in NM (range, 0-1; p=0.007). According to a ROC curve analysis, the CTC-test provided a significant diagnostic performance in discrimination between MPM and NM (AUC= 0.623; P=0.036). Among MPM pts, CTC-positivity and CTC-count were significantly increased with tumor progression (p=0.026 and p=0.008, respectively). For all MPM pts, there was no significant difference in overall survival between CTC-positive and negative pts. However, in a planned subset analysis, CTC was a significant factor to predict poor prognosis (median survival time, 8.0 months for CTC-positive pts, and 20.3 months for negative pts; p=0.012) in pts with epithelioid-type MPM in which CTC was exclusively positive; a multivariate analysis confirmed that CTC, along with PS, was an independent prognostic factor (HR=2.38; P=0.006). Conclusions: CTC was a significant diagnostic marker in discrimination between MPM and NM. CTC-positivity was a significant and independent prognostic factor to predict a poor prognosis of epithelioid MPM. [Table: see text]

NGR-hTNF as second-line treatment in malignant pleural mesothelioma (MPM).

7076 Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) peptide for selectively targeting tumor necrosis factor (TNF) to cancer endothelial cells. Tumor hypervascularity is an independent predictor of poor overall survival (OS) in MPM patients (pts). Methods: We report long-term results of a phase II trial that assessed NGR-hTNF in MPM pts with performance status (PS) ≤ 2 and radiologic progressive disease (PD) after a pemetrexed-based regimen. NGR-hTNF was given at 0.8 µg/m2 every 3 weeks (q3w) in 43 pts and weekly (q1w) in 14 pts. Primary endpoint was progression free survival (PFS), with restaging done q6w by MPM-modified RECIST criteria, while secondary aims included disease control (DC) rate and OS. We also tested the impact on outcome of neutrophil to lymphocyte ratio (NLR) at baseline (median 3; interquartile range 2-5). Median follow-up was 32.5 months (95% CI 27.5-37.5). Results: Baseline characteristics were (n=57): median age 57 years; M/F 35/22; PS 0/1-2 31/26; EORTC score good/poor 45/12. Median treatment free interval on prior therapy was 4.3 months. Only one drug-related grade ≥ 3 adverse events (AEs) was noted, common grade 1/2 AEs being transient chills (75%). No higher toxicity was reported using the q1w schedule. Median PFS was 2.8 months (95% CI 2.2-3.3). DC rate was 46% (95% CI 32-59; 26/57 pts; 1 partial response, 25 stable diseases) and was maintained for a median time of 4.7 months (95% CI 4.0-5.4). OS rates at 1 and 2 years were 47% and 16%, respectively. Median OS was longer in pts with DC than in those with early PD (16.2 and 8.3 months, respectively; p=.02). According to schedule, 6-month PFS rates were 11% and 36% and 2-year OS rates were 12% and 29% for q3w and q1w, respectively. In pts with DC, median PFS were 4.4 and 9.1 months and median OS were 13.3 and 24.8 months for q3w and q1w, respectively. By Cox analyses, a PS of 0 (p=.01) and a low baseline NLR (p=.004) were the only variables associated with improved OS. Median OS in pts stratified by NLR ≤ 2, 3 to 4, and ≥ 5 were 15.7, 10.5, and 4.2 months, respectively (p=.0002 for trend). Conclusions: NGR-hTNF showed promising PFS and OS in this study. A double-blind phase III trial is currently testing best investigator choice ± NGR-hTNF q1w in pemetrexed-pretreated MPM pts (NCT01098266).

Long-term survivors (LS) of malignant pleural mesothelioma (MPM): An effort to gain knowledge of this uncommon biology.

e21033 Background: The median overall survival (OS) of MPM patients (pts) is 10-month. However a small number of pts survive beyond 24 months (mos) and are considered LS. Here we report on the clinical features of a series of LS MPM patients from an highly asbestos-polluted geographic area. Meanwhile, as part of a new work in progress, we are trying to identify some biological and molecular characteristics possibly associated with this favourable behaviour. Methods: We went through our MESO database of 397 cases diagnosed between march 2003 and december 2009 at Alessandria and Casale Monferrato Hospitals and screened 32 MPM pts whose survival was at least 24 mos (LS). These data were born out by the Piedmont mesothelioma registry. Paraffin embedded tumor tissue is available for immunohistochemistry and molecular studies (programmed necrosis and apoptosis, PDGFR and EGFR signalling pathways) in 25 pts. Moreover blood derivatives and primary cell lines from 9 and 6 pts respectively, are stored in the Alessandria MPM Biobank and are available for biological studies. (i.e. VEGF). Results: Median age at diagnosis was 60 years (range 43-79), histology was epithelioid in 30, sarcomatoid in 1 and biphasic in 1. 11 pts underwent EPP and 5 pleurectomy. 11 pts received neoadjuvant/adjuvant chemotherapy. 11 pts underwent radiotherapy. All pts but 1 received palliative chemotherapy (pCT), median number of pCT lines was 2 (range 0-6), best response to first pCT line was PD in 31% (10), SD in 40% (13), PR in 13% (4) and 16% were not evaluable (5). With a median follow-up of 51 mos the median OS was 38 mos (range 24-69). Conclusions: In these 32 LS MPM pts, except from epithelioid histology, we failed to identify any clinical feature that could stimulate further investigation. Though the small number does not allow any conclusion, it is intriguing that response to first line pCT seems to be lower than that reported in literature. This once more suggests that dimensional response is not the best surrogate for favourable outcome and prompts us to look for alternative prognostic factors. Tumor samples and fluid specimens from most of these pts are available. Molecular and biological studies are ongoing, and results thereof will be presented.

NGR-hTNF in previously treated patients with malignant pleural mesothelioma (MPM) .

7089 Background: NGR-hTNF exploits the tumor-homing peptide NGR for selectively targeting tumor necrosis factor to tumor blood vessels. Methods: Here we report the long-term results of a phase II trial testing NGR-hTNF in 57 MPM patients (pts) who had failed a pemetrexed-based regimen. NGR-hTNF was given as 1-hour infusion at 0.8 µg/m2 every 3 weeks (q3w; n=43) or weekly (q1w; n=14) in a subsequent cohort. Moreover, we assessed the impact on outcome of the systemic neutrophil-to-lymphocyte ratio (NLR), an index of the host immune response to tumor. Median baseline NLR was 3 (range 1-23). Results: In the whole study population (n=57), one grade 3 drug-related toxicity was observed and common grades 1-2 were transient chills (75% of pts). There was no higher toxicity using the q1w schedule. Median progression-free survival (PFS) was 2.8 months (95% CI 2.2-3.3). The disease control rate was 46% (26/57 pts; 95% CI 33-60%) and was maintained for a median time of 4.7 months (95% CI 4.0-5.4). With a median follow up of 28.6 months, the overall survival (OS) rates at 1 and 2 years were 47% and 15%, respectively. The 6-month PFS and 2-year OS rates were 11% and 10% in q3w cohort vs 36% and 29% in q1w cohort, respectively. In pts with disease control (n=26), median PFS and 2-year OS rate were 4.4 months and 11% in q3w cohort vs 9.1 months and 57% in q1w cohort, respectively. In a landmark analysis set at 2 months (1st restaging), median OS was longer in pts who had achieved disease control compared with those who had progressed (14.7 vs 6.8 months; p=0.03). By multivariate analyses, a PS of 0 (HR=0.38; p=0.02) and a baseline NLR ≤ 3 (HR=0.40; p=0.005) were associated with longer survival, while no associations were detected between OS and age, sex, histology, EORTC score and treatment-free interval on prior therapy. Median OS were 17.4 vs 8.0 months in pts with PS 0 or PS 1-2 and 15.7 vs 5.6 months in pts with NLR ≤ or > 3, respectively. Conclusions: Based on these results, NGR-hTNF 0.8 µg/m2 q1w is currently tested in a placebo-controlled phase II trial as a maintenance treatment in MPM pts who did not progress after 6 cycles of first-line chemotherapy and in a double-blind phase III trial evaluating best investigator’s choice ± NGR-hTNF in relapsed MPM.

Retreatment with pemetrexed-based chemotherapy (PBC) in patients with malignant pleural mesothelioma (MPM): An observational study.

e18106 Background: The role of second-line therapy in MPM patients (pts) is currently undefined. Recent case series have suggested a possible role of re-treatment PBC. Aim of this study was to evaluate this therapeutic option in a consecutive series of pts previously treated with first-line PBC. Methods: Pts with partial response (PR) or stable disease (SD) for at least 3 months after first-line PBC were eligible for the study. Pts receiving retreatment with PBC either as second-line (2L) or further-line (> 2L) therapy were considered. Results: 34 pts were retrospectively evaluated (2L: 20 pts; > 2L: 14 pts). Median age was 65 (range 36-81). EORTC prognostic score was poor in 19 pts, good in 12, not available in 3. In 2L setting 1 RC, 5 PR, 9 SD were observed, whereas 1 SD was observed in > 2L, for an overall disease control rate (DCR) of 47%. 17 pts (50%) had progressive disease (2L: 4 pts; > 2L: 13 pts). Median progression free survival (mPFS) was 3.1 mo (1.1-24.3 mo). Pts receiving PBC as 2L therapy had a longer mPFS (4.8 vs 2.1 mo; p < 0.001). Pts with a good EORTC score had a longer mPFS (4.1 vs 2.8 mo; p.02). Median overall survival (OS) was 10,1 mo (1.8-49.2 mo). Overall survival (OS) and PFS after re-treatment with PBC were correlated to first-line progression time (FLPT) (FLPT < 6 mo, 6-12 mo, > 12 mo, OS was 2.6 vs 7.8 vs 14.8 mo; PFS was 1.4 vs 2.7 vs 4.8 mo; p < 0.01). A longer OS was observed in pts with a good EORTC score (p.02), in pts receiving PBC as 2L therapy (p.02) and achieving a DC (p < 0.002). Grade 3/4 haematological toxicity was observed in 5 pts (14.7%). Nonhematological toxicity was mild, with 1 case of grade 3 constipation. Conclusions: Re-treatment with PBC seems to be a possible option in the second-line setting in MPM pts achieving a durable DC with first-line treatment. Further evaluation in a prospective trial is warranted. No significant financial relationships to disclose.

A retrospective analysis of second-line chemotherapy for malignant pleural mesothelioma (MPM).

7040 Background: Chemotherapy is the only option for MPM. Cisplatin + pemetrexed became the standard in the first-line (FL), while the role of a second-line (SL) remains controversial. Methods: We retrospectively collected data of all consecutive MPM patients (pts), from 8 italian institutions, receiving SL chemotherapy after a platinum based FL treatment from 1996 to 2008. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), best overall response rate (ORR) and prognostic factors. Kaplan Meier curves and Log Rank were used for statistical analysis. Results: Of 414 MPM pts treated in FL setting, 161 underwent a SL chemotherapy (63% male; median age 62.5 years). Main regimens were: platinum rechallenge (21 pts, 13.1%), pemetrexed rechallenge: (23 pts - 14.4%), pemetrexed + platinum rechallenge (32 pts-20%), biological agents (23 pts-14.3%) and others (62 pts-38.2%). 89 pts achieved disease control (partial remission + stable disease) with a SL regimen (55,6%) (median OS 10,23 months (mths), median PFS 5.72 mths). OS was statistically significantly higher in pts rechallenged with platinum + pemetrexed (20.56 vs 8.49 mths – HR 0.39 95%IC 0.21-0.71; p = 0.0015), while PFS wasn't (9.77 vs 5.39 mths – HR 0.71 95%IC 0.47-1.08; p = 0.111). PFS (p < 0.0001) and OS (p < 0.0001) were statistically significant in pts responding to FL and with an epithelial histology (p = 0.0008). Univariate and multivariate logistic analysis showed that the only factors for the choice of SL regimen were response after FL and smokers. Conclusions: The benefit of SL is strictly dependent on histology and response to FL. According to our data, rechallenge with platinum-based regimens seems the best option. No benefit has been proven in favour of polichemotherapy regimens in respect to single agents. The superiority of cisplatin + pemetrexed rechallenge has been demonstrated also at the multivariate analysis adjusted for time to SL and histology. The role of platinum-based rechallenge in SL should be further investigated, considering also that a SL has palliative intent on the basis of histology and of the extent of response to FL treatment. No significant financial relationships to disclose.

Circulating tumor cells (CTCs) and endothelial cells (CECs) in the diagnosis of malignant pleural mesothelioma (MPM): A single institutional prospective study

e22107 Background: Circulating tumor cell (CTC), a surrogate of distant metastasis, and circulating endothelia cell (CEC), a surrogate of angiogenesis, are potentially useful in the diagnosis of malignant tumors. Following a promising result of our preliminary study showing the diagnostic value of CTC/CEC in malignant pleural mesothelioma (MPM)(Tanaka F, et al. ASCO 2008), we conducted a prospective study. Methods: Patients (pts), who presented at our institute with suspicion or diagnosis of MPM, were eligible in the study. CTCs and CECs in peripheral blood (7.5mL and 4.0mL, respectively) were captured and quantitatively evaluated with the “CellSearch” system without knowledge of clinical characteristics of patients. Results: A total of 92 pts were enrolled into the study, and the final diagnosis was MPM in 68, other malignant tumors in 7, and non-malignant diseases in 17 pts ( Table ). CTC was positive (CTC-count, 1 or more per 7.5mL of the peripheral blood) in 35%(24/68) of MPM pts (range of CTC-count, 0–27 cells/7.5 mL). Among non-malignant pts, 3 pts (18%) showed a positive-CTC, but no patient showed 2 or more CTCs in 7.5mL of the peripheral blood. The mean CEC-count (/4.0mL) was significantly higher in MPM pts than in non-malignant pts (105.1 versus 40.2; p=0.047). When the cut-off value of CEC-count for the diagnosis of MPM was defined as 50(cells/4.0mL), the sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of malignant diseases were 66%, 70%, 93%, and 26%, respectively. There was no correlation between CTC-positivity and clinical stage of MPM pts, but was a trend of increase in the mean CEC-count along with tumor progression (mean CEC-count for stage I, II, III, and IV pts: 63.0, 82.4, 95.6, and 116.7, respectively). Conclusions: CTC and CEC are useful clinical markers in the diagnosis of MPM. [Table: see text] No significant financial relationships to disclose.

Open-label study of pemetrexed alone for chemonaive patients and pre-treated patients with malignant pleural mesothelioma: Outcomes of the International Expanded Access Program (EAP)

7709 Background: In a previous phase II study of chemonaive malignant pleural mesothelioma (MPM) patients (pts), single-agent pemetrexed (P) resulted in a 14.1% response rate (RR) and median survival of 10.7 mos (95% CI 7.7–14.5) (Scagliotti 2003). Likewise, the P arm in a phase III study of pre-treated MPM pts yielded an 18.7% RR (40.7% with stable disease, SD) and median survival of 8.4 mos (95% CI 6.2–10.5) (Jassem 2006). The EAP provided 3311 MPM pts with access to P alone, P plus cisplatin, or P plus carboplatin in 13 countries. In this abstract we report on the safety and efficacy data of those MPM pts treated with P alone. Methods: Eligible pts had histologic or cytologic diagnosis of MPM and were either chemonaïve or previously treated with =1 line(s) of chemotherapy. Pts pre-treated with P were allowed if they had experienced clinical benefit from the prior P. Treatment consisted of P (500 mg/m2) once (day 1) every 21 days with standard pre-medication of vitamin B12, folic acid, and dexamethasone. Investigator-determined response (RR) and survival data (with censoring) were recorded at the end of study participation. Myelosuppression data (CTC) were also collected. Results: 812 MPM pts (319 chemonaïve; 493 pre-treated) received =1 dose of P and were evaluated for safety, and 643 pts (247 chemonaïve; 396 pre-treated) were evaluated for efficacy (RR and survival). In chemonaïve pts with MPM, the median age was 69 yrs (range: 39–87 yrs), 78.1% were male, and 71.6% had a KPS ≥80 (of the 93% who had PS evaluated). In pre-treated pts with MPM, the median age was 63 yrs (range: 31–85 yrs), 75.9% were male, and 74.5% had a KPS ≥80 (of the 95% who had PS evaluated). Both groups received a median of 4 cycles (chemonaive group range 1–18; pretreated group range 1–23). See the table for efficacy and safety data. Conclusions: Results of the EAP confirm earlier phase II and phase III studies. No significant financial relationships to disclose. [Table: see text]

DNA methylation profile predicts survival of patients with resected malignant pleural mesothelioma (MPM)

7712 Background: Methylation in different tumor suppressor genes is among the most frequent alterations reported in MPM patients (pts). DNA methylation increases upon immortalization and transformation of human mesothelial cells, and demethylating agents were found to have some activity in MPM. In this study we analysed the methylation status of the promoter region of four candidate genes in MPM: p15INK4BINK4B, p16INK4AINK4A, RASSF1A and NORE1A. Methods: Samples of 79 consecutive MPM pts who underwent surgical procedures (41 extrapleural pneumonectomy (EPP), 32 partial pleurectomy, 6 diagnostic biopsy) at our Institution from 1997 to 2005 were analyzed. DNA was isolated from each paraffin-embedded MPM; the methylation status of the four genes was evaluated by a methylation-specific PCR method (MSP). Correlations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined in all pts and in the EPP subgroup. Proliferation index was evaluated as percentage of nuclear immunoreactivity/10 high-power field using a mouse monoclonal antibody anti-human Ki-67, clone MIB-1 (DAKO Corporation, Carpinteria, CA). Results: The MSP analysis documented gene promoter methylation in at least one gene in 30 cases (38%). The methylation frequency of each gene was: p15INK4B 15 cases (19%), p16INK4A 9 (11.4%), RASSF1A 16 (20.2%), Nore1A 4 (5.1%). Of the 30 methylated MPMs, 18 (60%) showed only one methylated gene, 10 (33.3%) were methylated in two genes and 2 (6.7%) in three. Methylation in at least one gene was associated to a higher proliferation index (P=0.058, ANOVA), but not to OS, in the whole study population. In pts treated with EPP, the 22 methylated cases showed a trend to a worst OS in comparison to 19 unmethylated cases (median OS 16 months vs 35 months, P=0.066, HR=2.01, 95% CI 0.94–4.30, Cox regression), independently by histology and nodal status. Conclusions: In pts treated with EPP, the methylation profile of p15INK4BINK4B, p16INK4AINK4A, RASSF1A and NORE1A appeared to be an independent prognostic factor for OS. The methylation status was correlated to proliferation rate, indicating a potential role of these oncosuppressor genes in the neoplastic progression of MPM. No significant financial relationships to disclose.