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S. Kao
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ORAL 26 - Clinical Trials 2 (ID 127)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A. Scherpereel, C. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 702+704+706
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ORAL26.07 - Early Signs of Clinical Activity of a MicroRNA-Based Therapy in a Phase I Study in Recurrent Malignant Pleural Mesothelioma (ID 1101)
11:50 - 12:01 | Author(s): S. Kao
- Abstract
- Presentation
Background:
Recently we demonstrated that members of the miR-15/16 family of microRNAs are implicated as tumor suppressors in malignant pleural mesothelioma (MPM) (Reid et al, Ann Oncol, 2013). MesomiR 1 is a first-in-man study testing TargomiRs (miR-15/16-derived mimics packaged in EDV[TM]nanocells [EDVs] targeted with EGFR antibodies) in MPM patients.
Methods:
In this phase I study (ClinicalTrials.gov: NCT02369198) a standard 3-6 patient dose escalation cohort design examining weekly/twice weekly administration of TargomiRs is followed. Patients tolerating weekly/twice weekly TargomiR infusions well are allowed to continue experimental therapy for at least 8 weeks. Fifty percent of the MTD previously established for EDVs was chosen as the first dose level to be studied and corresponded to 5 billion EDVs containing 1.5 μg miR-15/16 mimics. Based on prior experience with EDVs, patients who presented with elevated IL-6 levels were given a dose adaptation period of two weeks before receiving phase I doses. Premedication consisted of dexamethasone, promethazine and paracetamol and patients were monitored for a minimum period of 3 hours after TargomiR infusion. Response assessment (CT, FDG-PET, pulmonary function) was scheduled for patients completing 8 weeks of treatment. Quality-of-Life (QoL) questionnaires (EORTC) were requested on a weekly basis.
Results:
Ten MPM patients have enrolled to date. The majority of patients receiving 5 billion TargomiRs experienced a period of shivering/rigor 80-90 minutes after the start of the infusion, sometimes associated with burning/painful sensations in the area of disease. Overall TargomiR treatment was well tolerated and no patient failed to complete the first (8 weeks) treatment period. Laboratory examination revealed a steep but transitory rise in inflammatory cytokines, neutrophilia and lymphopenia shortly after TargomiR infusion, sometimes accompanied by mild elevation of liver enzymes. QoL assessment (9 patients) showed improving scores in 3 patients, stabilization in 4 and slightly lower scores in 2 patients. Response assessment (modified RECIST) in the 6 patients completing 8 weeks of treatment to date: 1 PR (see Figure 1, reconfirmed after 12 and 16 weeks), 4 SD and 1 PD. Figure 1. FDG-PET scintigraphy before (left) and after (right) 8 weeksFigure 1 of TargomiR treatment (patient 5)
Conclusion:
Early MesomiR 1 data revealed that infusions with 5 billion TargomiRs were well tolerated. Transient inflammatory (cytokine-mediated) reactions were noted shortly after TargomiR administration. One objective response was recorded while stable disease and stable QoL scores were noted in the majority of patients completing 8 weeks of experimental treatment.
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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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P2.08-004 - Healthcare Professional Perceptions of Chemotherapy in Treatment of Malignant Pleural Mesothelioma (MPM) (ID 3240)
09:30 - 09:30 | Author(s): S. Kao
- Abstract
Background:
Background: An evidence-based chemotherapy utilisation model for MPM suggests rates of use should be around 65%. Actual Australian rates are about 54%. Aim: To examine healthcare professional perceptions of chemotherapy use and barriers to it in MPM patients.
Methods:
Methods: Healthcare professionals caring for people with MPM were invited via email from professional groups, to complete a purpose designed online survey. Data were collected from January-July 2014. Descriptive data are presented.
Results:
Results: Surveys were completed by 102 doctors (Respiratory Physicians=53, Medical Oncologists (MO)=35, Other=15) and 19 nurses. Doctors mean age 47 (31-75) years, 74% male, 49% worked only in public system, 57% did not have lung cancer nurse specialist, and saw mean of 7 new patients with MPM annually. Nurses mean age 45 (29-68) years, all female, 53% worked only in public system, and saw mean of 12 (1-40) new patients with MPM annually. 74% of doctors and 53% of nurses believed >11% of MPM patients potentially eligible for chemotherapy do not receive it. Clinician barriers most commonly endorsed include: clinician nihilism 70%, 37%; non-referral to MO 47%, 63%; lack of cancer services 43%, 53%; no MDT review 40%, 32% for doctor, nurse respectively. 74% of nurses also indicated delayed diagnosis and 58% lack of clinician knowledge about treatment.
Conclusion:
Conclusions: Healthcare professionals’ estimates of potentially eligible patients with MPM who do not receive chemotherapy are consistent with or higher than evidence-based estimates. Barriers to chemotherapy access endorsed suggest strategies to increase knowledge of evidence-based treatment and address clinical nihilism are required.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-058 - Is Targeted next Generation Sequencing Superior to Older Methods at Identifying Actionable Mutations in Selected NSCLC Patients? (ID 2545)
09:30 - 09:30 | Author(s): S. Kao
- Abstract
Background:
Mutation testing for clinically actionable somatic mutations is standard of care for patients with lung adenocarcinoma. Multiplex cancer panels that simultaneously assess for a range of possible mutations are available for next generation sequencing (NGS) platforms covering a wider range of genes than previously available, but it is uncertain if these provide more clinically useful information than older multiplex systems.
Methods:
We undertook targeted next generation sequencing (NGS) of paraffin embedded tumour tissue from a cohort of 13 never smokers and 18 unselected patients who underwent surgical resection of lung adenocarcinoma using the Truseq Amplicon Cancer Panel that assesses hot spots in 48 genes using the Illumina platform. Control normal tissue was obtained from non-involved lymph nodes or normal lung parenchyma obtained from the resection specimens. Results were compared to those obtained using OncoCarta™ v1.0 panel that assesses hot spots in 19 genes using mass spectrometry.
Results:
3 of the samples from the never smokers were unsuitable for NGS analysis as they failed quality control. Of the 10 samples that could be assessed, 6 (60%) had EGFR mutations (3 L858R and 3 exon 19 deletions), 1 (10%) had a KRAS G12D mutation and 5 (50%) had T53 mutations (3 in association with an EGFR mutation). Other mutations identified were ATM, PTEN and PDGFRA mutations in one of the patients that also had an EGFR mutation. All of the EGFR and KRAS mutations were also identified using the OncoCarta™ panel. Of the 3 samples that could not be assessed by NGS, 1 had an exon 19 deletion in EGFR and 1 had a BRAF V600M mutation. In the unselected patient population all of the samples passed quality control and were suitable for both NGS and mass spectrometry. Using NGS, 10/18 (55.6%) had a KRAS mutation, 3 (16.7%) had an EGFR mutation, 7 (38.9%) had a TP53 mutation, 2 (11.1%) had PIK3CA mutations and 1 (5.6%) each had a BRAF, ERBB4, MET, HRAS, STK11, HRAS, PDGFRA, CTNNB1, NOTCH1 or SMARCB1 mutation. Using the OncoCarta™ panel, all of the EGFR and KRAS mutations were identified along with only 1 of the PIK3CA mutations. The BRAF G469S mutation was not identified by mass spectrometry.
Conclusion:
NGS using a targeted cancer panel identifies more mutations than older generation multiplex mutation testing but has a higher failure rate. In the never-smoker patient group, no additional clinically actionable mutations were identified by NGS that were not found by the OncoCarta™ panel. In patient populations with a high rate of EGFR mutations, such as never smokers, there may not be much advantage to using more expensive broader NGS cancer mutation panels.
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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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P3.08-007 - Fibulin-3: A Potential Prognostic Biomarker in Malignant Pleural Mesothelioma? (ID 1668)
09:30 - 09:30 | Author(s): S. Kao
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive asbestos-induced cancer arising from the mesothelium lining the thoracic cavities. The definitive diagnosis of MPM in most instances depends on the availability of a biopsy. A number of biomarkers have been proposed to assist in making the MPM diagnosis but none of them has yet reached the accuracy required for routine clinical use. Among the candidates is the secreted extracellular glycoprotein Fibulin-3 (FBLN3) (Pass et al, NEJM 2012; 367(15)). In this study, we have further investigated the potential of FBLN3 to serve as a biomarker for MPM.
Methods:
Cellular and secreted FBLN3 was measured (ELISA) in MPM and normal mesothelial cell lines, plasma of xenograft tumour-bearing mice, plasma from two independent series of MPM and non-MPM patients, and in malignant and non-malignant pleural effusions. The diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and the Kaplan-Meier method, respectively.
Results:
FBLN3 levels were significantly higher in MPM cells than in mesothelial cells, with a strong correlation between secreted and cellular levels. Human FBLN3 was also detectable in the plasma of tumour-bearing mice, suggesting that MPM cells were the origin of circulating FBLN3. Plasma FBLN3 levels found in MPM patients were lower than previously reported (Pass et al, NEJM 2012; 367(15)), but were comparable to those appearing in subsequent validation studies (Creaney et al, Thorax 2014; 69(10), Corradi et al, Anticancer Res 2013; 33(12)). Plasma FBLN3 was significantly elevated in MPM patients from a Sydney cohort, but far less in a Vienna cohort and the diagnostic accuracy of FBLN3 was insufficient in both cohorts [63%, (95%CI: 50.1-76.4) and 56% (95%CI: 41.5-71.0), respectively]. FBLN3 levels found in pleural effusions were comparable to those reported in previous studies, but the difference between cases and controls did not reach significance. In our series low levels of pleural effusion FBLN3 were again associated (p=0.002) with prolonged survival. In multivariate analysis taking histological subtype, age and gender into account FBLN3 remained significant with a hazard ratio of 9.92 (95%CI: 2.14–45.93).
Conclusion:
FBLN3 is overexpressed in MPM cell lines and may point to a potential oncogenic role for this protein. In contrast to the initial report linking FBLN3 to diagnosis in MPM, the levels of FBLN3 measured in plasma and pleural fluid of our series of MPM patients lacked diagnostic accuracy. However, the potential prognostic value of FBLN3 levels measured in pleural fluid was confirmed and in line with previous validation studies. These data underline the importance of validation studies for newly proposed biomarkers.
