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M. Thomas
Moderator of
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MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiotherapy
- Presentations: 12
- Moderators:M. Thomas, P. Mitchell
- Coordinates: 12/06/2016, 16:00 - 17:30, Stolz 1
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MA13.01 - Markerless Tumour Tracking during Lung Radiotherapy Using Intrafraction X-Ray Imaging (ID 5533)
16:00 - 16:06 | Author(s): C.(. Shieh, V. Caillet, M. Dunbar, P. Keall, N. Hardcastle, J.T. Booth, C. Huang, C. Haddad, T. Eade, I. Feain
- Abstract
- Presentation
Background:
Lung tumours often exhibit large and unpredictable motion that can severely compromise radiotherapy outcomes. Markerless tumour tracking can enable wide access to motion-adaptive radiotherapy, negating the risks and costs associated with implanting markers. The main barrier to markerless tumour tracking is the inferior tumor visibility on x-ray images due to overlapping anatomic structures. The aim of this study is to develop a markerless tumor tracking method for lung radiotherapy using intrafraction x-ray imaging.
Methods:
The markerless tumour tracking method (Figure1a) consists of four steps: (1) Building a tumour and anatomic model from the cone-beam CT (CBCT) acquired prior to treatment, (2) Using the anatomic model to remove the contribution of anatomic structures on intrafraction x-ray images, (3) Locating the tumour on the intrafraction 2D x-ray image via template matching using the tumour model, (4) Determining the tumour 3D position by a Kalman filter. The proposed method was retrospectively validated on (i) 11 CBCT scans from four patients with central tumours, and (ii) a kV fluoroscopic scan during a stereotactic ablative radiotherapy (SABR) treatment from the Light SABR trial (NCT02514512). Tracking errors were estimated using the motions of markers or beacons implanted near the tumours. Figure 1
Results:
Markerless tumour tracking successfully tracked tumours in all cases at every imaging angle. The mean 3D tracking error ranged from 1.8-4.1mm for the 11 CBCT scans, and was 3.0mm for the SABR case. Compared with the current standard of care, i.e. a single estimation of tumour position prior to treatment from the pre-treatment CBCT, markerless tumour tracking reduced tumour localization error by 0.9-7.9mm. Tracking errors in the left-right, superior-inferior, and anterior-posterior directions are shown in Figure1b.
Conclusion:
A markerless tumour tracking method was developed and shown to improve tumour localization accuracy in 12 lung cancer cases. This method can potentially enable wide access to motion-adaptive radiotherapy.
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MA13.02 - First-In-Human Clinical Experience with Real-Time Tumor Targeting via MLC Tracking for Stereotactic Radiotherapy of Lung Cancer (ID 5532)
16:06 - 16:12 | Author(s): J.T. Booth, V. Caillet, N. Hardcastle, C. Haddad, K. Szymura, R. O'Brien, B. Harris, T. Eade, P. Keall
- Abstract
- Presentation
Background:
MLC tracking is an emerging technology to improve tumor targeting and reduce normal tissue irradiation during radiotherapy. The purpose of this work is to present the early clinical experience from the first-in-human trial of real-time tumor targeting via MLC tracking for stereotactic ablative body radiotherapy (SABR) of lung cancer.
Methods:
Full ethics approval through an Australian ethics board has been received for recruitment of 20 patients with stage 1 lung cancer or lung metastases into the MLC tracking clinical trial (NCT02514512). To date, seven recruited patients have each had three electromagnetic beacons inserted near the tumor. An MLC tracking SABR plan was generated with planning target volume (PTV) expanded 5mm from end-exhale tumor volume (GTV). For comparison a conventional motion-encompassing SABR plan was generated with PTV expanded 5mm from a 4DCT-derived internal target volume. Treatment was delivered using a standard linear accelerator using in-house developed software to continuously adapt the MLC motion based on the Calypso beacons’ movement. Tumor motion, treated volume and reconstructed delivered dose were compared between MLC tracking and conventional motion-encompassing treatment planning.
Results:
All seven patients have been treated successfully with MLC tracking (29 successful fractions). The MLC tracking PTV for all patients has been smaller than with ITV based planning (range 12% to 41% reduction, or 2 to 18 cm[3] with MLC tracking). Subsequent reductions in normal lung dose were observed. Tumor motion was seen to vary in motion range from the planning 4DCT during treatment; significantly, larger motion was observed during treatment that exceeded standard PTV boundaries. Reconstruction of delivered treatments confirmed the accurate delivery of MLC tracking, with 100% prescribed dose delivered to the GTV.Figure 1
Conclusion:
The first treatments with MLC tracking have been successfully performed in seven lung cancer patients. Reductions in treated volumes were observed, which translated to reductions in delivered lung dose.
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MA13.03 - Analysis of Intra-Thoracic Anatomical Changes Observed in Clinical Workflow of Cone-Beam CT Guided Radiotherapy for Lung Cancer (ID 4478)
16:12 - 16:18 | Author(s): J. Belderbos, M.M.G. Rossi, M. Kwint, S.V. Beek, J. Sonke
- Abstract
- Presentation
Background:
Objectives: In lung cancer patients treated with image-guided radiotherapy we use daily Cone-Beam CT (CBCT) guidance for setup verification and to check on intra-thoracic anatomical changes (ITACs). ITACs like tumor baseline shifts, the occurrence or dissolving of an atelectasis, tumor progression or regression, pleural fluid- and infiltrative changes have been reported in 72% of lung cancer patients (Kwint M R&O 2014) during the course of irradiation. A traffic light protocol has been in use by the radiation technologists since 2010 to classify anatomical changes seen on the CBCT with anticipated different influences on the dose distribution using 4 action levels. The purpose of this study was to quantify how often the ITACs occurred in daily clinical practice and for which action level.
Methods:
All lung cancer patients irradiated in 2015 (excluding stereotactic treatments) with a dose >44 Gy were included. All patients had a daily CBCT guided online correction protocol and the traffic light action level of each CBCT was recorded. The following action levels have been defined: code red for immediate consultation with the physician before beam-on, code orange for a decision on the notification of the physician before the next fraction, code yellow to inform the physician; no action is required- and green for no change so no intervention necessary. We also analyzed the percentage of patients that received a new planning-CTscan and/or a new treatment plan.
Results:
In 2015 a total of 299 lung cancer patients were conventionally irradiated with radical intent and 5971 CBCT scans were made. Of these CBCTs 51% were scored as code green, 24% as code yellow, 24% as code orange and code red in less than 1% of the CBCTs. Forty patients (13%) had a new treatment plan, of which 34 patients (11%) had a new planning CT-scan and 6 patients (2%) had a new treatment plan on the original planning CT-scan.
Conclusion:
Image-guided irradiation for 299 conventionally fractionated lung cancer patients (>44 Gy) in 2015 revealed lTACs in 25% of the CBCT’s made and a physician’s decision on the notification was necessary. A total of 13% of the patients treated received an unscheduled adaptive treatment plan during the course of treatment. The traffic light protocol in daily clinical workflow worked well as a tool to prioritize a physician’s decision based on the ITACs seen on the CBCT images.
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MA13.04 - Discussant for MA13.01, MA13.02, MA13.03 (ID 7088)
16:18 - 16:30 | Author(s): C. Pöttgen
- Abstract
- Presentation
Abstract not provided
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MA13.05 - Nivolumab in Non-Small Cell Lung Cancer (NSCLC): The Real-Life Data (ID 5582)
16:30 - 16:36 | Author(s): E. Dudnik, M. Moskovitz, S. Daher, S. Shamai, E. Hanovich, Y. Shechtman, M. Abu-Amna, A. Zer, M. Wollner, J. Bar, O. Merimsky, A. Cyjon, T. Shochat, N. Peled
- Abstract
- Presentation
Background:
Nivolumab has been recently approved by the FDA as a 2[nd]-line treatment of NSCLC. The data regarding its efficacy in the real-life setting is lacking.
Methods:
260 consecutive patients with advanced NSCLC treated with nivolumab at five cancer centers in Israel between January 2015 and March 2016 were observed for OS and toxicity. OS was analyzed by the Cox proportional-hazards regression model.
Results:
Patient baseline characteristics: median age 67y (range 41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; Non-sq/Sq/other 70%/23%/7%; KRASm/EGFRm/ALK+/other genetic aberration/none/NA 7%/5%/0%/4%/42%/42%; brain metastases 21%; liver metastases 21%; treatment (Tx) line: 1st/2nd/3rd+-line/NA 6%/64%/26%/4%. Median duration of follow-up was 4.3 mo (range 0.1-13.8); median Tx duration was 2.7 mo (range 0.1-15.5); median number of Tx cycles delivered was 6 (range 1-26). 130 (50%) patients died; median OS comprised 6.6 mo (95%CI 5.6-8.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS (table 1). Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 8.6 mo and 3.5 mo, respectively. Safety data is presented in table 2. Figure 1Figure 2
Conclusion:
Nivolumab has reasonable efficacy and good safety profile in the real-life setting. ECOG PS ≥2 is associated with poor prognosis.
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MA13.06 - Integrative Genomic Profiling Identifies BRAF Mutations as Novel Radiotherapeutic Targets in Adenocarcinomas of the Lung (ID 6199)
16:36 - 16:42 | Author(s): E.K. Chie, P. Gopal, M.E. Abazeed
- Abstract
- Presentation
Background:
Patients with non-small cell lung cancer (NSCLC) display a wide spectrum of oncologic outcomes, suggesting significant underlying biologic diversity. However, current radiotherapeutic management is largely homogeneous for a given stage, To advance genotype-directed radiotherapy in NSCLC, we sought to identify genetic determinants of radioresistance by leveraging cancer genomic data with a recently developed high-throughput platform for measuring radiation survival.
Methods:
We used our recently validated high-throughput proliferation assay to profile 104 lung cancer cell lines, including 89 NSCLC and 15 small cell lung cancer (SCLC) lines, for radiation survival. Survival curve analyses permitted quantitative assessment of radiosensitivity. Genomic correlates of radiosensitivity were explored by calculating the information-based similarity metric and correlating genomic parameters by accessing Oncomap data from the Cancer Cell Line Encyclopedia, the COSMIC database of the Cancer Genome Project, and The Cancer Genome Atlas.
Results:
Radiation survival across lineages reflected clinical experience regarding differential response to fractionated radiation inasmuch as lung squamous cell carcinoma and adenocarcinoma (ACA) had similar radiosensitivity, whereas SCLC and carcinoid were, respectively, more and less radiosensitive. Importantly, radiosensitivity varied more within a lineage than across lineages, with a 6-fold difference in integral survival among ACA lines. Correlation with cancer genomic data revealed BRAF mutations within the most resistant ACA lines (P = 0.0097, FDR = 0.957). A majority of the mutations identified by our analysis have been previously annotated by The Cancer Genome Atlas lung ACA dataset and all hypermorphic mutations identified were located in the highly conserved kinase domain. The majority of mutations have been known to enhance kinase activity in melanoma in a fashion analogous to the well-known BRAF V600E mutation. In line with these findings, we showed that kinase domain mutations were hypermorphic as measured by MEK and ERK1/2 phosphorylation. We also showed that exposure of wild type BRAF cells to radiation results only in a transient activation of MEK and ERK1/2. The MEK inhibitor selumetinib selectively decreased the growth of cells with kinase domain BRAF mutations and sensitized these cells to radiation.
Conclusion:
BRAF mutations are associated with radiation resistance in lung ACA. Our data nominates MEK inhibitors, a drug class currently in clinical use, as a targeted therapeutic in select BRAF-mutant lung ACA. Further investigation has the potential to yield an additional genotype-directed therapy that could impact up to 4-6% of patients with lung ACA, a frequency comparable to that of ALK rearrangements (4%) or EGFR mutations (10%).
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MA13.07 - Tumor-Targeted Radiation Promotes Abscopal Efficacy of Regionally Administered CAR T Cells: A Rationale for Clinical Trial (ID 5456)
17:24 - 17:30 | Author(s): M. Zeltsman, J. Villena-Vargas, A. Rimner, M. Mayor, D. Jones, P.S. Adusumilli
- Abstract
- Presentation
Background:
Our laboratory has demonstrated the augmented anti-tumor efficacy of intrapleurally administered cancer-antigen mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T cells (Sci Transl Med 2014), and translated the approach to a clinical trial (NCT02414269) for thoracic malignancies. We hypothesized that regionally administered MSLN CAR T cells can circulate systemically to achieve abscopal anti-tumor efficacy in an antigen-specific manner, and the abscopal efficacy can further be promoted by tumor-targeted radiation therapy (RT).
Methods:
Using optimized protocols that would permit non-necrotic, well-vascularized tumor growth in pleura, chest wall, peritoneum and flank, tumors were established in immunodeficient (NOD/SCID gamma) mice using mesothelioma or lung adenocarcinoma (LAC) cells. Tumor burden progression, MSLN-targeted CAR T-Cell accumulation at primary and distant tumors was monitored by noninvasive bioluminescence imaging (BLI) and tumor volume measurements.
Results:
A single dose of MSLN CAR T cells administered intrapleurally proliferated (Figure 1A left panel), circulated extrapleurally and accumulated at abscopal sites, including the lymph nodes, chest wall, peritoneum, and flank within 3-5 days, with subsequent T-cell proliferation at abscopal sites (Figure 1A right panel). Primary tumor-targeted, single-dose, thoracic RT prior to T-cell administration augmented T-cell accumulation as demonstrated by BLI (Figure 1B) and tumor T-cell quantification (p<0.01). In a mouse model of primary pleural, abscopal antigen-expressing and non-expressing flank tumors (Figure 1C), a single, low-dose, non-cytotoxic thoracic RT enhanced abscopal site CAR T-cell accumulation that resulted in tumor regression (p=0.01; Figure 1D). Figure 1
Conclusion:
Regionally administered mesothelin-targeted CAR T cells proliferate and eradicate the primary tumor, accumulate and demonstrate anti-tumor efficacy at abscopal sites prior to eradication of the primary tumor in an antigen-specific manner. A single low-dose primary tumor-targeted radiation therapy promotes scopal and abscopal anti-tumor efficacy. These results provide rationale to initiate a clinical trial of combination regional therapies with radiation therapy and CAR T cells.
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MA13.08 - Discussant for MA13.05, MA13.06, MA13.07 (ID 6953)
16:42 - 16:54 | Author(s): M. Pless
- Abstract
- Presentation
Abstract not provided
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MA13.09 - Serial FDG and FLT PET/CT during Curative-Intent Chemo-Radiotherapy for NSCLC Impacts Patient Management and May Predict Clinical Outcomes (ID 4257)
16:54 - 17:00 | Author(s): D. Ball, S.J. Everitt, R.J. Hicks, J. Callahan, A. Herschtal, T. Kron, N. Plumridge, M. Mac Manus
- Abstract
- Presentation
Background:
FDG-PET/CT is the gold-standard for non-small cell lung cancer (NSCLC) diagnosis, staging and tumour delineation prior to chemo-radiation therapy (CRT). FDG-PET is superior to CT for subsequent response assessment. Sequential interim metabolic and proliferative tumour response assessment with FDG and 3'-Fluorothymidine (FLT) respectively, prior to and during CRT is novel and may predict outcome.
Methods:
Patients with FDG-PET-stage I-III NSCLC who were prescribed radical chemo-RT (60 Gy in 30 fractions @ 5/wk) were enrolled. FDG and FLT PET/CT scans were performed at baseline and at weeks 2 and 4 of CRT. Intra-treatment tumour response judged by reduction in FDG and FLT uptake was categorised as complete (CR)/partial response (PR), stable (SD) or progressive disease (PD) using EORTC criteria. Overall Survival (OS) and Progression Free Survival (PFS) were measured relative to intra-treatment scan dates and plotted using Kaplan-Meier curves. Univariate Cox regressions were used to calculate associations between 1. SUVmax of baseline FDG and FLT GTV and 2. intra-treatment FDG and FLT response with patient outcomes (OS and PFS).
Results:
Sixty patients were recruited between 2009-13; male 62%; median age 66 years, adenocarcinoma (42%). Two-year OS and PFS were 0.51 and 0.26 respectively. Of 332 PET/CT scans analysed, study scans provided additional information to FDG~BL~ in 21 (35%) patients. Distant metastasis was detected in 3 patients on FLT~BL~ and in 2 patients on FDG/FLT~wk2~ changed treatment intent to palliative. Loco-regional progression during RT was observed in 5 (8%) patients, prompting larger RT fields. FLT~wk2~ response (SD vs CR/PR vs PD) was associated with OS [HR (95%CI) 1 vs 2.02 (0.87, 4.65) vs 20.09 (4, 114), p=0.012] and PFS [1 vs 2.01 (0.92,4.37) vs 32.41 (3,348), p=0.024]. Associations between the baseline FDG and FLT SUV~max ~and patient outcomes were not significant, including OS where FDG SUVmax HR [95% CI] was 1.04 [0.98, 1.10], p=0.25 and FLT SUVmax HR [95% CI] was 1.07 [0.93, 1.22], p=0.33.
Conclusion:
Tumour response on FLT~wk2~ was associated with OS and PFS. The possible association between worse clinical outcomes and early suppression of FLT uptake during CRT may be a result of repair of tumour DNA damage. Baseline FLT, FLT~wk2~ and FDG~wk2~ detected rapid distant and loco-regional progression in 10 (17%) patients prompting changes in treatment intent and RT fields.
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MA13.10 - Magnetic Resonance Imaging-Guided Delivery of Lung Stereotactic Radiotherapy Using Patient-Controlled Visual Guidance (ID 5293)
17:00 - 17:06 | Author(s): S. Tetar, F. Lagerwaard, M.A. Palacios, N. Haasbeek, O. Bohoudi, B. Slotman, A. Bruynzeel, S. Senan
- Abstract
- Presentation
Background:
Treatment-related toxicity is more common following stereotactic ablative radiotherapy (SABR) for central lung tumors, than is the case for peripheral tumors [Tekatli 2015]. Further reductions in doses to critical central structures are possible using respiration-gated SABR delivery, but insertion of fiducial markers for gating is also associated with toxicity. We describe a novel approach for clinical delivery of breath-hold gated SABR under continuous MRI-guidance.
Methods:
The MRIdian® system permits tumor visualization at 4 frames/second during treatment delivery, with radiation beam-holds whenever the target is outside a prespecified gating window. The gating procedure is as follows: a 17 second inspiration breath-hold MR scan is performed for planning before each SABR fraction (resolution 1.6×1.6×3.0 mm). Image registration is performed, and contours adapted when necessary. A 3mm PTV margin is added, and planned dose distribution recalculated for the ‘anatomy of the day’, and reoptimized. A sagittal plane is chosen for tumor tracking and gating, with a planning target margin of 3 mm. The sagittal tracking view from the MRIdian console is projected on a MR-safe monitor (Cambridge Research), and patients can continuously observe the tracking image using a mirror inside the bore.
Results:
Since May 2016, 30 fractions of MR-guided gated delivery have been performed in 5 cancer patients with 6 central tumors. All MR-based breath-hold PTV’s were smaller (mean 19.8 ± 13.3 cc) than a conventional free-breathing, motion-encompassing approach (mean 36.1 ± 21.9 cc). Plans of a single case are shown in Figure 1. Video-assisted visual feedback achieved a breath-hold gating efficiency of 52% (range 27-88%).Figure 1
Conclusion:
For high-risk SABR cases, use of MR-guided, video-assisted breath-hold gated SABR delivery constitutes a novel treatment method, allowing for minimization of mobility- and setup margins, and for improved verification of SABR delivery. Data from additional patients undergoing treatment will be presented.
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MA13.11 - Investigating the Feasibility of Establishing a Prospective Cohort of Lung Cancer Patients Following Radiotherapy with Curative Intent (ID 5602)
17:06 - 17:12 | Author(s): L. Calman, S. Taylor, R. Foster, A. Richardson, P. Smith, J. Baird, J.G. Edwards, C. Faivre-Finn, C. Foster
- Abstract
- Presentation
Background:
Worldwide lung cancer is the biggest cause of cancer mortality (Cancer Research UK, 2012) and is the UK’s second most commonly diagnosed malignancy (Macmillan Cancer Support, 2013). Early detection and treatment significantly improves five year survival rates but curative treatments can impact on patients’ health and wellbeing. To date little research has been conducted to establish the support needs and recovery patterns of health and wellbeing among lung cancer patients treated with curative intent radiotherapy. This limits our ability to identify those most at risk of poorer health and wellbeing outcomes and target services effectively to support patients better. This study assesses the feasibility of collecting patient reported outcomes measures (PROMs) and clinical details to understand recovery after curative intent radiotherapy treatment for lung cancer.
Methods:
This mixed methods study used a prospective, longitudinal cohort design. Eligible patients awaiting curative intent radiotherapy were recruited from six UK sites between October 2015 and June 2016. Questionnaires were completed before undergoing radiotherapy and 3 months later. The questionnaires included validated patient reported outcome measures, including quality of life, symptoms, social support, wellbeing and socio-demographic details. Participants’ medical details were collected by healthcare professionals (HCPs) including cancer type, stage, treatment, and comorbid conditions. Study procedures were evaluated in a qualitative process evaluation.
Results:
Of 229 eligible patients, 136 consented to the study with 73% uptake of those approached. A further 13 patients provided reduced consent to collect demographic and medical information only. Preliminary results: response rates 76% at baseline and 65% at 3 months. Of baseline responders: 59% were male; the median age was 70 years; 29% lived alone; 61% were home owner-occupiers and 20% were current smokers. Baseline EORTC-QLQ-C30 results showed a mean global health status score of 56.6 and patients were most affected by dyspnoea and fatigue with mean scores of 48.8 and 45.0. These are in line with expected scores based on reference data. To date 9 HCPs, 7 patients and 2 stakeholders have been interviewed as part of the process evaluation, study processes and procedures are deemed acceptable to participants.
Conclusion:
This study demonstrates it is feasible to recruit a cohort of lung cancer patients prospectively to assess wellbeing and patterns of recovery following radiotherapy. This novel approach to understanding lung cancer patients’ experiences of survival will enhance our ability to target appropriate and timely support to those most at risk of poorer health and wellbeing.
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MA13.12 - Discussant for MA13.09, MA13.10, MA13.11 (ID 7089)
17:12 - 17:24 | Author(s): A. Juretic
- Abstract
- Presentation
Abstract not provided
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Author of
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.02 - Clinical Research Platform into Molecular Testing, Treatment, Outcome (CRISP): A Prospective German Registry in Stage IV NSCLC AIO-TRK-0315 (ID 5911)
11:06 - 11:12 | Author(s): M. Thomas
- Abstract
- Presentation
Background:
Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore registry data are of ever increasing importance to patients, physicians and reimbursement institutions.
Methods:
Therefore, we have started a prospective, clinical registry for patients with metastatic non-small cell lung cancer. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of first-line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing.
Results:
This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death. The first patients have been included as of December 2015. As of yet, 82 centers have been initiated, 211 patients have been recruited. Preliminary data will be presented at the meeting in terms of molecular test rates, demographic data as well as treatment stratification in the 1[st] line setting.
Conclusion:
The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany. ClinicalTrials.gov Identifier: NCT02622581 CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-003 - A Phase II Study Evaluating the Combination of Everolimus with Carboplatin/Paclitaxel as 1st Line Treatment in Patients with Advanced LCNEC (ID 4370)
14:30 - 14:30 | Author(s): M. Thomas
- Abstract
Background:
Approximately 3% of all lung cancers are made up of large cell neuroendocrine carcinoma of the lung (LCNEC). These tumors in general have a bad prognosis and currently there are only very limited treatment options, including platinum derivatives and etoposide. The PI3/AKT/mTOR pathway is known to be dysregulated in neuroendocrine tumors (NETs). Since the mTOR inhibitor RAD001 (everolimus) already has proven effectiveness in different types of NETs, we tested whether everolimus might be also an effective treatment option in advanced LCNEC patients.
Methods:
In this multi-center, open-label, phase II study, everolimus was combined with platin-based chemotherapy in patients with histologically confirmed stage IV LCNEC according to WHO criteria. Further inclusion criteria were measurable disease according to RECIST 1.1 and adequate bone marrow, renal, and liver function. Main exclusion criteria were symptomatic CNS metastases and prior treatment for advanced LCNEC. Enrolled patients received everolimus once a day in combination with 4 cycles of carboplatin and paclitaxel, followed by daily everolimus maintenance therapy. The primary objective was to evaluate the efficacy by assessing the proportion of progression-free patients after three months of treatment.
Results:
Ten German trial sites enrolled altogether 49 patients (mean age: 62 ± 9 years; 71% men). The primary endpoint (proportion of pts progression-free at month 3) was achieved by 24 patients (49%), assessed by an independent central imaging reviewer. Further efficacy evaluation showed an overall response rate (ORR) until month 3 of 45%, a disease control rate (DCR) until month 3 of 73.5%, a median progression-free survival (PFS) of 4.3 months, and a median overall survival (OS) of 9.8 months. At least one toxicity occurred in 86% of all enrolled patients with grade 3/4 toxicities in 51%. Most frequent toxicities were diarrhea, fatigue, anemia, and neutropenia.
Conclusion:
The results show that a combined therapy of carboplatin and paclitaxel with the mTOR inhibitor everolimus is an alternative treatment option for LCNEC patients. When comparing to other trials, the effectiveness is comparable to a treatment regimen of cisplatin and etoposide.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-034 - The Pregnancy Associated Endometrial Protein Glycodelin as a Biomarker for Malignant Pleural Mesothelioma (ID 5422)
14:30 - 14:30 | Author(s): M. Thomas
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a short survival time arising from the mesothelial cells of the pleura. MPM is mainly associated with asbestos exposure and a strong inflammatory reaction. The common treatment of MPM combines macroscopic complete resection and adjuvant or neoadjuvant chemotherapy, respectively. Soluble mesothelin and osteopontin are current available biomarker for malignant mesothelioma with moderate sensitivity and specificity. Glycodelin is an immune system modulator well described during pregnancy. It is involved in invasion of the trophoblast and in regulation of the immunotolerance between the maternal immune system and the fetus.
Methods:
With a commercial ELISA, we measured the glycodelin serum concentrations of patients with MPM. In addition, we analyzed the glycodelin gene expression using quantitative PCR and stained glycodelin in formalin-fixed paraffin embedded tissue slides.
Results:
We found high glycodelin concentrations in the serum of patients with MPM compared to benign lung diseases. Patients with high glycodelin serum concentrations exhibited a worse overall survival. Moreover, glycodelin serum levels correlated with tumor response to treatment. A comparison of soluble mesothelin-related proteins (SMRP) and glycodelin in the serum of a large patient cohort demonstrated that the detection of both soluble factors can increase the reliable diagnostic of MPM. Glycodelin mRNA and protein was highly expressed in MPM tumors compared to normal lung tissue.
Conclusion:
In this study, we first described the expression of glycodelin in MPM. Altogether, glycodelin seems to be a new potential serum biomarker for the aggressive malignant pleural mesothelioma.
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P2.01-059 - Regulation of Glycodelin Expression - An Immunomodulatory and Pregnancy Associated Protein in NSCLC (ID 5345)
14:30 - 14:30 | Author(s): M. Thomas
- Abstract
Background:
Glycodelin (gene name: progesterone-associated endometrial protein, PAEP) is a protein initially described as an immune system modulator during the establishment of pregnancy. Former studies determined an atypical expression and secretion of glycodelin in non-small cell lung cancer (NSCLC), the most common type of lung cancer. To date, there is not much known about the signaling pathway which regulates PAEP/glycodelin expression in cancer. However, initial experiments already revealed an inducing effect of epidermal growth factor (EGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), lysophosphatidic acid (LPA) and Phorbol 12-myristate 13 acetate (PMA) on PAEP/glycodelin expression in two NSCLC cell lines (H1975 and 2106T). In this study, we analyzed an extended number of possible regulatory candidates to acquire a more detailed view on the regulatory pathway of PAEP/glycodelin in NSCLC.
Methods:
A lung adenocarcinoma (H1975) and a lung squamous cell carcinoma cell line (2106T) were transfected with siRNA targeting nuclear factor κB1 (NFκB1) or treated with human chorionic gonadotropin (hCG), transforming growth factor-β (TGF-β) 1, -2, -3, protein kinase C (PKC) activator bryostatin 1 and PKC inhibitor GF109203x, respectively. Additionally, combined treatments with GF109203x and TGF-β 1,-2, EGF or HB-EGF were performed. PAEP expression in the manipulated cells was determined by quantitative polymerase chain reaction (qPCR), while glycodelin expression or secretion was detected by western blot analysis.
Results:
NFκB1 siRNA transfection resulted in decreased PAEP and glycodelin amounts (H1975 and 2106T), whereas hCG (H1975 and 2106T) and TGF-β 1, -2, -3 (2106T) treatment led to higher levels. In bryostatin treated cells (H1975 and 2106T), PAEP/glycodelin expression was upregulated. The contradictory effect could be demonstrated for cells treated with the PKC inhibitor GF109203x alone and in combination with TGF-β 1,-2, EGF or HB-EGF (H1975 and 2106T).
Conclusion:
This study revealed that there are different regulation mechanisms of PAEP/glycodelin induction in NSCLC. Especially, PKC seems to be involved as a key molecule. The investigated candidates which play a crucial role in driving this signaling pathway are all known to promote the development of cancer. Elucidating the regulatory pathway of the immune system modulating protein glycodelin might reveal a potential strategy to weaken the immune system defense of lung tumors.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-025 - Randomized, Double-Blind, Phase 3 Study Comparing Biosimilar Candidate ABP 215 with Bevacizumab in Patients with Non-Squamous NSCLC (ID 6068)
14:30 - 14:30 | Author(s): M. Thomas
- Abstract
Background:
ABP 215 is a biosimilar candidate that is similar to bevacizumab, a VEGF inhibitor, in analytical and functional comparisons. Pharmacokinetic similarity between ABP 215 and bevacizumab has been demonstrated in a phase 1 study. Here we present results from a pivotal phase 3 clinical study in non–small-cell lung cancer (NSCLC).
Methods:
In this double-blind, active-controlled study in adults with non-squamous NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel, subjects were randomized (1:1) to receive investigational product (IP; ABP 215 or bevacizumab 15 mg/kg) Q3W for 6 cycles as an IV infusion. Clinical equivalence was demonstrated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) of the objective response rate (ORR; primary endpoint) with pre-specified margin of (0.67, 1.5) Secondary endpoints were risk difference (RD) of the ORR, duration of response (DOR), progression-free survival (PFS), treatment-emergent adverse events, and overall survival (OS).
Results:
A total of 642 subjects (ABP 215 [Arm 1], n=328; bevacizumab [Arm 2], n=314) were randomized. Demographic and baseline characteristics were balanced between arms. There were 128 (39.0%) responders in Arm 1 and 131 (41.7%) responders in Arm 2. The RR for ORR was 0.93 (90%CI, 0.80–1.09). The RD for ORR was −2.90% (90%CI, −9.26%–3.45%). Among the responders the estimated median DOR was 5.8 months in Arm 1 versus 5.6 months in Arm 2. The estimated median PFS in Arm 1 was 6.6 months versus 7.9 months in Arm 2; the analysis included all 256 PFS events, 131 (39.9%) in Arm 1 and 125 (39.8%) in Arm 2. The safety population included 324 treated subjects in Arm 1 and 309 in Arm 2; 139 (42.9%) subjects in Arm 1 and 137 (44.3%) in Arm 2 experienced grade ≥3 TEAEs. TEAEs leading to IP discontinuation affected 61 (18.8%) subjects in Arm 1 and 53 (17.2%) in Arm 2; 85 (26.2%) subjects in Arm 1 and 71 (23.0%) in Arm 2 experienced at least one serious AE; 13 (4.0%) in Arm 1 and 11 (3.6%) in Arm 2 had a fatal TEAE. OS analysis included 79 deaths, 43 (13.3%) in Arm 1 and 36 (11.7%) in Arm 2. Binding antibodies developed during the study in 4 (1.4%) subjects in Arm 1 versus 7 (2.5%) in Arm 2; no subject tested positive for neutralizing antibodies.
Conclusion:
The study met the primary and secondary objectives demonstrating that ABP 215 and bevacizumab are clinically equivalent.
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P2.03a-030 - nab-Paclitaxel/Carboplatin Induction Therapy in Squamous (SCC) NSCLC: Interim Quality of Life (QoL) Results From ABOUND.sqm (ID 4343)
14:30 - 14:30 | Author(s): M. Thomas
- Abstract
Background:
Despite a high symptom burden in many patients with advanced NSCLC, limited data exist on QoL with first-line chemotherapy. Here we report results of an interim QoL analysis in patients with SCC NSCLC treated with nab-paclitaxel/carboplatin in the induction part of the ongoing ABOUND.sqm study.
Methods:
Chemotherapy-naive patients with advanced SCC NSCLC received 4 cycles of induction therapy with nab-paclitaxel 100 mg/m[2] on days 1, 8, and 15 + carboplatin AUC 6 on day 1 (21-day cycles). Patients without progression after induction received (2:1) maintenance nab-paclitaxel 100 mg/m[2] on days 1 and 8 (21-day cycles) + best supportive care (BSC) or BSC alone until progression/unacceptable toxicity. The primary endpoint is progression-free survival (randomization to maintenance). Patient-reported QoL (exploratory endpoint) was assessed on day 1 of each cycle using the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L).
Results:
207 patients were treated in the induction phase. Median age was 68 years; 66% of patients were male, and 99% had an ECOG PS 0-1. Out of 200 patients treated for ≥ 2 cycles, 180 (90%) completed baseline + ≥ 1 postbaseline QoL assessments. The mean change from baseline in LCSS symptom burden index and total score ranged from 6.6%-10.3% and 5.5%-9.5%, respectively. Clinically meaningful improvements (≥ 10 mm [visual analog scale]) from baseline were observed in composite LCSS pulmonary symptom items of cough, shortness of breath, and hemoptysis in 46% of patients. For individual EQ-5D-5L dimensions, ≥ 82% of patients maintained/improved from baseline and ≥ 33% reported complete resolution (Table).Figure 1
Conclusion:
In this interim analysis, 4 cycles of nab-paclitaxel/carboplatin treatment led to clinically meaningful improvements in LCSS pulmonary symptom items. Complete resolution of problems reported at baseline in EQ-5D-5L dimensions was observed in ≥ 33% of patients at least once during treatment. NCT02027428
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-025 - 9-Year Experience: Prophylactic Cranial Irradiation in Extensive Disease Small-Cell Lung Cancer (ID 4017)
14:30 - 14:30 | Author(s): M. Thomas
- Abstract
Background:
~In 2007, a EORTC study demonstrated a beneficial impact on overall survival with the use of prophylactic cranial irradiation in extensive disease small cell lung cancer. Nevertheless, there is ongoing debate over the role of PCI as patients in this trial did not undergo imaging of the brain prior to treatment, and a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with a negative pre-treatment brain MRI. 87% of our patients received brain imaging prior to PCI.~
Methods:
We examined the medical records of 137 patients with extensive disease small cell lung cancer who initially responded to chemotherapy and received PCI between 2007 and 2015. The outcomes, including the development of brain metastases and OS following PCI were analyzed. Survival and correlations were calculated using log-rank, univariate, and multivariate Cox proportional hazards-ratio analyses.
Results:
Median OS after PCI was 12 months and the median nPFS after PCI was 19 months. There was no significant survival difference in patients who received an MRI prior to PCI compared to patients who received a contrast enhanced computer tomography (CT) (p=0.20). Univariate analysis for overall survival did not show a statistically significant effect for known cofactors. Figure 1 Figure: OS (A) and nPFS (B) in patients with ED SCLC treated with PCI. .
Conclusion:
We present the 9-year clinical experience with PCI in ED SCLC patients from one of Europe’s largest Lung Cancer Centres. PCI leads to a nearly doubled median OS compared to the irradiation arm of the EORTC trial with a 2-months prolonged median OS compared to the irradiation arm of the Japanese trial. PCI should remain standard of care for all patients with SCLC who have a response to initial chemotherapy. Contrast enhanced brain MRI instead of CT for staging prior to PCI is recommended if possible.
