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D.A. Fennell
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-027 - Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Metastatic Pleural Mesothelioma (ID 5671)
14:30 - 14:30 | Author(s): D.A. Fennell
- Abstract
Background:
Mesothelioma is a rare but aggressive cancer with a poor prognosis. Mesothelin is a cell surface protein that is highly expressed in mesothelioma and other epithelial cancers. Anetumab ravtansine (BAY 94-9343), a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4, has shown encouraging efficacy in mesothelioma patients in a phase I study. To further explore the possible benefit of antibody-drug conjugate therapy for mesothelioma, we initiated a randomized, open-label, active-controlled, phase II trial to evaluate the efficacy and safety of anetumab ravtansine in patients with metastatic pleural mesothelioma (MPM) overexpressing mesothelin and who have previously progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).
Methods:
Patients (≥18 years) with unresectable locally advanced or metastatic MPM are eligible. Patients should have recurrent or relapsing disease after having previously receiving first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab. Obligatory biomarker sampling will be performed on all patients at pre-screening and mesothelin-positivity as determined by Ventana MSLN (SP74) companion diagnostic assay as a requirement for entry. The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS) per modified RECIST criteria for MPM per central review. The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Approximately 210 patients will be randomized in a 2:1 ratio to receive anetumab ravtansine 6.5 mg/kg Q3W or vinorelbine 30 mg/m[2] QW. Novel study methods include a grading system for AEs of special interest and the PRO instruments.
Results:
This trial is open and currently accruing patients globally.
Conclusion:
Section not applicable.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-005 - Inhibition of PRMT5 is Synthetic Lethal in Mesotheliomas Harboring MTAP Loss (ID 6078)
14:30 - 14:30 | Author(s): D.A. Fennell
- Abstract
Background:
Mesothelioma remains an incurable cancer with limited therapy. Genetically targeted personalised treatment strategies are currently lacking. Mesotheliomas harbor frequent loss of chromosome 9p21.3 locus encoding for CDKN2A and frequently encompassing methyladenosine phosphoryl transferase (MTAP). Loss of MTAP has recently been shown to be associated with dependency on the symmetrical demethylation of arginine-4 on histone H4 methyltransferase PRMT5. We sought to determine whether mesothelioma cells with MTAP HD would be vulnerable to inhibition of PRMT5, and to explore the pharmacodynamics associated with its suppression.
Methods:
Genome-wide copy number variation (CNV) analysis was undertaken in 94 patients. CNVs were determined using the array based platform, Affymetrix Oncoscan v3. Multiregional whole exome sequencing was also performed on samples from 6 patients. The expression of MTAP and the effect of the drugs tested on H4R3Me2s was evaluated by western blot. Cell growth was analysed by clonogenic assay after focused RNAi targeting MTAP and/or PRMT5, or treatment with a PRMT5 inhibitor
Results:
Oncoscan analysis identified homozygous loss of CDKN2A in 50%, and heterozygous loss in 20.2% of patients. Homozygous loss of MTAP was seen in 39.3% and heterozygous loss in 28.7%, 76.6% of patients had concurrent loss of CDKN2A and MTAP. Homozygous MTAP deletion was found to be present in all regions of tumour ie a truncal deletion, in 3 out of 6 patients. In 65 patients treated with surgery only, homozygous loss of CDKN2A or MTAP was prognostic for progression free survival (CDKN2A: 7.5 vs. 32.9 months, HR 4.536 95%CI 1.765-11.659, p=0.002; MTAP: 7.5 vs. 18.4 months, HR 3.289 95%CI 1.314-8.237, p=0.007). To determine the dependency of MTAP negative cells on PRMT5, we used either siRNA targeting PRMT5 or a PRMT5 inhibitor. PRMT5 silencing did not induce measurable apoptosis however a significant suppression of clonogenic activity was observed after 10 days in MTAP negative cells(H2591). The same effect was observed after concurrent silencing of PRMT5 and MTAP in MTAP positive mesothelioma cells(MPP89). We then utilised a PRMT5 small molecule inhibitor, EPZ015666, to recapitulate RNAi knockdown. Although a clear suppression of H4R3Me2s was observed after 96 hours treatment, the relative potency on clonogenic assay was less than RNAi.
Conclusion:
Homozygous deletion of MTAP is a common genetic event in mesothelioma. Suppression of PRMT5 represents a novel potential approach for targeting mesotheliomas with 9p21.3 loss. The discrepancy between small molecule inhibitors and RNAi, suggests that PRMT5 dependence may require functions that extend beyond its methyltransferase function.
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P3.03-021 - When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All? (ID 5025)
14:30 - 14:30 | Author(s): D.A. Fennell
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Untreated, MPM has a median survival time of 6 months, and most patients die within 24 months of diagnosis. Therefore an urgent need exists to identify new therapies for treating MPM patients. The potential for therapeutically targeting receptor tyrosine kinase (RTK) signalling networks is emerging as a critical mechanism in ‘oncogene addicted’ cancer, with RTK inhibitors evolving as areas of considerable importance in cancer therapy. Furthermore, RTK hetero-dimerization has emerged as a key element in the development of resistance to cancer therapy. As such TKIs which target several RTKs may have superior efficacy compared with TKIs targeting individual RTKs. We and others have identified c-MET, RON, Axl and Tyro3 as RTKs frequently overexpressed and activated in MPM, making these attractive candidate therapeutic targets. A number of orally bioavailable small molecule inhibitors have been developed which can target these receptors. LCRF0004 specifically targets RON, whereas ASLAN002 (BMS-777607) or Merestinib (LY2801653) are orally bioavailable small molecule inhibitors which inhibit c-MET, RON, Axl and Tyro3 at nanomolar concentrations. These drugs may therefore have applicability in the treatment/management of MPM.
Methods:
A panel of MPM and normal pleural cell lines were screened for expression of Tyro3, c-MET, RON and Axl by RT-PCR, and subsequently examined in a cohort of patient samples comprising benign, epithelial, biphasic, and sarcomatoid histologies by qPCR. The effects of two small molecule inhibitors LCRF0004, ASLAN002 on MPM cellular health were assessed in vitro. The effects of LCRF0004 and ASLAN002 were subsequently examined in an in vivo SQ xenograft tumour model.
Results:
Expression of various RON isoforms, c-MET, Tyro3 and Axl were observed in all cell lines. Significantly higher expression of all genes were found in the malignant tumour material versus benign pleura and this was validated in other datasets. Both LCRF0004 and ASLAN002 demonstrated significant anti-tumour efficacy in vitro. In xenograft models ASLAN002 was far superior to LCRF0004.
Conclusion:
Our results suggest that a multi-TKI, targeting the RON/MET/TAM signalling pathways, may be a more effective therapeutic strategy for the treatment of MPM as opposed to targeting RON alone.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.09 - Phase 3 Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, with Docetaxel versus Docetaxel in Advanced Non-Small Cell Lung Cancer (GALAXY-2) (Abstract under Embargo until December 6, 7:00 CET) (ID 5232)
10:05 - 10:15 | Author(s): D.A. Fennell
- Abstract
- Presentation
Background:
Heat shock protein 90 functions as a chaperone to stabilize oncoproteins. Ganetespib (G), a highly potent Hsp90 inhibitor, has demonstrated efficacy in combination with docetaxel (D) over D alone in the second-line therapy of patients with advanced adenocarcinoma of the lung in a phase 2 study.
Methods:
GALAXY-2 is a randomized (1:1), international, open-label study of D with or without G. Patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) of adenocarcinoma histology, EGFR and ALK wild-type, diagnosed ≥ 6 months prior to study entry, one prior systemic therapy and ECOG PS 0-1 were eligible. D was given at 75 mg/m[2] on day 1 of three-week cycle; D was given on day 1 with G at 150 mg/m[2 ]on Days 1 and 15 of each cycle. Patients were stratified by performance status (PS), LDH, and geographic region. Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and OS in elevated LDH (eLDH) patients. We report the results of a planned interim analysis at 336 events, which occurred on October 5, 2015, with type I error level set at 0.01 (2 sided stratified log-rank test).
Results:
677 patients were randomized with 335 patients in G+D arm and 337 patients in D arm. Baseline characteristics: females 60%, age < 65 68%; never-smoker 18%; PS 0 36%; eLDH 29%; North America/Western Europe 39%. The median number of cycles delivered was 5 in G+D and 4 in D arm. There was no difference in median OS (mOS) for the two arms: 10.9 months with G+D versus 10.5 months with D alone. The hazard ratio for OS was 1.111 (95% CI 0.899-1.372), which met the early stopping criteria for futility. Median PFS was similar in the two arms: 4.2 versus 4.3 months, G+D and D, respectively (HR 1.161, 95% CI 0.961-1.403). There was no improvement with the addition of G for any secondary endpoint, including survival in the eLDH and EGFR and ALK negative populations, response rate, or progression due to new metastatic lesions. The most common grade 3/4 treatment-emergent adverse event in both arms was neutropenia (31.1% versus 24.3%, G+D and D, respectively).
Conclusion:
The addition of ganetespib to docetaxel did not result in improved efficacy for salvage therapy of patients with advanced stage lung adenocarcinoma.
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SC06 - Novel Therapies in Malignant Pleural Mesothelioma and Thymic Malignancies (ID 330)
- Event: WCLC 2016
- Type: Science Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
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SC06.02 - Stratified Therapy for Malignant Pleural Mesothelioma (ID 6622)
14:50 - 15:10 | Author(s): D.A. Fennell
- Abstract
- Presentation
Abstract not provided
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