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Eilon D Kirson
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EP1.06 - Mesothelioma (ID 196)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.06-07 - In Vivo Studies of Tumor Treating Fields to Upper Torso in Combination with Chemotherapy Show No Additional Toxicities (ID 1789)
08:00 - 18:00 | Author(s): Eilon D Kirson
- Abstract
Background
Tumor Treating Fields (TTFields) are low intensity, intermediate frequency alternating electric fields targeting rapidly dividing cells. TTFields (200 kHz) are FDA-approved for the treatment of glioblastoma based on phase 3 studies demonstrating efficacy and a high safety profile. TTFields are currently being tested as a treatment option for other solid tumors in the brain, abdomen, and torso. We evaluated if the safety profile of TTFields is maintained at various frequencies in the upper torso.
Method
TTFields (150 kHz) were applied for 1-4 weeks using the Novo-TTF 100 system to rat and rabbit torso at 2-3 V/cm, which are intensities and frequencies known to be effective for the treatment of NSCLC and mesothelioma. The safety of TTFields in combination with liposomal doxorubicin and cyclophosphamide or paclitaxel was tested in animals. Throughout the treatment course, all animals underwent daily clinical examination by a certified experienced veterinarian and their body weight was determined on a weekly basis. Extensive blood workup, ECG, and temperature measurements were performed in the rabbit experiments. At the end of treatment, animals were euthanized and an experienced independent pathologist performed histological comparative evaluation of all major internal organs.
Result
No changes in the following parameters were observed in activity level, food intake, drinking, stools, motor neurological status, and respiration. Further, no changes in weight were observed between the TTFields treated and relevant control groups. No significant changes were observed in complete blood count and differential between TTFields treated animals and relevant control groups. Histological analysis did not reveal any increase in pathological findings in the TTFields treated animal groups.
Conclusion
These results demonstrate the safety of TTFields application at frequencies of 150 kHz to the torso. No additional toxicities were observed with the combination of TTFields and chemotherapy agents vs chemotherapy agents alone. This work further supports the safety profile of TTFields and offers opportunities for combining TTFields with various chemotherapy agents in lung cancers.
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EP1.18 - Treatment of Locoregional Disease - NSCLC (ID 208)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.18-18 - Body Shape and Tissue Composition Influences Uniform Distribution of Tumor Treating Fields Intensity Delivered to the Lungs (ID 2459)
08:00 - 18:00 | Author(s): Eilon D Kirson
- Abstract
Background
Tumor Treating Fields (TTFields) are low intensity, alternating electric fields in the intermediate frequency range that disrupt mitosis. TTFields are approved for the treatment of glioblastoma. A Phase 3 study investigating the efficacy of TTFields in Non-Small Cell Lung Cancer is ongoing [LUNAR NCT02973789].
TTFields are delivered through two pairs of transducer arrays placed on the patient's skin. Since the efficacy of TTFields increases with intensity, identifying factors that influence field intensity in the lungs is beneficial to understand how body shape and tissue composition influence the field intensity. We present a computer-simulation-based study investigating the effect of body size, shape, and composition on TTFields distribution in the lungs.
Method
This study was performed using the Sim4Life software package and realistic computational phantoms: female (ELLA), male (DUKE), and obese male (FATS). Various array layouts were placed on the models, and the distribution of TTFields within their lungs were calculated and compared.
Result
For all models, uniform field distributions within the lungs were obtained when the arrays were axially-aligned with the parenchyma as much as anatomically possible. The layouts that generated the highest average field intensities were those in which one pair of arrays delivered an electric field from the anterolateral to the posterior-contralateral aspect of the patient and the second pair inducing the field from the anterior-contralateral to the posterolateral aspect of the patient. In all models, these layouts led to average field intensities in the lungs above the therapeutic threshold (>1 V/cm). The highest field intensities were seen in DUKE's lungs and the lowest field intensities in FATS's lungs. Analysis suggests that field attenuation was caused primarily by layers of fat. Hence, the lower field intensities in the lungs of ELLA and FATS can be largely attributed to the thick layers of fat present in FATS and the fatty tissue in ELLA's breasts.
Conclusion
This study provides insights into how TTFields distribution in the lungs is influenced by body composition. These findings will help to optimize the placement and design of transducer array placement for the treatment of lung cancers.
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P1.06 - Mesothelioma (ID 169)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.06-17 - Tumor Treating Fields (150 kHz) Combined with Cisplatin or Pemetrexed Inhibits Mesothelioma Cells in Vitro and in Vivo (ID 1904)
09:45 - 18:00 | Author(s): Eilon D Kirson
- Abstract
Background
Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer mostly linked to asbestos exposure. The standard of care (SOC) therapy for unresectable MPM is cisplatin plus pemetrexed. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. We explored the potential use of TTFields alone and in combination with SOC as a treatment for MPM.
Method
NCI-H2052 and MSTO-211H cells were treated at various TTFields frequencies for 72 hours using the inovitro system. The combined treatment of TTFields and cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, clonogenic potential and induction of apoptosis were determined. TTFields (1.2 V/cm, 150 kHz) were applied for 8 days to rats injected to the intrapleural cavity with IL-45 cells, and overall survival was tested. TTFields (2-3 V/cm) were applied to the torsos of Sprague-Dawley rats at 150 kHz for 2 weeks and all major internal organs were histologically compared.
Result
TTFields optimal frequency was 150 kHz for both human cell lines. TTFields application (1.1 V/cm, 72 hours) at 150 kHz led to 45%-51% reduction in cell counts and 46%-64% additional reduction in clonogenic potential. The combined treatment of TTFields and cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis, and reduced clonogenic potential as compared to each modality alone (p<0.0001(. TTFields significantly prolonged the survival of rats compared to control group. Histological analysis did not reveal any increase in pathological findings with 150 kHz TTFields applied to the rat torso.
Conclusion
These results demonstrate that TTFields are a potentially effective and safe treatment for mesothelioma. The combination of TTFields with cisplatin or pemetrexed further enhances treatment efficacy. These preclinical data are consistent with those reported in a recent MPM phase 2 study (STELLAR; EF-23 trial, NCT02397928), which showed improved overall survival for combined treatment with TTFields plus pemetrexed and a platinum agent compared with historical control data, with no increase in systemic toxicity. The combination of TTFields with pemetrexed or cisplatin may further enhance treatment efficacy in mesothelioma.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-03 - Tumor Treating Fields Plus Standard of Care Treatment in Stage 4 Non-Small Cell Lung Cancer (NSCLC): Phase 3 LUNAR Study (ID 1094)
10:15 - 18:15 | Author(s): Eilon D Kirson
- Abstract
Background
Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic treatment that disrupts the formation of the mitotic spindle and dislocation of intracellular constituents. TTFields plus temozolomide significantly extended survival in newly diagnosed glioblastoma. Efficacy of TTFields in NSCLC has been shown in preclinical models. Safety of TTields in combination with pemetrexed has been reported in a phase 2 clinical study. Robust efficacy of concurrent application of TTFields and anti PD-1 therapy has been demonstrated in a mouse model of lung cancer. These data suggest that combining TTFields with anti-PD-1 may achieve tumor control by further enhancing antitumor immunity. In this Phase 3 LUNAR study [NCT02973789], we investigated if the addition of TTFields to immune checkpoint inhibitors or docetaxel increases overall survival (OS).
Method
Patients (N=534), with squamous or non-squamous NSCLC, are stratified by their selected standard therapy (immune checkpoint inhibitors or docetaxel), histology and geographical region. Key inclusion criteria are disease progression, ECOG 0-2, no electronic medical devices in the upper torso, and absence of brain metastasis. TTFields (150 kHz) are applied to the upper torso for >18 hours/day until progression in the thorax and/or liver. The primary endpoint is superiority in OS between patients treated with TTFields in combination with the standard of care treatments versus standard of care treatments alone. Key secondary endpoints compare the OS in patients treated with TTFields and docetaxel versus docetaxel alone, and patients treated with TTFields and immune checkpoint inhibitors vs those treated with immune checkpoint inhibitors alone. An exploratory analysis will test non-inferiority of TTFields with docetaxel compared to checkpoint inhibitors alone. Secondary endpoints include progression-free survival, radiological response rate, quality of life based on the EORTC QLQ C30 questionnaire. The sample size is powered to detect a HR of 0.75 in TTFields-treated patients versus control group. In January 2019, an independent Data Monitoring Committee (DMC) performed a review of the LUNAR trial data collected to that point. The DMC concluded that no unexpected safety issues could be found in patients treated with the combination of immune checkpoint inhibitors and TTFields, and recommended continuation of the LUNAR study as planned.
Result
"Section not applicable"
Conclusion
"Section not applicable"
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-21 - Efficacy and Safety of Tumor Treating Fields Delivery to the Thorax by Computational Simulations (ID 2354)
10:15 - 18:15 | Author(s): Eilon D Kirson
- Abstract
Background
Tumor Treating Fields (TTFields), an anti-mitotic therapy low intensity, intermediate frequency, alternating electric fields, are approved for glioblastoma. The STELLAR phase 2 registration trial recently demonstrated a significant extension in overall survival in mesothelioma patients treated with TTFields and standard of care chemotherapy vs historical control data on chemotherapy alone. The results highlight the potential benefit of TTFields to treat cancer located in the thorax.
Preclinical studies show that efficacy increases with the intensity of the electric field. Optimizing treatment requires a thorough understanding of how TTFields distribute within the body. Simulations can be used to evaluate the treatment safety by assessing tissue heating associated with absorption of the electric field. We present a simulation based study on field distribution and associated heating when delivering TTFields to the thorax.
Method
We delivered TTFields to the thorax of realistic computational phantoms of a male, female, and obese male (ZMT, Zurich, Switzerland). The field was delivered to the computational phantoms using transducer arrays similar to those used to deliver TTFields to the thorax with the NovoTTF-100L. The field intensities within the lungs of the models were evaluated. Specific Absorption Rate (SAR), a metric for assessing heating due to electromagnetic absorption, was calculated.
Result
The highest field intensities within the lungs were obtained when the arrays were axially-aligned with the parenchyma as anatomically possible. Field intensities throughout the lungs exceeded the therapeutic threshold of 1 V/cm in all models. Within the internal organs, SAR values were below the allowed level of 10 W/kg set out in the ICNIRP guidelines for occupational exposure. Maximum SAR levels did not exceed 20 W/kg. Occupational exposure standards typically incorporate a safety factor of around 10 when setting basic restrictions, therefore this level of SAR is considered safe and unlikely to lead to heat-related tissue damage.
Conclusion
TTFields can be delivered to the lungs at therapeutic levels that do not cause damage through tissue heating.
