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Dean A Fennell
Moderator of
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 11
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.01 - A Phase II Study of Nivolumab: A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT) (ID 9111)
11:00 - 11:05 | Presenting Author(s): Yasushi Goto | Author(s): Morihito Okada, T. Kijima, K. Aoe, Terufumi Kato, N. Fujimoto, Kazuhiko Nakagawa, Y. Takeda, T. Hida, K. Kanai, F. Imamura, S. Oizumi, T. Takahashi, M. Takenoyama, H. Tanaka, Yuichiro Ohe
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and limited treatment options beyond progression after platinum-based combination with pemetrexed chemotherapy. Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a humanized monoclonal antibody, PD-1 immune-checkpoint inhibitor, has demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Here, we report the preliminary results of a phase II study to evaluate the efficacy and safety of Nivolumab in previously treated Japanese MPM patients (pts): ONO-4538-41/JapicCTI-No.163247.
Method:
This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including platinum-based combination therapy with pemetrexed. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable disease and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS).
Result:
From July to October 2016, 34 pts were enrolled in 15 centers. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6%. Median follow-up was 6.7 months. Independent review committee-assessed 6-month ORR was 29.4% (n=10, 95%CI: 16.8-46.2) and objective responses were observed across tissue types, epithelioid 7/27 (25.9%), sarcomatoid 2/3 (66.7%), biphasic 1/4 (25.0%). 13 pts (38.2%) had stable disease, resulting in a 6-month DCR of 67.6%. Median PFS was 6.1 months (95%IC: 2.9-NR). Median OS has not been reached. 6-month PFS and OS rates are 50.9% (95%CI: 32.7-66.5) and 85.3% (95%IC: 68.2-93.6). 23 (67.6%) pts experienced drug-related adverse event (DRAE), and 7 (20.6%) experienced grade 3/4 DRAEs. 2 pts required dose discontinuation because of pneumonitis (Grade2 and 3).
Conclusion:
Single-agent Nivolumab has significant activity in 2[nd]/3[rd] line MPM pts and met the primary endpoint, suggesting that Nivolumab has a potential to be a new therapeutic option for MPM.
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MA 19.02 - Tremelimumab plus Durvalumab in First- or Second-Line Mesothelioma Patients: Final Analysis of the NIBIT-MESO-1 Study (ID 9202)
11:05 - 11:10 | Presenting Author(s): Luana Calabro | Author(s): A. Morra, D. Giannarelli, G. Amato, E. Bertocci, A. D'Incecco, R. Danielli, L. Brilli, F. Giannini, M. Altomonte, A.M. Di Giacomo, M. Maio
- Abstract
- Presentation
Background:
The anti-CTLA-4 tremelimumab as monotherapy showed initial signs of activity in second-line malignant mesothelioma (MM) patients (Calabrò et al., Lancet Oncol, 2013; Calabrò et al., Lancet Respir Med, 2015), though it failed to improve the overall survival (OS) of second or third line mesothelioma patients compared to placebo in the DETERMINE study (Maio et al., Lancet Oncol, in press). These results and the efficacy of targeting the PD-1/PD-L1 axis in a variety of tumor types, prompted the NIBIT-MESO-1 study aimed at investigating the activity and safety of tremelimumab combined with the anti-PD-L1 durvalumab in MM patients. Here, we report conclusive efficacy and safety analysis from the fully-enrolled NIBIT-MESO-1 study.
Method:
The NIBIT-MESO-1 is a phase II, open-label, single Center study. Forty MM patients received tremelimumab at 1 mg/Kg i.v. every 4 weeks (Q4W) for 4 doses, and durvalumab at 20 mg/Kg i.v. Q4W for 13 doses. Primary objective is immune-related (ir)-objective response rate; secondary are ir-disease control rate, ir-progression free survival, OS, and safety. Tumor assessment per ir-modified RECIST or ir-RECIST 1.1 for pleural or peritoneal MM, respectively, was performed at baseline and q12 weeks. Adverse events (AEs) were recorded according to CTC v4.0.
Result:
From October 2015 to October 2016, 40 MM patients (38 pleural and 2 peritoneal), median age 64 years (range 41-80), ECOG performance status 0 (n = 19) or 1 (n = 21) were enrolled in the study. MM histology was epithelioid (n = 32), biphasic (n = 5), sarcomatoid (n = 2) or undefined (n = 1). As of April 2017, 12 first or 28 second-line MM patients received a median of 6 doses of therapy (range = 1-13). Ten ir-objective responses (9 confirmed) were observed (25%), and 25 patients reached an ir-disease control rate (62.5%). The median OS was not reached with a median follow-up of 9.5 months (inter-quartile range: 6.2-12.5 months). Thirty patients (75%) experienced any grade irAEs: grade 1-2 irAEs were observed in 67.5% and grade 3-4 irAEs in 17.5%. AEs were generally manageable and reversible per protocol guidelines.
Conclusion:
These data suggest that the combination of tremelimumab and durvalumab is active, with a good safety profile in MM patients, and warrant further exploration. Clinical trial information: .
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MA 19.03 - Nintedanib + Pemetrexed/Cisplatin in Malignant Pleural Mesothelioma (MPM): Phase II Biomarker Data from the LUME‑Meso Study (ID 8111)
11:10 - 11:15 | Presenting Author(s): Anna Nowak | Author(s): F. Grosso, N. Steele, Silvia Novello, Sanjay Popat, L. Greillier, T. John, Natasha B Leighl, Martin Reck, Nick Pavlakis, J.B. Sørensen, David Planchard, G.L. Ceresoli, B. Hughes, Julien Mazieres, Mark Socinski, A. Salnikov, T. Kitzing, J. Braunger, K. Pietzko, Giorgio Vittorio Scagliotti
- Abstract
- Presentation
Background:
Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.
Method:
Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.
Result:
Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.
Conclusion:
These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.
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MA 19.04 - Discussant - MA 19.01, MA 19.02, MA 19.03 (ID 10829)
11:15 - 11:30 | Presenting Author(s): Glen Reid
- Abstract
- Presentation
Abstract not provided
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MA 19.05 - Pegylated Arginine Deiminase Potentiates PD-1/PD-L1 Immune Checkpoint Blockade in Malignant Mesothelioma (ID 9207)
11:30 - 11:35 | Presenting Author(s): Peter Szlosarek | Author(s): R. Khadeir, M. Sheaff, M. Locke, K. Lau, B. Wu, J. Bomalaski, S. Martin, S. Quezada
- Abstract
Background:
Malignant pleural mesothelioma is a difficult to treat asbestos-driven cancer that is on the increase globally. The urea cycle and tumor suppressor enzyme argininosuccinate synthetase 1 (ASS1), involved in arginine synthesis, is downregulated in half of mesotheliomas which are then sensitive to arginine deprivation therapy. Trials of the arginine depletor pegylated arginine deiminase, ADI-PEG20, have confirmed single-agent and combination safety and efficacy in patients with mesothelioma. Here, we explored the immunometabolic consequences of ASS1 loss in mesothelioma uncovering a role for combining ADI-PEG20 with PD1/PD-L1 checkpoint blockade.
Method:
Three ASS1-negative and one ASS1-positive MPM cell lines were assessed for PD-L1 expression by real-time quantitative PCR, western blot and FACS analysis. Cell lines were manipulated for ASS1 overexpression (endogenous and genetic) and siRNA followed by gene expression analysis. Cell lines were cultured with and without ADI-PEG20 and assessed for PD-L1 expression and cytokine production by ELISA. An immunocompetent murine tumor model of ASS1 loss mimicking aggressive mesothelioma was treated with PBS control, ADI-PEG20, anti-PD-1 antibody, and ADI-PEG20 plus anti-PD-1 antibody. Tumors were harvested and analysed for immune cell subsets by FACS. Finally, human mesothelioma biopsies from trials of ADI-PEG20 were analyzed for ASS1 and PD-L1 and immune cell subsets.
Result:
PDL1 protein was absent in the three ASS1 negative MPM cell lines but was present in the ASS1 positive cell line. Transfection of ASS1 in the ASS1 negative MPM cell lines led to an increase in PD-L1 expression, which was reversible following ASS1 knockdown. Induction of PD-L1 expression by forced ASS1 overexpression was accompanied by an increase in interferon type I signaling. Similar results were obtained in a mesothelioma cell line developing resistance to ADI-PEG20 under long-term culture. Next, ADI-PEG20 treatment triggered release of interferon-alpha/beta which induced PD-L1 expression by 24hrs in the ASS1-negative MPM cell lines before declining by 48hrs. Analysis of MPM biopsies of patients progressing on ADI-PEG20 revealed upregulation of ASS1 and a concomitant increase in tumoral PD-L1 and CD3 positive T cells. ADI-PEG20 synergized with PD-1 blockade in the immunocompetent murine tumor model that was refractory to PD-1 inhibition.
Conclusion:
ASS1 and ADI-PEG20 modulate PDL1 expression via type I interferon signaling in malignant mesothelioma cell lines. Arginine deprivation with ADI-PEG20 combined with PD-1 blockade is synergistic and warrants further exploration in the clinic. A phase 1 trial of ADI-PEG20 combined with PD1 blockade is planned in patients with ASS1-negative cancers, including malignant mesothelioma.
Information from this presentation has been removed upon request of the author.
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MA 19.06 - Multiple Mechanisms Contribute to Downregulation of Tumour Suppressor microRNAs in Malignant Pleural Mesothelioma (ID 9745)
11:35 - 11:40 | Presenting Author(s): Marissa Williams | Author(s): Michaela B Kirschner, Yuen Yee Cheng, K.H. Sarun, B. McCaughan, S. Kao, Nico Van Zandwijk, Glen Reid
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a disease with an almost invariably fatal diagnosis with limited therapeutic options. Characteristic patterns of deregulated microRNA expression have been demonstrated in MPM, and many downregulated microRNAs have been shown to have tumour suppressor activity. However, apart from silencing of miR-34b/c by promoter hypermethylation and co-deletion of miR-31 with the CDKN2A locus, the mechanisms responsible for downregulation of other tumour suppressor miRNAs such as miR-16 are yet to be elucidated.
Method:
Tumour samples (n=60) were from MPM patients undergoing extrapleural pneumonectomy, and samples of pleura (n=23) collected from patients undergoing cardiac surgery were used as normal controls. MPM cells lines were obtained from the ATCC. Expression levels of mature microRNAs in MPM tumour samples and cell lines, and pri-miRs and miRNA host genes in cell lines, were determined by RT-qPCR. Copy number variation (CNV) was analysed by droplet digital PCR (ddPCR), and methylation was inferred by miRNA expression following decitabine treatment. MYC was analysed by Western blot, and expression modulated by siRNAs.
Result:
Analysis of microRNA expression in tumour samples revealed a consistent and significant downregulation of miR-15a (4-fold, P<0.01), 15b (10-fold, P<0.01), 16 (22-fold, P<0.05), 34a (1.6-fold, P<0.05), 34b (1.8-fold, P<0.01), 34c (2.3-fold, P<0.0001) and 193a (3.1-fold, P<0.001) compared with normal pleura. Copy number variation analysis showed evidence of heterozygous loss for miR-193a (4 of 5 cell lines) and miR-15a/16-1 (2 of 5), but no change in miR-15b/16-2. Treating cell lines with the demethylating agent decitabine resulted in dramatic upregulation only in the case of miR-34c. RNAi-mediated knockdown of c-MYC led to upregulation of miR-15b and 16, and to a lesser extent miR-15a, as well as a consistent increase in the miR-15b/16-2 host gene SMC4 and the miR-15a/16-1 host gene DLEU2. Analysing the expression of these microRNAs in the tumour samples revealed a strong correlation between miR-15b and 16 (R[2]=0.793) and miR-34b and 34c (R[2]=0.753), but not between others.
Conclusion:
Our data suggest that a combination of deletion, hypermethylation and transcriptional regulation contribute to the downregulation of miR-15a/b, 16, 34a/b/c and 193a. In MPM, unlike other cancers, the downregulation of miR-15a/16-1, miR-15b/16-2 appears to be due to transcriptional changes rather than deletion or promoter hypermethylation. MYC appears to contribute to miR-16 downregulation primarily via control of SMC4 and the miR-15b/16-2 locus, suggesting that the transcriptional control of miR-16 expression by c-Myc contributes to the malignant phenotype of MPM.
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MA 19.07 - Does Loss of Smad7 Lead to Increased Aggressiveness of Malignant Pleural Mesothelioma? (ID 8459)
11:40 - 11:45 | Presenting Author(s): Michael Grusch | Author(s): J. Gerstmayr, E. Lang, D. Falch, C. Pirker, V. Laszlo, B. Dome, W. Klepetko, Mir Alireza Hoda, W. Berger
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is characterized by aggressive growth, limited therapeutic options and rapid recurrence following treatment. A better understanding of biological factors underlying MPM aggressiveness offers the chance to improve therapeutic strategies. Growth factors of the TGF-beta superfamily including TGF-beta itself, activins and BMPs have been repeatedly linked to MPM growth. In the current study, we focus on the role of Smad7, a key intracellular antagonist of TGF-beta and activin signaling, in MPM.
Method:
A panel of 17 human MPM cell lines was screened for tumorigenicity in SCID mice. Comparative genomic hybridization and whole genome gene expression arrays were used for identification of genes correlating with tumorigenicity. Immunoblotting and qPCR were used to detect Smad7 expression levels in cell lines. For ectopic overexpression of Smad7 in MPM cells, a retroviral expression system was used. Various in vitro assays, immunoblotting and reporter gene assays were employed to characterize the effect of Smad7 overexpression on MPM cell proliferation, migration, signal transduction and drug response.
Result:
When human MPM cell lines were dichotomized into tumorigenic ones and non-tumorigenic ones based on their ability to form tumors in SCID mice, loss of Smad7 was one of the most conspicuous associations with tumorigenicity identified in CGH arrays. The tumorigenic group also showed a reduced Smad7 transcript expression in gene expression microarrays. Based on these data we screened a larger panel of MPM cell lines for Smad7 mRNA and protein expression and identified cell lines with high, medium and low Smad7 expression. We generated a retroviral expression construct and established an isogenic subline overexpressing Smad7 from the MPM cell line VMC33 that shows low endogenous Smad7 expression. Compared to parental VMC33 cells or VMC33-RFP cells, which overexpress red fluorescent protein and were used as control, VMC33-Smad7 cells showed a reduced growth rate and diminished clone forming capacity in vitro. VMC33-Smad7 also showed reduced cell migration, but no difference in invasion could be detected. Since Smad7 was described as antagonist of TGF-beta, we tested its effect on TGF-beta signaling with a reporter gene assay and indeed found a blunted response to TGF-b in Smad7 overexpressing cells. With respect to sensitivity against kinase inhibitors targeting TGF-beta receptors, VMC33-Smad7 showed a decreased response to galunisertib and SB-431542 compared to VMC33-RFP.
Conclusion:
Taken together, these data suggest that Smad7 may have a growth limiting function in MPM, possibly by antagonizing growth-promoting TGF-beta and/or activin signals.
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MA 19.08 - Discussant - MA 19.05, MA 19.06, MA 19.07 (ID 10830)
11:45 - 12:00 | Presenting Author(s): Yoshitaka Sekido
- Abstract
- Presentation
Abstract not provided
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MA 19.09 - The Role of Neoadjuvant Chemotherapy in Patients with Malignant Pleural Mesothelioma (ID 10187)
12:00 - 12:05 | Presenting Author(s): David Harpole | Author(s): S.L. Voigt, M. Joshi, P.J. Speicher, B.C. Tong, M.W. Onaitis, Jeffrey Crawford, Thomas D'Amico
- Abstract
- Presentation
Background:
The treatment of localized malignant pleural mesothelioma (MPM) involves multimodality therapy, however, there is no standard of care with respect to operative procedure and timing of chemotherapy. We analyzed data from a single institution to identify whether the use of pemetrexed-platinum neoadjuvant chemotherapy impacts survival.
Method:
Patients with histologically-proven MPM who had surgery from 1996 to 2016 were identified. Follow-up was complete for a median of 24 months. Survival was calculated from time of diagnosis to last follow up or death. Univariate and multivariate Cox proportional hazards were used.
Result:
From 1996 to 2016 we identified 376 patients. Mean age was 66+/-8 years and 54 (14%) were female. There was no difference in survival for pleurectomy/decortication or extrapleural pneumonectomy. Neoadjuvant chemotherapy significantly improved survival compared to surgery followed by chemotherapy (table 1). Multivariate analysis was significantly associated for increased survival for epithelioid histology, T-status, node positivity, and neoadjuvant chemotherapy (table 2).Table 1. Univariate Analysis
Variable (n) Median survival (mo.) P value Gender Male (322) Female (54) 13.6 17.2 P=0.043 Histology Epithelial (252) Mixed (91) Sarcomatoid (26) 18.3 12.1 6.5 P<0.0001 T stage T 1-2 (33) T 3-4 (343) 42.6 14.3 P=0.0002 N status N 0 (129) N 1-2 (113) 23.1 11.3 P<0.0001 Neoadjuvant chemotherapy Yes (153) No (223) 19.8 11.3 P<0.0001 Table 2. Cox Proportional Hazards Model
Cox proportional hazards model including histology, t-status, n-status, and neoadjuvant chemotherapy C-index: 0.69Covariate Hazard Ratio 95% CI p-value Histology (ref: Epithelioid) Biphasic Sarcomatoid ref 1.66 4.24 [ref] [1.17-2.36] [1.77-10.1] ref 0.005 0.001 T-status 3-4 vs 1-2 3.07 [1.32-7.15] 0.009 Node-positivity 1.93 [1.40-2.66] <0.001 Neoadjuvant chemotherapy 0.65 [0.47-0.91] 0.011
Conclusion:
Our results suggest that neoadjuvant chemotherapy increases survival and likely enhances the complete resection rate. These data are being evaluated in a multi-institutional cohort of five major mesothelioma programs in North America to improve guidelines for mesothelioma therapy.
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MA 19.10 - Comparative Value of MR and CT for Tumor Volumetric and Clinical Staging of Malignant Pleural Mesothelioma (ID 10122)
12:05 - 12:10 | Presenting Author(s): Ritu R Gill | Author(s): D. Murphy, R. Seethamraju, Raphael Bueno, W.G. Richards
- Abstract
- Presentation
Background:
Tumor volumetrics is currently being explored as a means of enhancing the accuracy of clinical staging of malignant pleural mesothelioma (MPM). In a recent multicenter study (JTO 2016, 11(8):1335-1344) evaluating feasibility of volume estimation using CT (VolCT), clinical staging by CT was poorly correlated between readers and underestimated pathological stage, but correlation of VolCT estimates between two experienced readers was high (rho = 0.82). MR has been found superior to CT in evaluating certain staging parameters, and may enhance volumetrics based on improved contrast. Here we evaluate the relative performance and reproducibility of MR for volumetrics (VolMR) and clinical staging of MPM in a single institution cohort.
Method:
Patients with MPM who underwent surgical resection between 2009 and 2014 with preoperative CT and MR imaging were studied. MR images were acquired using a uniform clinical protocol. VolMR was performed independently by two observers, one an experienced radiologist and one fellow. Vitrea (Vital Images) software was used for volumetric calculations and estimates were compared using Spearman correlation. Clinical staging accuracy (AJCC 7[th] edition criteria; versus pathological stage) and interobserver variability were also evaluated. VolMR and VolCT were performed for all cases by the experienced radiologist and qualitatively compared.
Result:
The study cohort comprised 139 patients, 113 (81%) men, median age 68 (30-82), with 74 (53%) epithelioid subtype tumors. Pathological stage was I: 14 (10%); II: 16 (12%); III: 75 (54%); IV: 34 (24%). Clinical staging by MR was concordant between reviewers for 86 (62%) cases, and with pathological stage for 65 (47%) and 63 (45%) respectively. VolMR was significantly correlated both between reviewers (rho = 0.99) and with VolCT (rho = 0.68). VolMR tended to result in higher volume estimates (median 633, IQR 365-885 cc) than VolCT (median 239, IQR 75-597 cc).
Conclusion:
VolMR was found to be feasible and reproducible, independent of observer experience. Clinical AJCC staging by MR was found to compare favorably to staging by CT in terms of both interobserver variablilty and prediction of pathological stage. Although MR is not yet universally available and has the disadvantages of higher cost, requirement for optimization and longer scan times, it may neverthheless offer improved accuracy and reproducibility of clinical staging and volumetric analysis. Further evaluation in larger multi-institutional cohorts is warranted.
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MA 19.11 - Discussant - MA 19.09, MA 19.10 (ID 10831)
12:10 - 12:25 | Presenting Author(s): T. John
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.12 - Discussant - MA 02.09, MA 02.10, MA 02.11 (ID 10781)
12:15 - 12:30 | Presenting Author(s): Dean A Fennell
- Abstract
- Presentation
Abstract not provided
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OA 02 - Mesothelioma: Challenges For New Treatment (ID 653)
- Event: WCLC 2017
- Type: Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:S. Hasegawa, Anna Nowak
- Coordinates: 10/16/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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OA 02.01 - Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Malignant Pleural Mesothelioma (ID 9377)
11:00 - 11:10 | Author(s): Dean A Fennell
- Abstract
- Presentation
Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4. We report the results of a randomized phase II trial of anetumab ravtansine compared to vinorelbine in patients with advanced malignant pleural mesothelioma (MPM) who have high mesothelin expression and have progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).
Method:
Patients (≥18 years) with locally advanced or metastatic MPM with progressive disease following first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab, were eligible. Patients were pre-screened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. The primary efficacy endpoint was progression-free survival (PFS) per central radiologic review using modified RECIST criteria for MPM. Secondary objectives included overall survival, tumor response, and safety. Patients were randomized in a 2:1 ratio to anetumab ravtansine 6.5 mg/kg Q3W IV or vinorelbine 30 mg/m[2] QW IV.
Result:
A total of 166 patients were randomized to anetumab ravtansine and 82 to vinorelbine; 3 and 10 patients, respectively, not receiving treatment were included for efficacy but not safety assessments. The treatment arms were evenly balanced, with 73% male, 64% ECOG performance status 1, 96% epithelioid histology, and a mean 2.5 (±2.4) months since last progression. The median duration of treatment (anetumab vs vinorelbine) was 12.6 weeks (range 3-61) vs 13.0 weeks (range 1-43). Treatment-emergent grade (G) ≥3 adverse events (AEs) were seen in 85 (52.1%) and 53 (73.6%) of patients, respectively. G3/G4 neutropenia (22.2%/16.7%) occurred in the vinorelbine arm whereas corneal epitheliopathy (39.3% all grade, 1.8% G3) was distinct for the anetumab ravtansine arm. Serious AEs (any grade) were similar; 52 (31.9%) vs 25 (34.7%). Treatment-emergent AEs leading to dose modification were 42.9% in the anetumab ravtansine arm and 80.6% in the vinorelbine arm. There was one treatment-related G5 event in each arm. Median PFS was 4.3 months (95% CI:4.1, 5.2) for anetumab ravtansine vs 4.5 months (4.1, 5.8) for vinorelbine; hazard ratio 1.22 (0.85, 1.74), p=0.859. Fourteen (8.4%) patients in the anetumab ravtansine arm had an objective response vs 5 (6.1%) in the vinorelbine arm, with no complete responses. Interim median overall survival was 10.1 mo (7.6, -) vs 11.6 mo (7.7, 12.5), respectively, p-value 0.721.
Conclusion:
In relapsed MPM, anetumab ravtansine was not superior to vinorelbine with respect to PFS.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-013a - CONFIRM: A Phase III Randomized Trial to Evaluate the Efficacy of Nivolumab versus Placebo in Relapsed Mesothelioma (ID 8542)
09:30 - 09:30 | Presenting Author(s): Dean A Fennell
- Abstract
Background:
Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Despite a significant number of clinical studies in the second line setting, no randomized study has been positive. Early promising signals of activity relating to both PD-L1 and PD-1 targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint, and support the development of a randomized phase III trial to evaluate the efficacy of nivolumab. CONFIRM is the first ever placebo controlled, randomized phase III trial of a PD-1/PD-L1 immune checkpoint inhibitor in mesothelioma.
Method:
The primary objective is to determine whether nivolumab increases overall survival (OS) in relapsed mesothelioma. Secondary objectives are to determine whether nivolumab a) increases progression-free survival, b) increases response rate, c) has good safety/tolerability, and d) results in acceptable patient quality of life and cost per quality adjusted life year. A translational study will be undertaken to determine the correlation between OS and i) PD-L1 expression, ii) mutational burden (estimated by genome-wide analysis of copy number alterations), iii) immunotranscriptomic profile. Developed by researchers at the Universities of Leicester and Southampton on behalf of the UK NCRI Lung Clinical Studies Group the trial is co-ordinated by the Cancer Research UK Southampton Clinical Trials Unit in the UK, within the Centre of Cancer Immunotherapy. The trial will recruit 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy, from UK sites between March 2017 and 2021. We are also investigating opening recruitment to international sites. Patients will be randomized 2:1 (treatment: control), stratified according to epithelioid vs. non-epithelioid and center, to receive 240mg nivolumab (anti PD-1 antibody) monotherapy or saline placebo as a 30-minute intravenous infusion. Allocation will be double-blind. Treatment will be on day one of each 14-day cycle, until disease progression for a maximum of 12 months. Trial follow up will continue for 6 months after the last participant has progressed, or completed or discontinued treatment. The trial is powered (80%, with 2-sided 4% significance level) to detect a hazard ratio of 0.7 using an adjusted Cox regression model (time-to-event) and will be analyzed using intention-to-treat. This trial is funded by Cancer Research UK (C16728/A21400) and Bristol Myers Squibb (CA 209-841). Trial registrations: NCT03063450 and ISRCTN79814141.
Result:
Section not applicable
Conclusion:
Section not applicable
