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    MA09 - Lung Cancer Surgical and Molecular Pathology

    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Moderators:
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      MA09.01 - Correlation of Pre-Operative Cancer Imaging Techniques with Post-Operative Macro and Microscopic Lung Pathology Images  

      15:15 - 15:20  |  Presenting Author(s): Stephen James Harrow  |  Author(s): Gabriel Reines-March, Craig Dick, Xiangyang Ju, Stephen Marshall

      • Abstract

      Background

      This research project aims to investigate the performance of several PET radiotracers in lung cancer by aligning PET-CT and pathology imagery acquired from the same patients at different points in time. The discrimination of tumour substructures is of great importance in therapy planning, as a given treatment may be better adapted depending on the local characteristics of the carcinoma.

      Method

      Due to the high deformability of lung tissue, several intermediate steps must be used for merging pathology and pre-operative PET-CT in a coherent manner. Firstly, the tumour volume is reconstructed from the macroscopic images taken during dissection. For this purpose, an enhanced dissection protocol is used, where the lung specimen is placed in a bespoke slicing rig and embedded in agar to hold it in place. Using a threaded plunger, the specimen is pushed upwards in 5mm steps, sliced and photographed. This procedure allows us to obtain slices of uniform thickness. Secondly, microscopic digital slides of the cancerous tissue are merged with the macroscopic 3D model. Finally, the whole volume is fused with the pre-operative PET-CT scan, using a non-linear deformable model.

      Result

      Preliminary results obtained with a synthetic phantom allowed us to analyse the accuracy of the tumour 3D reconstruction algorithm from planar macroscopic slices. Using these findings, we could optimise the interpolation and segmentation routines for building an accurate 3D model of the tumour mass. During our first trial with lung tissue (on-going work), each cross-sectional slice was photographed, the tumour boundary was delineated in each image by a pathologist (CD), and from these contours a high-resolution 3D tumour model was built. Next, the corresponding microscopic digitised slices were merged. To date, ten patients have been identified and consented, therefore allowing us to test our algorithm on different cases and assess its performance.

      Conclusion

      We demonstrate a novel set of methods for co-registration of pre-operative PET-CT to macro and microscopically defined lung tumours. This proof of principle now allows interrogation of the raw data from PET-CTs using a range of tracers and the development of algorithms that identify substructure detail within a tumour mass, which could lead to tailored radiotherapy for individual tumours based on tracer patterns and uptake.

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      MA09.02 - Tumor Size and Frozen Section Should Be Considered Jointly to Predict the Final Pathology for Lung Adenocarcinoma

      15:20 - 15:25  |  Presenting Author(s): Erjia Zhu  |  Author(s): Chang Chen

      • Abstract

      Background

      Invasive adenocarcinoma intraoperatively misdiagnosed as adenocarcinoma in situ or minimally invasive adenocarcinoma is more likely to undergo potentially insufficient resection. The purpose of our study was to evaluate the diagnostic accuracy of frozen section.

      Method

      We retrospectively reviewed 1,111 lung adenocarcinomas to evaluate the diagnostic performance of frozen section. A derivation cohort consisting of 436 cases of AIS or MIA diagnosed by frozen section in the same period were analyzed to find predictive factors for invasive adenocarcinoma as the final diagnosis. Validation cohorts were included to confirm the results.

      Result

      Intraoperatively measured tumor size was the only independent factor for invasive adenocarcinoma as the final diagnosis (P = 0.001) in the derivation cohort, and was confirmed by validation cohorts. Fifty-nine misdiagnosed invasive adenocarcinomas in the three cohorts consisted of 54 lepidic predominant type, 1 papillary and 4 acinar predominant type. There were no positive N1, N2 node, pleural, lymphatic and vascular invasion cases found. Thirty-seven (37/59, 63%) cases of misdiagnosis were attributed to sampling error, which was the main reason.figure1.jpgfigure3.jpg

      Conclusion

      Adenocarcinoma in situ or minimally invasive adenocarcinoma ≥ 1 cm by frozen section were more likely to be invasive adenocarcinoma because of sampling error.

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      MA09.03 - Multiple Pathological Variables Predict Efficacy of Adjuvant Chemotherapy in Primary Lung Adenocarcinoma

      15:25 - 15:30  |  Presenting Author(s): John Le Quesne  |  Author(s): Marco Sereno, Claire Smith, Madhumita Das, Robert Hastings, Grace Rake, David Moore

      • Abstract

      Background

      Adjuvant chemotherapy has become established as a vital complement to surgery over the last decade, and improves survival by targeting micrometastatic disease which is clinically inaparrent at the time of surgery. However, in comparison to other common malignancies, the guidelines for the administration of adjuvant chemotherapy in lung cancer are rudimentary, being based solely upon clinical stage II and above at the time of surgery. We set out to discover pathological factors with the potential to better identify patients who are likely to benefit from this vital therapy.

      Method

      662 cases of primary lung adenocarcinoma treated with surgery with curative intent were identified from 2005-2014; 109 received adjuvant chemotherapy. Comprehensive survival/recurrence data, pathological data, and treatment history data were collected. Detailed histopathological data (growth pattern, vascular invasion, pleural stage) were collected by review of scanned histopathological images.

      Multivariate Cox regression survival models were used to identify interactions between clinicopathological variables and adjuvant chemotherapy. A propensity score matching approasch was used to reduce selection biases in the data.

      Result

      The existing stage criteria for the recommendation of adjuvant chemotherapy are stage pN1/2 and size>40mm; only nodal invasion interacts with chemotherapy in an OS model (interaction term HR=0.67 P=0.017). However, signficant interactions are seen with predominant growth pattern (HR=0.47 P=0.001 ), pleural stage (HR=0.62 P=0.002 ), and vascular invasion (HR=0.56 P=0.033).

      We reduced selection bias by balancing treated and untreated groups by propensity matching for all prognostic variables. In the matched dataset, patients with predominantly in situ tumours experience no benefit of chemotherapy (HR=1.81 P=0.18), while higher-grade cases show substantial benefit (HR=0.53 P=0.01). Similar benefits were seen for patients with increasing pleural stage and vascular invasion.

      In a multivariate model designed to identify which variable(s) had the most ability to predict treatment efficacy, only tumour growth pattern showed a significant interaction with chemotherapy treatment (HR=0.51 P=0.01 ).

      Conclusion

      We find that the existing stage-based criteria for adjuvant chemotherapy can be much improved. Low-grade cases experienced only negative effects of chemotherapy, while higher-grade cases showed a benefit. Pleural stage and vascular invasion were also significantly predictive. We suggest that the current criteria may be leading to substantial over- and under-treatment. A nuanced algorithm for the identification of patients likely to benefit from chemotherapy, which includes these additional pathoogical measures, may significantly improve patient outcomes. This would be especially impactful to the majority of surgical patients for whom no personalised therapy is as yet available.

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      MA09.04 - Discussant - MA 09.01, MA 09.02, MA 09.03

      15:30 - 15:45  |  Presenting Author(s): Natasha Rekhtman

      • Abstract

      Abstract not provided

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      MA09.05 - Can We Predict Radiosensitivity in Non-Small Cell Lung Cancer?

      15:45 - 15:50  |  Presenting Author(s): Juvenal Baena  |  Author(s): Christopher Talbot, John Le Quesne

      • Abstract

      Background

      Patients with lung cancer receive different treatments depending on their detailed clinical-pathological context. However, over 70% of patients are treated with radiotherapy, which is of varying efficacy. Rather surprisingly, no biomarkers are currently used to predict tumour response and to aid with radiotherapy dosing or regimen. The aim of this study is to identify histopathological features which may predict tumour radiosensitivity in patients with NSCLC.

      Method

      We have identified a set of 67 NSCLC cases with a history of radiotherapy for which pre-treatment archival tissue and CT imaging follow-up is available from the period 2009 to 2014. Digital images of archival diagnostic tissue sections were examined to derive morphological measures with the potential to predict radiosensitivity. Quantitative radiological measures of response up to 6 months after radiotherapy were derived. Since radiographic measurements were taken at variable time-points, we standardised by inferring the fractional maximum diameter of the tumour 100 days after radiotherapy (FRT100)

      Result

      The density of multipolar mitoses seen microscopically is related to radiosensitivity (regression against FRT100: R2 = 0.14, p=0.005*) and a trend toward a negative relationship with neuroendocrine differentiation (R2 =0.06, p=0.058). The presence of multipolar mitoses was further associated with poor overall survival ( Univariate Cox p= 0.02*). Patients with radiological evidence of good response (ie low FRT100) showed a time-dependent survival benefit (p=0.02*), while after 2 years tendency of both groups was similar. Patients showing squamous differentiation had a poor prognosis, with no overall survival after 4 years, while 21.8% of the ACA were still alive after 4 years (p= 0.04*)

      Conclusion

      Multipolar mitoses and neuroendocrine differentiation may be predictive histological markers of radiosensitivity in NSCLC. More samples are being gathered, and immhunohistochemical and DNA sequence biomarkers of radiosensitvity are currently being assessed.

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      MA09.06 - The Newly Recognized Filigree Pattern of Micropapillary (MIP) Lung Adenocarcinoma (LADC) is as Clinically Important as the Classical Pattern

      15:50 - 15:55  |  Presenting Author(s): Katsura Emoto  |  Author(s): Takashi Eguchi, Raj G. Vaghjiani, Yusuke Takahashi, Natasha Rekhtman, Prasad S. Adusumilli, William D Travis

      • Abstract

      Background

      Filigree pattern is a newly recognized addition to the morphological spectrum of the poor prognostic category of micropapillary (MIP) LADC. However, its morphologic features and clinical importance are not well understood. The aim of this study was to investigate the morphologic spectrum and clinical significance of filigree MIP pattern.

      Method

      Filigree pattern was defined as tumor cells growing in delicate lace-like narrow stacks of cells (at least 3 piled-up nuclei) without fibrovascular cores, with frequently visible attachments to alveolar walls. This differs from the 2015 WHO description of classical MIP pattern as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores. In order to assess for filigree vs classical MIP, we documented the frequency and extent of both patterns in 1325 Stage I LADC. These were correlated with recurrence free probability (RFP) and lung cancer-specific survival (LCSS) using Kaplan-Meier analysis.

      Result

      In addition to 87 MIP predominant ADC previously diagnosed, we identified 57 more cases of MIP predominant LADC due to the new criteria of MIP filigree pattern. Of these 57 cases, 37, 16, and 4 cases were reclassified from papillary, acinar, and solid predominant LADCs, respectively. Survival curves of previously diagnosed MIP and newly diagnosed MIP for RFP showed a similar worse prognosis compared to other LADC histologic subtypes (previously diagnosed MIP vs newly diagnosed MIP, 5-year RFP 66% vs 68% [Figure]) as well as LCSS (previously diagnosed MIP vs newly diagnosed MIP, 5-year LCSS 82% vs 85%). When the MIP cases were divided into filigree or classical predominant MIP, no significant prognostic differences were observed between the two groups.

      figure filigree.jpg

      Conclusion

      The lack of significant prognostic difference between filigree vs classical predominant MIP LADC supports our proposal that the filigree pattern is an important addition to the morphologic spectrum of the MIP subtype.

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      MA09.07 - Developing a Pathological Grading System in Predicting Prognosis for Invasive Mucinous Adenocarcinomas

      15:55 - 16:00  |  Presenting Author(s): Wei-Chin Chang  |  Author(s): Yu Zhi Zhang, Eric Lim, Andrew G Nicholson

      • Abstract

      Background

      Invasive mucinous adenocarcinoma (IMA) is a variant of lung adenocarcinoma with a predominance of mucinous type neoplastic epithelial cells, often showing aerogenous spreading and multifocality. The correlation between histopathological features and prognosis has not been well studied due to its relatively rare incidence compared to non-mucinous adenocarcinoma. Our study aims to evaluate the significance of histopathological features in relation to clinical outcome.

      Method

      We reviewed a series of 101 cases of IMAs resected between 2000 to 2012, comprised of stage I~IV tumours. Five pathological features were scored for each tumour: predominant histological pattern (lepidic: 1, acinar/papillary: 2, solid/micropapillary/cribriform: 3), nuclear atypia (mild:1, moderate: 2, severe: 3), mitotic activity per 2mm2 (<4: 0, ≥4: 1), necrosis (absent: 0, present: 1), lymphovascular invasion (absent: 0, present: 1), and pleural invasion (PL0: 0, PL1: 1, PL2: 2, PL3: 3). Each pathological feature was correlated with disease-free (DFS) and overall survival (OS). Cases were then divided into three grades based on the total pathological score (grade I: 2-4, grade II: 5-7, grade III: 8-11) and correlated with outcome.

      Result

      Nuclear atypia, mitotic activity, lymphovascular invasion, and pleural invasion showed significant correlation with OS (p < 0.05). Histological pattern and necrosis showed no significant correlation in relation to OS (p = 0.09). Pleural invasion and lymphovascular invasion were significantly correlated with DFS (p < 0.05), while a trend was noted for nuclear atypia (p = 0.086). No correlation with DFS was seen for histological pattern (p = 0.499), necrosis (p = 0.464), and mitotic activity (p = 0.931). There was an inverse correlation between OS and grade, with grade III tumours showing a significantly worse prognosis (p = 0.001). There was no significant difference in DFS between the three groups (p = 0.201).

      Conclusion

      Our pathological scoring system was able to stratify IMAs into three separate groups with statistically significant differences in overall survival between grade III and grades I/II tumours.

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      MA09.08 - Discussant - MA 09.05, MA 09.06, MA 09.07

      16:00 - 16:15  |  Presenting Author(s): Lucian R Chirieac

      • Abstract

      Abstract not provided

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      MA09.09 - EBUS-TBNA in Assessing PD-L1 Expression in NSCLC

      16:15 - 16:20  |  Presenting Author(s): Jason S Agulnik  |  Author(s): Goulnar Kasymjanova, Hangjun Wang, Lama Sakr, David Small, Victor Cohen, Alan Spatz

      • Abstract

      Background


      Pembrolizumab is the only immunotherapy approved as a first line agent for metastatic NSCLC in patients with high programmed death‐ligand 1 (PD‐L1) expression. The standard samples for PD-L1 testing are considered surgical or core biopsies. In this study, our primary objective is to identify the adequacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) tumor samples in detecting PD-L1 expression.

      Method

      Between July 2016 and April 2017 a total of 1352 consecutive cases of non-small cell lung cancer (NSCLC) were identified. 29 specimens were deemed inadequate (less than 100 viable tumor cells) and were excluded. 1323 specimens analyzed included surgical samples (N=238), small biopsy (N=744) and cytology cell blocks (N=341). Cytology cell blocks were from EBUS-TBNA (N=190), fine needle aspiration (FNA) (N=61) and pleural/pericardial fluid (N=90). PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1-49% and ≥ 50% tumor cells.

      Result

      Most of the 1323 specimens (84%) were non-squamous carcinomas. Overall yield for TPS > 50% was 36%. Rate of PD-L1 positivity was no different in non-squamous (37%) compared to squamous (32%). Diagnostic yield of PD-L1 for different sample types varied substantially (Table 1). The EBUS-TBNA samples had the highest yield for TPS ≥ 50% (p=0.025).

      TPS Surgical resection Small biopsy EBUS-TBNA FNA Fluid cytology Total
      Adequacy 100% 99% 98% 96% 92% 98%
      ≥ 50% 69 (29) 269 (36) 84 (44) 21 (34) 38 (42) 481
      1-49% 87 (37) 274 (37) 57 (30) 22 (36) 22 (24) 462
      <1% 82 (35) 201 (27) 49 (26) 18 (30) 30 (33) 380
      Total 238 744 190 61 90 1323
      Conclusion

      Our results show that cytology cell blocks could be considered as a valuable resource for PD-L1 testing in advanced NSCLC. Future studies are warranted to explore clinical correlation of PD-L1 on EBUS-TBNA samples and immunotherapy outcome.

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      MA09.10 - Molecular Profiling and PD-L1 Status in 900 Cases of Surgically Resected Non-Small Cell Lung Cancer with Clinical and Pathological Correlation

      16:20 - 16:25  |  Presenting Author(s): Zhaolin Xu  |  Author(s): Mathieu Castonguay, Wenda Greer, Akram Alwithenani, Drew Bethune, Arik Drucker, Gordon Flowerdew, Marika Forsythe, Daniel French, Harry Henteleff, Michael Johnston, Mary Macneil, Wojciech Morzycki, Madelaine Plourde, Stephanie Snow, Alexi Surette

      • Abstract

      Background

      Precision medicine provides efficient treatment options for lung cancer patients as it targets the individual tumor’s genetic makeup. Recent development of immune therapy based on immune checkpoint inhibitor also provides hope for patients. Currently lung cancer mutational data available in the literature are mainly from advanced stage non-small cell lung cancer. There is insufficient information from early stage lung cancer patients. PD-L1 status in relation to clinical and pathological characteristics is also unclear. This study tried to address these issues from 900 cases of surgically resected lung cancer.

      Method

      Multiplexed molecular profiling in 900 surgically resected lung cancer specimens. A panel of gene including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK was tested. PD-L1 was also evaluated by immunohistochemistry using pharmDx22C3. Tumor proportional score (TPS) in a 10% increment was measured. Mutational status and PD-L1 TPS in each cancer subtype in relation to cancer pathological characteristics were investigated. Correlations between gene mutation, PD-L1 status and cancer staging were performed. Gene mutation and PD-L1 status with patients’ demographic information such as gender, age, smoking history, as well as survival data after surgery were also analysed.

      Result

      This cohort includes adenocarcinoma (65%), squamous cell carcinoma (24%), large cell carcinoma (6%), other subtypes (5%). Stage I accounts for 56%, stage II, 26%, stage III, 16%, stage IV, <2% with a mean age of 66 years. In adenocarcinoma, KRAS accounts for 36%, EGFR 10%, BRAF 1%, PIK3CA 1%, ALK 0.2%, no mutations 52%. Only 5% squamous cells carcinoma showed mutations.

      PD-L1 TPS <1% accounts for (37%), TPS 1-9% (18%), TPS 10-19% (7%), TPS 20-29% (5%), TPS 30-39% (5%), TPS 40-49% (1%), TPS 50-59% (5%), TPS 60-69% (4%), TPS 70-79% (4%), TPS 80-89% (5%), TPS 90-99% (7%) and unsuccessful (2%). EGFR mutations were significantly associated with female (p<0.001) and never smokers (p<0.001), with well differentiated adenocarcinoma (p<0.001), and with absence of vascular invasion (p<0.01). KRAS mutations were more prevalent in younger age group (p=0.003). Poorly differentiated cancer histology was associated with absence of KRAS or EGFR mutations. There was no significant association between PD-L1 expression and age, sex, pathological stage and smoking status. PD-L1 expression was significantly associated with vascular invasion (p=0.035). EGFR mutations were significant associated with absence of PD-L1 expression (p=0.02), but no association between KRAS mutations and PD-L1 expression (p=0.10).

      Conclusion

      This study provides comprehensive information enhancing our knowledge in depth about driver gene mutations and immune checkpoint PD-L1 status in non-small cell lung cancer patients.

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      MA09.11 - Genomic Landscape and its Correlation with TMB, CD8 TILs and PD-L1 Expression in Chinese Lung Squamous Cell Carcinoma

      16:25 - 16:30  |  Presenting Author(s): Tao Jiang  |  Author(s): Jinpeng Shi, Chunyan Wu, Henghui Zhang, Caicun Zhou

      • Abstract

      Background

      The current study aimed to comprehensively depict the genomic landscape of Chinese lung squamous cell carcinoma (LSCC) and investigate its correlation with tumor mutation burden (TMB), CD8 tumor infiltrating lymphocytes (TILs) density and PD-L1 expression.

      Method

      Whole-exome sequencing (WES) were performed on tumor tissue collected from 189 patients with surgically resected LSCC. TMB was defined as total number of nonsynonymous single nucleotide and indel variants. High TMB was defined as greater than 75th percentile. CD8+ TILs and PD-L1 expression were assessed by immunohistochemistry. We determined the 5% of CD8+ TIL or PD-L1 expression as the cut-off point for high/low CD8+ TIL or PD-L1 positive/negative expression.

      Result

      We found recurrent mutations (>5%) in 8 genes, including TP53, KMT2C, NFE2L2, KEAP1, CDKN2A, PTEN and FBXW7. FGFR1 and PIK3CA amplifications were found in 19% and 11% of samples. 24.9% of patients had high TMB. Except for expected differences by smoking status, baseline clinical variables were similar between those with high and low TMB. Interestingly, FGFR1, PIK3CA or SOX2 amplification was independently associated with higher TMB (P=0.020, P=0.017, P=0.029; respectively). Patients with copy number variations had significantly higher TMB than those without (P=0.009). Positive PD-L1 and CD8+ TILs expression were identified in 24.3% and 78.8% of all cases. Baseline features were comparable between those with positive and negative CD8+ TIL or PD-L1 expression. NFE2L2 mutation and PIK3CA amplification were independently associated with significantly higher PD-L1 expression (P=0.003, P=0.014; respectively). TP53 mutations were associated with higher CD8+ TILs expression (P=0.008), but FGFR1 amplification was correlated with lower CD8+ TILs expression (P=0.042). Of note, there is no association between TMB and PD-L1 expression (r=0.052, P=0.476), or CD8+ TILs expression (r=0.026, P=0.718). None of TMB, PD-L1 and CD8+ TIL expression could individually predict overall survival (OS). However, combination of TMB and PD-L1 could stratify total populations into two groups with distinct prognosis. Patients with negative PD-L1 expression and high TMB had the worst prognosis (P=0.008). Additionally, combination of TMB and CD8+ TIL expression could also divide total populations into two groups with different prognosis (worst prognosis in negative CD8+ TIL expression and high TMB, P=0.022).

      Conclusion

      This was the first and most large-scale study to comprehensively portray genomic landscape of Chinese LSCC. The current study provides several meaningful and referential findings for the future design of clinical trials in LSCC, especially immunotherapy based on immune checkpoint inhibitors.

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      MA09.12 - Discussant - MA 09.09, MA 09.10, MA 09.11

      16:30 - 16:45  |  Presenting Author(s): Philippe Joubert

      • Abstract

      Abstract not provided

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    MS09 - Tumour Board - Tissue Acquisition and Staging

    • Type: Mini Symposium
    • Track: Interventional Diagnostics/Pulmonology
    • Moderators:
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    MS10 - Part Solid Nodules, GGN and STAS

    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Moderators:
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      MS10.01 - Radiographic Differences Between Presumed AIS and MIA

      15:15 - 15:30  |  Presenting Author(s): Mini Pakkal

      • Abstract

      Abstract not provided

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      MS10.02 - Importance of CT in the Pathologic Assessment of Tumor Sized in Subsolid and Part-Solid Adenocarcinoma

      15:30 - 15:45  |  Presenting Author(s): Erik Thunnissen

      • Abstract

      Abstract

      Importance of CT in the Pathologic Assessment of Tumor Sized in Subsolid and Part-Solid Adenocarcinoma

      Non-solid nodules (previously also called ground glass opacity) is a finding on thin-section CT that is defined as “hazy increased attenuation of the lung with preservation of bronchial and vascular margins”.1This is in contrast to consolidation that is defined as a “homogeneous increase in pulmonary parenchymal attenuation that obscures the margins of vessels and airway walls” (also called ‘solid´ component).

      The resolution of the CT differs few orders of magnitude from the resolution of the microscope. Therefore, non-solid nodule is not one disease: pathological examination reveals several different diseases. The radiological GGO change is actually due to a reduction of air, while a certain amount of air remains present. At the microscopic level this may be caused by either i) partial filling of the alveolar airspaces, ii) thickening of the parenchymal interstitium and alveolar walls, iii) relative increase in perfusion, or iv) any combination of these factors.1,2Alveolar spaces may become partially filled by several ways, such as transudative fluid, blood, inflammatory cells or debris, or amorphous material as seen in cardiogenic pulmonary edema, diffuse alveolar hemorrhage, pneumonia, and pulmonary alveolar proteinosis. Alveolar walls and septal interstitium may become thickened secondary to edema, neoplastic proliferation, fibrosis, and noncaseating granulomatous deposition as seen in cardiogenic pulmonary edema, lung adenocarcinoma other malignancies, nonspecific interstitial pneumonia, and sarcoidosis. Partial alveolar filling and interstitial thickening coexist in many disease entities. Thus the non-solid nodule is a non-specific finding that may be caused by various disorders, including inflammatory disease, pulmonary fibrosis, alveolar haemorrhage or neoplasms3.

      Part-solid nodules (PSNs): Nodules with a solid component obscuring the underlying lung parenchyma other than blood vessels on thin-section CT scans viewed on CT lung window settings. Subsolid nodules comprise the non-solid and part-solid nodules.

      The histopathology of the solid component may be inflammation1) e.g. aspergillosis, organising pneumonia3,4, non-specific fibrosis and invasive adenocarcinomawith prominent lepidic component3,56and rarely lymphoma4or a combination of both. As subsolid nodules are an appearance on CT that may histologically represent different diseases, the term “Natural history of subsolid or part solid nodule” is a misnomer. Spread through air spaces is an immature concept under debate, where an underlying artifact is far from unrealistic.7

      The chance on lymph node metastases is very low in GGO with total and solid size < 1cm. Only one case with solid size between 0.5 and 1.0 cm8has been reported so far.

      Usually, in patients with multiple AIS sufficient molecular differences are detected to classify the individual lesions as multiple primary tumors. However, in an occasional patient with multiple GGO/AIS the differences in two of several comparisons were so limited that an argument for ‘early metastases was formulated9.

      Although it may be important for prognosis to measure the solid size for radiologists and invasive size for pathologists for prognostic reasons, sufficient reproducibility of these parameters has not been proven. These challenges emphasize the need for further standardization10.

      References

      1. El-Sherief, A. H. et al.Clear Vision Through the Haze: A Practical Approach to Ground-Glass Opacity. Curr. Probl. Diagn. Radiol.43,140–158 (2014).

      2. Hewitt, M. G., Miller, W. T., Reilly, T. J. & Simpson, S. The relative frequencies of causes of widespread ground-glass opacity: A retrospective cohort. Eur. J. Radiol.83,1970–1976 (2014).

      3. Kim, H. Y. et al.Persistent Pulmonary Nodular Ground-Glass Opacity at Thin-Section CT: Histopathologic Comparisons 1. Radiology245,267–275 (2007).

      4. Lee, H. J. et al.Nodular ground-glass opacities on thin-section CT: size change during follow-up and pathological results. Korean J. Radiol.8,22–31 (2007).

      5. Son, J. Y. et al.Quantitative CT Analysis of Pulmonary Ground-Glass Opacity Nodules for the Distinction of Invasive Adenocarcinoma from Pre-Invasive or Minimally Invasive Adenocarcinoma. PLoS One9,e104066 (2014).

      6. Kakinuma, R. et al.Natural history of pulmonary subsolid nodules: A prospective multicenter study.J. Thorac. Oncol.11,1012–1028 (2016).

      7. Blaauwgeers, H., Russell, P. A., Jones, K. D., Radonic, T. & Thunnissen, E. Lung Cancer. Pulmonary loose tumor tissue fragments and spread through air spaces ( STAS ): Invasive pattern or artifact ? A critical review. 123,107–111 (2018).

      8. Seok, Y. et al.Frequency of Lymph Node Metastasis According to the Size of Tumors in Resected Pulmonary Adenocarcinoma with a Size of 30 mm or Smaller. J. Thorac. Oncol.9,818–824 (2014).

      9. Li, R. et al.Early metastasis detected in patients with multifocal pulmonary ground-glass opacities (GGOs). Thorax73,290–292 (2018).

      10. Yip, R. et al.Controversies on lung cancers manifesting as part-solid nodules. Eur. Radiol.28,747–759 (2018).

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      MS10.03 - CT Versus Needle Biopsy Assessment Before Resection of Part Solid Nodules

      15:45 - 16:00  |  Presenting Author(s): Young Tae Kim

      • Abstract

      Abstract

      Increasing number of lung cancer screening program detects pulmonary ground glass nodules (GGN) and those are frequently found to be an adenocarcinoma or its precursors, particularly if they are persistent or increase in size.

      Preoperative diagnosis of GGNs by trans-bronchial or trans-thoracic fine-needle aspiration biopsy can be performed with reasonable diagnostic accuracy 1. However, they have limitation for the pathologic confirmation of GGNs as they can fail to sample small invasive foci 2, 3. In addition, hemoptysis has been reported to occur more frequently after needle biopsy in GGNs 4. Accordingly, needle biopsy for GGNs are not used in our current practice and if the suspicion for malignancy is high on CT, surgical biopsy is performed without preoperative needle biopsy. Recently published Fleischner recommendations for the management of GGNs may help to make a clinical decision.

      During the surgery, especially in minimally invasive surgery, GGNs are often difficult to palpate. Thus, preoperative marking techniques have been utilized for localization of the GGNs using various methods 5. That can be done either percutaneously or transbronchially, using various materials including a dye, colored collagen, barium, lipiodol, micro coil, metallic wire, or fiducial 6. In our center, we have been using various methods for preoperative localization and but currently, we favor to use electromangetive navigational bronchoscopy (ENB) guided dye marking technique.

      Once surgery is decided, deciding the extent of resection is another issue. The size of solid portion measured on the CT can be helpful. If it is less than 5 mm, a simple wide wedge resection can be performed by which the goal of diagnosis and treatment can be achieved. If it is larger than 5 mm, the specimen is examined by frozen section and if the malignancy is confirmed, anatomic lung resection is conducted.
      However, the CT findings have not yet proven sufficiently reliable to guide the management plan. Intraoperative frozen section diagnosis is an alternative that can guide the extent of the subsequent surgical procedure. The problem of frozen section is, however, the fact that deflated lung specimens often makes the correct diagnosis difficult. To obviate this problem, the technique of inflating the lung specimen with the embedding medium for frozen section (EMIT) has been used, which allows better interpretation, and facilitated correct diagnosis in the frozen section 7. In our center, we have been using EMIT and found a high diagnostic accuracy with the concordance rate of 90.6% between EMIT and permanent pathology. Based on our experience, it is our current practice to perform a wide wedge resection of the GGNs and send the specimen for EMIT. If the result of EMIT is pre-invasive lesions (benign, AAH, AIS, or MIA), we do not perform additional resection. If the invasive adenocarcinoma is diagnosed, we prefer to proceed anatomic lung resection with systematic lymph node dissection.

      Several studies showed that limited resection could be beneficial, especially in early stage lung adenocarcinoma, including GGN 8. On the contrary, in one prospective study that reported a long-term outcome, limited resection of GGNs showed a low disease-control rate. They reported adenocarcinomas developed in four out of 26 patients in the surrounding area of initial resection site after more than five years 9. However, as GGNs usually show favorable prognosis, limited resection could be generally recommended 10. Additionally, in cases of deeply located GGNs, where wedge resection is not technically feasible, direct segmentectomy without wedge biopsy for the purpose of diagnosis and treatment, is recommended. For the segmentectomy, various technics can be used, but it is our current practice to use ENB guided dye marking to define an adequate parenchymal resection margin during the segmentectomy.

      To summarize, although there are several CT findings that can differentiate between pre-invasive and invasive lesions, those findings have not yet proven sufficiently reliable to guide the management plan for GGNs. In addition, attempt to sample solid component in GGNs using a biopsy needle is often not feasible and therefore, not helpful for being used in clinical decision. Currently, the best practice for the management of GGNs is to carefully follow the patient with CT, and if malignancy is suspected, to perform a surgical biopsy with the guide of various localization methods and/or other innovative methods to differentiate between pre-invasive versus invasive adenocarcinoma.

      1. Yamagami T, Yoshimatsu R, Miura H, et al. Diagnostic performance of percutaneous lung biopsy using automated biopsy needles under CT-fluoroscopic guidance for ground-glass opacity lesions. Br J Radiol 2013;86:20120447.
      2. Kim TJ, Lee JH, Lee CT, et al. Diagnostic accuracy of CT-guided core biopsy of ground-glass opacity pulmonary lesions. AJR Am J Roentgenol 2008;190:234-239.
      3. Lu CH, Hsiao CH, Chang YC, et al. Percutaneous computed tomography-guided coaxial core biopsy for small pulmonary lesions with ground-glass attenuation. J Thorac Oncol 2012;7:143-150.
      4. Choi JW, Park CM, Goo JM, et al. C-arm cone-beam CT-guided percutaneous transthoracic needle biopsy of small (</= 20 mm) lung nodules: diagnostic accuracy and complications in 161 patients. AJR Am J Roentgenol 2012;199:W322-330.
      5. Ikeda K, Nomori H, Mori T, et al. Impalpable pulmonary nodules with ground-glass opacity: Success for making pathologic sections with preoperative marking by lipiodol. Chest 2007;131:502-506.
      6. Zaman M, Bilal H, Woo CY, et al. In patients undergoing video-assisted thoracoscopic surgery excision, what is the best way to locate a subcentimetre solitary pulmonary nodule in order to achieve successful excision? Interactive cardiovascular and thoracic surgery 2012;15:266-272.
      7. Marchevsky AM, Changsri C, Gupta I, et al. Frozen section diagnoses of small pulmonary nodules: accuracy and clinical implications. The Annals of thoracic surgery 2004;78:1755-1759.
      8. Cao C, Gupta S, Chandrakumar D, et al. Meta-analysis of intentional sublobar resections versus lobectomy for early stage non-small cell lung cancer. Ann Cardiothorac Surg 2014;3:134-141.
      9. Nakao M, Yoshida J, Goto K, et al. Long-term outcomes of 50 cases of limited-resection trial for pulmonary ground-glass opacity nodules. J Thorac Oncol 2012;7:1563-1566.
      10. Shao G, Ren W, Feng Z, et al. The role of video-assisted thoracoscopic surgery in management of the multiple ground-glass nodules. Indian J Cancer 2015;52 Suppl 2:e75-79

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      MS10.04 - Therapeutic Implications of Spread Through Air Spaces (STAS)

      16:00 - 16:15  |  Presenting Author(s): William D Travis  |  Author(s): Rania Gaber, Shaohua Lu, Takashi Eguchi, Natasha Rekhtman, Prasad S. Adusumilli

      • Abstract

      Abstract

      Spread through air spaces (STAS) is a recently recognized pattern of invasion in lung cancer defined as spread beyond the edge of the main tumor into the air spaces surrounding the tumor. It was originally described as a poor prognostic factor in Stage I lung adenocarcinoma.1 STAS has been observed in 15-62% of lung adenocarcinomas and associated with poor prognosis in multiple independent cohorts worldwide.2-4 In addition, it has now been shown to occur with prognostic significance in most all major types of lung cancer including squamous cell carcinoma (SQCC),5 small cell carcinoma SCLC),6 large cell neuroendocrine carcinoma (LCNEC),6 atypical carcinoid (AC)6 and pleomorphic carcinoma.7 Three dimensional evaluation has shown most STAS clusters are attached to alveolar walls rather than floating in air spaces suggesting a mechanism of detachment then reattachment perhaps by vessel co-option.8

      Criteria for STAS

      The original definition of STAS by Kadota et al and the 2015 WHO consisted of tumor cells within the first alveolar air spaces in the lung parenchyma beyond the edge of the main tumor. It can occur as one of three morphologic patterns including 1) micropapillary structures within air spaces; 2) solid nests or tumor islands and 3) scattered discohesive single cells.1, 9 The solid nest pattern is characteristic in other lung cancer histologies. Although other criteria have been proposed our group has used these same criteria for STAS to demonstrate its prognostic significance in SQCC, LCNEC, SCLC and AC. Warth et al defined STAS with different criteria including a detachment of small solid cell nests of least 5 tumor cells where < 3 alveolar spaces were regarded as limited STAS and tumor cells nests >3 alveolar spaces away from the tumor as extensive STAS.4

      Distance of and Quantitation of STAS

      Gaber R et al found that circumferential STAS was associated with a higher risk of recurrence free probability (RFP) than focal STAS (5yr RFP in circumferential vs focal; 67% vs 87%, p=0.027) and that longer distance of STAS was associated with a higher risk of recurrence (5yr RFP >7 alveoli vs ≤ alveoli, 69% vs 91%, p=0.003).9 However, Quantitation of STAS was not prognostic (5yr RFP in >3/HPFs vs ≤3/HPF, 75% vs 88%, p=0.15).9 Uruga H et al found that high vs low STAS (≥5 vs 1-4 single cells or clusters) was an independent predictor of worse (p=0.015).2 Warth did not find a prognostic difference between extensive vs limited STAS as described above.4

      Implications of STAS for Radiation Therapy

      In the setting of sterotactic body radiation therapy (SBRT) for lung cancer, the documentation of microscopic extension has been appreciated for many years.10 Radiologic and pathologic studies have shown that tumor cells can extend beyond the edge of the tumor from 1.3 centimeters to 2.6 cm.10 Although the concept of STAS emerged many years later, it provides morphologic and clinical support to radiation therapists concerns to address microscopic extension and STAS in planning the radiation field.

      Implications of STAS for Surgical Management

      There is limited data evaluating pathologists ability to recognize STAS in frozen section. Kameda et al found the sensitivity and specificity of frozen section for prediction of STAS were 71%, 92.4% respectively and the accuracy was 80%.11 Kappa statistics for interobserver agreement were 0.4-0.74.

      Walts AE et al studied frozen section for evaluation of STAS and recommended that current evidence did not warrant frozen section evaluation for STAS.12 However, frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and an 8% negative predictive value. So from the two studies, it appears if a pathologist sees STAS on a frozen section there is a 92-100% likelihood it will be present on permanent sections. Both of these were retrospective studies where tissue sampling for frozen sections was not made to include the tumor edge and adjacent lung to search for STAS. More studies are needed to evaluate the potential role of frozen section in detecting STAS and guiding intraoperative decisions by surgeons.

      REFERENCES

      1. Kadota K, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      2. Uruga H, et al. Semiquantitative Assessment of Tumor Spread through Air Spaces (STAS) in Early-Stage Lung Adenocarcinomas. J Thorac Oncol 2017;12:1046-51.

      3. Toyokawa G, et al. Significance of Spread Through Air Spaces in Resected Pathological Stage I Lung Adenocarcinoma. Ann Thorac Surg 2018.

      4. Warth A, et al. Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma. The American journal of surgical pathology 2015;39:793-801.

      5. Lu S, et al. Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer-Specific Death in Squamous Cell Carcinoma. J Thorac Oncol 2017;12:223-34.

      6. Aly RG, et al. Spread through air apsaces (STAS) correlates with prognosis in lung neuroendocrine tumors (LNET). Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2018;31:724.

      7. Shintaro Y, et al. Tumor spread through air spaces identifies a distinct subgroup with poor prognosis in surgically resected lung pleomorphic carcinoma. Chest 2018;in press.

      8. Yagii Y, et al. Three-Dimensional Assessment of Spread Through Air Spaces in Lung Adenocarcinoma: Insights and Implications. J Thoracic Oncol 2017;12 (Suppl 2): S1797, 2017.

      9. Gaber R, et al. Circumferential distribution and distance from main tumor of tumor spread through air spaces (STAS) are prognostic. J Thoracic Oncol 2017;12:S1864.

      10. van Loon J, et al. Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features. Int J Radiat Oncol Biol Phys 2012;82:448-56.

      11. Kameda K, et al. Can tumor spread through air spaces (STAS) in lung adenocarcinomas be predicted pre- and intraoperatively? J Thoracic Oncol 2017;12:S209.

      12. Walts AE, et al. Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces. Arch Pathol Lab Med 2018;142:59-63.

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      MS10.05 - Should We Resect GGNs

      16:15 - 16:30  |  Presenting Author(s): Kenji Suzuki

      • Abstract

      Abstract not provided

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      MS10.06 - Q&A

      16:30 - 16:45

      • Abstract

      Abstract not provided

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    MS11 - Stigma and Lung Cancer: Unintended Translational Consequences of Effective Tobacco Control

    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Moderators:
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      MS11.01 - Identifying Consequences of Stigma on Lung Cancer Care Delivery and Patient Outcomes

      15:15 - 15:35  |  Presenting Author(s): Heidi Hamann

      • Abstract

      Abstract

      Lung cancer stigma (the experience and internalization of negative appraisal and devaluation from others) is a formidable barrier to fulfilling the promise of high quality patient care and reduced lung cancer burden. Attention to the robust causal connection between smoking and lung cancer, although crucial for tobacco control, may have unintended consequences that generate blaming responses and biased negative perceptions toward lung cancer patients. Lung cancer stigma can have far-reaching, deleterious effects that range from reduced involvement in prevention and early detection interventions, negative psychosocial impact, impaired patient-clinician communication, inadequate access to diagnosis and treatment, and limited funding and public support for lung cancer research and care. The goals of this presentation are to describe the nature of lung cancer stigma and highlight research that addresses consequences of stigma on lung cancer care delivery and patient outcomes. The presentation also focuses on multilevel interventional opportunities to mitigate the negative effects of stigma.

      Based on both qualitative and quantitative assessment, our team has identified three primary components of patient-reported lung cancer stigma: perceived stigma, internalized stigma, and constrained disclosure (Hamann et al., 2018). Cross-sectional data indicate associations between stigma and impaired patient/provider communication, higher rates of depressive symptoms, and reduced engagement in care among lung cancer patients. Recent work has also demonstrated potential provider-level stigma toward lung cancer patients, with implications for treatment decisions and other aspects of lung cancer care. Interventional opportunities include patient-based education and counseling to address the psychosocial and behavioral consequences of lung cancer stigma. Focusing on provider communication training also represents a promising opportunity to reduce stigma toward lung cancer patients.

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      MS11.02 - Stigma of Tobacco and Lung Cancer: A South American Perspective

      15:35 - 15:55  |  Presenting Author(s): Clarissa Baldotto

      • Abstract

      Abstract not provided

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      MS11.03 - Prevalence of Perceived Lung Cancer Stigma Among Medical and Nursing Students

      15:55 - 16:15  |  Presenting Author(s): Jamie L Studts

      • Abstract

      Abstract not provided

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      MS11.04 - Taking a Smoking History in the Context of Lung Cancer Treatment: Missed Opportunities for Stigma-Reducing Empathic Encounters with Throacic Oncologists

      16:15 - 16:35  |  Presenting Author(s): Peter G Harper

      • Abstract

      Abstract not provided

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      MS11.05 - Q&A

      16:35 - 16:45

      • Abstract

      Abstract not provided

  • +

    MS12 - Immunotherapy and RT

    • Type: Mini Symposium
    • Track: Treatment of Locoregional Disease - NSCLC
    • Moderators:
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      MS12.01 - Biology IO+RT

      15:15 - 15:35  |  Presenting Author(s): Dirk De Ruysscher

      • Abstract

      Abstract

      Checkpoint inhibitors have changed the outcome of patients with metastatic non-small cell lung cancer (NSCLC) in first and in second line, with improved progression-free survival (PFS), overall survival (OS) and quality of life.

      Radiotherapy has consistently been shown to activate key elements of the immune system that are responsible for resistance for immune therapy. Radiation upregulates MHC-class I molecules that many cancer cells lack or only poorly express, tumor-associated antigens, provokes immunogenic cell death, activates dendritic cells, decreases regulatory T-cells (Tregs) in the tumor, broadens the T-cell repertoire and increases T-cell trafficking, amongst many other effects. Radiation may convert a completely or partly poorly or non-immunogenic tumor immunogenic. Radiotherapy in combination with different forms of immune therapy such as anti-PD-(L)1, anti-CTLA4,immunocytokines, dendritic cell vaccination and Toll-like receptor agonists improved consistently local tumor control and very interestingly, lead to better systemic tumor control (the “abscopal” effect) and the induction of specific anti-cancer immunity with a memory effect. Moreover, as PD1/PD-L1 is upregulated by radiation and radiation can overcome resistance for PD-(L)1 blockage, their combination is logical. The best timing, sequencing and dosing of all modalities is a matter of intense research, but in pre-clinical models, the concurrent administration of anti-PD-(L)1 was superior to sequential.

      Clinical studies in NSCLC such as the subgroup analysis of the KEYNOTE-001 trial, the PACIFIC trial and the phase II results of NICOLAS support the rationale to view radiation as an immunotherapeutic drug that may enhance the immune response without limiting side effects when combined with the correct immunotherapy drugs for a given tumor and patient.

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      MS12.02 - Clinical Data Available

      15:35 - 15:55  |  Presenting Author(s): Feng-Ming (Spring) Kong

      • Abstract

      Abstract

      The role of radiation is evolving in the era of immunotherapy. The abscopal effect of radiation on immune modulation has been discussed and researched greatly during recent days, and there is a significant amount of laboratory data suggesting its positive effect on tumor control. This presentation will focus on an objective review of clinical evidences for the clinical significant outcomes of radiation on immune function aiming to maximize the positive effect of Radiation Immunomodulation. Standing from the clinic, I will not only review the GOOD side of abscopal effect, i.e. the increased tumor control distant from a focused local radiation, and examine the BAD effect of radiation immunomodulation, i.e. radiation immunosuppressive effect which can worsen the tumor control outcome and overall survival. Starting from an overview of these two conflicted effects of all solid tumors in general, the presentation will specifically focus on the literature of radiation immunomodulation effects in patients with non-small cell lung cancer. Predictive and correlative biomarkers for both GOOD and BAD effects will also be reviewed through thorough literature search. The ultimate goal of this presentation is to motivate us, the oncologists to search, and research on finding a way to deliver a more effective radiation therapy and a more effective way of combined therapy with radiation and immunotherapy, to maximize the GOOD abscopal benefit while minimize the BAD effects of radiation on immunofunction.

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      MS12.03 - Ongoing Studies

      15:55 - 16:15  |  Presenting Author(s): Francoise Mornex

      • Abstract

      Abstract not provided

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      MS12.04 - Implications for Routine Practice

      16:15 - 16:35  |  Presenting Author(s): Paul Mitchell

      • Abstract

      Abstract

      Over the last 3 years checkpoint inhibitors (CPI) have become established as key components in the treatment of stage III and IV NSCLC. The established CPI are PD-1 and PD-L1 inhibitors and more recently CTLA4 inhibitors, with ongoing research into other modulators of T-cell function. Used alone, these agents have their greatest efficacy in a subset of patients while combination with other treatment modalities may enhance efficacy. Already concurrent pembrolizumab and chemotherapy has been shown to be more effective than chemotherapy alone for first-line metastatic NSCLC. 1 In the clinic there are two major issues to consider when combining immunotherapy and radiotherapy. The first is safety, particularly when irradiating lung or the brain. The second issue is, can we harness radiotherapy to improve the efficacy of immunotherapy?

      Pneumonitis is a major concern when combining radiotherapy to the lung. Lower dose palliative radiotherapy is less of a concern but when treating primary lung cancer with curative intent, especially concurrent with chemotherapy, toxicity may impact on patient survival. In the phase III PACIFIC trial, of the 476 stage III NSCLC patients who received concurrent chemoradiation to the lung followed by durvalumab consolidation, grade ≥3 pneumonitis was 4.5% and no different from chemoradiation alone. 2 In 93 stage III patients treated with concurrent chemoradiation followed by 12 months pembrolizumab consolidation grade ≥3 pneumonitis was 6.5%. 3 We now have safety data for stage III patients with nivolumab given concurrently with thoracic chemoradiotherapy, followed by consolidation nivolumab. For the 58 patients evaluable for toxicity in the NICOLAS trial, grade ≥3 pneumonitis was 10.3%. 4

      We now also have safety data for SABR (Stereotactic Ablative Radiotherapy) combined with CPI. Seventy nine patients (53 NSCLC) received SABR to multiple metastases, followed within 7 days by pembrolizumab. The toxicity was as expected for pembrolizumab alone. 5 Similarly Campbell has reported on treatment with concurrent SABR and pembrolizumab with either melanoma or NSCLC, with no increased toxicity. 6 Treating brain melanoma metastases with radiosurgery concurrent with ipilimumab in 57 patients, Mortier found toxicity to be as expected for immunotherapy alone 7 , while a similar study by the same group found toxicity was not increased beyond that for pembrolizumab alone.

      There have been multiple reports, mostly of single cases, whereby local radiotherapy to a tumour causes shrinkage of a distant non-irradiated metastasis, termed an abscopal effect. 8 It is hoped that likewise radiotherapy will enhance the effectiveness of CPI. Prior to CPI entering the clinic, in the START trial stage III patients treated with consolidation tecemotide (liposomal MUC1) vaccine following concurrent chemoradiation showed a 10 month survival advantage not seen in those who had received sequential chemoradiotherapy. 9,10 Although overall the START trial was negative for the primary endpoint, this suggested that concurrent chemoradiotherapy might enhance immunogenicity. In the PACIFIC trial of stage III NSCLC, all patients received concurrent chemoradiation. Patients randomised to a year of consolidation durvalumab had markedly improved PFS (HR 0.52) irrespective of tumour PD-L1 expression, and overall survival data are awaited. 2 There are also now data suggesting an outcome benefit for NSCLC patients treated with concurrent SABR and CPI. In the PEMBRO-RT trial 74 NSCLC patients were randomised to receive SABR (3 x 8GY) to a single metastasis followed within 7 days by pembrolizumab, or pembrolizumab alone. 11 All endpoints trended in favour of the combination. The primary endpoint of response rate at 12 weeks was 39% vs 21% (p=0.28), for SABR + CPI vs CPI respectively, while PFS (HR 0.61 p=0.08) and OS (HR 0.58 p=0.1) favoured combined SABR and pembrolizumab. A similar trial, NIVORAD, is being conducted by the ALTG co-operative group, where patients are randomised to receive nivolumab with or without SABR to a metastasis site during week 2. 12

      There are now good data to indicate that combining CPI and radiotherapy is safe, including radiotherapy to the lung and to the brain. Sequential concurrent chemoradiation in stage III NSCLC followed by durvalumab is highly effective. Emerging data suggest that radiotherapy may enhance the effectiveness of immunotherapy in stage IV disease but further randomised data are required.

      1 Gandhi L. Pembrolizumab plus chemotherapy in metastatic NSCLC. N Engl J Med 2018: 378; 2078-2092

      2 Antonia S. Durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2017; 377: 1919-1929

      3 Durm G. Phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III NSCLC. J Clin Oncol 2018; 36: suppl. abstract 8500

      4 Peters S. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first-line chemo-RT regimen in unresectable locally advanced NSCLC – the ETOP NICOLAS phase II trial. J Clin Oncol 2018; 36: suppl. abstract 8510

      5 Luke J. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumours. J Clin Oncol 2018; 36: 1611-1618

      6 Campbell AM. Final results of a phase 1 prospective trial evaluating the combination of stereotactic body radiotherapy with concurrent pembrolizumab in patients with metastatic NSCLC or melanoma. J Cin Oncol 2018; 36: suppl. abstract 9099

      7 Mortier L. Ipilimumab combined with stereotactic radiosurgery in melanoma patients with brain metastases: A multicentre, open label, phase 2 trial. J Clin Oncol 2018; 38: suppl. abstract 9250

      8 Siva S. Asbcopal effects after conventional and stereotactic lung irradiation of NSCLC. J Thorac Oncol 2013.

      9 Butts C. Tecemotide (L-BLP-25) versus placebo after chemoradiotherapy for stage III NSCLC (START): a randomized double-blind phase 3 trial. Lancet Oncol 2014; 15(1): 59-68

      10 Mitchell PL. Tecemotide in unresectable stage III NSCLC in the phase III START study: updated overall survival, further endpoints and biomarker analysis. Ann Oncol 2015; 26; 1134-1142

      11 Theelen WSME. Randomized phase II study of pembrolizumab after stereotactic body radiotherapy versus pembrolizumab alone in patients with advanced NSCLC: The PEMBRO-RT study. J Clin Oncol 2018; 36: suppl. abstract 9023

      12 Mitchell PLR. NIVORAD: a randomised phase 2 trial of nivolumab and stereotactic ablative radiotherapy in advanced NSCLC progressing after first or second line chemotherapy. J Clin Oncol 2017; 35: suppl. TPS9097

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      MS12.05 - Q&A

      16:35 - 16:45

      • Abstract

      Abstract not provided

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    OA07 - Oligometastasis: What Should Be the State-Of-The-Art?

    • Type: Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Moderators:
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      OA07.01 - Phase II Study of Pembrolizumab for Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT)

      15:15 - 15:25  |  Presenting Author(s): Joshua Michael Bauml  |  Author(s): Rosemarie Mick, Christine Ciunci, Charu Aggarwal, Christiana Davis, Tracey Evans, Charuhas Deshpande, Linda Miller, Pooja Patel, Evan Alley, Christina Knepley, Faith Mutale, Roger B Cohen, Corey J Langer

      • Abstract

      Background

      Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide benefit after LAT. We completed a Phase II study evaluating the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy would be effective in the setting of a minimal disease burden.

      Method

      Eligibility stipulated oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts began pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for up to a year in the absence of progression (PD) or toxicity. Progression-free survival (PFS) and overall survival (OS) were measured from the start of LAT. A sample size of 42 pts would provide 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.

      Result

      Since January 2015, 45 pts have been enrolled. Median age is 64 years; 53% male; 89% Caucasian; 89% current and former smokers. Most common metastatic sites are lung (16 pts), brain (18), liver (9), and bone (9). LAT included surgery (30 pts), SRT (30), and chemoradiotherapy (23). Adverse events have been mostly mild. There were two episodes of Grade 3 pneumonitis, two episodes of Grade 3 colitis, and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 20.1 mos. To date, 19 pts have had PD or died. Median PFS was 25 mos. PFS rates (+ SE) at 12, 18 and 24 mos are 72%+7%, 54%+9% and 50%+9%, with 10 free of PD/death beyond 24 mos. To date, 10 pts have died. Median OS has not yet been reached. OS rates (+ SE) at 12, 18 and 24 mos are 91%+4%, 82%+7% and 73%+8%, with 14 pts alive beyond 24 mos. Median PFS was 16.9 mos for pts with metachronous disease (n=33), not yet reached for pts with synchronous disease (n=12). Median OS has not yet been reached in either group.

      Conclusion

      Pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. PFS appears quite favorable, preliminarily Final analysis will be performed September 2018. Updated survival estimates and biomarker data will be presented.

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      OA07.02 - ATOM: A Phase II Study to Assess Efficacy of Preemptive Local Ablative Therapy to Residual Oligometastases After EGFR TKI

      15:25 - 15:35  |  Presenting Author(s): Oscar S.H. Chan  |  Author(s): Kwok Chi Lam, Jacky Yu Chung Li, Frankie Choi, Catherine Wong, Amy Chang, Frankie Mo, Ki Wang, Rebecca Yeung, Tony S. Mok

      • Abstract

      Background

      NSCLC patients (Pts) harboring EGFR mutation invariably develop resistance to EGFR TKI at a median time of 9-13 months. Prior studies have showed that local ablative therapy (LAT) upon oligoprogression (OP) can extend the duration of TKI therapy effectively. We postulate that residual positron emission tomography (PET) avid lesions after initial treatment of EGFR TKI may harbor resistant clones and preemptive LAT may improve progression free survival (PFS).

      Method

      This single-arm phase II study aims to determine the efficacy of preemptive LAT to residual metabolic active oligo-metastases after initial TKI. Pts with stage IIIB/ IV EGFR M+ NSCLC who possessed oligoresidual (OR) disease (≤ 4 PET-avid lesions with SUV ≥2.5) after a 3-mth TKI therapy were enrolled. Those with initial PR underwent screening PET-CT. PET avid ORs would be treated by LAT, either by stereotactic ablative radiotherapy (SABR) or surgery per clinicians’ discretion. TKI was continued after LAT until it was considered ineffective. PET-CT was done on the 3rd and 12th month post-LAT (or at progression), apart from regular imaging. Further LAT was allowed if OP was detected. Primary endpoint was PFS rate at 1 year from enrollment. Overall survival (OS), treatment safety and comparison with screen failure cohorts were secondary endpoints.

      Result

      18 Pts were enrolled from 2014-17. Recruitment was stopped before the planned number (n = 34) due to slow accrual. Two were not analyzed due to consent withdrawal and significant protocol violation. Median follow up was 28.7 mth. Among the 16 analyzed Pts, the 1 year PFS rate (i.e. 15 mth post TKI) was 62.5%. OS data was not yet mature. All LAT were done by SABR, and none experienced ≥grade 3 SABR related toxicities. Compared with screen failure cohort (n = 43, metabolic CR or PR with residual disease not fulfilling LAT criteria), the 1 year and 2 year PFS favored treatment arm, though statistically not significant (62.5% vs 47.1%, 30.0% vs 7.9%; p = 0.15).

      Conclusion

      The 1-yr PFS rate is encouraging. A trend of improved long term PFS is noted in Pts receiving preemptive LAT to residual PET-avid OM after initial TKI compared with Pts without LAT. Further studies are warranted.

      Clinical Trial information: NCT01941654

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      OA07.03 - Addition of Local Therapy to EGFR TKI Showed Survival Benefit in EGFR-Mutant NSCLC pts with Oligometastatic or Oligoprogressive Liver Metastases

      15:35 - 15:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Caicun Zhou, Huijuan Wang, Qian Chu

      • Abstract

      Background

      Our previous study demonstrated that EGFR-mutant NSCLC patients (Pts) with liver metastases (LM) showed poor response to EGFR-TKIs than those without LM, suggesting that additional treatment is warranted. Recently, several clinical studies indicated that local therapy (e.g. surgery and radiotherapy) could significantly improve progression-free survival (PFS) in NSCLC Pts with oligometastatic or oligoprogressive disease. This study aimed to investigate whether addition of local therapy to EGFR-TKIs could provide a better survival benefit than TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM.

      Method

      Pts with EGFR-mutant NSCLC and LM were enrolled. Oligometastatic LM was defined as < 5 sites in liver without extrahepatic metastases at initial diagnosis. Oligoprogressive LM was defined as < 5 sites in liver without extrahepatic metastases during TKIs therapy. For oligoprogressive cohort, PFS1 was calculated from time of initiation of TKI therapy to first RECIST 1.1 defined progress disease (PD) or death. PFS2 was calculated from time of initiation of TKI therapy to off-TKI PD.

      Result

      Totally, 135 cases with EGFR-mutant NSCLC and LM were eligible (64 with oligometastatic LM and 71 with oligoprogressive LM). In oligometastatic cohort, 20 Pts received EGFR-TKIs (E) and 23 Pts received EGFR-TKIs plus local therapy (E+LT) as first-line treatment. The addition of local therapy showed a significantly longer PFS (12.9 vs. 7.9 m, P = 0.041) and OS (36.8 vs. 21.3 m, P = 0.034) than EGFR-TKIs alone. In oligoprogressive cohort, 24 Pts received continuation of EGFR-TKIs plus local therapy (cE+LT) and 25 Pts received switch therapy (ST). Median PFS1 was similar. Median PFS2 (13.9 vs. 9.2 m, P = 0.007) and OS (28.3 vs. 17.1 m, P = 0.011) was significantly longer in cE+LT group than in ST group. Multivariate analysis revealed that addition of local therapy was independently associated with prolonged PFS (HR = 0.435, P = 0.028) and OS (HR = 0.434, P = 0.071) in Pts with oligometastatic LM. Distant metastatic sites were the major pattern of failure in EGFR-TKI plus local therapy group while locoregional recurrence including primary lesions and LM was the major reason in TKI alone group.

      Conclusion

      The current study suggested that EGFR-TKIs plus local therapy demonstrated the prolonged survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM. These findings suggest that local therapy should be further explored in large-scale, strictly designed clinical trials as a standard treatment option in this clinical scenario.

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      OA07.04 - Discussant - OA 07.01, OA 07.02, OA 07.03

      15:45 - 16:00  |  Presenting Author(s): Gregory M.M. Videtic

      • Abstract

      Abstract not provided

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      OA07.05 - Local Ablative Therapy Improves Survival in Patients with Synchronous Oligometastatic NSCLC Harboring EGFR Mutation Treated with EGFR-TKIs

      16:00 - 16:10  |  Presenting Author(s): Yaping Xu  |  Author(s): Qinghua Xu, Fei Zhou, Hui Liu, Caicun Zhou

      • Abstract

      Background

      Non-small-cell lung cancer (NSCLC) is the most common cause of cancer deaths worldwide. Patients with oligometastatic disease can represent an indolent phenotype that could benefit from local ablative therapy(LAT). Howerver, whether first-line continual EGFR-TKIplus LAT could have potential benefit in EGFR-mutant NSCLC patients with oligometastatic disease remains undetermined.

      Method

      Patients with stage IV EGFR-mutant NSCLC and no more than five metastases at diagnosis in 2 months were enrolled. All patients were treated with first-line EGFR-TKIs. Consolidation LAT included radiotherapy or surgery. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves.

      Result

      From October 2010 to May 2016, 145 patients were enrolled, including 51 (35.2%) who received consolidation LAT to all oligometastatic sites (All-LAT group), 55 (37.9%) who received consolidation LAT to either primary tumor or oligometastatic sites (Part-LAT group), and 39 (26.9%) who did not receive any consolidation LAT (Non-LAT group). The median PFS in All-LAT, Part-LAT, and None-LAT group were 20.6 months, 15.6 months, and 13.9 months, respectively (P<0.001). The median OS in All-LAT, Part-LAT, and None-LAT group were 40.9 months, 34.1 months, and 30.8 months, respectively (P<0.001). The difference was significant between All-LAT group and Part-LAT or Non-LAT group but was not significant between Part-LAT and Non-LAT group. The median OS was significantly improved with consolidation LAT for primary tumor (40.5 versus 31.5 months, P<0.001), brain metastases (38.2 versus 29.2 months, P=0.002), adrenal metastases (37.1 versus 29.2 months, P =0.032). Adverse events (Grade≥3) due to radiotherapy included pneumonitis (7.7%) and esophagitis (16.9%).

      Conclusion

      The current study demonstrated that consolidation LAT to all sites was a feasible option among patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with consolidation LAT to partial sites or observation alone.

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      OA07.06 - Efficacy of Local Consolidative Therapy for Oligometastatic Lung Adenocarcinoma Patients Harboring EGFR Mutations.

      16:10 - 16:20  |  Presenting Author(s): Fang Hu  |  Author(s): Jianlin Xu, Bo Zhang, Changhui Li, Wei Nie, Ping Gu, Ping Hu, Huimin Wang, Yujun Zhang, Yinchen Shen, Shuyuan Wang, Baohui Han, Xueyan Zhang

      • Abstract

      Background

      For oligometastatic lung adenocarcinoma patients with sensitive EGFR mutations, the role of local consolidative therapy (LCT) remains debatable. The purpose of this study was to investigate the efficacy of LCT in these patients.

      Method

      Advanced stage patients with oligometastatic lung adenocarcinoma who harboring EGFR mutation were identified at the Shanghai Chest Hospital from 2010 to 2016.

      Result

      A total of 253 patients (149 patients who received LCT plus EGFR-TKIs [combination group] and 104 patients who received EGFR-TKIs [TKI monotherapy group] were included. The median PFS time in the combination group was 14 months versus 9 months in the TKI monotherapy group (HR=0.57, 95% [CI] 0.44, 0.79, p<0.01, Figure 1 A). The median OS time in the combination group was 33 months versus 20 months in the TKI monotherapy group (HR=0.56, 95% [CI] 0.41, 0.75, p<0.01, Figure 1D). Survival benefit was independent of EGFR mutation type (PFS: 19del, p=0.02, Figure 1B; 21L858R, p<0.01, Figure 1C; OS: 19del, p=0.0189, Figure 1E; 21L858R, p<0.01, Figure 1F) and metastatic sites .figure 1.jpg

      Conclusion

      LCT combined with TKI therapy was feasible and significantly improved PFS and OS among oligometastatic lung adenocarcinoma patients with sensitive EGFR mutations, and thus, should be considered as an important medical treatment during clinical management.

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      OA07.07 - PFS and OS Beyond 5 years of NSCLC Patients with Synchronous Oligometastases Treated in a Prospective Phase II Trial (NCT 01282450)

      16:20 - 16:30  |  Presenting Author(s): Dirk De Ruysscher  |  Author(s): Rinus Wanders, Lizza Hendriks, Angela Van Baardwijk, Bart Reymen, Ruud Houben, Gerben Bootsma, Cordula Pitz, Anne-Marie C. Dingemans

      • Abstract

      Background

      There is increasing interest in the treatment of synchronous oligometastases of NSCLC. Two randomized studies demonstrated an increased PFS by adding a radical local treatment to systemic therapy in responding patients, but long-term data are lacking. We previously reported a median PFS of 12 months and a median OS of 13.5 months in 39 radically treated patients with synchronous oligometastases in a prospective study (De Ruysscher J Thorac Oncol 2012). As the minimal follow-up is now exceeding 6 years, we here report the long-term PFS and OS.

      Method

      Prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was required.

      Result

      Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment.

      Median overall survival (OS) was 13.5 months (95% CI 7.6-19.4); 1-, 2-, 3-, 4-, 5, 6-year OS was 56.4%, 23.3%, 12.8 %, 10.3 %, 7.7 %, 5.1 % (2 patients), respectively.

      Median progression-free survival (PFS) was 12.1 months (95% CI 9.6-14.3); 1-, 2-, 3-, 4-, 5, 6-year PFS was 51.3%, 13.6 %,12.8 %, 7.7 %, 7.7 %, 2,5 % (1 patient), respectively.

      Of the 3 patients with a PFS after 5 years, 1 had a squamous cell cancer T2N2 with a single pathologically proven bone metastasis in the sternum, 1 had a NSCLC-NOS T4N0 with a single adrenal metastasis, and 1 a T1N2 adenocarcinoma with a pathologically proven contralateral lung metastasis. The latter patient is still free of disease.

      Two patients developed a second primary cancer: 1 tongue carcinoma after 70 months and 1 an adenocarcinoma in the contralateral lung after 71 months. Both patients died of their second cancer.

      Three patients (7.7 %) had a local recurrence, all in the PTV of their primary tumor.

      Only one patient was treated with a TKI (gefitinib) at progression.

      Conclusion

      After radical treatment of oligometastases, approximately 8 % of the patients achieve a PFS after 5 years. Entering patients in trials combining local therapy with novel systemic agents (e.g. chemo-immunotherapy) remains mandatory.

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      OA07.08 - Discussant - OA 07.05, OA 07.06, OA 07.07

      16:30 - 16:45  |  Presenting Author(s): Sue S Yom

      • Abstract

      Abstract not provided

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    OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment

    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Moderators:
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      OA08.01 - Long-Term Efficacy and Safety of Nivolumab in Second- or Third-Line Japanese Malignant Pleural Mesothelioma Patients (Phase II: MERIT Study)

      15:15 - 15:25  |  Presenting Author(s): Takashi Nakano  |  Author(s): Morihito Okada, Takashi Kijima, Keisuke Aoe, Tatsuya Kato, Nobukazu Fujimoto, Kazuhiko Nakagawa, Yuichiro Takeda, Toyoaki Hida, Kuninobu Kanai, Fumio Imamura, Satoshi Oizumi, Toshiaki Takahashi, Mitsuhiro Takenoyama, Hiroshi Tanaka, Yuichiro Ohe

      • Abstract

      Background

      Malignant Pleural Mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and no treatment is approved for patients (pts) progressing after 1st line pemetrexed-platinum doublet. Here, we report latest analysis of MERIT study in previously treated Japanese MPM pts to update the previous report (WCLC 2017, Goto Y, et al).

      Method

      This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including pemetrexed-platinum doublet. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable lesion and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.

      Result

      Thirty-four pts received Nivolumab in this study. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6% and PD-L1 (≧1%)/PD-L1 (<1%)/not evaluable: 58.8%/35.3%/5.9%. At a median follow-up of 16.8 months (range: 1.8-20.2), ORR was 29.4 % (n=10, 95%CI: 16.8-46.2). DCR was 67.6% (n=23, 95%CI: 50.8-80.9). Median DOR was 11.1 months (95%CI: 3.5-16.2). Median PFS was 6.1 months (95%CI: 2.9-9.9) in all pts, 7.2 months (2.8-15.0) in PD-L1 (≧1%) and 2.9 months (1.4-9.3) in PD-L1 (<1%). Median OS was 17.3 months (95%CI: 11.5-NR) in all pts, 17.3 months (8.2-NR) in PD-L1 (≧1%), 11.6 months (5.8-NR) in PD-L1 (<1%), across tissue types, 15.7 months (95%CI: 8.0-NR) in epithelioid and not reached in sarcomatoid/biphasic pts. Six- and 12-month survival rates were 85.3% (95%CI: 68.2-93.6) and 58.8% (95%CI: 40.6-73.2). Twenty-six (76.5%) pts experienced treatment-related adverse event (TRAE), and 11 (32.4%) experienced grade 3/4 TRAEs. Most commonly reported TRAEs were skin disorder (n=6, 17.6%), elevated lipase (n=5, 14.7%), elevated amylase and diarrhea (n=4, 11.8%). Four pts required dose discontinuation because of interstitial pneumonia (n=2, grade2 and 3) and pneumonitis (n=2, grade3).

      Conclusion

      Nivolumab shows durable long term efficacy and manageable safety profile in Japanese 2nd/3rd line MPM pts.

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      OA08.02 - DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result

      15:25 - 15:35  |  Presenting Author(s): Anna K. Nowak  |  Author(s): Peey-Sei Kok, Willem Joost Lesterhuis, Brett G.M Hughes, Chris Brown, Steven Chuan-Hao Kao, Deme Karikios, Thomas John, Nick Pavlakis, Kenneth O’byrne, Sonia Yip, Wei-Sen Lam, Karen Briscoe, Chris S. Karapetis, Martin R Stockler

      • Abstract

      Background

      We report here the final results of a single-arm, phase 2 trial designed to determine the activity, safety and tolerability of durvalumab, cisplatin and pemetrexed as first line therapy in MPM. ANZ Clinical trial registry number: ACTRN12616001170415

      Method

      Participants were considering first line chemotherapy for MPM, were unsuitable for radical surgery, had an un-irradiated target lesion, and had good performance status (ECOG PS 0-1). Objective tumour response (OTR) and progression free survival (PFS) were assessed primarily according to the modified Response Evaluation Criteria in Solid Tumors for MPM (mRECIST) and as secondary endpoints according to RECIST modified for immunotherapy (iRECIST). Study treatment was durvalumab 1125mg, cisplatin 75mg/m2, and pemetrexed 500mg/m2 all given intravenously on day 1, and repeated every 3 weeks for a maximum of 6 cycles, followed by durvalumab 1125 mg every 3 weeks until progression, unacceptable toxicity, or a maximum total of 12 months. The primary endpoint was PFS at 6 months (PFS6). The sample size of 54 provided 90% power to distinguish the observed proportion PFS6 from a null hypothesis of 45% versus an alternative of 65% with a 1-sided alpha of 5%. Tissue and blood samples were required and collected for translational correlative studies.

      Result

      We recruited 54 participants from Dec 2016 to Sep 2017. Median age was 68 (range 42-82), 82% were male, 60 had ECOG PS 0, and 82% had epithelioid histology. Dose intensities were 97% for cisplatin and 94% for durvalumab. The proportion PFS6 was 57% (31/54, 90% CI 45-68%); median PFS was 6.9 months (95% CI 5.5-9.0). The OTR rate was 48% (95% CI 35-61%) according to mRECIST and 50% (95% CI 37-63) according to iRECIST. The median duration of response was 6.5 months. Grade 3-5 adverse events occurred in 36 participants, including neutropenia in 13%, nausea in 11%, anaemia in 7%, fatigue in 6% and any grade peripheral neuropathy in 35%. There were 4 deaths on study, none attributed to durvalumab. Immune-related adverse events occurred in 17 participants, and were of grade 3 or worse in 8, including increased lipase (1), pancreatitis (1), and renal impairment (1).

      Conclusion

      The combination of durvalumab, cisplatin, and pemetrexed has demonstrated sufficient activity, safety, and tolerability as first line therapy in MPM to warrant further evaluation in a large-scale, randomised phase 3 trial.

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      OA08.03 - Phase II Trial of Pembrolizumab (NCT02399371) In Previously-Treated Malignant Mesothelioma (MM): Final Analysis

      15:35 - 15:45  |  Presenting Author(s): Arpita Desai  |  Author(s): Theodore Karrison, Pamela Rose, Yi-Hung Carol Tan, Bianca Hill, Erika Pemberton, Christopher Straus, Tanguy Seiwert, Hedy Lee Kindler

      • Abstract

      Background

      We conducted a phase II trial to assess the activity of pembrolizumab in a non-selected population of mesothelioma patients and determine a PD-L1 expression threshold.

      Method

      Eligible patients had histologically-confirmed pleural or peritoneal MM, PS 0-1, prior pemetrexed/platin, disease progression on ≤2 prior regimens. Pembrolizumab 200 mg was administered Q21 days; CT scans were obtained Q9 weeks. The primary endpoints determined: 1) the objective response rate (ORR) in an unselected and a PD-L1 positive population; 2) the optimal threshold for PD-L1 expression using the 22C3 IHC tumor cell/tumor proportion score (TPS) assay. Proceeding to a second stage required ≥3 responses in 35 PD-L1 unselected patients in Part A. Part B would PD-L1 preselect only if a threshold was determined in Part A. At WCLC 2016, we reported 7 responses in Part A, and no PD-L1 threshold was identified (ROC 0.62). Thus, Part B enrolled 30 additional patients without biomarker enrichment.

      Result

      65 patients enrolled 5/15-2/18; 1 withdrew. PS 0: 53%; male: 77%; median age: 68 (range 26-85); 1 prior chemotherapy 61%; pleural 87.5%; epithelioid 76.6%, biphasic 15.6%, sarcomatoid 7.8%. Mean cycles: 9 (range 1-34). Partial response: 19%, stable disease: 47%, disease control rate: 66%. ORR by histology: epithelioid 16%, biphasic 10%, sarcomatoid 40%. ORR by disease site: pleural 20%, peritoneal 12.5%. Median progression-free survival: 4.5 months (95% CI: 2.3, 6.2). Median overall survival: 11.5 months (95% CI: 7.6, 14). Grade ¾ toxicity: adrenal insufficiency 3%, pneumonitis 3%, rash 3%, colitis 1.6%, confusion 1.6%, hepatitis 1.6%, hyperglycemia 1.6%. Grade 5: hepatitis 1.6%, unknown 1.6%. PD-L1 expression by TPS (N = 62): none (< 1%) 45%; low (1-49%) 32%; high (≥50%) 23%. ORR by TPS: none 7%, low 26%, high 31%. PD-L1 did not correlate with RR as a continuous metric (ROC area 0.65; 95% CI: 0.48, 0.82), though there was a trend towards a higher ORR in PD-L1 ≥1% (28%) compared with PD-L1 <1% (7%). Median PFS by TPS: none 3.1 months, low 6.2 months, high 6.1 months; 1-year PFS by TPS: none 7%; low 7%; high 31%.

      Conclusion

      Single-agent pembrolizumab has robust activity in PD-L1 unselected, previously-treated mesothelioma. There were no unexpected toxicities. Responses were more frequent in pleural and sarcomatoid MM. Although an optimal PD-L1 threshold could not be identified, a trend towards a higher response rate and more durable PFS with increasing PD-L1 expression was observed. Funded in part by a Mesothelioma Foundation grant.

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      OA08.04 - Discussant - OA 08.01, OA 08.02, OA 08.03

      15:45 - 16:00  |  Presenting Author(s): Thomas John

      • Abstract

      Abstract not provided

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      OA08.05 - Quantifying Tumour Infiltrating Lymphocytes (TILs) in Malignant Pleural Mesothelioma (MPM) -Defining the Hot, the Warm and the Cold Tumours.

      16:00 - 16:10  |  Presenting Author(s): Thomas John  |  Author(s): Bibhusal Thapa, Marzena Walkeiwicz, Gareth Rivalland, Carmel Murone, Khashayar Asadi, Stephen Arthur Barnett, Simon Knight, Shona Hendry, Prudence Russell

      • Abstract

      Background

      Immunological infiltrates into tumor tissues have been associated with improved prognosis in many cancers including breast, colorectal, cervical, melanoma and lung. While most studies evaluating TILs have been based on evaluation of individual types of T lymphocytes, more recently, a morphological assessment of the TILs based on a simple hematoxylin & eosin (H&E) slide examination has been shown to be an independent positive prognostic factor in HER2 positive early stage breast cancer and lung cancer. We used similar methods to explore the immune microenvironment in a large mesothelioma cohort.

      Method

      Using full face sections of MPM tumour samples, we assessed lymphocytes infiltrating tumour stroma.TILs score was calculated as a % of stromal area assessed to be covered by TILs by an experienced pathologist. Tissue microarrays (TMA) were constructed and stained with PD-L2, LAG3 and TIM3 antibodies. These data were combined with PD-L1 expression, CD4+ and CD8+ infiltration in the same cohort reported previously. We explored the clinical and pathological correlates of the level of TILs.

      Result

      Amongst 329 patients evaluated, 308 samples were evaluable for TILs characterisation. The scores ranged from 0-90 (median 30). Stratified using tertiles, 142 patients had low TILs, 68 had medium and 98 had high TILs. High TILs were seen in patients who were PD-L1 (Chi square test p = 0.002) and PD-L2 positive (Chi square test p <0.0001) and of non-epithelioid histological subtype (Fischer’s exact test p = 0.01). On univariate analysis, PD-L2 positivity (HR = 3.2; CI = 2.2-4.6; Log rank P < 0.0001), high TILs (HR = 2.03; CI = 1.5-2.6; Log rank P < 0.0001), and high TIM3+ lymphocytes (HR = 1.3; CI = 1.0-1.7; Log rank P < 0.04) were found to be related to poorer overall survival (OS). On multivariate analysis, higher TILS was found to remain significantly associated with poorer OS along with non-epithelioid histology and poor physiological status.

      Conclusion

      High TILs correlated with non-epithelioid histology and greater expression of PD-L1 and PD-L2. In contrast to other tumor types, a high TIL infiltrate was negatively prognostic.

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      OA08.06 - Tumour Suppressor MicroRNAs Modulate Drug Resistance by Targeting Anti-Apoptotic Pathways in Malignant Pleural Mesothelioma (MPM)

      16:10 - 16:20  |  Presenting Author(s): Yuen Yee Cheng  |  Author(s): Marissa Williams, Monica Phimmachanh, Patrick Winata, Glen Reid

      • Abstract

      Background

      Malignant Pleural mesothelioma (MPM) is an aggressive thoracic malignancy with limited treatment options. MPM has a poor prognosis, predominately due to its inherent drug resistance and its limited response to current therapies. Aberrant microRNA expression is a common event in neoplasms with many implicated in chemo-resistance, however their role in MPM drug resistance is largely unexplored.

      Method

      To investigate the role of microRNAs in MPM drug resistance, we generated MPM cell lines with acquired drug resistance to cisplatin, gemcitabine and vinorelbine by periodic treatment with the IC50 of each chemotherapeutic agent. Expression levels of mature microRNAs were compared between parental MPM cell lines and cell lines with acquired drug resistance using RT-qPCR. BCL2 is an anti-apoptotic gene and a known target of miR-15a/16-1 and miR-34a. To determine if microRNAs potentiate drug sensitization via a Bcl-2 mediated anti-apoptotic pathway, drug sensitivity assays were carried out following reverse-transfection with microRNA mimics and Bcl-2 siRNAs combined with cisplatin, gemcitabine and vinorelbine treatment. Following microRNA mimic transfection in 6-well plates, levels of apoptosis and necrosis were determined by PI and annexin V staining while Bcl-2 mRNA and protein expression was determined by RT-qPCR and Western blotting respectively.

      Result

      Expression of miR-15a/16-1 and miR-34a was downregulated in MPM cells with acquired resistance to cisplatin, gemcitabine and vinorelbine, compared to the parental counterpart. Transfection with mimics corresponding to miR-15a/16-1 were most effective in improving sensitivity to all chemotherapeutics tested in drug resistant cell lines. In parental cell lines, miR-15a/16-1 mimic induced sensitization was also observed but restoration of miR-34a and miR-34b was also capable of improving response to cisplatin and vinorelbine. Forced miR-15/16 and miR-34a expression also sensitized both parental and resistant cell lines to cisplatin, gemcitabine and vinorelbine via induction of apoptosis; their ability to increase levels of drug-induced apoptosis suggest they may sensitize cells to chemotherapeutics via an anti-apoptotic mechanism involving Bcl-2. miR-15a/16-1 and miR-34a transfection caused Bcl-2 mRNA and protein reduction, confirming their regulation of Bcl-2 in MPM. Furthermore, siRNA induced knockdown of Bcl-2 also induced a modest improvement in drug sensitivity.

      Conclusion

      Restoration of microRNA expression sensitized both drug resistant and parental cell lines to chemotherapeutic agents and increased levels of drug-induced apoptosis. Taken together, this data suggests that miR-15a/16-1 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells in part by modulation of apoptotic mechanisms via targeting Bcl-2.

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      OA08.07 - In Silico Discovery of Unannotated miRNAs in Malignant Pleural Mesothelioma Reveals Novel Tissue-of-Origin Markers

      16:20 - 16:30  |  Presenting Author(s): Brenda C. Minatel  |  Author(s): Erin A Marshall, Christine Anderson, Kevin W. Ng, Katey S.S. Enfield, Adam P Sage, Zhaolin Xu, Wan Lam, Victor D Martinez

      • Abstract

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive disease. One of the major clinical challenges associated with MPM is the lack of biomarkers capable of distinguishing primary MPM from cancers that have metastasized to the pleura. The current gold standard consists of a panel of positive and negative protein markers to confirm tissue-of-origin; however, many cases remain undistinguishable from other thoracic cancers. Recent studies have suggested that the human genome encodes more microRNAs (miRNAs) than currently annotated. These undescribed sequences have been shown to display enhanced tissue and lineage specificity. Therefore, we hypothesize that MPM tumors express a specific set of previously unannotated miRNA sequences with tissue-specific expression capable of distinguishing MPM from other thoracic diseases.

      Method

      Novel miRNA candidates were detected from small RNA-sequencing data generated by The Cancer Genome Atlas (TCGA) (n=87 MPM) using the miRDeep2 algorithm, a well-established novel-miRNA prediction algorithm. The possible biological roles of these miRNA candidates were investigated by performing a genome-wide 3’UTR target prediction analysis. Additionally, their tissue-specificity was assessed using expression profiles of 1,093 lung tumors from four independent cohorts of adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Finally, we developed a miRNA-based classifier model using the weighted voting class prediction method to distinguish MPM from other thoracic cancers.

      Result

      Our initial analysis revealed 424 miRNA candidates, which were subsequently filtered by RNA structure, abundance of sequencing reads, and genomic location, resulting in 154 previously unannotated miRNA sequences. Interestingly, the novel miRNAs were predicted to target protein-coding genes involved in MPM biology, including the Ataxia Telangiectasia Mutated (ATM) gene, a tumour-supressor gene frequently mutated in MPM. Likewise BRCA1 Associated Protein 1 (BAP1), involved in the DNA damage response pathway, was also a predicted target. Principal component analyses revealed that novel-miRNA expression was able to distinguish MPM from LUAD and LUSC. Furthermore, our miRNA-based classifier model revealed 10 novel miRNAs capable of successfully identifying 86 out of the 87 MPM cases (98.80%) and 100% of LUAD cases (true positive rate = 98.85%, false positive rate = 1.150%).

      Conclusion

      Here, we provide evidence for the presence of 154 previously unannotated miRNA species relevant to MPM. These miRNAs not only significantly expand the miRNA repertoire but also unveil specific roles in MPM biology. Most importantly, the strikingly high sensitivity and specificity of the novel miRNA-based classifier in distinguishing MPM from LUAD illustrates the potential of using these novel miRNAs to supplement current clinical markers to define MPM.

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      OA08.08 - Discussant - OA 08.05, OA 08.06, OA 08.07

      16:30 - 16:45  |  Presenting Author(s): Emanuela Felley-Bosco

      • Abstract

      Abstract not provided

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    OA09 - Prevention and Cessation

    • Type: Oral Abstract Session
    • Track: Prevention and Tobacco Control
    • Moderators:
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      OA09.01 - 5As to 3As: Evolution of the Systematic Approach to Smoking Cessation in Ontario’s Regional Cancer Centres

      15:15 - 15:25  |  Presenting Author(s): William Kenneth Evans  |  Author(s): Erin Cameron, Mohammad Haque, Naomi Schwartz, Sahara Khan, Rebecca Truscott

      • Abstract

      Background

      Smoking is responsible for approximately 30% of all cancer deaths in Canada, and more than 85% of lung cancer cases. Cancer patients who continue to smoke experience decreased treatment efficacy and safety, increased toxicities, greater risk of cancer recurrence and second primaries, poorer quality of life, and decreased survival. Evidence suggests that quitting smoking after diagnosis can significantly reduce these adverse effects. In 2012, Cancer Care Ontario (CCO) introduced a Framework for Smoking Cessation to be implemented across the province’s 14 Regional Cancer Centres (RCCs). In 2017, the Framework was revised from a 5As (Ask, Advise, Assess, Assist, Arrange) to a 3As (Ask, Advise, Act) brief intervention model.

      Method

      The transition to a 3As model was based on emerging evidence, feedback from CCO’s Smoking Cessation Advisory Committee and Regional Smoking Cessation Champions, as well as learnings from a preliminary program evaluation. The revised Framework recommended an “opt-out” approach to referring smokers to cessation services. Following an environmental scan and site visit with each RCC to assess the current state, site-specific action plans were developed to promote alignment with the revised Framework. Action steps were given priority ratings in the areas of data capture, referrals, and resources. Two phone calls were held with each RCC to monitor progress on action plan implementation. Knowledge translation resources were created to support healthcare providers’ uptake of the 3As model.

      Result

      Smoking cessation interventions are often perceived by health care providers as time-consuming; the 3As model made the intervention briefer but no less effective. Over 3,000 knowledge translation resources were distributed to support healthcare providers working directly with cancer patients, including pocket cards and posters with suggested scripts. While the revised Framework officially launched in April 2018, early adopters of the 3As model and opt-out approach have seen improved performance on the Accepted a Referral indicator (proportion of smokers who accepted a referral to cessation services). In 2017, one RCC’s rate tripled from 10.1% to 30.9% in 6 months, while another improved from 13.2% to 36.9% in the same period.

      Conclusion

      To improve program effectiveness, CCO’s smoking cessation initiative transitioned from a 5As to a 3As model and an opt-out referral process. Frontline staff have indicated a willingness to adopt the simplified approach, and early results show a promising increase in the number of smokers who are connected to smoking cessation services.

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      OA09.02 - Acceptance of Smoking Cessation Services in Cancer Care Ontario’s Lung Cancer Screening Pilot for People at High Risk

      15:25 - 15:35  |  Presenting Author(s): William Kenneth Evans  |  Author(s): Gail Elizabeth Darling, Beth Miller, Erin Cameron, Monica Yu, Martin Tammemägi

      • Abstract

      Background

      Participation in lung cancer screening can be a teachable moment for smoking cessation. Current smokers who attend for lung screening may also be motivated to quit. In June 2017, Cancer Care Ontario launched organized lung cancer screening at 3 pilot sites in Ontario with smoking cessation embedded in the screening pathway. Participants are recruited through primary care providers and public-facing messaging.

      Method

      Smoking cessation services (SCS) are offered to all current smokers (anyone who smoked a cigarette in the past 30 days) interacting with the pilot. Individuals found ineligible for screening are offered a direct referral to the Canadian Cancer Society’s Smokers’ Helpline. Screen-eligible individuals are scheduled for smoking cessation counselling during their baseline low-dose computed tomography (CT) appointment, using an opt-out approach. Hospital-based SCS are provided by trained counsellors and consist of 10 minutes (minimum) of behavioural counselling, a recommendation or prescription for pharmacotherapy, and arrangements for proactive follow-up. The proportions of current smokers who accept referral to SCS and who attend hospital-based smoking cessation counselling are being monitored throughout the pilot. A participant satisfaction survey is completed after the screening appointment (if applicable). Data on quit rates, quit attempts, heaviness of smoking and relapse among screening participants is being captured.

      Result

      Between June and October 2017, 50% of the 1241 individuals who underwent risk assessment to determine eligibility for screening were current smokers. Of the 808 individuals eligible for screening, 63% were current smokers: 52% were male, (age 55-64, 61%; 65-74, 39%), 55% had a high school education or less. 27% of ineligible individuals were current smokers. 83% of all current smokers (regardless of screen-eligibility) accepted a referral to SCS. Of screen-eligible current smokers, 89% accepted hospital-based cessation counselling; 88% of those who had a baseline low-dose CT in the reporting period attended a hospital-based counselling session. 93% of survey respondents (response rate 56%) reported being satisfied with the smoking cessation counselling they received.

      Conclusion

      Acceptance of SCS by current smokers in Cancer Care Ontario’s lung cancer screening pilot is very high. A large majority of screened current smokers have attended a hospital-based counselling session, and satisfaction with this service was high. These findings suggest that an opt-out approach is acceptable to individuals motivated to attend a lung screening program. The final pilot evaluation in spring 2020 will evaluate the success of the smoking cessation initiative by assessing quit attempts, quit rates and relapse among screening participants.

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      OA09.03 - Discussions Between Health Professionals and Smokers About E-Cigarettes: Results from the ITC Policy Evaluation Project

      15:35 - 15:45  |  Presenting Author(s): Shannon Gravely  |  Author(s): James F Thrasher, K. Michael Cummings, Janine Ouimet, Ann McNeill, Gang Meng, Eric N. Lindblom, Ruth Loewen, Richard O’connor, Mary E. Thompson, Sara C. Hitchman, David Hammond, Bryan W. Heckman, Ron Borland, Hua Hie Yong, Tara Elton-Marshall, Maansi Bansal Travers, Coral Gartner, Geoffrey T. Fong

      • Abstract

      Background

      The current scientific evidence on the effectiveness of e-cigarettes for smoking cessation is limited, but shows e-cigarettes may be at least as effective as nicotine replacement therapy (NRT), which is a standard treatment for cessation and broadly recommended by health professionals (HPs). E-cigarettes are now more popular for cessation than licensed NRT and prescription medications in countries such as England, the United States (US), and Canada; however, debate exists on whether HPs should advise smokers to use e-cigarettes, particularly for those who have medical comorbidities (e.g., chronic lung disease). The present study included smokers from four countries to examine: (1) the prevalence of: (i) HP advice to quit smoking, (ii) discussions about e-cigarettes, and (iii) recommendations to use e-cigarettes; and (2) smoker’s characteristics associated with discussing e-cigarettes and receiving advice to use them.

      Method

      Data come from the 2016 International Tobacco Control (ITC) Policy Evaluation Project Four-Country Tobacco and E-cigarette Survey, which includes nationally representative samples of adult (≥18 years) smokers from Canada (n=1,922), the US (n=1,501), England (n=2,105), and Australia (n=1,038). Participants eligible for analysis had visited a HP in the last year.

      Result

      Among all smokers who visited a HP in the last year, 47.5% received advice to quit smoking, 6.8% reported discussing e-cigarettes, and 2.1% of smokers were recommended to use an e-cigarette (36.1% of those who had a discussion). Discussions and e-cigarette recommendation were more common among smokers who were: younger, highly educated, advised to quit smoking, more frequent e-cigarette users, positive about e-cigarettes, and believed that the public approved of vaping. While smokers with diabetes (p=0.026) or cancer (p=0.018) were more likely to discuss e-cigarettes with a HP, they were not more likely to be recommended to use them. Smokers with chronic lung disease were more likely to be recommended to use an e-cigarette than smokers without lung disease (p=0.026).

      Conclusion

      These findings suggest that HPs are not taking advantage of discussions with smoking patients to encourage cessation, to provide information about different smoking cessation methods (e.g., suggest e-cigarettes as a cessation aid for smokers who are not willing or able to quit with other strategies), and to encourage smokers who are not inclined to quit to use e-cigarettes as a less-harmful alternative to smoking. More research is urgently needed to assess whether e-cigarettes are a viable alternative to cigarettes for people with lung disease to help them stop smoking and prevent further lung deterioration.

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      OA09.04 - Discussant - OA 09.01, OA 09.02, OA 09.03

      15:45 - 16:00  |  Presenting Author(s): Betty Tong

      • Abstract

      Abstract not provided

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      OA09.05 - Potential Reduction in Lung Cancer Mortality in the US from 2015-2065: A Comparative Modeling Approach

      16:00 - 16:10  |  Presenting Author(s): Jihyoun Jeon  |  Author(s): Theodore R. Holford, David T. Levy, Eric J. Feuer, Pianpian Cao, Jamie Tam, Lauren Clarke, John Clarke, Chung Yin Kong, Rafael Meza

      • Abstract

      Background

      Tobacco control efforts implemented since the 1960s in the US have led to considerable reductions in smoking and smoking-related diseases including lung cancer. It is, however, unclear to what extent tobacco use and lung cancer mortality will be further reduced during the next half century due to control efforts that have already been implemented until 2015. To address this question, we developed simulation models that explicitly relate smoking temporal patterns to future lung cancer rates.

      Method

      Four independent lung cancer natural history models were developed using US smoking (1964-2015) and lung cancer mortality (1969-2010) data. Each model projected lung cancer mortality by smoking status (ages 30-84) from 2015 to 2065 under a status quo scenario, in which current smoking patterns are assumed to continue into the future. Sensitivity analyses were conducted comparing optimistic and pessimistic assumptions relative to the status quo.

      Result

      Models validated well to observed lung cancer mortality. Under the status quo scenario, age-adjusted lung cancer mortality is projected to drop 79% from 2015 to 2065. Concomitantly, the annual number of lung cancer deaths is projected to decrease from 135,000 to 50,000 (63% reduction). Despite these decreases, 4.4 millions deaths from lung cancer are projected to occur in the US from 2015-2065.

      Conclusion

      Tobacco control efforts since the 1960’s will continue to lead to reductions in lung cancer rates well into the next half century. Nonetheless, additional prevention efforts are required to sustain and expand these gains, and further reduce the lung cancer burden in the US.

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      OA09.06 - Molecular Alterations and Estimated Indoor Radon in NSCLC Patients from the French National Cancer Institute Registry: Radon France Study

      16:10 - 16:20  |  Presenting Author(s): Laura Mezquita  |  Author(s): Fabrice Barlesi, Edouard Auclin, David Planchard, Angela Botticella, Anas Gazzah, Pernelle Lavaud, Frank Aboubakar Nana, Cecile Lepéchoux, Benjamin Besse

      • Abstract

      Background

      Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. We assessed the correlation between the radon exposure areas in France and the molecular alterations nationally registered in non-small cell lung cancer (NSCLC) patients.

      Method

      We retrospectively collected all NSCLC tested for EGFR, BRAF, HER2 and KRAS mutations (m) and ALK and ROS1 rearrangements (r) on the 28 French Plateform led by INCa (French National Cancer Institute). The prevalence of molecular alterations by region was correlated to the indoor radon risk area based on the official French (Institut de Radioprotection et de Sûreté Nucléaire, INSN, France). Paris and its region Ile-de-France were not included in this analysis due to its high rate of patients that are native from other regions.

      Result

      116.424 NSCLC were included. Overall, KRAS was positive in 27,7% (27.314/98.522), EGFR in 11,27% (13.125/116.424), ALK in 3,2% (2.928/91.291), BRAF in 2,3% (2.419/105.919), ROS1 in 1,12% (373/33.222) and HER2 in 0,8% (816/97.749) of all cases.

      We stratified the French regions in 3 areas based on their exposure to radon: high (Auvergne-Rhône-Alpes, Bretagne, Normandie, Pays de la Loire), intermediate (Bourgogne-Franche-Comté, Nouvelle Aquitaine, Occitanie, Provence-Alpes-Cote-d'Azur) and low explosure (Centre Val-de-Loire, Grand Est, Hauts de France). The prevalence of driver alterations (EGFR, BRAF, HER2 and ROS1 were significantly higher in high exposure area. The prevalence of KRAS mutations was significantly higher in low exposure area.

      Low risk

      Intermediate

      High

      P

      EGFR mutation

      1962 (10%)

      4338 (11%)

      4176 (11.4%)

      <0.0001

      ALK rearrangement

      577 (3.3%)

      1019 (3%)

      896 (3%)

      0.35

      BRAF mutation

      327 (1.8%)

      830 (2.4%)

      692 (2.4%)

      0.0001

      HER2 mutation

      109 (0.6%)

      266 (0.9%)

      252 (0.8%)

      0.01

      ROS1 rearrangement

      61 (0.9%)

      133 (0.9%)

      126 (1.3%)

      0.005

      KRAS mutation

      4717 (29.8%)

      9215 (28.2%)

      7895 (27%)

      <0.0001

      Molecular drivers*

      3037 (3.9%)

      6587 (4.4%)

      6142 (4.4%)

      <0.0001

      * EGFR, BRAF & HER2 mutations, ALK & ROS1 rearrangements; KRAS mutation excluded.

      Conclusion

      NSCLC molecular alterations that are linked to low tobacco consumption were higher in the French region with high radon exposure. Role of the radon in lung cancer carcinogenesis of specific molecular subtypes should be further explored.

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      OA09.07 - Association Between Outdoor Air Pollution And Lung Cancer in Female Never Smokers

      16:20 - 16:30  |  Presenting Author(s): Renelle L Myers  |  Author(s): Michael Brauer, Sim Ladhar, Sukhinder Atkar-Khattra, John Yee, Cheryl Ho, Anna McGuire, Kyle Grant, Alex Lee, Barbara Melosky, Sophie Sun, Martin Tammemägi, Stephen Lam

      • Abstract

      Background

      Long term exposure to ambient particulate matter (PM2.5) has been associated with an increased risk of developing lung cancer, and is estimated to be responsible for ~23% of global lung cancer deaths. No current lung cancer screening risk prediction model uses air pollution as an individual risk factor in its risk calculation. As smoking rates decrease globally, and air pollution increases, it is important to assess the effect of long term outdoor air pollution exposure on lung cancer risk especially in never smokers.

      Method

      We enrolled 421 patients with newly diagnosed lung cancer presenting to BC Cancer and conducted a detailed residential history from birth to estimate their air pollution exposure since 1996 when accurate high-resolution concentration estimates of PM2.5 particulate matter derived from satellite observations and ground measurements became available. The average PM2.5 exposure was quantified by combining residential histories with exposure data.

      Result

      The demographics of the 262(62%) ever smokers, and 159(38%) never smokers with lung cancer are shown in Table 1. Median exposure of all cancer patients was 7.1 PM2.5 ug/m3 (IQR 6.8-7.3; Range 4.3-65.8). Of the ever smokers, 6.1% had a PM2.5 >10 ug/m3 whereas 15.1% of the never smokers had a PM2.5 >10 ug/m3. Among never smokers with lung cancer with high PM2.5 exposure >10 ug/m3, 74% were female and 83% were of Asian descent. Using a logistic regression model, we demonstrated a significant association between air pollution exposure and never smokers compared to ever smokers in women: Odds Ratioper_1_LN-transformed unit = 12.05 (p<0.001). This association was absent in males (interaction p=0.006).

      Conclusion

      table1.jpgIn women with lung cancer, outdoor air pollution exposure was significantly higher in never smokers than in ever smokers. This association was not observed in men with lung cancer.

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      OA09.08 - Discussant - OA 09.05, OA 09.06, OA 09.07

      16:30 - 16:45  |  Presenting Author(s): Douglas Arenberg

      • Abstract

      Abstract not provided

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    PC03 - Controversies in Management of Resectable Thymoma

    • Type: Pro-Con Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Moderators:
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      PC03.01 - Post-Operative Radiation Therapy or NOT: PRO

      15:15 - 15:25  |  Presenting Author(s): Conrad B Falkson

      • Abstract

      Abstract

      Thymic epithelial tumors are rare tumors which has been an obstacle to performing prospective randomized studies. There is definite evidence that these tumors are radio-responsive but the exact role of radiation remains unclear. An additional confounding factor is that until the proposed standardization of classification and staging by the International Thymic Malignancy Interest Group (ITMIG) there has been significant inconsistency of interpretation of both histology and staging leading to inconsistency in recommendation for post-operative radiation. Radiation fields, techniques and doses have also been very variable. Literature informing about post-operative radiation is largely reliant on single institution data and mostly retrospective work which introduces inherent bias. More recently consortiums (such as JART and ChART) were formed to try and combine data. Unfortunately most of these databases were primarily surgical based and indications for radiation and radiation techniques are not well defined. The largest data base of thymic tumors is the one established by ITMIG which has facilitated international collaboration and establishing of large retrospective and prospective databases.

      In this debate we will review the literature supporting the role of radiation in the post-operative setting after thymectomy. Recent studies from different institutions have produced very different results for post-operative radiotherapy and we will compare these to try to define why the results are different. The patient must have sufficient risk to justify radiation It has clearly been demonstrated that complete surgical resection is the most important prognostic factor. Improved outcomes with postoperative radiation will depend on appropriate patient selection. We will try to define the patient population that might benefit from treatment. We will also try to answer the question of routine postoperative treatment in more advanced stage disease, or only if resection is incomplete? We will explore how histology impacts on the decision to offer post-operative radiation?

      We will also try to define what fields would be appropriate, what techniques would be optimal and what doses should be delivered. The thymus resides in the mediastinum adjacent o heart, lungs and great vessels. Despite improved conformal techniques of radiation these organs still receive radiation and the potential damage from the radiation is not well quantified.

      International collaboration with standardization of definitions and complete radiation data is ultimately the only way we will achieve knowledge to advise the exact role of post operative radiation.

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      PC03.02 - Post-Operative Radiation Therapy or NOT: CON

      15:25 - 15:35  |  Presenting Author(s): Daniel Gomez

      • Abstract

      Abstract

      The role of postoperative radiation therapy in the context of resectable thymoma remains controversial. Indeed, data is conflicting, with some historical studies demonstrating an advantage to this approach, and others failing to show a benefit over surgery +/- systemic therapy. In the absence of randomized studies, it is difficult to draw conclusions regarding the appropriate approach. However, available data do not support the routine use of postoperative radiation therapy in this context. Decisions regarding management after resection should be made with the input from the multidisciplinary team, with discussions focusing on margin status, histology, extent of disease, and intraoperative concerns.

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      PC03.03 - Discussion

      15:35 - 15:45

      • Abstract

      Abstract not provided

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      PC03.04 - Debate on Standard Surgical Approaches - Minimally Invasive Thymectomy

      15:45 - 15:55  |  Presenting Author(s): Shaf Keshavjee

      • Abstract

      Abstract not provided

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      PC03.05 - Debate on Standard Surgical Approaches - Open Thymectomy

      15:55 - 16:05  |  Presenting Author(s): Meinoshin Okumura

      • Abstract

      Abstract

      The first case of total thymectomy for myasthenia gravis was done by Sauerbruch in 1911, which was through cervical incision. The first case of thymoma resection through median sternotomy was done by Blalock in 1934. Before video-assisted thoracoscopic surgery (VATS) was introduced to thymectomy by Yim et al in 1993, median sternotomy had been the main approach for resection of the thymus and thymic tumors.

      Approach through median sternotomy holds several variations, such as, partial sternotomy, full sternotomy, full sternotomy with lateral thoracotomy, and hemi-clam shell approach.

      Partial sternotomy usually splits the two thirds to three fourths of the caudal side of the sternum, resulting in difficulty in resecting the lesions near diaphragm. In case of thymectomy, however, for non-thymomatous myasthenia gravis, resection of peri-thymic fat tissue around the upper poles of the thymus is more important than the lower poles because of ontogeny of the thymus. Partial sternotomy requires skin incision of less than 10cm, and therefore, is less invasive compared to full sternotomy. Thus, it is reasonable to choose partial sternotomy in thymectomy for non-thymomatous myasthenia gravis. Actually, Masaoka adopted partial sternotomy for their original extended thymectomy, and Maggi also chose partial sternotomy for thymectomy for myasthenia gravis. In addition, partial sternotomy is sufficient for resection of a small non-invasive thymoma if not located near diaphragm. The advantage of sternotomy compared with unilateral or bilateral VATS approach is no need to access to the thoracic cavity, because the mediastinal pleura can be dissected from the fat tissue of the anterior mediastinum, which can reduce the possibility of intraoperative pleural implantation of tumor cells.

      Full sternotomy is the most commonly selected approach for resection of anterior mediastinal tumors, and especially, useful in resecting a large or invasive thymic tumor. Thymoma and thymic carcinoma often involve the superior vena cava or brachiocephalic vein, and cardio-pulmonary bypass is required in reconstruction of the great vessels. In these cases, median sternotomy is the most appropriate approach. While simple full sternotomy is sufficient for partial resection of the lung when involved by a tumor, lateral thoracotomy at the 4th intercostal space is sometimes added when concomitant upper lobectomy is required. When extrapleural pneumonectomy for stage 4A thymoma is intended, posterolateral thoracotomy is added in addition to full sternotomy by changing the patient’s position from the prone to the decubitus position.

      Hemi-clam shell approach is another variation of median sternotomy when combined resection of the involved organs is required. In this approach, sternum is split from the sternal notch to the level of 4th intercostal space, and there, lateral thoracotomy is added. This approach enables the procedures of various kinds of lung resection.

      Japanese Association for Thoracic Surgery (JATS) has conducted nation-wide survey of the general thoracic surgery in Japan annually since 1986. According to JATS survey, the number of VATS in surgery for thymic epithelial tumors has increased gradually since late 1990’s. In 2013, surgical resection of thymic epithelial tumor was done in 2230 cases in Japan. Approach through VATS or thoracotomy with VATS procedure was selected in 843 patients, indicating that the proportion of VATS rose up to 38% during 20 years. The remaining 1387 patients are presumed to experience median sternotomy, indicating that median sternotomy was chosen in 62% of operations of thymic epithelial tumors. In thymoma, median sternotomy was chosen in 1139 (60%) out of 1904 cases. On the other hand, in thymic carcinoma or neuroendocrine tumors, median sternotomy was chosen in 248 (76%) out of 326 cases, suggesting that invasive or aggressive tumors are resected using median sternotomy.

      Japanese Association for Research of the Thymus (JART) conducted Japanese nation-wide database study in 2013, and collected the clinical data of 2835 patients undergoing surgical treatment between 1991 and 2010. Because VATS thymectomy was introduced in the middle 1990’s in Japan, the patients treated from 2001 to 2010 were focused in this review. 1978 cases were treated during those 10 years among the JART database. 1542 patients experienced median sternotomy with or without addition of lateral thoracotomy, indicating that 78% of the entire cases were operated by median sternotomy-based surgery. Lateral thoracotomy was chosen in 92 patients, which corresponds to only 4.7% of the entire cases. The proportion of median sternotomy according to TNM-based pathological stage was 74% in stage I, 87% in stage II, 91% in stage IIIA, and 91% in stage IIIB, suggesting that VATS is likely to be indicated to less invasive tumors. Although a study using JART retrospective database revealed that the long-term outcome of VATS for thymic epithelial tumors is compatible with that by open procedure, recurrence after VATS resection for thymoma larger than 5cm was reported, suggesting limited indication of VATS thymectomy. Thus, further experience of VATS or RATS procedure is required to determine the definitive indication of thoracoscopic approach, and open surgery using median sternotomy has still its role as one of the standard procedures.

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      PC03.06 - Discussion

      16:05 - 16:15

      • Abstract

      Abstract not provided

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      PC03.07 - Adjuvant Chemotherapy for Thymic Carcinoma - YES

      16:15 - 16:25  |  Presenting Author(s): Giulia Pasello

      • Abstract

      Abstract

      The role of postoperative treatment in thymic carcinoma is still a controversial issue, because of the low level evidence supporting clinical management of this cancer, made of cohort studies, retrospective studies and case reports, but no randomized clinical trials. Stage is not the only factor we should consider when the choice of postoperative chemotherapy is discussed; completeness of resection and histologic subtype have their own relevance. Thymic carcinoma accounts for about 20% of all thymic cancers, most cases diagnosed as Masaoka-Koga stage III. In this scenario, about 60% of the cases relapses at 10 years. Time of relapse and sites of disease progression should be carefully reviewed when we consider potential benefit of postoperative systemic treatment; thymic carcinomas relapse earlier and commonly at distant sites compared with thymoma, with significantly different 5 years overall survival and progression free survival. Histology preserves its association with progression free survival as radicality of resection. One reason for the controversies about the prognostic role of histology itself may be found in the difficult diagnosis of the specific subtypes as defined by WHO. Across series a complete Interobserver agreement was reported in 10 to 50% of the cases. Most difficulties seem to be the differential diagnosis among B tumors, and a better agreement was achieved when B2-B3 thymoma were grouped together with carcinoma, suggesting overlapping features among them and supporting evidence that type B3 thymomas and thymic carcinomas form a biologically different group. Complete resection of thymic carcinoma is possible in 60%-70% of the cases, achieving 5-Y and 10Y survival of 60% and 40% respectively. Type of resection and Masaoka stage seem to be correlated with survival and cumulative incidence of recurrences. However, a prognostic role of adjuvant treatment, particularly radiotherapy, is shown with possible effect not only in overall survival but also in relapse free survival. On the basis of the available data, it would be tempting to suggest a possible role for chemotherapy in R1-R2, independently by stage, preferably associated with radiation. On the other hand guidelines suggest a role for adjuvant chemotherapt in resectable thymic carcinoma R1 and, in R0 cases, in stage III or in those cases become resectable after induction chemo, independently by stage e type of resection, especially if not received before. The upcoming IASLC/ITMIG staging system, which re-defines Masaoka-Koga stage III downstaging some situations to stage I and II (as mediastinal pleural or pericardial involvement) could potentially influence adjuvant chemo in stage III thymic cancer. Stage III will be distinguished into T3, potentially resectable upfront, and T4, which might need induction chemo. Adjuvant chemoregimens may be chosen on the basis of drugs combinations effective in the palliative setting; platinum-based doublet plus etoposide or taxanes, or multiple drug regimens including anthracycles are the most used, no data favoring one regimen over the others. Response rates among 60 to 100% in main phase II trials are reported, with primary chemotherapy alone or plus concomitant radiotherapy, in all thymic malignancies. Higher response rates with anthracycles in thymoma and cisplatin in thymic carcinoma are suggested by literature evidence.

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      PC03.08 - Adjuvant Chemotherapy for Thymic Carcinoma - NO

      16:25 - 16:35  |  Presenting Author(s): Sukhmani Kaur Padda

      • Abstract

      Abstract

      Thymic carcinoma is a more aggressive neoplasm than its more common counterpart thymoma, with a higher cumulative incidence of recurrence and worse overall survival when matched by stage and complete resection status.1 Large retrospective database studies provide support for adjuvant radiation for completely resected thymic carcinoma. Therefore, the Thymic Carcinoma Working Group of the International Thymic Malignancy Interest Group (ITMIG) has recommended adjuvant radiation for completely resected Masaoka stage II and III thymic carcinoma.2 In a recent survey of thymic carcinoma management patterns among 100 ITMIG physicians, the role of adjuvant chemotherapy was highlighted as an area of controversy.2 The survey responders provided the following recommendations after completely resected stage II and III thymic carcinoma, respectively: 51% and 14% observation, 25% and 42% adjuvant radiation alone, 13% and 34% adjuvant radiation and chemotherapy, and 11% and 10% adjuvant chemotherapy alone. There is data that neoadjuvant chemotherapy may be useful for locally advanced thymic carcinoma, as it may facilitate surgical resection and improve the chances of a complete resection, a known strong prognostic factor.3 However, data supporting the use of adjuvant chemotherapy for thymic carcinoma is limited and its potential to decrease local recurrence and distant metastases after achievement of a complete resection is controversial.

      In one of the largest known datasets of thymic carcinoma, including 1042 cases pooled from the ITMIG and European Society of Thoracic Surgeons (ESTS) retrospective databases, 764 cases had available chemotherapy information. Sixty-one percent (n=463) of patients received neoadjuvant or adjuvant chemotherapy, with 22% receiving chemotherapy in the neoadjuvant setting, 31% in the adjuvant setting, and 8% in both the neoadjuvant and adjuvant setting.4 Chemotherapy was more frequently given to patients with Masaoka stage III-IV disease. The most common adjuvant treatment strategies included adjuvant chemotherapy and radiation (26%) and adjuvant radiation alone (22%), although 10% of patients received both neoadjuvant chemotherapy and adjuvant radiation. In a univariate analysis, chemotherapy was associated with an improved overall survival but was not associated with recurrence-free survival. Because of the limited sample size, it was unclear which multimodality treatment strategy improved overall survival such as delivery of chemotherapy in the neoadjuvant or adjuvant setting. However, chemotherapy was not a significant factor for clinical outcomes in a multivariate analysis.

      There are other smaller database studies investigating adjuvant chemotherapy for thymic carcinoma. Due to both the retrospective nature of the studies and small sample sizes, it is difficult to evaluate the independent impact of adjuvant chemotherapy on clinical outcomes, as chemotherapy was often given in conjunction with radiation. Across these studies, there is no clear indication of benefit of adjuvant chemotherapy for resected thymic carcinoma. In the Japanese Association for Research on the Thymus (JART) database report on 155 patients with stage II and III thymic carcinoma, adjuvant chemotherapy was not a significant factor for relapse-free survival in a multivariate model that also included adjuvant radiation, stage, and resection status.5 In the Chinese Alliance for Research of Thymoma Database (ChART) report on 329 patients with thymic carcinoma, there was no difference in overall survival between patients who received adjuvant chemotherapy and those who did not in the overall cohort and in Masaoka-Koga stage subsets and resection status categories.6 However, of the 148 patients who received adjuvant chemotherapy, 127 received sequential chemotherapy and radiation. In a study from the National Cancer Database, there were 468 patients with thymic carcinoma who underwent surgery alone and 557 who underwent surgery and adjuvant radiation, with 28% and 56% also receiving adjuvant chemotherapy, respectively.7 Chemotherapy was not associated with overall survival in both univariate and multivariate analyses. Finally, in a meta-analysis of 973 patients with thymic carcinoma, the rate of adjuvant chemotherapy was 21.2-61.5% among those who received adjuvant radiation and 6.7-50% among those who did not, with four of the studies demonstrating no significant association between adjuvant chemotherapy and survival in both univariate and multivariate analyses.8

      Several retrospective database studies have shown no clear benefit of adjuvant chemotherapy for patients with resected thymic carcinoma, although these datasets have their limitations. Many additional questions remain about adjuvant chemotherapy including the indications for recommending adjuvant chemotherapy; the details of the chemotherapy such as the regimen and number of cycles; and the timing of initiation of chemotherapy after surgery and how it should be integrated with perioperative radiation. In summary, there is lack of data to support the routine use of adjuvant chemotherapy after complete resection of thymic carcinoma and further study is required.

      References:

      1. Detterbeck FC, Stratton K, Giroux D, et al. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014;9:S65-72.

      2. Shepherd A, Riely G, Detterbeck F, et al. Thymic Carcinoma Management Patterns among International Thymic Malignancy Interest Group (ITMIG) Physicians with Consensus from the Thymic Carcinoma Working Group. J Thorac Oncol 2017;12:745-751.

      3. Hamaji M, Ali SO, Burt BM. A meta-analysis of induction therapy for advanced thymic epithelial tumors. Ann Thorac Surg 2015;99:1848-1856.

      4. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg 2015;149:95-100, 101 e101-102.

      5. Omasa M, Date H, Sozu T, et al. Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study. Cancer 2015;121:1008-1016.

      6. Fu H, Gu ZT, Fang WT, et al. Long-Term Survival After Surgical Treatment of Thymic Carcinoma: A Retrospective Analysis from the Chinese Alliance for Research of Thymoma Database. Ann Surg Oncol 2016;23:619-625.

      7. Jackson MW, Palma DA, Camidge DR, et al. The Impact of Postoperative Radiotherapy for Thymoma and Thymic Carcinoma. J Thorac Oncol 2017;12:734-744.

      8. Hamaji M, Shah RM, Ali SO, et al. A Meta-Analysis of Postoperative Radiotherapy for Thymic Carcinoma. Ann Thorac Surg 2017;103:1668-1675.

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      PC03.09 - Discussion

      16:35 - 16:45

      • Abstract

      Abstract not provided

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    PC04 - Targeted Therapy for NSCLC

    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Moderators:
    • +

      PC04.01 - Optimal Sequencing of EGFR TKI Therapy (Gefitinib/Erlotinib/Afatinib First versus Osimertinib First)

      15:15 - 15:27  |  Presenting Author(s): James Chih-Hsin Yang

      • Abstract

      Abstract

      Patients with advanced non-small cell lung cancer harboring epidermal growth factor receptor(EGFR) mutations should be treated with EGFR tyrosine kinase inhibitor as first line treatment based on several large randomized phase III studies comparing first/second generation EGFR TKI vs. chemotherapy. The standard of care of using gefitinb/erlotinib/afatinib as first line treatment has been challenged recently from a few progress made from recent reports. First challenge is the selection of first generation gefitnib/erlotinib versus second generation afatinib or recent reported dacomitinib as first line treatment. Two randomized studies comparing afatinib versus gefitinib (Lux-Lung-7) or dacomitinib versus gefitinib (ARCHER1050) demonstrate progression survival improvement for 2nd generation EGFR TKI versus 1st generation EGFR TKI in patients with common EGFR mutations. In addition ARCHER1050 showed a statistical difference in overall survival (OS) for dacomitinib. The advantage of 2nd generation EGFR TKI as first line treatment are the coverage of HER2 inhibition, and probably deeper response due to irreversible inhibition of EGFR pathways. The higher duration of response should be balanced with higher side effect due to potent wild type EGFR inhibition in normal cells that caused severe side effects. The second improvement of first line therapy was shown in two Japanese studies randomizing erlotinib versus erlotinib and bevacizumab. Bevacizumab seemed to improve PFS substantially in both phase II and phase III studies. However, OS difference has not been observed, for reason not clearly understood. A 3rd approach using first generation EGFR TKI upfront was the success of combination of gefitinib and pemetrexed and carboplatin over gefitinib in a Japanese study resulted in PFS and OS improvement. These three approach need to be further studied for universal application. However, the PFS of these three approach seemed to be close or higher than first line osimertinib (approximately 19 months) achieved by the phase III randomized study FLAURA or phase II AURA expansion cohorts. Since the salvage strategy of osimertinib failure is still under intensive investigation due to heterogeneous resistance that can be caused by osimertinib prolonged use, the use of osimertinib as first line treatment should be considered only as an option rather than standard, pending the above mentioned PFS and OS improvement in these novel strategies to be compared to osimertinib in the future (if there will be studies). In conclusion, we had made substantial advanced for the treatment of EGFR mutation positive NSCLC patients. Yet the best sequence of treatment should be further studied since long term control close to cure is always our ultimate goal for treatment of these patients.

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      PC04.02 - Optimal Sequencing of EGFR TKI Therapy - 3rd Generation First

      15:27 - 15:39  |  Presenting Author(s): Karen L. Reckamp

      • Abstract

      Abstract

      Lung cancer is a heterogeneous genomic disease defined by molecular pathways that mediate oncogenesis which are often driven by genetic alterations and targeted therapies are available to modulate these pathways and improve patient outcomes.1 Non-small cell lung cancer (NSCLC) has been at the forefront of expanding knowledge of genomic alterations to inform therapeutic options that improve cancer patient outcomes. Signaling through the epidermal growth factor receptor (EGFR) can modulate multiple intracellualar pathways, including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-AKT, and signal transducer and activator of transcription proteins (STATs). Activating mutations in the epidermal growth factor receptor (EGFR) gene have been associated with improved progression free survival when patients are treated with EGFR tyrosine kinase inhibitor (TKI) therapy.1 Progress has been made in identifying these mutations and providing targeted therapy to improve outcomes for patients. Despite these advancements, tumors develop resistance and patients still succumb to the lung cancer, so overcoming the resistance became a priority. With the identification of third-generation EGFR TKIs, such as osimertinib,2 clinical benefit was maintained after tumor progression on first-generation EGFR TKIs, and questions regarding the optimal sequencing of EGFR TKIs emerged.

      Mutations in the TK domain of the EGFR gene demonstrate increase sensitivity to EGFR TKI in NSCLC.3,4 Gefitinib was the first EGFR TKI to demonstrate PFS benefit over chemotherapy as front line treatment of patients with EGFR mutant NSCLC.1 This was the first study to definitively identify mutation status as an important predictive marker for EGFR-TKI therapy and support molecular selection for patients with metastatic NSCLC. Multiple subsequent trials with gefitinib, erlotinib and afatinib confirmed enhanced PFS for front line EGFR TKI therapy.

      Developing appropriate therapies for EGFR-TKI-resistant disease requires a detailed understanding of mechanisms of resistance. Secondary mutations have been described that may arise that render initially sensitive tumors that harbor EGFR mutations, resistant to EGFR therapy. Multiple mechanisms of resistance have been identified, but approximately 50-60% of EGFR mutant NSCLC develops a T790M resistance mutation.5-7 Osimertinib was developed to overcome T790M resistance and block mutant EGFR while sparing wild type EGFR. Treatment following the development of T790M resistance led to improved objective response rates (ORR) and PFS for patients with EGFR mutant NSCLC.8 Early evidence suggested that osimertinib could be effective as first-line treatment,9 and had the potential benefit to prevent the most common cause of resistance. In the phase III FLAURA trial, 556 patients were randomized to osimertinib or standard, first generation EGFR TKI (erlotinib or gefitinib).10 The primary endpoint was progression free survival (PFS), and demonstrated an improvement for osimertinib at 18.9 months (95% CI, 15.2-21.4) compared to standard EGFR TKI at 10.2 months (95% CI, 9.6-11.1) with a hazard ratio (HR) 0.45 (95% CI, 0.37-0.57) and p< 0.001. The PFS for patients with central nervous system metastases remained higher for osimertinib at 15.2 months (95% CI, 12.1-21.4) compared to standard EGFR TKI at 9.6 months (95% CI, 7.0-12.4) with a hazard ratio (HR) 0.47 (95% CI, 0.30-0.74) and p< 0.001. The improvement of PFS in patients with brain metastases augments the clinical benefit to patients who may avoid or defer radiation treatments to the brain. Overall survival (OS) was immature with a trend toward improvement with osimertinib. ORR was similar in both arms, 80% (95% CI, 75-85) for osimertinib and 76% (95% CI, 70-81) for standard EGFR TKI therapy (95% CI, 70-81). These results have led to the US Food and Drug Administration approval of osimertinib as front line therapy for patients with advanced EGFR mutant NSCLC. Providing a drug with less toxicity and increased efficacy as a first-line option improves quality of life and outcomes for patients. New mechanisms of resistance will develop and must be overcome, but third-generation EGFR TKI therapy is now the new standard of care for front line therapy in metastatic EGFR mutation positive NSCLC.

      References

      1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.

      2. Wakelee HA, Gettinger S, Engelman J, et al. A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Cancer chemotherapy and pharmacology 2017;79:923-32.

      3. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39.

      4. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.

      5. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7.

      6. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine 2011;3:75ra26.

      7. Ohashi K, Sequist LV, Arcila ME, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A 2012;109:E2127-33.

      8. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99.

      9. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36:841-9.

      10. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.

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      PC04.03 - Adjuvant Targeted Therapy for pts with Genomic Alterations - Yes

      15:39 - 15:51  |  Presenting Author(s): Shun Lu

      • Abstract

      Abstract

      1. Introduction:

      In recent years, the discovery of targetable gene alterations such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements has revolutionized the therapeutic approach to advanced NSCLC. The outstanding activity shown by EGFR-and ALK- tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients with EGFR mutations or ALK rearrangements, respectively, leads to the logical question of what role these agents may have if used in the adjuvant setting.

      2.Rationale for adjuvant targeted therapy

      At the present time there is no evidence suggesting a worse prognosis for EGFR-mutated NSCLC in early stage disease [1]. Similarly, retrospective studies exploring the impact of ALK rearrangements in early stage NSCLC suggested that ALK status lacks a prognostic role, as no significant difference in DFS was found between ALK-rearranged and ALK-negative patients [2-3]. Nevertheless, EGFR mutations and ALK rearrangements are both highly predictive of response to selected targeted therapy in advanced NSCLC.

      3.Prospective trials

      Prospective trials of an EGFR-TKI as adjuvant treatment

      Author, phase

      Stage, biomarker selection

      No. of pts, design

      Length of exposure to EGFR-TKI

      Primary end-point

      Results for primary end-point

      Goss et al., 3 (NCIC CTG BR.19) [4]

      IB–IIIA, unselected

      503, gefitinib vs. placebo

      2 years

      OS

      HR =1.24, P=0.14

      Kelly et al., 3 (RADIANT) [5]

      IB→IIIA, EGFR + by IHC and/or FISH

      973, erlotinib vs. placebo (2:1)

      2 years

      DFS

      HR =0.90, P=0.324

      Pennel et al., 2 (SELECT) [6]

      IA→IIIA

      100, erlotinib

      2 years

      DFS

      2-year DFS rate =90%

      Li et al., 2, randomized [7]

      IIIA (N2), EGFR mutation

      60, CBDCA/PEM → gefitinib vs. carboplatin/pemetrexed

      6 months

      DFS

      HR =0.37, P=0.014

      Feng et al., 2, randomized [8]

      IB (high risk)*→IIIA, EGFR mutation

      41, platinum-based chemotherapy → icotinib vs. platinum-based chemotherapy

      4–8 months

      DFS

      2-year DFS 90.5% vs. 66.7%, P=0.066

      Wu et al., 3 (CTONG 1104) [9]

      II–IIIA (N1,N2), EGFR mutation

      222, gefitinib ×2 years vs. cisplatin/vinorelbine

      2 years

      DFS

      28.7 vs. 18.0 months, HR =0.60, P=0.05

      EVAN

      IIIA (N2), EGFR mutation

      222, erlotinib ×2 years vs. cisplatin/vinorelbine

      2 years

      2 years -DFSR

      81.35% vs. 44.62%, P<0.001

      Ongoing randomized phase 3 trials of an EGFR-TKI as adjuvant treatment for patients with EGFR mutant NSCLC

      Clinical trial

      Region

      Stage, planned accrual, EGFR mutation

      Study design

      Primary end-point

      NCT02125240 (ICWIP)

      China

      II→IIIA, 300, ex19del and L858R

      Rand. to icotinib ×2 years vs. placebo ×2 years (platinum-based chemotherapy ×4 cycles)

      DFS

      NCT01996098 (ICTAN)

      China

      II→IIIA, 477, ex19del and L858R

      Rand. to icotinib ×12 months vs. icotinib ×6 months vs. observation (platinum-based chemotherapy ×4 cycles)

      DFS

      NCT02193282 (ALCHEMIST)

      U.S.

      IB (≥4 cm)-IIIA, 450, ex19del and L858R without T790M

      Rand. to erlotinib ×2 years vs. placebo ×2 years (after standard adjuvant chemotherapy)

      OS

      NCT02201992 (ALCHEMIST)

      U.S.

      IB (≥4 cm)-IIIA, 378, ALK-positive

      Rand. to crizotinib ×2 years vs. placebo for 2 years (after standard adjuvant chemotherapy)

      OS

      WJOG6401L

      Japan

      II→IIIA, 230, ex19del and L858R without T790M

      Rand. to gefitinib ×2 years vs. cisplatin/vinorelbine ×4 cycles

      5-year DFS

      NCT02448797 (EVIDENCE)

      China

      II→IIIA, 320, ex19del and L858R

      Rand. to icotinib ×2 years vs. cisplatin/vinorelbine ×4 cycles

      DFS

      NCT02518802

      China

      II→IIIA (N1, N2), 220, ex19del and L858R

      Rand. to cisplatin/pemetrexed ×4 cycles + gefitinib ×2 years vs. cisplatin/pemetrexed ×4 cycles

      DFS

      NCT01996098 (ICTAN)

      China

      II→IIIA, 477, ex19del and L858R

      Rand. to icotinib ×12 months vs. icotinib ×6 months vs. observation (platinum-based chemotherapy ×4 cycles)

      DFS

      NCT02511106 (ADAURA)

      International

      IB→IIIA, 700, ex19del and L858R ± other EGFR mutation

      Rand. to osimertinib ×2 years vs. placebo ×2 years (standard adjuvant chemotherapy allowed)

      DFS

      4.Conclusions and future directions

      A critical issue is how to select the patients who may need adjuvant targeted therapy. Measurement of residual disease by circulating tumor cells and/or DNA could help identify the high-risk population. However, for these patients it should be clarified whether targeted therapy should be used sequentially after platinum-based chemotherapy or as stand-alone treatment; therefore, better understanding of the biology at recurrence and novel testing strategies for residual disease are crucial in order to help select those patients who could benefit the most from adjuvant targeted therapy.

      5.Reference:

      (1)Liang W, He Q, Wang W, et al. The impact of EGFR mutations on the prognosis of resected non-small cell lung cancer: a meta-analysis of literature. Ann Oncol 2017;28:abstr ii20-3.

      (2)Paik JH, Choi CM, Kim H, et al. Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma. Lung Cancer 2012;76:403-9.

      (3)Pan Y, Zhang Y, Li Y, et al. ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: a comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features. Lung Cancer 2014;84:121-6.

      (4)Goss GD, O'Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol 2013;31:3320-6.

      (5)Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-14.

      (6)Pennell NA, Neal JW, Chaft JE, et al. SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. J Clin Oncol 2014;32:abstr 7514.

      (7)Li N, Ou W, Ye X, et al. Pemetrexed-carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA-N2 non-small cell lung cancer harbouring EGFR mutations: a randomized, phase II study. Ann Surg Oncol 2014;21:2091-6.

      (8)Feng S, Wang Y, Cai K, et al. Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy. PLoS One 2015;10:e0140794.

      (9)Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148.

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      PC04.04 - Adjuvant Targeted Therapy for pts with Genomic Alterations - No

      15:51 - 16:03  |  Presenting Author(s): Lecia Sequist

      • Abstract

      Abstract not provided

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      PC04.05 - NGS/Whole Exome Sequencing for Routine Use

      16:03 - 16:15  |  Presenting Author(s): Daniel S.W. Tan

      • Abstract

      Abstract not provided

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      PC04.06 - Focused Panels for Molecular Profiling for Routine Use

      16:15 - 16:27  |  Presenting Author(s): Fernando Lopez-Rios

      • Abstract

      Abstract not provided

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      PC04.07 - Q&A

      16:27 - 16:45

      • Abstract

      Abstract not provided