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Martin Forster



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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): Martin Forster

      • 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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    P1.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 944)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.12-20 - Overall Survival with Lurbinectedin Plus Doxorubicin in Relapsed SCLC. Results from an Expansion Cohort of a Phase Ib Trial. (ID 13245)

      16:45 - 18:00  |  Presenting Author(s): Martin Forster

      • Abstract
      • Slides

      Background

      Lurbinectedin (PM01183, L) is a new anticancer drug that binds to DNA, inhibits transactivated transcription and modulates tumor microenvironment. Preclinical evidence of synergism was observed for PM01183 in combination with doxorubicin (DOX).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This multicenter, phase Ib clinical trial found impressive activity in second-line SCLC patients (ORR 67%). An expansion cohort with reduced dose (L 2mg/m2+ DOX 40mg/m2) was implemented to improve safety. SCLC patients <75 years with ECOG PS 0-1 and with no more than one prior chemotherapy line and stable brain metastases were included. DOX was interrupted after 10 cycles continuing with PM01183 alone. Primary G-CSF prophylaxis was not mandatory.

      4c3880bb027f159e801041b1021e88e8 Result

      27 patients treated. Males: 75%; median age: 64 (49-77) years; ECOG PS 0-1: 32%-68%; CNS involvement: 4%; bulky disease (>50 mm): 75%. 88% responded to 1st line (CR in 4%). Median chemotherapy-free interval (CTFI) was 3.5 months (m). 22% refractory (CTFI <30 days) 15% resistant (R) (CTFI 30-90 days) and 63% sensitive (S) (CTFI>90 days). Overall confirmed ORR was 37% (CR in 4%), and 53% (CR in 6%) in S patients. Overall median PFS was 3.4 m (95% CI, 1.5-6.2), being 1.5 m (95%CI, 0.8-3.4) in R pts, and 5.7 m in S patients. Overall survival (OS) data are summarized in the following table.

      OS

      Overall

      Resistant

      Sensitive

      Overall (n=27)

      7.9 m

      (95% CI: 4.9-11.5)

      4.9 m

      (95% CI: 2.3-6.7)

      11.5 m

      (95% CI: 6.0-16.6)

      Excluding CTFI<30days (n= 21)

      10.2 m

      (95% CI: 6.0-12.1)

      6.7 m

      (95% CI: 5.1-8.4)

      11.5 m

      (95% CI: 6.0-16.6)

      Data shown are median and 95% CI.

      Grade 4 neutropenia, anemia or thrombocytopenia appeared in 64%/0%/7% of patients, respectively, and febrile neutropenia (G3/4) occurred in 10%. Non-hematological toxicity was mild and mainly due to fatigue (G3=18%) and nausea (G3=7%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lurbinectedin/DOX combination showed remarkable activity as second line in SCLC, especially in sensitive patients (CTFI>90 days). Activity is higher than that reported for CAV or topotecan. OS shows an outstanding improvement in this second-line setting, especially when excluding refractory pts. A phase III clinical trial (ATLANTIS, NCT02566993) is currently ongoing evaluating this combination in relapsed SCLC patients

      6f8b794f3246b0c1e1780bb4d4d5dc53

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