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Katherine A Vallis



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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): Katherine A Vallis

      • Abstract

      Background

      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.

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    P3.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 983)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.17-18 - Towards Individualizing Patient Selection in Proton Therapy for Lung Cancer Using the Model-Based Approach (ID 13191)

      12:00 - 13:30  |  Author(s): Katherine A Vallis

      • Abstract

      Background

      Intensity modulated proton therapy (IMPT) has the potential to reduce dose to adjacent normal tissue compared to photon therapy. Although dosimetric advantages can be seen, these results need to translate to clinically meaningful benefit. We aim to identify patients who would benefit from IMPT over photon volumetric modulated arc therapy (VMAT) in locally advanced lung cancer using recently published normal tissue complications probabilities (NTCP) models for heart and lung.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      VMAT and robust optimised-IMPT plans were assessed to a physical dose of 70Gy in 35 fractions according to RTOG 1308 protocol. Risk estimates of grade 3+ cardiac toxicities and dyspnoea were calculated based on NTCP models which incorporated dose metrics and individual patients’ baseline risk-factors (RF) (cardiac: pre-existing heart disease (HD), lung: patient-reported outcome dyspnoea grade). Risk estimates were calculated and compared based on the pre-treatment patients’ RF and in the hypothetical scenarios where all patients had baseline HD or grade 1 dyspnoea. The difference between the probability estimates of VMAT and IMPT were determined (ΔNTCP). The models were applied in the different scenarios to ten proxy patients. These patients were retrospectively identified to ensure different anatomical locations (lobes and mediastinal/hilar regions) were represented (GTV median: 106cc, range: 15–404cc). Five patients had planning target volume (PTV) overlapping with the heart.

      4c3880bb027f159e801041b1021e88e8 Result

      There was no significant difference in target coverage between VMAT and IMPT. Protons delivered a lower dose and to heart and lung in all patients (p<0.05, lung: V20, V5, mean lung dose; heart: V30, V5 and mean heart dose). When the risk estimates were calculated according to the patients’ baseline RF, only three had an estimated ΔNTCP≥5%- all based on cardiac toxicities (AR VMAT vs IMPT: 38% vs 10%, 13% vs 10%, 18% vs 9%). Of the three, two patients had pre-existing HD. The relative risk reduction with IMPT varied between none to 0.74. Using ΔNTCP≥5% as a threshold, when all patients were considered to either have baseline HD or grade 1 dyspnoea, the same three patients were selected based on cardiac toxicities and two based on lung toxicity. Predictors of ΔNTCP≥5% for cardiac toxicities were pre-existing cardiac disease, tumour volume extending to the level of T7 vertebrae or below, degree of overlap between PTV and heart.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In an unselected patient group, not all patients would benefit from IMPT. Although the validity of photon NTCP models in proton is unclear, appropriate models could be used to aid randomised control trial design.

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