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Marianne Nicolson



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    MA12 - Mesothelioma Surgery and Novel Targets for Prognosis and Therapy (ID 913)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 202 BD
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      MA12.05 - Phase 1 Study of HSP90 Inhibitor Ganetespib with Pemetrexed and Cisplatin/Carboplatin Chemotherapy for Pleural Mesothelioma (ID 11921)

      11:00 - 11:05  |  Author(s): Marianne Nicolson

      • Abstract
      • Presentation
      • Slides

      Background

      There have been no new licenced therapies for mesothelioma in over a decade. Ganetespib is a small-molecule heat-shock protein 90 (Hsp90) inhibitor, with significant activity for down-regulating Hsp90 client protein levels. Prior evidence indicates efficacy for ganetespib in mesothelioma through critical survival pathways and synergies with antifolates and platinum chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a dose-escalation study of ganetespib in patients with pleural malignant mesothelioma and ECOG 0-1. Ganetespib was combined with standard pemetrexed/platinum therapy, using either cisplatin (GCisP), or carboplatin (GCarbP). Three ganetespib cohorts were: 100, 150 & 200mg/m2 given days 1 and 15, every 21 days. GCisP was evaluated using a 3+3 design. GCarbP followed an accelerated titration run-in using single patients, switching to a 3+3 design after one dose limiting toxicity (DLT). DLT was assessed during cycles 1-2 for GCisP and cycle 1 for GCarbP. Genomic instability was inferred by array-based analysis of somatic copy number.

      4c3880bb027f159e801041b1021e88e8 Result

      27 patients were treated (GCisP, n=16; GCarbP, n=11). Median age 66 (range 37-76), 6 PS-0/21 PS-1, and 25 male. Only 3 patients experienced DLTs, all at 200mg/m2: grade 3 nausea (GCisP, n=1; GCarbP, n=1); grade 2 infusion-related reaction (GCarbP, n=1). This dose was the maximum tolerated dose. Partial tumour response rate was 61% (14/23 evaluable patients); 7 patients had tumour burden reduction of >50% (Figure). PFS was better using 200mg/m2 versus 100mg/m2 (hazard ratio 0.32, 95%CI 0.11-0.95, p=0.04). One patient remains progression-free even after 37 months. Total loss of heterozygosity (LOH) was correlated with increased tumour burden (n=7, correlation=0.7, p=0.078).

      meso02abstract_bestresponse.png

      Figure. Best tumour response (% change in tumour burden from baseline)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Ganetespib plus pemetrexed and platinum chemotherapy was well-tolerated in patients with pleural mesothelioma, with evidence of activity, particularly at the recommended dose of 200mg/m2. LOH correlated with poorer response to this triplet combination.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-25 - Analysis of EGFR Mutations Using Circulating Tumour DNA (ctDNA) in Non-Small Cell Lung Cancer Patients in North East Scotland (ID 13346)

      16:45 - 18:00  |  Author(s): Marianne Nicolson

      • Abstract
      • Slides

      Background

      Treatment with 1st or 2nd generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) can benefit patients with EGFR-TKI sensitising mutations but eventually patients develop resistance. The main cause of resistance - EGFR c.2369C>T (T790M) mutation - can now be targeted using 3rd generation EGFR-TKIs. EGFR testing using ctDNA provides a minimally invasive method of mutation detection. This study aimed to:

      1) Validate the Roche CE-IVD cfDNA workflow for EGFR mutation detection.

      2) Assess the usefulness of monitoring patients using ctDNA EGFR testing throughout EGFR-TKI treatment, particularly to determine whether EGFR c.2369C>T resistance mutation could be detected prior to clinical progression

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Control samples with known allele frequencies and 86 blood samples, collected from 17 patients throughout EGFR-TKI treatment, were analysed. The ctDNA was extracted using the cobasĀ® cfDNA sample preparation kit and mutation analysis conducted by the cobasĀ® EGFR mutation test v2. The semi-quantitative index (SQI) was used to indicate intra-patient fluctuations in mutation level between sequential samples. Mutation results were correlated with clinical status.

      4c3880bb027f159e801041b1021e88e8 Result

      Control samples proved the method was highly sensitive, with the ability to detect a range of EGFR mutations present at 1% allele frequency, with 100% specificity. A valid result was obtained for all patient samples tested. Radiological/clinical assessment of 11/17 patients indicated progression; 6/11 (55%) displayed T790M in ctDNA which was detectable prior to clinical progression in 4 patients. Other well documented resistance mechanisms were not sought in this study. The original EGFR mutation was not detected in sequential ctDNA samples during treatment in 7 patients. Within this group, 3/7 patients continued to respond well to treatment. However, 4/7 displayed signs of clinical progression including brain metastasis only progression. The lack of mutation detection in these patients may be due to false negative results relating to inadequate ctDNA level, in particular due to the blood-brain barrier.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Analysis of controls and sequential samples obtained from patients undergoing EGFR-TKI treatment showed the technique to be sensitive and specific with the ability to detect original sensitising mutations and emergence of T790M. There is evidence that this technique can be useful in identifying the T790M mutation prior to signs of clinical progression, and that results from ctDNA generally correlate well with clinical status.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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