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R. Hassan
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MINI 25 - Trials, Radiation and Other (ID 142)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 15
- Moderators:J.M. Clavero, R. Hassan
- Coordinates: 9/08/2015, 16:45 - 18:15, 702+704+706
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MINI25.01 - A Phase II Study of Dovitinib in Previously-Treated Malignant Pleural Mesothelioma: The Ontario Clinical Oncology Group DOVE-M Trial (ID 1302)
16:45 - 16:50 | Author(s): S.A. Laurie, D. Hao, N. Leighl, J. Goffin, A. Khomani, M. Filion, G.R. Pond, M.N. Levine
- Abstract
- Presentation
Background:
Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFR.
Methods:
This open-label multicentre phase II trial enrolled consenting adult patients with advanced, histologically-confirmed MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Patients were ECOG PS < 2 and had adequate end-organ function. Dovitinib was administered orally at 500 mg/day for 5 days on, 2 days off; cycle length was 28 days. Two dose reductions (to 300 mg) for toxicity were permitted. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. Pre- and cycle 1 day 15 on-treatment diffusion-weighted pleural MRI was evaluated for its potential as an early marker of drug effect. The primary end-point was the proportion of patients progression-free at 3 months (PF3). A two-stage design was used: H0: 3-month PFS=40% versus HA: 3-month PFS=65% (roughly corresponding to a median PFS of 4.5 months), with α=0.05, β=0.20. If 6 of 12 PF3 in stage I, an additional 14 patients would be enrolled, with dovitinib of interest if > 15 of 26 PF3.
Results:
12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1-8). Commonly observed and / or grade 3 at least possibly related adverse events (any grade / grade 3, %): diarrhea (67 / 0%) vomiting (50 / 0%) fatigue (42 / 8 %), nausea (42 / 8 %), rash (0 / 17 %), syncope / generalized muscle weakness / elevated ALT (0 / 8 % each). No hyperphosphatemia was observed. 7 patients had at least one dose interruption (5 in cycle 1) and 5 had a dose reduction (1 to 300 mg); median dose intensity during cycles 1 and 2 was 80 %. 3 patients discontinued due to clinical progression by day 1 cycle 2. Best response: 1 unconfirmed PR, 4 SD, 2 PD and 4 inevaluable (3 with clinical PD; 1 intercurrent illness). The median PFS was 2.6 months and the median OS was 4 months. PF3 was 50%; although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population.
Conclusion:
Dovitinib has minimal activity and a toxicity profile comparable to other VEGFR inhibitors in previously-treated MPM; it is not clear if FGFR is effectively targeted. Correlative studies are ongoing and may help to clarify the role of the FGFR in MPM. [NCT01769547].
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- Abstract
- Presentation
Background:
To observe the efficacy and safety of intra-thoracic chemotherapy of recombinant human endostatin (Endostar) combined with cisplatin in the treatment of malignant pleural effusion.
Methods:
A total of 84 patients with malignant pleural effusion were randomly divided into intra-thoracic chemotherapy of Endostar combined with cisplatin group (combination group) and single cisplatin group (single group). Before treatment, pleural effusion was completely resolved. Combination group was treated with intra-thoracic injection of 40～50 mg cisplatin and 60 mg Endostar twice a week, and 4 times were as a cycle at most. Single group was only treated with cisplatin, and other operations were the same as the combination group. RECIST1.0 hydrothorax evaluation criteria and NCI-CTC AE 3.0 version classification criteria were applied to evaluate the efficacy and adverse reactions, respectively.
Results:
The response rates of initially-treated patients in combination group and single group were 63.6% and 40.6%, respectively, and significant difference was presented (X[2]＝2.737, P＝0.022). The response rates of all patients in combination group and single group were 58.1% and 36.6%, respectively, and the difference was significant (X[2]＝4.877, P＝0.019). The progression-free survival (PFS) in combination group was dramatically longer than in single group (95 d vs. 53 d; X[2]＝3.872, P＝0.039). No adverse reactions at degree Ⅳ were observed in all groups. Incidences of adverse reactions including neutropenia, anemia, fatigue and increase of blood pressure in combination group were all higher than in control group, but there was no statistical significance (P＞0.05).
Conclusion:
Intra-thoracic injection of cisplatin alone is effective for treating patients with malignant pleural effusion, and its efficacy is better in combination with Endostar. Cisplatin combined with Endostar has a synergistic effect and better safety, being worthy of further popularization in clinic.
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MINI25.03 - Potent Anti-Mesothelioma Activity by the Novel Naftopidil Analogue HUHS1015; Preclinical Evidence for Treatment (ID 2733)
16:55 - 17:00 | Author(s): K. Kuribayashi, R. Ieki, T. Otsuki, A. Gotoh, A. Tanaka, T. Nishizaki, T. Nakano
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is usually a fatal neoplasm, and current therapeutic interventions are far from satisfactory. Naftopidil, an α1-adrenoceptor antagonist, is used clinically for the treatment of benign prostate hypertrophy, and has been found to reduce the incidence of prostate cancer and to inhibit prostate cancer cell proliferation via G1 cell cycle arrest. Recently, naftopidil has been demonstrated to induce apoptosis in mesothelioma cells by activating caspase-8 and the effector caspase-3 independently of α1-adrenoceptor suppression. Hence, a more potent naftopidil analogue, HUHS1015, was synthesized. The current study evaluates the inhibitory effect of HUHS1015 on malignant mesothelioma cell proliferation in preclinical models and assesses whether HUHS1015 can be the basis for new drug for the treatment of MPM.
Methods:
We treated the human MPM cell lines MSTO-211H, NCI-H28, NCI-H2052 and NCI-H2452 with HUHS1015, and evaluated cell viability using the MTT method. Additionally, NCI-H2052 tumor xenograft models in BALB/c-nu/nu mice were utilized to investigate anti-mesothelioma activity in vivo.
Results:
HUHS1015 reduced the viability of MPM cells more potently than cisplatin or paclitaxel at concentrations higher than 30 μM, and the drug induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. The effect of HUHS1015 on the expression of Bcl-2 family mRNAs in MSTO-211H and NCI-H2052 cells was tested using real-time RT-PCR. Puma, Hrk, and Noxa mRNAs were up-regulated in both cell lines. In the NCI-H2052 mouse xenograft models, HUHS1015 strongly suppressed tumor growth.
Conclusion:
These results indicate that HUHS1015 may be an effective anticancer drug candidate for the treatment of MPM. HUHS1015 induces apoptosis of MPM cells through modulation of a mitochondrial pathway, and future clinical investigations with this drug are warranted for mesothelioma.
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MINI25.04 - Utilizing Molecular Profiling to Identify Potential Therapies in Sarcomatoid Lung Cancer (ID 655)
17:00 - 17:05 | Author(s): J. Wang, D. Arguello, Z. Gatalica, S. Reddy, P. Fidias
- Abstract
- Presentation
Background:
Sarcomatoid lung cancer (SLC) is an aggressive subset of poorly differentiated non-small cell lung carcinoma (NSCLC), comprising just one percent of all NSCLC. Further elucidation of this unique histological entity has been hampered by a lack of large-scale clinical trial evidence. The National Comprehensive Cancer Network (NCCN) contains no clear direction regarding optimal management. The purpose of this study, therefore, is to identify potential therapeutic options for this disease using a multiplatform, biomarker-directed approach.
Methods:
In total, 48 SLC specimens analyzed via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH) were retrospectively evaluated.
Results:
High rates of PD-L1 (83.3%, 5/6) and PD-1 (80.0%, 4/5) protein expression by IHC imply benefit to recently-approved compounds. EGFR amplification by ISH (18.8%, 3/16) and MET amplification (9.5%, 2/21) were independent of EGFR mutation in this group. No ALK, HER2 or ROS1 ISH abnormalities were detected. Mutational analysis shows the highest mutation rates in TP53 (50.0%, 7/14), KRAS (44.4%, 16/36), cKIT (5.3%, 1/19), EGFR (5.1%, 2/39) and BRAF (4.8%, 1/21). The two EGFR mutations detected were L858R and exon 20 insertion.
Conclusion:
Multiplatform profiling identified multiple potential actionable targets with various approved therapies. PD-1 and PD-L1 overexpression rate was comparable to that published in sarcomatoid renal cell carcinoma. Therefore, new immunotherapies should be prospectively tested in sarcomatoid disease specific trials based on high PD-1/PD-L1 overexpression. Our finding of low EGFR mutational frequency is consistent with previous, published findings in this disease. Lower rates of ALK, ROS1, and EGFR are not surprising given SLC’s association with smoking. Clinical trials evaluating the benefit of imatinib and vemurafenib in subgroups with cKIT or BRAF mutations may be worthwhile.
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MINI25.05 - Discussant for MINI25.01, MINI25.02, MINI25.03, MINI25.04 (ID 3430)
17:05 - 17:15 | Author(s): A. Tsao
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Controversy over adjuvant radiation of thymoma has raged on among experts for decades. 20-30% thymoma patients present with myasthenia gravis (MG). The co-existence of MG and thymoma makes the surgical treatment and adjuvant radiation more complicated. The aim of this article is to investigate whether patients with MG and thymoma should receive mediastinal radiation therapy and when after extended thymectomy.
Methods:
Between 2002 and 2012, 159 patients with MG and thymoma underwent extended thymectomy. These patients were subdivided into 3 groups: Group 1 (n=89), patients having mediastinal radiotherapy within one month after surgery; Group 2, having mediastinal radiotherapy over three month after surgery (n = 49); and Group 3, without adjuvant radiation (n = 21).
Results:
152 patients underwent extended thymectomy by VATS, and 7 undergoing the trans-sternal approach due to thymoma invading great vessels. The resection was extended to the pericardium in 23 patients, the lung in 17 patients, and the innominate vein in 11 patients. There were no inoperable cases. The proportions of type A, AB, B1, B2, B3, and thymic carcinoma in this data were 0.6%, 19.5%, 25.8%, 32.7%,21.4%, and 0%, respectively. 146 patients were followed for 15 months to 12 years: 82 in Group 1, 45 in Group 2, and 19 in Group 3. Postoperative myasthenic crisis occurred in 38 cases: 16 cases in Group 1, 14 in Group 2, and 8 in Group 3. There was a significant difference in occurrence of postoperative myasthenic crisis between Group 1 and Group 3 (P=0.045). The rates of reaching CSR were 31.7% in Group 1, 22.2% in Group 2, and 21.1% in Group 3, respectively. The overall survival of Group 1, Group 2, and Group 3 were 90.2%, 86.7%, and 78.9%, respectively. 6 patients in Group 1 recurred, while 4 patients in Group 2 and 4 in Group 3 recurred. There was no lymph node metastasis detected. Kaplan-Meier survival curves demonstrate that there is no significant difference in overall survival among 3 groups. However, Cox regression analysis made by entering some factors including sex, age, and adjuvant radiation, revealed that adjuvant radiation might have significant influence in prognosis in thymoma patients ( P = 0.047). Figure 1
Conclusion:
Adjuvant radiation within one month after extended thymectomy may help decrease possibility of postoperative myasthenic crisis, raise the cumulative probabilities of reaching CSR, and might have significant influence in prognosis in thymoma patients with MG. In recurrence cases, no lymph node metastasis was detected
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MINI25.07 - Clinical Activity of Lucitanib in Advanced Thymic Epithelial Tumours (ID 2153)
17:20 - 17:25 | Author(s): B. Besse, N. Girard, A. Gazzah, C. Hierro, J. Tabernero, F. Debraud, G. Camboni, F. Dubois, C. Leger, F. Legrand, R. Robert, P. Therasse, J. Soria
- Abstract
- Presentation
Background:
Thymic epithelial tumours are rare malignancies for which there is no standard treatment for patients with advanced disease progressing on or after chemotherapy. Despite the lack of identified targets in thymic malignancies, several studies demonstrated that VEGFR and KIT pathways are the most relevant targets for therapeutic intervention. Lucitanib is an oral, potent, selective inhibitor of the tyrosine kinase activity of FGFR1-3, VEGFR1-3, and PDGFR α/β, all key targets involved in pro-angiogenic and proliferative pathways leading to tumour progression. Therefore, lucitanib could be a potential therapeutic alternative for patients with recurrent or refractory disease.
Methods:
This first in human study is currently evaluating oral lucitanib as monotherapy in various solid tumours. The escalation phase used a 3+3 design in patients with advanced solid tumours to establish the recommended phase II dose. Safety and efficacy were further evaluated in patients whose tumours were determined to be FGF aberrant (FGFR1 and/or 11q amplification) or in patients with tumours known to be anti-angiogenesis-sensitive such as thymic epithelial tumours. In addition, different doses and administration schedules were investigated.
Results:
Of the 134 patients treated in the study, 3 had B-type Thymoma (T) and 12 had Thymic Carcinoma (TC). Among these patients, median age was 54 years [range 37-72], 7 were males and 8 females. Twelve patients (80%) were treated at 12.5mg on daily basis. The other 3 patients (T) received 5, 15 and 20mg respectively. Patients had received a median of 2 previous anti-cancer treatments [range: 0-6]. Median duration of treatment with lucitanib was 7 cycles [range 2-44]. All patients were evaluable for anti-tumour activity according to RECIST v1.1. Two patients had confirmed partial response (1T / 1TC) lasting at least 7 months (TC patient is still ongoing) and 10 patients had a stable disease with 6 of them lasting at least 6 months. To date, 4 patients are still ongoing and receiving benefit from lucitanib independently of the number of previous regimens. The most common adverse events related to lucitanib in this population (all grades, all doses) were hypertension (80%), hypothyroidism (53%), proteinuria (53%) and diarrhoea (40%). There was no major bleeding event reported. These findings were in line with the overall safety profile of lucitanib already described.
Conclusion:
The results of this tumour cohort analysis suggest that lucitanib has signs of clinical activity in patients with advanced thymic epithelial tumours, and should be further investigated in dedicated studies.
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MINI25.08 - Systemic Treatment in Advanced Thymic Epithelial Tumors. Insights From a Prospective Cohort of 888 Patients Enrolled in RYTHMIC (ID 1166)
17:25 - 17:30 | Author(s): N. Girard, E. Dansin, H. Léna, E. Pichon, P. Thomas, J. Mazières, L. Thiberville, V. Westeel, G. Zalcman, C. Clément-Duchêne, G. Massard, X. Quantin, J. Bennouna, P. Fournel, T. Molina, B. Besse
- Abstract
Background:
RYTHMIC (Réseau tumeurs THYMiques et Cancer) is the French nationwide network for thymic malignancies. Starting 2012, all patients diagnosed with thymic tumor had to be enrolled, as recommended by the French National Cancer Institute, part of good clinical practice.
Methods:
RYTHMIC prospective database is hosted by the French Thoracic Cancer Intergroup (IFCT), and collects clinical, imaging, treatment, and follow-up data of patients discussed at the reference national multidisciplinary tumor board (MTB). Data cutoff was April 1[st], 2015 for this analysis.
Results:
1089 questions were raised at the MTB about the management of 888 patients with thymic epithelial tumor. Among assessable cases, Masaoka-Koga stage III-IV tumors accounted for 42% of cases; histology was thymoma in 82% of cases, and thymic carcinoma in 18% of cases. First-line treatment of locally advanced disease, and management (diagnosis and treatment) of recurrent disease led to raise 227 (21%), and 234 (21%) questions at the MTB, respectively, 312 (68%) of which were about the modalities of systemic treatment. Figure 2 shows the proposed regimens for primary (A) and exclusive (B) chemotherapy in treatment-naïve patients, and chemotherapy (C) and targeted agents (D) for recurrent tumors. Combination of cisplatin, adriamycin, and cyclophosphamide and carboplatine, paclitaxel were the most frequently proposed regimens as first- and second-line treatment, respectively. Figure 1 Figure 2
Conclusion:
RYTHMIC is an exhaustive registry of thymic malignancies, which provides unique insights in the management of advanced and recurrent tumors with systemic agents. Meanwhile, limited data have been made available in the literature so far, as clinical trials were conducted in small numbers of patients, and existing databases enrolled a majority of surgically resected, early-stage tumors. Through the use of targeted agents, RYTHMIC allows the rapid implementation of new results in clinical practice, while ensuring patients an equal access to therapeutic innovation. Supported by Institut National du Cancer
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- Abstract
- Presentation
Background:
Percutaneous cryoablation (PC) is an ablative technique, being used for local treatment of recurrent mesothelioma in patients following surgical lung sparing decortication and pleurectomy, and occasionally for palliative control of tumor extension to vital structures or pain control. The purpose of this study was to evaluate the safety and efficacy of PC in local control of recurrent mesothelioma.
Methods:
With IRB approval, patients with recurrent mesothelioma following lung sparing pleurectomy and decortication with at least one PC were identified from a database containing ablation information. Intra procedural and immediate post procedural hospital information was assessed for complications and follow up imaging was used to asses for late complications and recurrence. Patients were followed with CT and and PET/CT scans for 6 and some up to 12 months. Local recurrence determined by increased regional metabolic activity or increased size of post ablation zone at 6 months. A stepwise multiple logistic regression model was used to assess predictors of local recurrence after ablation, considering clinical variables including: stage at diagnosis, chemotherapy, radiation, recurrence time lag following surgery, and number of lesions at time of recurrence presentation, And PC variables including: size of the lesion, edge of ice ball beyond the tumor, number of probes, size of probes, number of cryo cycles, maximum and total freeze and thaw time.
Results:
From the database, 25 patients were identified who underwent a total of 117 outpatient cryoablations (range of 1-25). 4 ablations in 3 patients were performed for palliative and pain control indications. Lesions measured a mean of 32.5 mm (range 9-113) by 18.0 mm (range 6-60) in diameter. At 6 months 110/117 (94.0%) of ablations showed no recurrence. No major, but minor complications including hematoma, small pneumothorax and hemoptysis in one patient each and erythema in 3 chest wall subcutaneous lesions (5/117 =4.2%). Late complications in 4/117 (3.4%) ablations. Considering the clinical and cryoablation variables no recurrence was seen in patients having the edge of iceball more than 7 mm beyond the tumor.
Conclusion:
PCT can be used for management of recurrent mesothelioma following surgery with low recurrence rate of 6%, and limited procedural complications 4.2% and late complications of 3.4%. When performing PCT, at least 7 mm of the of iceball is needed to extend beyond the edge of tumor to limit local recurrence.
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MINI25.10 - Discussant for MINI25.06, MINI25.07, MINI25.08, MINI25.09 (ID 3431)
17:35 - 17:45 | Author(s): F. Mornex
- Abstract
- Presentation
Abstract not provided
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MINI25.11 - Optimization of Gross Tumour Volume Definition in Lung-Sparing Volumetric Modulated Arc Therapy for Pleural Mesothelioma (ID 2860)
17:45 - 17:50 | Author(s): A. Botticella, G. Defraene, K. Nackaerts, C. Deroose, J. Coolen, P. Nafteux, S. Peeters, D. De Ruysscher
- Abstract
- Presentation
Background:
High dose lung-sparing pleural radiotherapy for malignant pleural mesothelioma (MPM) is difficult. Given the steep dose gradient with volumetric modulated arc therapy (VMAT), accurate target delineation is critical. The optimal imaging modality to define radiotherapy target volumes has not been studied in depth. This is the aim of the present study.
Methods:
Twelve consecutive patients with a histopathological diagnosis of stage I-IV MPM (6 left-sided and 6 right-sided) were included. CT scans with intravenous (IV) contrast, [18]F-FDG PET/CT scans, MRI scans (post-contrast T1-weighted and T2-weighted) and diffusion-weighted images (DWI) were obtained and downloaded from the institutional database onto a standalone image fusion workstation (MIM Software Inc., Cleveland, OH, USA) for image registration and contouring. CT scans were rigidly co-registered with ~18~FDG-CT-PET, with MRI scans and with DWI scans. Four sets of pleural GTVs were defined: 1) a CT-based GTV (GTV~CT~); 2) a PET/CT-based GTV (GTV~CT+PET/CT~); 3) a T1/T2-weighted MRI-based GTV (GTV~CT+MRI~); 4) a DWI-based GTV (GTV~CT+DWI~). Only the pleural tumor was contoured; mediastinal nodes were excluded. In each of the 4 co-registrations, a “quantitative” and a “qualitative” (visual) evaluation of the volumes were performed. “Quantitative” evaluation was carried out through the coefficient of variation (COV; the ratio between the standard deviation [SD] and the mean: a measure of the dispersion of a distribution) and the Jaccard index (the ratio between the union and the intersection between two volumes: a measure of overlap). “Qualitative” evaluation consisted of a visual identification of any additional tumor site in each of the 4 obtained co-registrations.
Results:
Compared to CT-based GTV definition, PET/CT identified additional tumour sites in 12/16 patients. Compared to either CT or PET/CT, MRI and DWI identified additional tumour sites in 15/16 patients. Additional tumour sites were mainly the parietal pleura, the diaphragm and the chest wall. Mean GTV~CT~, GTV~CT+PET/CT~, GTV~CT+MRI~ and GTV~CT+DWI~ (+SD) were respectively 630.1 mL (+302.81), 640.23 (+302.83), 660.8 (+290.8) and 655.2 mL (+290.7). Mean Jaccard index was lower in MRI-based contours versus all the others.
Conclusion:
To the best of our knowledge, this is the first study showing that the integration of the MRI (T1/T2-weighted) and DWI into the target volume definition in lung-sparing hemi-thoracic VMAT in MPM may allow to improve the accuracy of target delineation and reduce the likelihood of geographical misses.
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MINI25.12 - Hospital Resource Utilization and Outcomes of Pleurectomy Compared to Extrapleural Pneumonectomy for Mesothelioma (ID 2539)
17:50 - 17:55 | Author(s): R.B. Cameron, O. Olevsky, M. Selch, M. Fishbein, F. Abtin, W..D. Wallace, R. Suh
- Abstract
Background:
Although extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) provide similar survival in malignant pleural mesothelioma (MPM), we sought to compare the two procedures in terms of another important outcome" hospital resource utilization (RU).
Methods:
With IRB approval, we retrospectively reviewed our prospective database to determine RU (ICU and hospital stay, mechanical ventilation, and central line use, etc) and Kaplan-Meier median survival (MS) for patient undergoing P/D. Our results are compared with similar findings for EPP reported in the literature.
Results:
We identified 121 pts on an "intent to treat" basis from 1997-2011. 94 (77.7%) were male. Mean age was 65.9 yrs (range 27-84). Comorbidities included hypertension 45.5%, coronary artery disease 11.6%, diabetes 10.7%, and vascular disease 6.2%. Mean surgical time was 7 hrs 57 mins (range 3 hrs 15 min–14 hrs 21 min). R1 resection was achieved in 116 (95.9%). Microscopic "margins" were assessed in 63 with 40 (63.5%) positive. Pathologic T- and N-staging is shown in Table 1. Morbidity was mostly limited to air leaks >10 days 41 (33.9%) and atrial arrhythmias 38 (31.4%). Three patients (2.5%) died. Relevant RU data included: intraoperative CVP lines 3 (2.5%), OR extubation 113 (93.4%), no ICU stay 99 (81.7%), and mean hospital stay 10 (range 5-103) days. RU data with P/D + RTx is compared to EPP as reported by others (figure 1). MS was 13.8 mos for all patients and 17.8 mos for epithelioid histology, which was better than biphasic (10.3 mos) and sarcomatoid (2.1 mos) subtypes (p<0.01). MS for 85/121 patients (70.2%) who completed P/D + RTx was 19.7 mos. MS for similar groups of EPP patients is reportedly 16.8-19 mos (eg, Thorac Cardiovasc Surg 1999;117(1):54-65 and J Clin Oncol 2009;27(18):3007-13).Conclusions: P/D +RTx provide essentially the same outcomes as EPP with less use of hospital resources
Figure 1T Stage N Stage 0 0 57(47.1%) 1 0 3(2.5%) 2 24(19.8%) 58(47.9%) 3 70(57.9%) 0 4 27(22.3%) -
Conclusion:
P/D provides essentially the same outcomes as EPP with less use of hospital resources.
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- Abstract
- Presentation
Background:
Surgical resection for pulmonary metstasis of osteosarcoma has been considered as the treatment of choice, however, it was not feasible to predict the benefit of metastasectomy for patients with multiple poor prognostic parameters. Survival prediction model can be very helpful for this purpose, so we made a nomogram based on parametric survival model(PSM) and regression trees from recursive partitioning analysis(RPA).
Methods:
We reviewed the clinical variables of patients who underwent single or multiple surgical resection for pulmonary metastasis of osteosarcoma between 1994 and 2012. Prognostic parameters were incorporated into PSM and RPA to build a nomogram and regression trees for the prediction of survival after single or multiple metastasectomy. The ‘rms’ and ‘rpart’ package of R(version 3.2.0) were used for this procedure. PSM was validated with C-index calculated by bootstrap method and then the parameters of PSM were used for RPA.
Results:
We analyzed 186 patients who received 294 metastasectomies. The number of second, third, and forth metastasectomy cases were 62, 28, and 11 respectively. Overall 5-year survival rate after first metastasectomy was 47%. Age, gender, number of metastatic nodules, frequency of metastasectomy, disease free interval before metastasectomy, size, subtype and resection margin of primary tumor were affecting overall survival. Nomogram and regression trees were displayed in figures. C-index of PSM was 0.71. Figure 1 Figure 2
Conclusion:
Our prediction model using a nomogram and regression trees can be easily employable for calculating survival benefits. Nomogram and RPA are complementary to each other. RPA displays comprehensive grouping of patients who have similar prognosis, while nomogram is useful for predicting hazard ratio of individual patient. In this study, our combined model constitutes a useful tool for predicting prognosis of patients who undergo repeated metastasectomy for osteosarcoma.
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MINI25.14 - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH): Descriptive Analysis and Overall Survival (ID 3153)
18:00 - 18:05 | Author(s): M. Kumar, C. Zhang, Z. Chen, M. Nelson, V. Ernani, G. Staton, S. Veeraraghavan, A. Gal, G. Sica, T.K. Owonikoko
- Abstract
- Presentation
Background:
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder characterized by proliferation of neuroendocrine cells in the bronchial wall and considered to be pre-invasive lesion for lung carcinoid tumors [1]. There is increasing rate of diagnosis of this condition due to widespread availability and use of cross sectional imaging. DIPNECH is reported as an incidental finding in approximately 5.4% of patients undergoing resection for lung neoplasms [2]. The optimal management of this condition is currently not well-established. The limited data regarding the clinicopathologic characteristics and long term outcome for patients with DIPNECH provided a strong rationale for this study.
Methods:
We employed medical records to obtain demographic, clinical characteristics and survival for patients diagnosed with DIPNECH at our institution between January 1990 to December 2014. A review of archival diagnostic material was conducted by expert pulmonary pathologists to confirm the original diagnosis. Differences in clinical characteristics and survival was assessed between patient groups defined by race, gender, age, smoking status, body habitus and treatment received. Survival was computed using the Kaplan–Meier method while univariate and multivariate models were employed to assess for significant association between patient survival and variables of interest.
Results:
A total of 27 patients were included in this analysis. The majority of patients were females (89%) and predominantly of Caucasian (66.7%) or Black (14.8%) race. The median age at diagnoses was 63 years (range: 20-77) and 61.5% of patients were non-smoker. Approximately 52% underwent surgical resection. The median overall survival (OS) was 151 months (95%CI: 39-165) while 1-year and 5-year survival rates were 95.2% and 73.2% respectively. Nineteen patients (71%) remain alive at the time of this analysis. Male patients (HR: 4.58, 95%CI: 0.76-27.67, p=0.098) and smokers (HR: 23.79; 95%CI: 0.98-579.54; p<0.052) appeared to have an inferior survival. No statistically significant difference in survival was recorded in patient subgroups defined by age, race, surgical intervention or body weight.
Conclusion:
DIPNECH is a rare condition with increasing rate of diagnosis. The overall prognosis is good in comparison to other lung neoplasms but up to a quarter of the patients do not survive beyond five years post diagnosis. Male gender and associated use of tobacco products may be associated with poor outcome. References: 1. Chassagnon, G., et al., DIPNECH: when to suggest this diagnosis on CT. Clin Radiol, 2015. 70(3): p. 317-25. 2. Ruffini, E., et al., The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothorac Surg, 2004. 26(1): p. 165-72.
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MINI25.15 - Discussant for MINI25.11, MINI25.12, MINI25.13, MINI25.14 (ID 3432)
18:05 - 18:15 | Author(s): J. Edwards
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI21.10 - The TORK/DNA-PK Inhibitor CC-115 Shows Combination Anti-Proliferative Effects with Erlotinib in NSCLC Cells Resistant to EGFR Inhibition (ID 641)
17:40 - 17:45 | Author(s): R. Hassan
- Abstract
Background:
In non-small cell lung cancer (NSCLC), activation of the phosphoinositide-3-kinase (PI3K)/mTOR pathway is common in tumors resistant to Epidermal Growth Factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). CC-115 (Celgene Corporation), an mTOR kinase inhibitor that targets both mTORC1 and mTORC2 as well as DNA-dependent protein kinase (DNA-PK), is currently under early clinical development. We evaluated CC-115 in combination with Erlotinib to overcome resistance to EGFR tyrosine kinase inhibition in non-small cell lung cancer (NSCLC) cell lines and xenografts in nude mice.
Methods:
In the present study we investigated whether CC-115 is able to increase the therapeutic effect of the EGFR TKI Erlotinib in several different NSCLC cell lines which exhibit intermediate or high resistance to EGFR TKIs: A549, H1975, H1650, HCC95, H2122 and H23. Mechanisms of inhibition were analyzed with assays for proliferation, apoptosis, and cell cycle progression. Cell signaling activity was analyzed using phospho-specific antibodies in Western blotting. Xenograft mice studies were performed to confirm the results in vivo.
Results:
CC-115 demonstrated anti-proliferative activity in NSCLC cell lines with various degrees of sensitivity as reflected in different IC50 values, ranging from 0.07 up to 6.9 mM. The anti-proliferative efficacy of Erlotinib was increased in the NSCLC cells synergistically by combination treatment with CC-115 with combination indices down to 0.04-0.2, indicating strong synergy. The synergistic, anti-proliferative effect of the combination treatment could be explained by increased cell cycle arrest and inhibition of signaling components in the mTOR pathway, especially 4E-BP1. In vivo studies in mice xenografts demonstrated a strong synergistic effect of the combination treatment of Erlotinib and CC-115.
Conclusion:
We demonstrate that the therapeutic effect of the EGFR tyrosine kinase inhibitor Erlotinib can be increased by simultaneous treatment with the mTOR kinase/DNA-PK inhibitor CC-115, justifying further clinical studies in lung cancer patients with primary or acquired resistance to EGFR TKIs.
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MS 17 - Immunotherapy for Mesothelioma (ID 35)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:D.A. Fennell, T. Nakano
- Coordinates: 9/08/2015, 14:15 - 15:45, 201+203
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MS17.02 - Immunotoxins and Mesothelin Antibody (ID 1923)
14:40 - 15:00 | Author(s): R. Hassan
- Abstract
- Presentation
Abstract:
Mesothelin is a tumor differentiation antigen that is highly expressed in several cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissue and its high expression in many solid tumors make it an attractive candidate for cancer therapy. Several drugs targeting mesothelin, including immunotoxins (SS1P, RO6927005), a chimeric monoclonal antibody (Amatuximab), an antibody drug conjugate (Anetumab Ravtansine), and a tumor vaccine (CRS-207), are in various stages of development to treat patients with mesothelin-expressing tumors. The first anti-mesothelin therapeutic agent to enter the clinic was the immunotoxin SS1P and it demonstrated that mesothelin could be successfully exploited as a target for cancer therapy and has led to a broad interest in developing different approaches for mesothelin immunotherapy treatment of solid tumors including malignant mesothelioma. Immunotoxins are targeted anti-cancer therapeutics that kill cancer cells by inhibition of protein synthesis using a cytotoxic bacterial toxin payload. In a phase I clinical trial SS1P had limited anti-tumor activity because it was immunogenic and patients develop antibodies to the drug limiting treatment efficacy. However, we have recently shown that co-administration of SS1P with a lymphocyte depleting regimen of pentostatin and cyclophosphamide can delay anti-drug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pre-treated mesothelioma patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and non-specific toxicity have been developed through protein engineering techniques. RO6927005 is a next generation anti-mesothelin PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity so that patients can receive multiple cycles of the drug. In pre-clinical studies RO6927005 has increased activity compared to SS1P against mesothelioma tumor cells directly obtained from patients as well as activity in mesothelioma tumor models either alone or in combination with chemotherapy. A phase I clinical trial of RO6927005 has just been initiated for patients with mesothelin expressing cancers including malignant mesothelioma. There are other antibody based therapeutics in advanced clinical development for treatment of malignant mesothelioma including amatuximab and anetumab ravtansine. In a phase II single arm trial of unresectable, chemotherapy naïve patients with pleural mesothelioma, amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Based on these results a registration front-line study of amatuximab with pemetrexed and cisplatin versus pemetrexed and cisplatin alone has been initiated for treatment of newly diagnosed patients with pleural mesothelioma. Anetumab Ravtansine (BAY 94-9343) is an antibody-drug conjugate in which a human anti-mesothelin monoclonal antibody is conjugated to the maytansinoid tublin inhibitor DM4. In preclinical studies it showed significant anti-tumor activity against mesothelioma cell lines as well as mesothelioma patient derived xenografts. Anetumab Ravtansine is currently being evaluated in patients with mesothelin expressing cancers who have failed standard therapies and represents a potential therapeutic option for treatment of patients with mesothelioma given the high and uniform expression of mesothelin in this tumor. Hopefully, these different approaches to exploit mesothelin for immunotherapy of malignant mesothelioma will result in new treatment options for these patients.
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ORAL 11 - Clinical Trials 1 (ID 100)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A.K. Nowak, F. Detterbeck
- Coordinates: 9/07/2015, 10:45 - 12:15, 702+704+706
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ORAL11.02 - Phase I Study of Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine (ID 1574)
10:45 - 10:56 | Author(s): R. Hassan
- Abstract
- Presentation
Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully humanized anti-mesothelin IgG1 antibody conjugated to a ravtansine, a maytansine derivative DM4 antitubulin cytotoxic agent. We report results from a phase I study evaluating the safety, PK and tumor response in patients (pts) with advanced solid tumors treated with anetumab, with a particular focus on patients with mesothelioma.
Methods:
Anetumab was given IV every 21 days (q3w) in 77 pts: 45 pts in 10 dose escalation cohorts from 0.15 to 7.5 mg/kg (21 mesothelioma, 9 pancreatic, 5 breast, 4 ovarian, 6 other), and 32 pts in 2 expansion cohorts (12 mesothelioma and 20 ovarian); 38 pts were treated at MTD in escalation and expansion cohorts (16 mesothelioma, 21 ovarian, 1 breast). Clinical and laboratory safety assessments were made on D1, D8 and D15 in C1-C3 and on D1 in subsequent cycles. Tumor assessments were made q6wks up to C8 and q12wks thereafter. Mesothelin expression in archival tumor samples was assessed retrospecively by IHC (SP74, Ventana).
Results:
Thirty-two males and 45 females were treated [mean age 62 yrs (range, 18-84 yrs), body weight 77 kg (44-113 kg), ECOG ≤1, median prior cytotoxic regimens: overall 4 (1-9), mesothelioma 1 (1-4)]. Non-tolerated anetumab dose was 7.5 mg/kg (DLTs: 1 pt with G2 keratitis and G3 neuropathy, 1 pt with G4 keratitis and G2 neuropathy). Anetumab MTD was 6.5 mg/kg (DLT: G3 AST increase). Only one DLT occurred at doses below MTD (G3 hyponatremia, 5.5 mg/kg). No drug-related deaths and few drug-related SAEs (7 total and 5 at MTD) were reported. Seventeen of 38 (45%) pts total or 7 of 16 (44%) mesothelioma pts at MTD had drug-related AE requiring dose reduction (G1-4 keratitis, G2-3 neuropathy, G3 fatigue, anorexia, asthenia, diarrhea, N&V, AST increase). LFT increases were the most common drug-related laboratory abnormality at MTD: AST in 7 pts (2 G3), ALT in 6 pts (no G3), alkaline phosphatase in 4 pts (one G3) and bilirubin increase in 1 pt (no G3). There were no drug-related G3 hematological abnormalities at any dose. Fourteen of 38 (37%) pts total or 4 of 16 (25%) mesothelioma pts at MTD had G1-4 keratitis (worst G3-4 in 3 pts, blurred vision in 10, dose reduction in 8, dose delay in 11, all fully reversible). Anetumab at the MTD showed a PR in 6 pts (19%) and SD in 18 pts (47%) overall. Five of 16 (31%) mesothelioma pts at the MTD had durable PR (>600 days in 4 pts) and 7 (44%) had SD. Five PRs occurred in 11 mesothelioma pts who received anetumab as second line treatment (45% response rate).
Conclusion:
Anetumab at the MTD (6.5 mg/kg) showed encouraging efficacy with durable PR in pts with advanced mesothelioma. At the MTD, all drug-related AEs were reversible and non-life-threatening but required dose reduction in about half of pts, most commonly due to G1-4 keratitis and G2-3 peripheral neuropathy. Given this benefit-risk ratio, the recommended phase II dose of anetumab in second line treatment of advanced mesothelioma is 6.5 mg/kg IV q3w.
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.01 - PD-L1 Is Highly Expressed in Malignant Mesothelioma and PD-1<sup>+ </sup>Lymphocytes within Malignant Effusions Induce PD-L1 Expression (ID 553)
16:45 - 16:56 | Author(s): R. Hassan
- Abstract
- Presentation
Background:
The PD-1 and PD-L1 pathway is an immune checkpoint, which protects normal tissues from immune attack by curbing the effector T-cell response but can also prevent anti-tumor immune response. However their role in mesothelioma is not well understood. The present study aimed to understand the PD-1 and PD-L1 expression levels and their interactions in mesothelioma patients.
Methods:
Sections of formalin-fixed, paraffin-embedded pleural and peritoneal mesothelioma tumor samples from patients who were evaluated for various clinical trials at the NCI Center for Cancer Research were tested for PD-L1 expression (Anti-PD-L1 rabbit monoclonal recombinant primary antibody MKP-1B-196-10; Merck-Serono). PD-L1 expression on primary and established mesothelioma cell lines, malignant pleural effusions and ascites of mesothelioma patients were assessed using a commercial anti-PD-L1 antibody and analyzed by flow cytometry. Paired malignant effusion and peripheral blood samples were tested for PD-1 and PD-L1 expression on immune cells. Co-cultures of autologous tumor cells and T cells grown from malignant effusions of a mesothelioma patient were evaluated to understand the PD-1 and PD-L1 interaction.
Results:
Tumor samples from 65 patients included 44 peritoneal and 21 pleural mesotheliomas; 55 with epithelioid histology and 10 of other subtypes (sarcomatoid 2, biphasic 3, uncategorized 5). 41 of 65 (63%) tumors were positive for PD-L1 expression (defined as >5% PD-L1 expression on tumor cells, of any intensity) with levels of expression ranging from 5% to 80% of tumor cells, and intensities from 1+ to 3+. 24 (37%) were negative including 10 with focal staining. A higher proportion of males had tumor PD-L1 expression than females (73% vs. 46%; p=0.04). There was no association between PD-L1 expression and primary site of disease, age, race, histology and distant metastasis. Patients with PD-L1 positive tumors had a numerically inferior overall survival than patients with PD-L1 negative tumors (23.0 months vs.33.3 months; p=0.35). All 6 primary and 4 established mesothelioma cell lines tested showed basal expression of PD-L1. This was enhanced on treatment with IFN-γ. The fraction of cells expressing PD-L1 in malignant effusions ranged from 17 to 43%. Malignant effusions from 2 of 3 patients had high PD-1 expression on both CD4[+] and CD8[+] T cells. In addition, CD8[+] T cells in malignant effusions had significantly higher levels of PD-L1 expression compared to CD8[+] T cells in peripheral blood (7.47±2.75 % T cells versus 1.97±1.22% T cells; p=0.03). Autologous lymphocytes when co-cultured with tumor cells from malignant effusion, recognized tumor cells and induced IFN-γ mediated PD-L1 expression on their surface.
Conclusion:
High PD-L1 expression in mesothelioma patient tumor samples and tumor cells derived from malignant effusions, as well as presence of PD-1[+] T cells in these effusions indicates the prominent role of PD-1/PD-L1 pathway in maintaining an immunosuppressive milieu in mesothelioma. Thus, inhibiting this pathway could be useful therapeutically.
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P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.08-001 - A Randomized, Placebo-Controlled Study of Amatuximab in Combination with Pemetrexed and Cisplatin (P/C) in Subjects with Pleural Mesothelioma (ID 829)
09:30 - 09:30 | Author(s): R. Hassan
- Abstract
Background:
Amatuximab is a 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 amatuximab potentially has anti-tumor activity via antibody-dependent cellular cytotoxicity. Amatuximab was studied in a Phase 2 malignant pleural mesothelioma (MPM) trial which demonstrated that the safety profile of amatuximab in combination with P/C was consistent with that seen previously for the P/C regimen. Although PFS was 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). The post-hoc PK/PD analysis demonstrated that amatuximab trough concentrations were a significant predictor of both OS and PFS where higher concentrations were associated with longer OS (583 days; p=0.0202 ) and PFS (238 days; p<0.001).
Methods:
560 subjects with previously untreated, unresectable malignant pleural mesothelioma (MPM) will receive P/C and are randomized 1:1 to receive weekly amatuximab, 5 mg/kg or saline placebo IV in this global study. The primary endpoint of the study is to demonstrate whether amatuximab in combination with P/C has superior OS compared with P/C in subjects with MPM. The secondary endpoints are to compare amatuximab versus placebo with regard to PFS, ORR, duration of response, health-related QOL (LCSS-Meso), and the safety of amatuximab when administered with P/C. Clinical trial information: NCT02357147.
Results:
Not applicable
Conclusion:
Not applicable
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-011 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase Ib Trial in Patients with Advanced Mesothelioma (ID 790)
09:30 - 09:30 | Author(s): R. Hassan
- Abstract
Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel group expansion trial in patients with metastatic or locally advanced solid tumors that includes a cohort of patients with advanced, unresectable mesothelioma.
Methods:
This trial cohort is enrolling patients with histologically or cytologically confirmed unresectable mesothelioma (pleural or peritoneal) that has progressed after treatment with either a platinum-pemetrexed–containing regimen or a platinum-based regimen followed by pemetrexed (or vice versa). Eligible patients must have available tumor archival material or fresh biopsy, and an ECOG performance status of 0 or 1 at trial entry, and disease with at least 1 measurable lesion that has not been irradiated. Exclusion criteria include prior therapy with immune checkpoint drugs, a known history of autoimmune disease, or recent anticancer treatment (within the 28 days prior to study start). Up to 50 eligible patients will receive avelumab at 10 mg/kg as an infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Treatment may be continued despite progression according to RECIST 1.1 if the patient’s clinical status is stable and, according to investigator opinion, there is no need to start salvage therapy. The primary objective of the trial is to assess the safety and tolerability of avelumab. Select secondary objectives include: assessment of best overall response (BOR) and progression-free survival (PFS) according to RECIST 1.1; assessment of immune-related BOR and immune-related PFS (using the modified Immune-Related Response Criteria); and assessment of overall survival. Association between tumor PD-L1 expression and efficacy will be evaluated. Changes in soluble factors and immune cell profiling will be characterized and immunomonitoring will occur at each visit. Tumor assessments will be performed every 6 weeks until progression. Tumor tissue from the most recent biopsy or surgical specimen will be collected prior to the initiation of trial treatment, and fresh biopsies may be optionally collected on day 43 and at the end-of-treatment visit. At each visit during the treatment phase, adverse events will be assessed and graded according to NCI-CTCAE v4.0. Enrollment in this study began in September 2014. *Proposed INN.
Results:
not applicable
Conclusion:
not applicable
