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R. Gaafar
Moderator of
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O22 - Mesothelioma III (ID 122)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Mesothelioma
- Presentations: 8
- Moderators:P. Baas, R. Gaafar
- Coordinates: 10/29/2013, 16:15 - 17:45, Bayside Gallery A, Level 1
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O22.01 - Next generation sequencing in malignant pleural mesothelioma: preliminary data from a retrospective cohort of 123 patients (ID 2290)
16:15 - 17:45 | Author(s): M. Lo Iacono, S. Novello, F. Grosso, S. Vatrano, L. Righi, M. Papotti, P. Bironzo, V. Monica, G.V. Scagliotti
- Abstract
- Presentation
Background
The median survival of patients with advanced stage malignant pleural mesothelioma (MPM) ranges between 9 and 12 months after diagnosis, regardless of the recent achievements with systemic therapies combining cisplatin and antifolates such as pemetrexed or raltitrexed. Since MPM is a relatively rare malignancy and early pre-neoplastic lesions are clinically difficult to be identified, the understanding of molecular pathogenesis including sequential accumulation of genetic/epigenetic alterations for MPM development has lagged behind other common malignancies. According to the COSMIC database the most frequently mutated genes in MPM include CDKN2A, NF2 and BAP1, followed by other 12 genes having been found mutated in a fraction of MPM cases (c-MET, VHL,WT1 among others). Clearly, a better and more systematic understanding of the role of genomic alterations in MPM is needed. In this retrospective study, a consecutive series of 123 formalin-fixed, paraffin embedded (FFPE) MPM tissue samples with clinical annotates, collected at two institutions, was retrospectively analyzed through Next-Generation Sequencing (NGS) technology to enhance knowledge about tumor-specific genomic profiling.Methods
Genomic DNA was extracted by tumour microdissected FFPE samples for all 123 patients. Amplicons NGS libraries for 50 Oncogene included in Ion AmpliSeq™ Cancer Hotspot Panel (CHP) v.2 were generated as indicated by manufacturer, and sequenced in Personal Genome Machine IonTorrent. Variant Caller included in Torrent Suite Software was utilised to identify mutations in the samples, annotation was performed with Annovar software. Genomic analysis for BAP1 and NF2 (not included in the CHP) is separately ongoing.Results
Of 123 advanced stage MPM patients, all treated with pemetrexed-based chemotherapy, 70% were males, current smokers 50%, median age 66.5 (range 36-82) years and histological subtypes were 96/22/5 epithelioid/biphasic/sarcomatous. With a cut off for allele frequency(AF)>=10% a total of 966 non-synonymous, 8 del-ins, 62 nonsense, 637 intronic, 204 regulatory and 1140 synonymous somatic sequence variations were detected in 107 patients already screened. Excluding synonymous mutations and irrespective of AF, the five most frequently altered genes were CSF1R (mut:154, pts:80), KDR (mut:148, pts:73), FLT3 (mut:132, pts:99), PIK3CA (mut:126, pts:60), TP53 (mut:111, pts:66). Evaluating mutations identified at least once, a correlation between HRAS and PIK3CA mutations and patient status (dead or alive) was observed (p=0.017 and p=0.039, respectively). Specifically, HRAS silent mutation p.H27H (rs12628) was responsible for the association (p=0.021) and occurred in 54% of 107 MPM compared to 30% of reported AF in available databases. PIK3CA p.I391M missense mutation (rs2230461; AF 24% in this series) was significantly associated to progression-disease (p=0.003). Among the other SNPs reported in at least 15 pts there are rs3729674(PIK3CA), rs1800863(RET), rs3822214(KIT), rs10006115(KDR), rs75580865(FLT3) and rs5030613(SMARCB1).Conclusion
These extremely preliminary data indicate that NGS technology is feasible in FFPE MPM tissues and some of the detected genetic mutations are novel observations of potential prognostic and therapeutic interest.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O22.02 - CD8 T-cell Infiltration and Tumor IL-7R Expression are Independent Prognostic Factors in Epithelioid Malignant Pleural Mesothelioma (ID 2935)
16:15 - 17:45 | Author(s): H. Ujiie, D. Buitrago, J. Nitadori, K. Kadota, L.M. Krug, W.D. Travis, V.W. Rusch, M. Sadelain, P.S. Adusumilli
- Abstract
- Presentation
Background
Following our publication (Cancer Immunol Immunother 2011) demonstrating the prognostic importance of chronic inflammatory cell infiltration in epithelioid malignant pleural mesothelioma (MPM), we investigated the prognostic significance of the immune microenvironment in the tumor nest and the tumor-associated stroma in epithelioid MPM.Methods
A tissue microarray (TMA) was constructed from 170 epithelioid MPM cases, with 6 representative tumor cores and 3 representative stromal areas. Immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) and interleukin receptors (IL-7R and IL-12Rβ2) were performed. TMA slides were analyzed for immune cell infiltration of tumor and stroma (low vs high, divided by use of the median), as well as for immune marker expression (sum of intensity and distribution). Overall survival (OS) was estimated using Kaplan-Meier analysis, and log-rank tests and Cox proportional hazards models were used to analyze the association between each marker and OS.Results
Analysis of single immune cell infiltration for all patients revealed that high tumor CD8+ T-cell infiltration, high CD20+ B-cell infiltration, and low tumor IL-7R expression correlated with higher OS (Figure). Combined tumor CD8+ and CD4+ cell infiltration significantly correlated with better OS (5-year OS, 36% [n=61] vs. 20% [n=96]; p=0.008). In a multivariate analysis including age, stage, lymph node metastases, lymphatic invasion, and vascular invasion, high CD8+ T-cell infiltration and low tumor IL-7R expression were independent predictors of OS (Table). Figure 1Figure 2Conclusion
Tumor CD8+ T-cell infiltration and tumor IL-7R expression are independently associated with survival, which highlights the biologic and prognostic significance of the immune microenvironment for patients with epithelioid MPM.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O22.03 - Durable cancer regressions in chemotherapy refractory mesothelioma patients with the anti-mesothelin immunotoxin SS1P and host immune depletion with pentostatin (P) and cyclophosphamide (C) (ID 1630)
16:15 - 17:45 | Author(s): R. Hassan, A. Miller, E. Sharon, A. Thomas, J.C. Reynolds, A. Ling, R.J. Kreitman, S. Steinberg, D.H. Fowler, I. Pastan
- Abstract
Background
SS1P is a recombinant immunotoxin targeting the tumor differentiation antigen mesothelin, which is highly expressed in mesothelioma. Anti-tumor activity of SS1P was limited in phase I clinical trials due to development of neutralizing antibodies (NAbs) that limited treatment to one cycle. In immunocompetent mice P and C (P-C) can abrogate development of anti-SS1P NAbs. This pilot study was performed to determine the impact of P-C-based immune depletion on anti-SS1P NAb formation and to assess safety of P-C-SS1P.Methods
Patients with progressive pleural or peritoneal mesothelioma who previously received platinum-based therapy were eligible. Up to 6 cycles of P 4 mg/m2 IV (cycle 1: days 1, 5, 9; cycle 2-6: day 1); C 200 mg PO (cycle 1: days 1-12; cycle 2-6: days 1-4) and SS1P IV (35 µg/kg, cycle 1: days 10, 12, 14; cycle 2-6: days 2, 4, 6) were administered (cycle 1 was 30 days and cycles 2-6 were 21 days) with restaging every 2 cycles in the absence of progressive disease and anti-SS1P NAbs.Results
Eleven patients were enrolled. The median age was 52 years (range 43-68); male 7, female 4; pleural 9, peritoneal 2; median number of prior treatments was 3 (range 2-6). Three out of 10 evaluable patients had partial response with tumor regressions of 74%, 70% and 44% with complete resolution of metabolic activity in two patients and >70% reduction in the third (Table). The overall survival of these patients is 17+, 15+ and 18+ months. In addition, one patient with stable disease and one patient with progressive disease had dramatic response to post-SS1P chemotherapy using drugs to which they had not responded previously. All five patients who responded are alive with overall survival ranging from 11 to 18 months. The regimen of P-C delayed development of NAbs to SS1P, thereby allowing multiple cycles of therapy with SS1P. Only 2 of 10 (20%) patients developed anti-SS1P NAbs after one cycle compared to 88% of patients who received single agent SS1P in a previous study (p=0.0001), thus meeting the primary endpoint. The regimen of P-C-SS1P was safe and well tolerated and no patient developed opportunistic infections. Grade ≥ 3 adverse events were P-C related lymphopenia (100%), transaminitis (18%) and SS1P related back pain (9%), non-cardiac chest pain (18%) and fever (9%).Pt Overall Tumor Response[†] Delayed Tumor Response[§] Post Study Chemo. Response to Post-SS1P Chemo. Overall Survival (months) 1 PR (-44%) Yes (7 m+) - - 18.2+ 2 PR (-74%) - - - 17.1+ 3 SD - Yes PR (-55%)* 15+ 4 PR (-70%) - - - 14.5+ 5 SD - - - 8.8 6 PD - - - 6.2 7 PD - - - 5.7 8 PD Yes (4 m+)** Yes 85% decrease in tumor [18]F-FDG uptake[¶] 10.6+ 9 PD - - - 4.2 10 SD - Yes No 7.3 PR, partial response; SD, stable disease; PD, progressive disease; [18]F-FDG, Fluorodeoxyglucose; [†]In patients with tumor response the maximum percent decrease in tumor dimensions is shown; [§]Months from study initiation when response first observed; * PR to post-SS1P treatment with previously ineffective chemotherapy; **Patient 8 had initial PD, but at 4 months had 25% reduction in size of one of the target lesions and marked decrease of metabolic activity by PET; [¶]Patient 8 had 85% reduction in metabolic activity compared to baseline and SD by CT scan on post- SS1P chemotherapy. Conclusion
SS1P and immune depletion with P-C results in significant and durable anti-tumor activity in heavily pre-treated chemotherapy refractory patients with mesothelioma. -
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O22.04 - DISCUSSANT (ID 3972)
16:15 - 17:45 | Author(s): P. Baas
- Abstract
- Presentation
Abstract not provided
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O22.05 - Exposure-response Relationship of Amatuximab (AMA) in Combination with Pemetrexed and Cisplatin (P/C) in Patients with Unresectable Pleural Mesothelioma (ID 1609)
16:15 - 17:45 | Author(s): J.D. Maltzman, B.A. Wallin, A. Gupta, J. Wustner, R. Hassan
- Abstract
- Presentation
Background
AMA is chimeric monoclonal antibody that binds to mesothelin, which is highly expressed in malignant mesothelioma and largely absent from normal tissue. In vitro studies indicate that AMA potentially has anti-tumor activity via antibody-dependent cellular cytotoxicity. AMA was studied in a Phase 2 mesothelioma trial.Methods
This was a global, single arm, open label Phase 2 trial in 89 patients with previously untreated epithelial or mixed histology unresectable malignant pleural mesothelioma. Subjects received P/C every three weeks for 4 to 6 cycles combined with AMA 5mg/kg on days 1 and 8 of each 21 day cycle. All patients were fully supplemented with folate and B12 as per pemetrexed label requirements. Single agent AMA was then continued in the same schedule until disease progression. The primary endpoint was progression-free survival (PFS) at 6 months with a secondary end point of overall survival (OS).Results
Median PFS was 6.1 months while median OS was 14.8 months. An evaluation of serum drug concentration relationship with clinical response noted that those subjects who achieved a median trough serum concentration of 32.9 µg/mL had an improved median PFS over those whose trough serum concentration was below the median (238 days vs 115 days, p<0.001). Similarly those subjects with a serum trough concentration of AMA above a median of 38.2 µg /mL had a median OS of 583 days while those with a median serum concentration of AMA below 38.2 µg /mL had a median OS of 375 days, p=0.0202. The most commonly reported adverse event was that of hypersensitivity to the chimeric antibody at first dose second cycle.Conclusion
The safety profile of AMA in combination with P/C was consistent with that seen previously for the PC regimen. Although PFS is not significantly different from historical results of P/C alone, the median OS was 14.8 months (as compared to 13.3 months for P/C[1]). PK/PD analysis demonstrated that AMA trough concentrations were a significant predictor of both PFS and OS where higher concentrations were associated with longer OS and PFS. [1]Reference: Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma. J Clin Oncol, 2003; 21:2636-2644.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O22.06 - Quality of Life Measurement Parallel Changes in Pulmonary Function in Patients Undergoing Pleurectomy and Decortication for Malignant Pleural Mesothelioma (ID 3444)
16:15 - 17:45 | Author(s): D. Burkholder, D. Hadi, H. Kindler, K. Todd, A. Durkin, W.T. Vigneswaran
- Abstract
- Presentation
Background
The role of maximal cyto-reductive surgery in malignant pleural mesothelioma (MPM) remains controversial. Although selected patients achieve long-term disease control following extended pleurectomy and decortication (PD), not all patients benefit. In addition surgical complications and side effects may adversely affect quality of life (QoL). We previously observed significant improvement in the quality of life following PD in patients who were symptomatic at baseline (Mollberg et al, Ann Thorac Surg 2012). In this study, we further examined the effects of PD on pulmonary function and correlated changes in pulmonary function with QOL.Methods
Consecutive patients with MPM undergoing PD were prospectively enrolled at a single center. The primary endpoint was to determine the effects of PD on QoL. Health related QoL was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 (EORTC QLQ-C30) before operation and at one,4-5, 7-8 , 10-11 and 12-13monthsmonths postoperatively. Pulmonary function testing was performed (PFTs) were measured immediately before the operation and at 6-7 months postoperatively. Patients were grouped according to the World Health Organization baseline performance status (PS) and compared.Results
Twenty-seven patients with a median age of 71 years old (range 59 to 91 years), 19 males and 8 females, were enrolled in the study from March 2010 to October 2012. At the time of the operation, 17 patients were WHO PS 0, 10 were PS 1. At baseline, the PS 1 patients had a significantly worse global QoL (p<.0001), functional (p<0.0001) and symptoms scores (p<0.0001). PS 0 patients had not significant change in global QoL or functional) and symptoms scores (except for emotional function and insomnia p<0.01) following the operation. In addition they demonstrated a significant decrease in FVC (p<0.003), FEV1 (p<0.005), TLC (<0.001) and DLCO (<0.009) following PD. PS 1 patients showed significant improvements in Global Health (p=0.05) functional measures (p< 0.01) and symptoms scores (p <0.03) at 4-5 months and this was maintained at 6-7 months following PD. Improvement also was noted in the FVC (p=0.09), FEV1(p=0.04) and DLCO (p=0.09) in these patients.Conclusion
At intermediate follow-up, extended PD for MPM had a negative impact on pulmonary function in minimally symptomatic patients without any significant improvement in QoL. In contrast, patients who were symptomatic at baseline significantly improved in QoL and showed a modest improvement in pulmonary function after PD. The change in pulmonary function may be partially responsible for the observed QoL in symptomatic patients undergoing PD.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O22.07 - Does surgery improve survival of patients with malignant pleural mesothelioma? A multicenter retrospective analysis of 1365 consecutive patients. (ID 2962)
16:15 - 17:45 | Author(s): A. Bille, F. Ardissone, P.G. Bovolato, C. Casadio, G. Garofalo, G.B. Ratto, L. Santambrogio, V. Torri, U. Pastorino
- Abstract
- Presentation
Background
Medical management of malignant pleural mesothelioma (MPM) has obtained a moderate survival improvement over the years, while surgery with pleurectomy / decortication (P/D) or extrapleural pneumonectomy (EPP) can be an option for selected patients with resectable disease. The aim of this study was to investigate the impact of surgical treatment on the outcome of patients with MPM.Methods
We retrospectively reviewed data from 1365 consecutive patients with histologically proven MPM, treated from 1982 to 2012 in six Institutions.Patients received either chemotherapy alone (n=172) or best supportive care (n=690) or surgical treatment (n=503), by either P/D (n=202) or EPP (n=301) with or without chemotherapy. All patients were followed up until death or for a minimum period of one year. The cox proportional hazards regression model was used to estimate relative improvements and to test the statistical hypothesis; a p-value less than 0.05 was considerd statistical significant.Results
Figure 1 Figure1. Kaplan-Meier survival curves according to the treatment (non surgical treatment vs EPP vs P/D) considering only patients with independent good prognostic factors After a median follow-up of 6.7 years (range 1.1-14.8), 230 (16.8%) patients were alive; median survival for patients who received palliative treatment or chemotherapy alone, P/D and EPP groups were 11.7 (95%CI: 10.5-12.5) months, 20.5 (95%CI: 18.2-23.1) months, and 18.8 (95%CI: 17.2-20.9) months, respectively. Testing the hypothesis of equal survival distributions the statistical significance was reached for the P/D and EPP groups versus non surgical treatment group (p <0.001) but not for the EPP versus P/D groups (p=0.885). The 30 day mortality was 2.6% after P/D and 4.1% after EPP (p=0.401). According to multivariate analysis (n=1227) age < 70, epithelial histology and chemotherapy were independent favourable prognostic factors. In the subset of 312 (25.4%) patients with all favourable prognostic factors median survival was 15.5 months after medical therapy alone, 19.4 months after P/D, and 18.7 months after EPP (Figure 1). A risk reduction of 31% (95%CI: 14-45%) for the P/D group and of 23% (95%CI: 7-36%) for the EPP group was observed compared to the medical treatment group.Conclusion
Our data suggest that patients with good prognostic factors had a similar survival whether they received medical therapy only, P/D or EPP. The modest benefit observed after surgery over medical treatment requires further investigation, and a large multicenter randomized trial, testing P/D after induction chemotherapy versus chemotherapy alone in MPM patients with good prognostic factors, is needed.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O22.08 - DISCUSSANT (ID 3973)
16:15 - 17:45 | Author(s): R. Hassan
- Abstract
- Presentation
Abstract not provided
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Author of
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P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.06-041 - Plasma Vascular endothelial growth factor 165(VEGF 165) in advanced Non-small cell lung cancer (ID 2927)
09:30 - 16:30 | Author(s): R. Gaafar
- Abstract
Background
Lung cancer is the leading cause of death among malignant tumors worldwide therefore it is important to develop novel diagnostic techniques.Methods
This is a prospective case control study including two groups of patients: Group I: healthy volunteers as control .Group II: Patients with advanced non-small cell lung cancer (NSCLC). Plasma VEGF 165 levels were measured at baseline by ELISA before first line Gemcitabine-Cisplatin regimen. High VEGF 165 cutoff taken was >703 pg/ml .Primary end point was comparison of plasma VEGF 165 levels in cases and controls. Secondary endpoint was correlation between High VEGF 165 and clinical response (CR), Progression free survival (PFS) and overall survival (OS) in advanced NSCLC patients.Results
35 patients with advanced NSCLC and 34 age and sex matched normal subjects as control were included and followed up during the period from 10/2009 to 10/2012 with median follow up of 10.5 months. Median plasma VEGF 165 level was 707 pg./ml in cases versus 48 pg./ml in controls, (p < 0.001).No significant correlation was found between plasma VEGF 165 level and clinical response(p < 0.5).No significant correlation was found between plasma VEGF 165 level and Median PFS and OS (p=1 and 0.7 respectively.Conclusion
Plasma VEGF 165 is a potential diagnostic marker in advanced NSCLS.
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P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.06-047 - Prognostic value of neutrophil lymphocyte ratio in second line advanced malignant pleural mesothelioma (ID 3135)
09:30 - 16:30 | Author(s): R. Gaafar
- Abstract
Background
Malignant pleural mesothelioma is a lethal disease and hence the strong need for identifying new prognostic factors.Methods
This is a retrospective study including all eligible patients with advanced malignant pleural mesothelioma (MPM) presenting to National Cancer Institute, Cairo University. Neutrophil lymphocyte (N/L) ratio was assessed before second line chemotherapy.2.5 was used as the cutoff point. Endpoints were assessment of correlation between N/L ratio and clinical response (CR), progression free survival (PFS) and overall survival (OS).Results
52 patients (19 stage III and 33 stage IV) MPM were included and followed up during the period from July 2009 till November 2012 with a median follow up period of 2.6 months. 87.5% of patients with N/L ratio > 2.5 showed progressive disease versus 91.7% in patients with N/L ratio <2.5. (P-value=0.66).6 months PFS was 11% for patients with N/L ratio > 2.5 versus 14% for patients with N/L ratio <2.5. (P-value =0.001). 6 months OS was 72% for patients with N/L ratio > 2.5 versus 66% for patients with N/L ratio <2.5. (P-value =0.4).Conclusion
N/L ratio is a potential prognostic marker for advanced MPM treated with second line chemotherapy.
