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Geoffrey S Higgins

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • 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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      P1.13-31 - Safety and Tumour Hypoxia Modifying Effect of Buparlisib with Radiotherapy in NSCLC: A Phase I Dose Escalation Study  (ID 12897)

      16:45 - 18:00  |  Author(s): Geoffrey S Higgins

      • Abstract


      The Ras/PI3K/Akt pathway plays an important role in determining intrinsic and extrinsic tumour radiosensitivity. Buparlisib (BKM120) is a highly specific pan class-1 PI3K inhibitor. Pre-clinically, this class of agents radiosensitises tumours by direct effects on intrinsic radiosensitivity and by reducing tumour hypoxia. We therefore assessed the safety and determined the maximum tolerated dose (MTD) of buparlisib in combination with radiotherapy in patients with NSCLC and investigated its effect on tumour hypoxia.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      BKM120 was a single centre, open-label, dose-escalation and dose-expansion phase 1 trial. Patients with advanced stage NSCLC received 2 weeks of oral buparlisib. Palliative thoracic radiotherapy (20Gy in 5 fractions) was delivered during the second week of treatment. 18F-fluoromisonidazole (FMISO) PET scans were used to assess tumour hypoxic volume (HV) before and after 1 week of buparlisib treatment. HV was defined as the volume with a tumour-to-blood F-MISO uptake ratio ≥ 1.4.

      4c3880bb027f159e801041b1021e88e8 Result

      From June 2013 to August 2017, 21 patients were recruited. 11 patients were registered to the dose escalation phase with 9 evaluable for MTD analysis: 3 in Cohort 1 (50mg OD), 3 in Cohort 2 (80mg OD) and 3 in Cohort 3 (100mg OD). No DLT was reported therefore 100mg OD was declared the MTD and 10 patients received this dose in the expansion phase. Of all patients who received buparlisib (n=21), 1 SAE (Grade 3 hypoalbuminaemia) was possibly related to buparlisib (5%). The most common buparlisib-related AEs were fatigue (8.3%) and nausea (3.3%). 93.9% of all AEs with any relation to buparlisib were ≤ Grade 2. There was no reported radiotherapy associated toxicity. 15 patients were evaluable for tumour hypoxia imaging analysis. Median change in HV in Cohort 1 (n=3), Cohort 2 (n=3) and Cohort 3 combined with the expansion cohort (n=9) was 7%, -18% and -20%, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first clinical trial of a specific PI3K inhibitor with concurrent radiotherapy in NSCLC. This combination was found to be safe and well-tolerated. This study provides clinical evidence that PI3K inhibition rapidly reduces tumour hypoxia and therefore warrants further trials combining this class of agents with radiotherapy.