Scientific Program

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    LA01 - IASLC Lectureship Award Session

    • Type: Lectureship Award Session
    • Track:
    • Moderators:
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      LA01.01 - Clifton F. Mountain Lectureship Award for Staging - Is There Still a Stage for Improvements in Staging?

      13:30 - 13:40  |  Presenting Author(s): Johan F. Vansteenkiste

      • Abstract

      Abstract not provided

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      LA01.02 - IASLC Lectureship Award for Radiation Oncology - Defining the Role of Radiotherapy for Lung Cancer: Past, Present and Future

      13:40 - 13:50  |  Presenting Author(s): Hak Choy

      • Abstract

      Abstract not provided

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      LA01.03 - Heine H. Hansen Lectureship Award for Small Cell Lung Cancer - New Opportunities in Small Cell Lung Cancer

      13:50 - 14:00  |  Presenting Author(s): Charles M. Rudin

      • Abstract

      Abstract not provided

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      LA01.04 - Adi F. Gazdar Lectureship Award for Translational Research - Genomic Alterations in Human Lung Cancers

      14:00 - 14:10  |  Presenting Author(s): Matthew Meyerson

      • Abstract

      Abstract not provided

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      LA01.05 - Tsuguo Naruke Lectureship Award for Surgery - The Value of Naruke Lymph Node Chart and the Creation of IASLC Chart in Lung Cancer

      14:10 - 14:20  |  Presenting Author(s): Hisao Asamura

      • Abstract

      Abstract not provided

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      LA01.06 - Daniel C. Ihde Lectureship Award for Medical Oncology - The Intersection of Science and Medicine

      14:20 - 14:30  |  Presenting Author(s): David P Carbone

      • Abstract

      Abstract not provided

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      LA01.07 - Robert J. Ginsberg Lectureship Award for Surgery - Honoring the Tradition of Surgically-Based Clinical Trials

      14:30 - 14:40  |  Presenting Author(s): Valerie W Rusch

      • Abstract

      Abstract not provided

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      LA01.08 - IASLC Lectureship Award for Nursing and Allied Health Professionals - The Right Hand: The Art of Collaboration

      14:40 - 14:50  |  Presenting Author(s): Kimberly Ann Rohan

      • Abstract

      Abstract not provided

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      LA01.09 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

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    MA25 - Oligometastasis: Defining, Treating, and Evaluating

    • Type: Mini Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Moderators:
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      MA25.01 - EORTC Lung Cancer Group Survey to Define Synchronous Oligometastatic Disease in NSCLC

      13:30 - 13:35  |  Presenting Author(s): Lizza Hendriks  |  Author(s): Antonin Levy, Thierry Berghmans, Corinne Faivre-Finn, Matteo Giaj Levra, Niccolo Giaj-Levra, Baktiar Hasan, Nicolas Girard, Laurent Greillier, Sylvie Lantuejoul, John G Edwards, Mary O’brien, Martin Reck, Benjamin Besse, Silvia Novello, Anne-Marie C. Dingemans

      • Abstract

      Background

      Synchronous oligometastasic disease (sOMD) has been described as a separate disease entity; however there is no consensus on what specific criteria constitutes sOMD in NSCLC. A consensus group (CG) was formed aiming to agree on a common sOMD definition (sOMD-d) that could be used in future clinical trials. A European survey was circulated to inform the discussion on sOMD-d.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      An EORTC Lung Cancer Group (LCG) / sOMD-d CG survey containing 31 questions on sOMD-d was distributed between 14/12/17 and 19/02/18 to EORTC LCG, sOMD-d CG, and several European thoracic oncology societies’ members.

      4c3880bb027f159e801041b1021e88e8 Result

      444 responses were analyzed (radiation oncologist: 55% [n=242], pulmonologist: 15% [n=66], medical oncologist: 14% [n=64]; 78% with >5 years’ experience in treating NSCLC). Belgium (14%, n=62), Italy (12%, n=55), Germany (11%, n=47), and Netherlands (10%, n=44) contributed most. 81% (n=361) physicians aimed to cure sOMD NSCLC patients and 82% (n=361) included the possibility to treat the patient with radical intent in their sOMD-d. The maximum number of metastases considered in sOMD-d varied: 19%, 42%, 4%, and 17% replied <2, 3, 4, and >5 metastases, respectively. 79% (n=353) stated that the number of organs involved was important for sOMD-d, and most (80%, n=355) considered that only <3 involved organs (excluding primary) should be included in the definition. 317 (71.7%) allowed mediastinal lymph node involvement (MLN) in the sOMD-d, and 22.1% of them counted MLN as a metastatic site. For 195/327 (60%), when N2/N3 disease is included in the sOMD-d, there is no specific issue regarding the MLN volume/location as long as radical treatment is possible. 384 (86%) considered pulmonary metastasis (outside primary tumor: M1a) as metastatic site. Most physicians confirmed sOMD patients with brain MRI (91%, n=403) and PET-CT (98%, n=437). For mediastinum staging, most (64%, n=285) respondents stated that histology/cytology should be obtained when PET-CT shows suspected lymph nodes or in case of a central primary tumor. Pathology proof of metastatic disease was necessary in sOMD for 315 (71%) physicians, and 37% (n=163) acknowledged that histology should be obtained from at least from one metastatic site. Preferred primary outcome parameter in clinical trials of sOMD was overall survival (73%, n=325).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although certain consensual answers were obtained (81% aimed to cure and >90% mandated baseline imaging with PET-CT and brain MRI), a number of issues remain unresolved and will require further discussion by a panel of experts to agree on a sOMD-d.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.03 - Defining Oligometastatic Non-Small Cell Lung Cancer (NSCLC): An Evolving Multidisciplinary Expert Opinion

      13:35 - 13:40  |  Presenting Author(s): Lizza Hendriks  |  Author(s): Christophe A. Dooms, Thierry Berghmans, Silvia Novello, Antonin Levy, Dirk De Ruysscher, Baktiar Hasan, Matteo Giaj Levra, Niccolo Giaj-Levra, Benjamin Besse, Johan F. Vansteenkiste, Anne-Marie C. Dingemans

      • Abstract

      Background

      Synchronous oligometastatic NSCLC definition varies between: 1 metastasis in 1 organ (TNM8), 1-3 metastases (ESMO), ≤3 metastases after systemic treatment with mediastinal nodes (MLN) counting as 1 site (Gomez, Lancet Oncol 2016) to 3-≥5 metastases in ongoing trials. A single definition is however needed to design and compare trials. To assess synchronous oligometastatic NSCLC definitions used by clinical experts in daily practice and its evolution, we redistributed a 2012-case based survey (Dooms et al, presented at WCLC 2013).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In December 2017, 10 real-life multidisciplinary team (MDT) discussed patients (all good condition, no significant comorbidities, 18FFDG-PET and brain MRI staged, all < 5 metastases, 9/10 ≤ 3 metastases, oncogene-addicted or wildtype NSCLC) were distributed to 33 international NSCLC experts involved in the EORTC oligometastatic NSCLC consensus group, questioning: 1) can you discuss these cases in your MDT?, 2) do these patients have oligometastatic disease? and 3) what is your treatment proposal for the oligometastatic disease patients? Current answers were compared to the previous ones, and the real-life treatment and survival of the patients was added.

      4c3880bb027f159e801041b1021e88e8 Result

      26/33 experts (24 centers) replied: 8 medical oncologists, 7 pulmonologists, 7 radiation oncologists, 4 thoracic surgeons. 62% discussed the cases in their MDT. 1 case had 100% oligometastatic disease consensus, 3 cases had > 90% consensus, the number of treatment proposals varied between 3 to 8 (Table). Radical treatment was more often offered in case of a single metastasis or N0 status. Compared to 2012 there was a trend towards a more conservative oligometastatic definition and chemotherapy was more often included in the treatment proposal.

      table 1
      Case TNM8

      oligometastatic

      yes answer %

      2012 / 2017

      Number of tx

      proposals

      2012 / 2017

      Radical tx

      answers %

      2012/2017

      Real life radical

      tx intent

      real life survival

      (months) /

      5Y survival

      EGFR+ T2aN3M1c (3 brain mets) 55 / 38 2 / 5 27 / 23 - 40.1 / -
      EGFR+ T4N0M1a (ground glass) 36 / 35 4 / 3 45 / 35 + 65.2 / +
      T2aN1M1b (solitary renal) 91 / 96 5 / 5 100 / 92 + 8.3 / -
      T1bN3M1b (solitary adrenal) 73 / 58 4 / 5 36 / 54 + 66.1 / +
      T2bN1M1c (adrenal + pelvic node) 55 / 50 2 / 5 36 / 46 - 18.6 / -
      T2aN0M1c (3 liver mets) 64 / 69 4/ 5 27 / 62 - 51.5 / -
      T2aN2M1b (solitary bone) 91 / 92 4 / 5 73 / 85 + 13.4 / -
      T3N1M1c (2 brain mets) 91 / 96 3 / 8 73 / 85 + 39.6 / -
      T2aN0M1c (1 lung, 1 pancreas) 82 / 69 5 / 4 64 / 50 + 74.0 / +
      T1bN0M1b (solitary bone) 100 / 100 3 / 5 82 / 92 + 11.6 / -

      8eea62084ca7e541d918e823422bd82e Conclusion

      Synchronous oligometastatic NSCLC definition was more conservative than in 2012 and linked to radical intent of treatment. Number of organs, MLN status and possibility for radical treatment seem to be components of daily practice synchronous oligometastatic definition.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      Recent prospective single centre studies reported improved outcomes in patients with sOMD-NSCLC who were treated with radical intent. Since then sOMD has been perceived as a separate disease entity. However, a clear definition of sOMD-NSCLC is lacking. We aimed to develop a definition and diagnostic criteria of sOMD-NSCLC following a consensus process.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A European multidisciplinary consensus group was established with representatives from different scientific societies. Consensus questions were extracted from a survey, case series and a systematic review. The questions were discussed, and the statement formulated during a consensus meeting in Dublin (23.01.18).

      4c3880bb027f159e801041b1021e88e8 Result

      Summary of consensus statement

      Defining sOMD-NSCLC

      Definition of sOMD is relevant for patients in whom a radical treatment is technically feasible with acceptable toxicity, taking into account all sites, that may modify the course of the disease leading to a long-term disease control.

      All sites must be technically and safely treatable.

      The maximum number of metastases/organs meeting the criteria involved will depend on the possibility of offering a treatment strategy with radical intent, taking into account local control and toxicity. Based on the systematic review, a maximum of 5 metastases and 3 organs is proposed.

      Diffuse serosal metastases and bone marrow involvement are excluded.

      Mediastinal lymph node (MLN) involvement should be considered as locoregional disease in the definition of sOMD-NSCLC.

      MLN involvement is of importance in determining if a radical local treatment of the primary tumour may be applied and the MLN will not be counted as a metastatic site.

      Staging of sOMD-NSCLC

      PET-CT and brain imaging are considered mandatory.

      In case of a solitary liver metastasis a dedicated MRI of the liver and for a solitary pleural metastasis, thoracoscopy and biopsies of distant ipsilateral pleural sites are advised.

      Staging of the mediastinum requires a minimum of a FDG-PET scan, with pathological confirmation preferred if this influences the treatment strategy.

      Pathological proof is required unless the MDT decides that the risk outweighs the benefit. Pathology proof is advised for single metastatic location and if it may change the therapeutic strategy, confirmation of the MLN involvement is recommended.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A multidisciplinary consensus statement on the definition and staging of sOMD-NSCLC was formulated taking into account results of a European survey, a systematic review and case discussion. This statement might be helpful to standardise inclusion criteria in future clinical trials. However, the definition of sOMD may change over time when more prospective data will become available.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.04 - Discussant - MA 25.01, MA 25.02, MA 25.03

      13:45 - 14:00  |  Presenting Author(s): Abraham J. Wu

      • Abstract

      Abstract not provided

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      MA25.05 - Characteristics &amp; Survival of Resected Stage IV Non-Small Cell Lung Cancer (NSCLC) in the Mid-South Quality of Surgical Resection Cohort

      14:00 - 14:05  |  Presenting Author(s): Nicholas R. Faris  |  Author(s): Yu-Sheng Lee, Matthew P Smeltzer, Meredith A Ray, Carrie L Fehnel, Cheryl Houston-Harris, Olawale Akinbobola, Philip Ojeabulu, Edward Owen, Richard Eubanks, Hector Dox, David Talton, Ganpat Valaulikar, Horace Lynn Wiggins, Bradley Wolf, Paul Steven Levy, Edward Todd Robbins, Raymond U. Osarogiagbon

      • Abstract

      Background

      Surgical resection is potentially curative in subsets of oligometastatic NSCLC. We evaluated the characteristics and survival of resected stage IV NSCLC in a population-based cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were included who had curative-intent resections from 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions in the mid-Southern USA from 2009-2018. Statistical analyses were performed using univariate and multiple Cox regression models.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 3092 resections, 96 (3.1%) were stage IV: 38 M1a, 54 M1b, and 4 M1c. Of the M1a patients, 1 had a pleural effusion, 37 had a contralateral lung nodule. The most common sites of extrathoracic metastasis were bone (13 (13.5%)), and brain (25 (26%)). Other extrathoracic sites were distant lymph nodes, liver, adrenals, thyroid, pancreas, colon, soft tissue, and esophagus.

      Stage IV patients had a younger median age (63 vs 67 (p<0.0001)), less Medicare coverage but more Medicaid or Commercial insurance (p=0.0248), fewer comorbid conditions (p=0.0096), higher cT (p<0.0001), and higher-grade tumors (p=0.0002).

      58% (22) of M1a patients did not receive treatment to the site of metastatic disease, compared to 72% (39) and 75% (3) of M1b and M1c, respectively (p=0.0086).

      For patients with bone metastases, median/5 year survival was 1.28 years/0%, compared to 5.16 years/51% for all other metastatic sites and 6.39 years/56% for non-stage IV NSCLC (p=0.0058) (Figure 1). In fully adjusted models, survival for Stage IV patients without bone metastasis did not differ significantly from Stage I-III patients (HR: 1.3, p=0.15). However, Stage IV patients with bone metastasis had significantly worse survival (HR:3.2, p=0.0006).

      image001.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Bone metastasis connotes a very poor prognosis in patients with oligometastatic NSCLC, but survival of patients with other sites of metastasis was remarkably good in this highly selected group of patients from a population-based multi-institutional cohort.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.06 - RPA Analysis for Oligometastatic Non-Small Cell Lung Cancer: Smoking Combine T3/4 Patients May Not Be Benefit from Local Consolidative Treatment

      14:05 - 14:10  |  Presenting Author(s): Jia-Tao Zhang  |  Author(s): Yi-Chun Tang, Si-Yang Liu, Song Dong, Xue-Ning Yang, Yi-Long Wu, Wen-Zhao Zhong

      • Abstract

      Background

      In the literature on oligometastasis, the relative importance of local consolidative treatment (LCT) has been gradually accepted. This study set out to investigate the prognosis heterogeneity and the effect of LCT for oligometastatic non-small cell lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified 436 patients in Guangdong General Hospital (GGH) from 2009 to 2016 with oligometastatic disease, and the factors predictive of overall survival (OS) were evaluated using Cox regression. Risk stratifications were defined using recursive partitioning analysis (RPA) on training set (2009~2014), which were further confirmed on validation set (2015-2016). And the effect of LCT for different risk groups was further examined by Kaplan-Meier method.

      4c3880bb027f159e801041b1021e88e8 Result

      Factors predictive of OS were: T stage (p=0.001), N stage (p=0.008), metastatic sites (p=0.031) and EGFR status (p=0.043). Prognostic risk RPA model was established, 4 risk groups were identified: Group I, never smokers and N0 disease (3-year OS: 55.6%, median survival time (MST)=42.8m); Group II, never smokers and N+ disease (3-year OS: 32.8%, MST=26.5m); Group III, smokers and T1/T2 disease (3-year OS: 23.3%, MST=19.4m); and Group IV, smokers and T3/T4 disease (3-year OS: 12.5%, MST=11.1m). Among four groups, OS significant differences were observed according to LCT except group IV (p=0.45).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This retrospective study identified the poor prognostic population (smoking combine T3/4 disease) of oligometastatic non-small cell lung cancer patients, and this population may not be benefit from local consolidative therapy.

      fig.png

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.07 - Effectiveness of Systemic Therapy Combined with Thoracic Radiotherapy for Patients with Oligometastatic NSCLC: A Pooled Analysis

      14:10 - 14:15  |  Presenting Author(s): Chunyu Wang  |  Author(s): Jingbo Wang, Xiaotong Lu, Luhua Wang

      • Abstract

      Background

      Local therapy combined with systemic therapy for oligometastases or oligo-recurrence (≤ 5 lesions) in NSCLC has become one of the hottest spots in recent years. At present , there is lack of results from randomised phase III trial in this regard. Therefore, we performed a pooled analysis, aiming to evaluate the effectiveness of the combination of systemic therapy and local thoracic radiotherapy for patients with oligometastatic NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Computerized search of the Pubmed database was performed using the following key words: non-small cell lung cancer, metastasis, stage IV, thoracic radiation. Abstracts were ruled out. In addition, we also reviewed the references listed in the identified articles and included eligible studies for integrity of the literature search. Combination therapeutic modality should include systemic therapy (chemotherapy or targeted therapy) and thoracic radiotherapy. Authors with more than 1 publication involving the same study population were included only once, and the one with most relevant and complete data were included. Literature retrieval was terminated by April 2018. All the analysis was performed in the Stata/SE 12.0.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 32 articles with full text were retrieved in our initial literature search. After reviewing these articles and corresponding references, 16 studies (9 retrospective studies vs. 7 prospective phase II studies) with a total of 791 oligometastatic NSCLC patients were finally identified as eligible for this analysis. The median progression free survival (PFS) ranged from 6.6 to 16.0 months and median overall survival OS ranged from 10.0 to 27.1 months. Four studies involving 256 patients reported the post-radiotherapy response, resulting in a pooled objective response (CR + PR) rate of 58% (95% CI: 0.41, 0.76). A total of 3 studies involving 168 patients provided comparison data on PFS between systemic therapy alone and systemic therapy plus thoracic radiotherapy, leading to a pooled hazard ratio (HR) of 0.42 (95% CI: 0.28, 0.64) for the combined modality group.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Consolidative thoracic radiotherapy in addition to systemic therapy may offer significant outcome benefits for oligometastatic NSCLC, leading to a numerically comparable response and survival to locally advanced NSCLC. Results from phase III randomized controlled trials are awaited.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.08 - Discussant - MA 25.05, MA 25.06, MA 25.07

      14:15 - 14:30  |  Presenting Author(s): Alysa Fairchild

      • Abstract

      Abstract not provided

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      MA25.09 - M1b Disease in the 8th Edition of IASLC Staging of Lung Cancer: Pattern of Single Extrathoracic Metastasis and Clinical Outcom

      14:30 - 14:35  |  Presenting Author(s): Hyesun Park  |  Author(s): Christine A Lydon, Tetsuro Araki, Hiroto Hatabu, Michael Rabin, Bruce E Johnson, Mizuki Nishino

      • Abstract

      Background

      The 8th edition of IASLC staging of lung cancer has revised M classification and defined M1b disease for single extrathoracic metastasis, which is distinguished from M1c with multiple extrathoracic metastases. We investigated the prevalence of M1b disease in stage IV NSCLC patients (pts), and studied the pattern of single extrathoracic metastasis and its relationship with overall survival (OS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      567 pts with stage IV NSCLC (236 males, 331 females, median age: 63) diagnosed in 2008-2012 were reviewed to determine M stage according to the 8th edition of IASLC staging of lung cancer (M1a: separate tumor nodules in a contralateral lobe, pleural/pericardial nodule or effusion; M1b: single extrathoracic metastasis; M1c: multiple extrathoracic metastasis in one or more organs). Clinical characteristics and OS were compared according to M stage.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 567 pts, 57 pts (10%; 95%CI: 7.6-13%) had M1b disease with single extrathoracic metastasis, while 119 pts (21%) had M1a and 391 pts (69%) had M1c disease. Squamous histology was more common in M1b (9/57; 16%) than in M1a (7/119; 6%) and M1c pts (22/391; 6%) (Fisher P=0.03). The median OS of M1b pts was 14.8 months (95%CI: 12.7-24.7 months), compared to 22.7 months (95%CI: 18.5-31.6 months) for M1a and 13.4 months (95%CI: 11.8-15.3 months) for M1c pts (log-rank P < 0.0001). Among 57 M1b pts, brain was the most common site of single metastasis (n=28; 49%), followed by bone (n=16; 28%), adrenal (n=7; 12%), liver (n=3; 5%), muscle (n=2; 4%), and distant node (n=1; 2%). M1b pts with liver metastasis had shorter OS than others (median OS: 8.1 vs. 16.1 months, log-rank P=0.046). Single metastasis in M1b pts were locally treated in 31 pts (54.5%). Brain metastasis was more frequently treated with local treatment than others (26/28, 92.9%vs. 5/29, 17%; p<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      M1b disease was noted in 10% of stage IV NSCLC pts. Squamous histology was more common in M1b than in M1a and M1c groups. Brain was the most common site of single metastasis and was often treated locally. Single liver metastasis in M1b disease was associated with shorter OS. The study characterized the unique clinical features of the new category of M1b disease among stage IV NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.10 - Complete Response by PET-CT After Radical Treatment in Oligometastatic Non-Small Cell Lung Cancer Predicts Longer Survival  

      14:35 - 14:40  |  Presenting Author(s): Oscar Arrieta  |  Author(s): Luis Antonio Cabrera-Miranda, Feliciano Barron, Zyanya Lucia Zatarain-Barrón, Laura-Alejandra Ramírez-Tirado, Miguel Angel Salinas Padilla, Jose Francisco Corona-Cruz, Andrés F. Cardona, Manuel Arguelles, Federico Maldonado, Monica Blake, Edgardo Jiménez-Fuentes, Osvaldo Aren

      • Abstract

      Background

      Evidence is rapidly accumulating for the use of radical treatment approaches for patients with oligometastatic Non-small cell lung cancer (NSCLC). Several limitations remain, however, to further strengthen the use of radical therapy as opposed to standard maintenance therapy, including a lack of robust markers to predict patient response. In this study, we assessed the utility of reaching a complete response (CR) by PET-CT in patients with oligometastatic disease after radical treatment (NCT02805530).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We included patients with stage IV NSCLC who presented with ≤5 synchronous, any-site metastases (oligometastatic disease) as assessed by PET-CT. Patients received 4 initial cycles of systemic treatment. Following, patients were evaluated by PET-CT and those with stable disease and partial response received radical treatment to the primary site and metastases (surgery, radiotherapy, chemotherapy plus radiotherapy, radiofrequency and SBRT alone or in any combination). Response to radical treatment was evaluated by PET-CT. Maintenance treatment was permitted.

      4c3880bb027f159e801041b1021e88e8 Result

      37 patients were included in the analysis. Mean age was 55.7. At diagnosis 43.2% of patients presented with CNS metastases. After 4 cycles of first-line therapy, 100% of patients received treatment to the primary site, while 83.8% also received therapy to metastases. Following radical treatment, 19 (51.4%) patients achieved a CR by PET-CT, while 18 (48.6%) had a partial response (NON-CR). Median PFS was 26.2 months (95%CI 12.2-40.1), and was positively affected by CR by PET-CT (NR vs. 14.3 [95%CI 11.9-16.7]; p<0.001). Median overall survival (OS) was NR. OS was also positively affected by CR by PET-CT (42-month survival: 82.5%±18 for CR vs. 34.4%±28 for NON-CR by PET-CT; p=0.01).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients with oligometastatic NSCLC who undergo radical treatment and reach a CR by PET-CT show a significant improvement in survival outcomes. Our results suggest that CR by PET-CT could serve as a surrogate marker for prolonged survival in this patient sufigure rc petct.pngbgroup.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.11 - Clinical and Molecular Predictors of Outcome in Patients with EGFR mutant NSCLC Brain Metastases treated with RT

      14:40 - 14:45  |  Presenting Author(s): Fabio Y Moraes  |  Author(s): Jessica Weiss, Mor Moskovitz, Hadas Sorotsky, Melania Pintilie, Natasha B Leighl, Penelope Bradbury, Geoffrey Liu, Gelareh Zadeh, Mark K. Doherty, Alborz Kia, Jonathan So, Michael Cabanero, Trevor J. Pugh, Vijithan Sugumar, Dax Torti, Ming Sound Tsao, Jonathon Torchia, David B Shultz, Frances A Shepherd, Benjamin H Lok

      • Abstract

      Background

      Brain metastases(BM) develop in ~45% of patients with EGFR mutant(EGFRm) non-small cell lung cancers(NSCLC). There are limited reports on clinical/molecular factors associated with BM outcomes after radiotherapy in EGFRm NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified patients with EGFRm NSCLC who presented with or developed BM and had their lung tumor resected. Clinical, demographic and TP53 status were collected from medical/pathology records. Whole-Exome Sequencing of the primary tumor was performed. Overall survival(OS) and intracranial progression(IP) were defined from start of BM treatment and correlated with clinical/molecular features. IP was defined from the date of BM treatment until any brain failure, either local(previously present BM) or distant(development of new BM). Categorical and continuous covariates were tested by Fisher exact or Mann-Whitney test, respectively. OS by Kaplan-Meier with groups compared by log-rank. For each model the Harrell Concordance Index(CI) was performed.

      4c3880bb027f159e801041b1021e88e8 Result

      From 41 eligible patients with BM, 9 were excluded due to sequencing quality. Of the 32 remaining patients, 20 (62%) had their BM treated with WBI (15 WBI alone and 5 TKIàWBI), 12 (38%) with TKI±SRS (9 TKI àSRS; 2 TKI alone and 1 SRS alone). Median age at BM was 59.5 years(y). Most of the cohort were female(81%), non-smoker(78%), non-Asian(62%) and 50% presented as stage III or higher at diagnosis. An EGFR exon 19 mutation was present in 72% of patients, 25% had 2 or more EGFRm, 15% with additional driver mutations and 53% with TP53 co-mutation. At a median follow-up of 1.21-y, no clinical/molecular factors(treatment, age, gender, ethnicity, smoking status, stage at presentation, EFGR exon 19 versus 21, number of EGFRm, additional driver mutations, TP53 co-mutation) correlated with survival. There was a trend for longer survival for patients treated with TKI±SRS(median 3.4y) compared to WBRT±TKI(median 1.4y); p=0.08 and for age at BM ≤59.5y(median 2.5y) compared to >59.5y (median 1.4y); p=0.2. Higher risk of IP was observed in younger patients (age as continuous variable) with HR of 0.94(95%CI 0.88-1.0), p=0.04; favoring older patients and remained significant after accounting for treatment modality on multivariate analysis p=0.03. No additional clinical/molecular factors correlated with IP.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our study, younger age at BM treatment was associated with higher IP. We also observed a trend for longer OS for younger patients(≤59.5y) and for patients treated with TKI±SRS. Our data suggest that younger patients with EGFR BM should undergo close intracranial follow up and that future studies to define the benefit of brain-directed multimodality treatment are warranted.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.12 - Discussant - MA 25.09, MA 25.10, MA 25.11

      14:45 - 15:00  |  Presenting Author(s): Michael Macmanus

      • Abstract

      Abstract not provided

  • +

    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1

    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Moderators:
    • +

      MA26.01 - Accumulation of Concomitant Mutations Involved in Drug Resistance in the Sequential ALK TKI Treatments of ALK-Positive NSCLC

      13:30 - 13:35  |  Presenting Author(s): Shun Lu  |  Author(s): Yongfeng Yu, Yan Ding, Xue Wu, Hairong Bao, Yang W. Shao

      • Abstract

      Background

      ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next-generation TKIs, have shown promising clinical outcomes for ALK-positive lung cancer patients. However, distinct resistant-mechanisms have been suggested for different ALK fusion variants in response to various TKIs. The genomic alterations associated with these heterogeneous resistant-mechanisms have not been adequately investigated, especially for patients received sequential ALK TKI treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The distribution of ALK fusion variants in 475 ALK-positive lung cancer patients (cohort I) out of 11842 lung cancer patients (4%) tested by next-generation sequencing were analyzed. In addition, mutation profiles of 416 cancer-relevant genes in the post-ALK TKI treatment tumor samples from 52 non-small cell lung cancer (NSCLC) patients (cohort II) who represent the similar distribution of ALK fusion variants as in cohort I were analyzed. Thirty-five patients received crizotinib treatment only (crizotinib group), whereas the other 17 patients were treated with multiple lines of ALK TKIs (multi-TKI group), including lorlatinib, alectinib, ceritinib and brigatinib.

      4c3880bb027f159e801041b1021e88e8 Result

      EML4-ALK v3 and v1 are the two most common ALK fusion variants in both cohorts. In cohort II, 18 different ALK activating mutations were found in 17 patients (49%) of the crizotinib group and 10 patients (59%) of the multi-TKI group, although with different mutation patterns. In the multi-TKI group, G1202R was the most frequent ALK activating mutation found in 35% of the patients, while L1196M (14%) and G1269A (11%) were more common in the crizotinib cohort. Of note, there was a significant enrichment of concomitant ALK activating mutations in the multi-TKI group (p=0.031), as well as a trend of increased number of patients carrying activation of ALK by-pass/downstream pathways (p=0.056) in this group compared with the crizotinib group, resulting in a significantly higher recurrence of dual activation of ALK and ALK by-pass/downstream pathways in the multi-TKI group (29%) than that in the crizotinib group (6%) (p=0.031). Patients with concomitant TP53 mutation had significantly shorter progression free survival (PFS) compared with TP53 wildtype patients upon crizotinib treatment (median PFS: 8 vs 13 months, HR 1.494, p=0.019) regardless of fusion variant types.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Significantly higher frequency of concomitant mutations, including concomitant ALK activating mutations, and dual activation of ALK and ALK by-pass/downstream pathways, was observed after multiple lines of ALK TKI treatments, indicating the diversity and complexity of resistance-mechanisms in response to next-generation ALK TKIs. Concomitant TP53 mutation might serve as a prognosis biomarker for worse clinical outcomes treated with crizotinib.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected 242 ALK-positive advanced NSCLC diagnosed between 2010 and 2018 in 23 Italian institutions (expanded data collection from Gobbini et al. Lung Cancer 2017). 138 patients received exclusively crizotinib as ALKi (not considered for this analysis). 78 patients received crizotinib and a new (second or third) generation ALKis as further treatments (group A). 26 patients performed a new generation ALKi as upfront agent (group B). These groups are larger than those considered in a previous analysis (15 and 8 patients, respectively).

      4c3880bb027f159e801041b1021e88e8 Result

      Study population clinical features and treatments received are summarized in Table 1.

      Group A

      Crizotinib followed by new generation ALKis

      N= 78

      Group B

      Upfront new generation ALKis

      N=26

      Treatments per line n(%)

      Crizotinib

      28(36)

      50(64)

      -

      -

      -

      -

      2(8)

      -

      Alectinib

      -

      11(14)

      18(23)

      5(17)

      7(27)

      -

      -

      -

      Ceritinib

      -

      9(12)

      23(30)

      3(4)

      8(31)

      8(31)

      1(4)

      -

      Brigatinib

      -

      6(8)

      6(8)

      2(3)

      -

      2(8)

      -

      2(8)

      Lorlatinib

      -

      -

      4(5)

      5(6)

      -

      -

      1(4)

      -

      Chemotherapy

      50(64)

      2(3)

      10(13)

      na

      11(42)

      6(23)

      1(4)

      Na

      Clinical features n(%)

      Age (range)

      58 (27-83)

      55 (24-82)

      Male

      37(47)

      10(38)

      p= 0.42

      Female

      41(53)

      16(62)

      Current smoker

      8(10)

      5(19)

      p= 0.23

      Never/former smoker

      70(90)

      21(81)

      ALKi beyond PD

      27(34)

      4(15)

      p= 0.06

      With a median follow-up of 22.6 months (CI 95% 20.09-25.10), 33 patients had died (32%). In group B, the median progression free survival (PFS) for new generation ALKis administered as first (14.0 months, CI 95% 9.52-18.471), second (12.7 months, CI95% 7.22-18.17) or third-line (12.8 months, CI95% 6.24-19.35) was not statistically different (p= 0.522). The median time from the start of crizotinib to the disease progression after the new generation ALKi sequentially performed (group A) was longer than that one detected in group B for the upfront new generation ALKis (29 vs 14 months, HR 2.47 [CI95% 1.35-4.50], p=0.003). This result was confirmed even considering the time lost between the two treatments in group A. The median overall survival (OS) was not reached. The 12-months OS rate was 97% in group A and 84% in group B.

      8eea62084ca7e541d918e823422bd82e Conclusion

      New generation ALKis maintain their efficacy regardless of the treatment setting considered. The sequential strategy seems to provide a substantial benefit, but a longer follow-up and larger samples are needed to clarify the survival impact.

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      MA26.03 - Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement

      13:40 - 13:45  |  Presenting Author(s): Zofia Piotrowska  |  Author(s): H Isozaki, JK Lennerz, Subba Digumarthy, Justin F Gainor, Nicolas Marcoux, M Banwait, D Dias-Santagata, A. John Iafrate, Mari Mino-Kenudson, Rebecca J Nagy, Richard B Lanman, E Evans, C Clifford, B Wolf, AN Hata, Lecia Sequist

      • Abstract

      Background
      The spectrum of acquired resistance (AR) to osimertinib is not yet fully characterized. We present a single-center cohort of osimertinib AR biopsies and results of a patient with RET-mediated AR treated with the investigational RET-specific TKI BLU-667 and osimertinib.
      a9ded1e5ce5d75814730bb4caaf49419 Method
      We assayed tissue via SNaPshot or Foundation One next-generation sequencing (NGS) and plasma via Guardant360 NGS under an IRB-approved protocol. In vitro studies assessed implications of RET fusions in EGFR-mutant cancers. We treated one patient with osimertinib/BLU-667 using an IRB and FDA-approved compassionate use protocol.
      4c3880bb027f159e801041b1021e88e8 Result
      41 EGFR-mutant patients with AR to osimertinib were assessed histologically and queried by tissue NGS (n=22), plasma NGS (n=9) or both (n=10). Key AR findings: SCLC transformation (2/32 tissue); EGFR C797S (5/32 tissue, 5/19 plasma, all cis with T790M); MET amplification (7/32 tissue, 3/19 plasma); BRAF rearrangement (2/32 tissue) and CCDC6-RET rearrangement (1/32 tissue, 1/19 plasma [distinct case]).
      CCDC6-RET was expressed in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells, which maintained MAPK signaling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitized cells expressing CCDC6-RET to EGFR inhibition.
      A 60-year-old woman with EGFR del19 progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib AR showed acquired CCDC6-RET (T790-wt). She began osimertinib 80mg/BLU-667 200mg daily x2 weeks, then BLU-667 was increased to 300mg daily. Her dyspnea improved within days of initiation. Scans after 8 weeks revealed a marked response with RECIST tumor shrinkage of 78% (Figure). She experienced only grade 1 toxicities of fatigue, leukopenia, hypertension, dry mouth, and elevated transaminases.
      8eea62084ca7e541d918e823422bd82e Conclusion
      RET rearrangements are rare but recurrent in EGFR-mutant patients with AR to osimertinib. In vivo models suggest they mediate AR and this patient provides proof-of-concept that combination EGFR+RET inhibition with osimertinib/BLU-667 is a well-tolerated and effective regimen for RET-mediated AR. Further study is ongoing.

      14731.jpg

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA26.04 - Discussant - MA 26.01, MA 26.02, MA 26.03

      13:45 - 14:00  |  Presenting Author(s): Caroline McCoach

      • Abstract

      Abstract not provided

    • +

      MA26.05 - Comprehensive Analysis of Treatment Response and Progression Pattern in Chinese Patients with Different ALK Fusion-Variants

      14:00 - 14:05  |  Presenting Author(s): Meng Qiao  |  Author(s): Chao Zhao, Xuefei Li, Tao Jiang, Fengying Wu, Xiaoxia Chen, Chunxia Su, Caicun Zhou

      • Abstract

      Background

      ALK inhibitors and chemotherapy are two major strategies in the treatment of patients with ALK-rearrangements in China. However, the respective treatment response varies and heterogeneous. This study aimed to comprehensively analyze the impact of ALK variants on different treatment response and explore progression pattern respectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed a cohort of 135 patients with determined ALK variants and medical record from January 2013 to July 2017 in Shanghai Pulmonary Hospital.

      4c3880bb027f159e801041b1021e88e8 Result

      figure 1.jpgThe most frequent ALK variant was variant 1 in 62 patients (46%), followed by variant 3a/b in 52 patients (38%) and variant 2 (12%). 69 (51.1%) of patients received chemotherapy, whereas 64 (47.4%) were treated with crizotinib and 2 (1.5%) with alectinib.The similar PFS was observed in patients ALK variant 1 and non-variant 1 regardless of first-line treatment strategy (crizotinib: 15.7 vs. 12.8 months, p=0.53; chemotherapy: 5.7 vs. 8.1 months, p=0.098). However, in the subgroup analysis, patients with ALK variant 1 and baseline brain metastasis had significantly shorter PFS in the first-line setting versus non-variant 1 (4.9 vs. 11.3 months, HR=2.96, p<0.01). Additionally, ORR was 21.6% and 50% in variant 1 and non-variant 1 patients with brain metastases, respectively. Moreover, in the analysis of progression pattern, 55 patients with ALK variant 1 and 57 patients with ALK non-variant 1 exhibited PD. As to ALK variant 1, the incidence of CNS relapse in patients treated with crizotinib was significantly higher than patients treated with chemotherapy (39.3% vs. 7.4%, p=0.005). In terms of ALK non-variant 1,the patients treated with chemotherapy had higher incidence of bone progression than patients treated with crizotinib (25% vs. 0%, p=0.021).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results firstly indicate the treatment-naïve patients with ALK variant 1 and baseline brain metastasis have inferior response to initial cancer treatment. Different ALK variants have distinct landscape of progression pattern when treated with crizotinib or chemotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      Metastasized NSCLC with an ALK fusion are sensitive to a range of tyrosine kinase inhibitors. ALK-positive NSCLC has been identified in the pivotal phase III trial with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC+ FISH-. The aim of this study was to collect ALK IHC+ cases and compare within this group response to crizotinib treatment of ALK FISH+ cases with ALK FISH- cases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A prospective multicenter investigator initiated research study was started in Europe. Stage IV ALK IHC+ NSCLC cases treated with crizotinib were collected centrally. Slides were validated centrally for ALK IHC (with 5A4 ETOP and D5F3 Ventana protocol) and ALK FISH (Vysis probes).

      4c3880bb027f159e801041b1021e88e8 Result

      The study started April 1, 2014 and closed in November 2017. Fifteen centers participated. Registration of 3523 ALK IHC tests revealed prevalence of 2.6% ALK IHC+ cases. Local ALK FISH analysis resulted in 46 concordant (ALK IHC+/FISH+) and 18 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 6 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The time to treatment failure did not differ for concordant nor discordant cases, and neither for local nor validated ALK testing (HR=0.78; 95% CI= 0.27-2.3; p=0.64) and (HR=2.2; 95% CI= 0.72-6.5; p=0.16), respectively). However, overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010), but not according to local testing (HR=1.7; 95% CI= 0.45-6.2; p=0.44).

      8eea62084ca7e541d918e823422bd82e Conclusion

      ALK IHC+ FISH- NSCLC cases are an infrequent finding. We recommend such cases to be validated carefully because our data indicate that ALK IHC+ FISH- cases have a worse survival when treated by crizotinib compared to ALK IHC+ FISH+ cases.

      This study was funded by an independent research grant by Pfizer

      6f8b794f3246b0c1e1780bb4d4d5dc53

      • Abstract

      Background

      ROS1 positive non-small cell lung cancer (NSCLC) patients can be treated with specific tyrosine kinase inhibitors including crizotinib. ROS1 positivity is often clinically detected by fluorescence in situ hybridization (FISH), however ROS1 IHC can be used to screen samples prior to FISH confirmation of ROS1 status. The ROS1 (SP384) antibody detects ROS1 with high sensitivity, specificity, and consistency. Consistent interpretation of a ROS1 IHC assay between pathologists is important patient evaluation. Here we present inter-reader precision of 12 pathologists across 60 FFPE cases stained with ROS1 (SP384).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort of 60 FFPE NSCLC cases stained with H&E, Rabbit Monoclonal Negative Control Ig, and ROS1 (SP384) were selected to represent positive, negative, and borderline ROS1 IHC status. Twelve practicing lung pathologists independently scored the cases as positive or negative around a cutoff of cytoplasm staining in > 30% tumor cells at a ≥2+ intensity level using Pathotrainer software (Pathomation bvba). Scoring was blinded to other readers and ROS1 status of the cases. Overall percent agreement (OPA), negative percent agreement (NPA), and positive percent agreement (PPA) were calculated in comparison to the group mode. Average overall percent agreement (AOPA), average positive agreement (APA), and average negative agreement (ANA) were calculated pairwise for each reader pair. Following independent assessment, participating pathologists conducted a discordant case review establishing consensus reads for all 60 cases and compared 44 cases to available FISH results.

      4c3880bb027f159e801041b1021e88e8 Result

      OPA of each of the 12 readers to the mode was 96.4% (95% CI 93.9-98.6) with PPA of 96.3% (95% CI 92.7-99.4) and NPA of 96.5% (95% CI 92.8-99.5). Pairwise AOPA between each of the 12 readers was 94.5% (95%CI 91.2-97.7) with APA 94.0% (95% CI 89.5-97.6) and ANA 95.0% (95%CI 91.2-97.9).

      Consensus IHC scores were concordant with FISH 90.0% (40/44 cases).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Inter-reader precision around a cutoff of >30% tumor cells with cytoplasmic staining at a ≥2+ intensity level was high in interpreting ROS1 (SP384) in NSCLC samples. Case review highlighted confirmation with FISH in questionable cases and staining patterns to be considered when interpreting ROS1 (SP384) IHC.

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      MA26.08 - Discussant - MA 26.05, MA 26.06, MA 26.07

      14:15 - 14:30  |  Presenting Author(s): Dong-Wan Kim

      • Abstract

      Abstract not provided

    • +

      MA26.09 - Lazertinib, a Third Generation EGFR-TKI, in Patients with EGFR-TKI-Resistant NSCLC: Updated Results of a Phase I/II Study

      14:30 - 14:35  |  Presenting Author(s): Byoung Chul Cho  |  Author(s): Ji-Youn Han, Sang-We Kim, Ki-Hyeong Lee, Dong-Wan Kim, Yun-Gyoo Lee, Gyeong-Won Lee, Jong-Seok Lee, Eun Kyung Cho, Joo-Hang Kim, Sung Sook Lee, Young Joo Min, Jin-Soo Kim, Sang Won Shin, Hye Ryun Kim, Min Hee Hong, Jin Seok Ahn, Seonmi Kang, Sohee Kim, Seong Bok Jang, Soongyu Choi, Myung-Ju Ahn

      • Abstract

      Background

      Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that can penetrate the blood-brain barrier, and targets the activating EGFR mutations Del19 and L858R, as well as the T790M mutation, while sparing wild type. We report the updated results from a Phase I/II study of lazertinib (NCT03046992)

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced and metastatic NSCLC who had progressed after treatment with EGFR-TKIs with/without asymptomatic brain metastases (BM) were enrolled in an open-label, multicenter, phase I/II study with dose-escalation and expansion cohorts. Lazertinib was administered once daily at doses between 20 to 320 mg in a 21-day cycle. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy. T790M status was confirmed in the dose-expansion cohorts.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 115 patients (median age 62 years, female 62%) were enrolled. The dose-escalation cohort included 38 patients administered with 20 to 320 mg across 7 dose levels, and 77 patients in the dose-expansion cohort were administered with 40 to 240 mg across 5 dose levels. No dose-limiting toxicities were observed in the dose-escalation cohort. Systemic exposure increased dose-dependently. Of the evaluable patients (n=110) at data cut-off, the objective response rate (ORR) was 65% (95% confidence interval [CI], 54.9 to 73.4). The ORR for 93 of the T790M+ patients was 69% (95% CI, 58.4 to 78.0). In patients with BM (n=12), the intracranial ORR was 50% (95% CI, 21.1 to 78.9). The most common treatment-emergent adverse events (TEAEs) were pruritus (19%), decreased appetite (17%), rash (14%), and constipation (12%). The most frequently reported TEAEs of grade ≥ 3 were hyponatraemia (2%), nausea (2%) and pneumonia (2%).

      ORR in T790M+ patients
      Dose QD 20 mg 40 mg 80 mg 120 mg 160 mg 240 mg
      Evaluable patients*, n 2 25 18 22 18 8
      ORR, n (%) 2 (100) 17 (68) 11 (61) 17 (77) 11 (61) 6 (75)
      * Patients were deemed evaluable for response if they underwent a post-baseline radiological assessment (RECIST 1.1) or were discontinued prior to the post-baseline assessment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lazertinib was safe, well-tolerated and exhibited promising systemic and intracranial antitumor activity in EGFR T790M+ NSCLC patients. The dose-expansion cohort as the first and second-line setting has been initiated from April 2018.

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      MA26.10 - CNS Activity of Ramucirumab in Combination with Osimertinib in Patients with Advanced T790M-Positive EGFR-Mutant NSCLC

      14:35 - 14:40  |  Presenting Author(s): Luis Paz-Ares  |  Author(s): David Planchard, James Chih-Hsin Yang, Ki Hyeong Lee, Pilar Garrido, Keunchil Park, Joo-Hang Kim, Dae Ho Lee, Huzhang Mao, Bo H Chao, Helena Yu

      • Abstract

      Background

      Many patients with NSCLC develop central nervous system (CNS) metastasis. Osimertinib, a novel third-generation EGFR tyrosine kinase inhibitor (TKI), has previously demonstrated CNS and systemic efficacy in patients with EGFR-mutant NSCLC. Combination of an EGFR TKI with a VEGF/VEGFR2-directed monoclonal antibodies (mAb) have shown promising results in EGFR-mutant NSCLC. Ramucirumab, human IgG1 VEGFR2 mAb, was used in combination with osimertinib. Planned exploratory and CNS response analyses aim to examine the safety/efficacy of ramucirumab+osimertinib in patients with CNS metastasis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this ongoing, open-label, multicenter Phase 1 study (NCT02789345), patients with T790M-positive EGFR-mutant (Ex19del or L858R) NSCLC who had relapsed after first-line EGFR TKI therapy were enrolled. Patients with asymptomatic and stable CNS metastasis (with/without prior radiotherapy) were eligible. Primary objective of the study was to assess safety and tolerability of ramucirumab+osimertinib. Secondary endpoints include objective response rate (ORR) and disease control rate (DCR). Exploratory endpoints relevant to CNS include CNS ORR and CNS DCR.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients (N=25) were 45-80 years (median 64) with ECOG-PS 0 (n=3) or 1 (n=22) and 10 patients had CNS metastasis at enrollment while 15 never had CNS metastasis. Patients with CNS metastasis could have had prior radiotherapy (n=7) or no radiotherapy (n=3) to the CNS. Median follow-up time was 7.23 months. Fifteen patients remained on study treatment (five with CNS metastasis, ten without). TEAEs of interest (CNS metastasis, no CNS metastasis), such as headache (4/10, 5/15), vomiting (3/10, 4/15), and nausea (2/10, 4/15), were observed with comparable rates in patients with or without CNS metastasis. One patient developed TEAE of cerebral hemorrhage (Grade 1), related to CNS metastasis, but unrelated to study treatment, according to the investigator. Another patient with CNS metastasis developed Grade 5 TRAE of subdural hemorrhage, unrelated to CNS metastasis, ~7 weeks after the last dose of ramucirumab. Only one patient with CNS metastasis had measurable CNS lesions (tumor shrinkage of 24% [SD] as best response). The other nine patients with CNS metastasis had non-measurable CNS lesions, one of whom had a CNS complete response; his systemic best response was SD. The rest of patients had CNS non-CR/non-PD. To date, one patient (1/25) developed CNS progression (due to new CNS lesion); her CNS best response was SD.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Ramucirumab+osimertinib showed potential antitumor activity in the CNS. Patients with CNS metastasis, with/without prior radiotherapy, appeared to tolerate this combination similarly to patients without CNS metastasis.

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      MA26.11 - Effects of Dose Modifications on the Safety and Efficacy of Dacomitinib for EGFR Mutation-Positive NSCLC

      14:40 - 14:45  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Tony S. Mok, Kazuhiko Nakagawa, Rafael Rosell, Ki Hyeong Lee, Jesus Corral, Maria Rita Migliorino, Adam Pluzanski, Rolf Linke, Geeta Devgan, Eric I. Sbar, Susan Quinn, Tao Wang

      • Abstract

      Background

      In patients with EGFR mutation-positive advanced stage NSCLC, first-line dacomitinib significantly improved PFS, OS, DoR and time to treatment failure vs gefitinib (ARCHER 1050; NCT01774721).1,2 Dacomitinib starting dose was 45 mg QD for all patients, with reductions to 30 or 15 mg QD permitted. We explored effects of dacomitinib dose reduction on safety and efficacy in this ongoing study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with newly diagnosed stage IIIB/IV or recurrent NSCLC harboring an EGFR mutation (exon 19 del or exon 21 L858R) randomized to dacomitinib received 45 mg PO QD. Study endpoints and protocol-defined dose reduction parameters were previously described.1 We evaluated reasons for dose reductions, and their effects on incidence and severity of common adverse events (AEs) and key efficacy endpoints (PFS, OS, ORR). Data cutoff dates: 17-Feb-2017 (OS), 29-Jul-2016 (other endpoints).

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, 150 (66.1%) patients dose reduced for AEs (87 and 63 reduced to 30 and 15 mg QD as lowest dose, respectively); most commonly for skin toxicities (62.6%) and diarrhea (14.0%). Median time to each successive dose reduction was ~12 weeks. Incidence and severity of AEs declined following dose reduction, including grade ≥3 diarrhea (11.3% before vs 4.0% after), dermatitis acneiform (15.3% vs 6.7%), stomatitis (3.3% vs 2.7%) and paronychia (7.3% vs 4.7%).

      PFS was similar in dose-reduced and all dacomitinib-treated patients (Figure).

      pfzusdt200581 dacomitinib dose reduction figure 02.jpg

      Median OS results were also similar (dose-reduced patients: 36.7 mo [95% CI: 32.6, NR]; all dacomitinib-treated patients: 34.1 mo [95% CI: 29.5, 37.7] as were ORRs (dose-reduced patients: 79.3% [95% CI: 72.0, 85.5]; all dacomitinib-treated patients: 74.9% [95% CI: 68.7, 80.4]).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Efficacy was similar in the dose-reduced patients and the overall study population. Incidence/severity of dacomitinib-related AEs decreased with dose reduction, thereby allowing patients to continue treatment.

      References:

      Wu, et al. Lancet Oncol. 2017.

      Mok, et al. J Clin Oncol. 2018.

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      MA26.12 - Discussant - MA 26.09, MA 26.10, MA 26.11

      14:45 - 15:00  |  Presenting Author(s): Liza Villaruz

      • Abstract

      Abstract not provided

  • +

    MA27 - Novel Drugs and PDX Models

    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Moderators:
    • +

      MA27.01 - Establishment of PDX From Tumors Characterized by EGFR Mutations or ALK Fusion Genes from Resections, Biopsies and Pleural Fluids

      13:30 - 13:35  |  Presenting Author(s): Sebastiao Martins-Filho  |  Author(s): Michael Cabanero, Nhu-An Pham, Erin L Stewart, Deepti Ravi, Devalben Patel, Judy McConnell, Alexandria Grindlay, Frances Allison, Ming Li, Frances A Shepherd, Ming Sound Tsao, Kazuhiro Yasufuku, Geoffrey Liu

      • Abstract

      Background

      Patient-derived xenograft (PDX) models allow for cancer tissue expansion, providing an effective method to evaluate tumor biology and mechanisms of response or resistance. Our study aims to establish models in patients enriched for lung adenocarcinoma (LUAD) with EGFR mutations or ALK fusion genes which respond initially to oral targeted therapy, but typically develop resistance and disease relapse within 2 years. The PDXs will be evaluated for their potential to model therapy outcomes, to determine resistance mechanisms and to evaluate novel therapy strategies to overcome resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From August 2015 to January 2018, we collected 109 samples from patients with EGFR- or ALK-driven LUAD and from never-smoker LUAD patients with unknown mutation status. Five samples with low tissue viability (i.e. necrotic) or very low tumor content (<100 malignant cells) were excluded. Adequate samples were implanted into the subcutaneous tissue of NOD-SCID mice. At this time, 16 samples have reached the study endpoint (tumor growth ≥1.5cm3) and 60 showed no tumor-growth following implantation (median follow-up: 8m). Results are currently pending for 18 models.

      4c3880bb027f159e801041b1021e88e8 Result

      Samples were collected from surgical resections (31, 36%), CT-guided biopsies (12, 14%), EBUS (19, 22%) and pleural fluid effusions (24, 28%). Most patients were female (51/86, 59%), never smokers (62/85, 73%), and had stage III or IV cancer (55/79, 70%). Mutations in EGFR and ALK were found in 55/81 (68%) and 12/84 (14%) primary cancers, respectively. Early-passage xenograft engraftment (XG) was observed in only 16 (19%) PDXs, including 9/55 (16%) EGFR- and 1/12 (8%) ALK-mutant cancers. The phenotype and molecular changes (EGFR and ALK) were consistent within the PDX model and its corresponding patient sample. Samples collected from surgical-resection specimens showed a trend towards higher engraftment rates (p=0.084). Conversely, the presence of EGFR or ALK mutations showed a trend towards non-engraftment (noXG, p=0.075). Patient smoking status and tumor stage did not influence engraftment rate. To identify reasons for no tumor-growth, we conducted histological analysis in the subcutaneous fat-pads (nodes in the implant sites) of 28 noXG mice. Interestingly, we identified small non-palpable foci of carcinoma in 8 animals (4 EGFR+ and 2 ALK+).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Environmental or molecular factors may impair engraftment rates of EGFR+ and ALK+ LUAD samples in PDX models. Nevertheless, these models recapitulate the primary disease and could be useful for population-based drug-screening studies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.02 - Hypofractionated Radiotherapy Normalizes Tumor Vasculature in Non-Small Cell Lung Cancer Xenografts Through p-STAT3/HIF-1 Alpha Pathway

      13:35 - 13:40  |  Presenting Author(s): Xiaorong Dong  |  Author(s): Xiong Chun Jin, Fan Tong, Chunhua Wei, Hui Lu

      • Abstract

      Background

      Our study aimed to investigate specific biological effect of hypofractionated radiotherapy (HFRT) on tumor angiogenesis, when compared with conventional radiotherapy (CRT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Firstly, models of nude mice as well as dorsal skinfold window chamber (DSWC) bearing H460 and HCC827 (NSCLC cell lines) were established. Tumors suffered irradiation with doses of 0 Gy (control group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). After irradiation, xenograft volumes were recorded every other day. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; α-SMA and CD34 immune-histochemical staining was employed to detect the micro-vessel density (MVD) and coverage rates of pericyte on tumor vessels; pimonidazole hydrochloride was used to detect hypoxia; western blotting and RT-PCR were used to detect the expression levels of p-STAT3, HIF-1α, SDF-1 and VEGFA. Then, S3I-201, the STAT3 inhibitor, was used to further verify the mechanism of the effect of HFRT on vascular normalization.

      4c3880bb027f159e801041b1021e88e8 Result

      Compared to CRT groups, the growth suppression effect of HFRT on tumor tissue was enhanced, accompanied by stronger effect on decrease in MVD, vascular normalization and improvement of tumor hypoxia. RT-PCR and western blotting exhibited that HFRT promoted the vascular normalization by activating STAT3/ HIF-1α signaling pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Compared to CRT, the pathway of p-STAT3/HIF-1α and its downstream angiogenic factors (VEGFA and SDF-1) might play important roles in forming of a window-period of vascular normalization in NSCLC, which contributed to the specific biological effect of HFRT on tumor vasculature.

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      MA27.03 - Multi-Omic Characterization of TKI-Treated Drug-Tolerant Cell Population in an EGFR-Mutated NSCLC Primary-Derived Xenograft

      13:40 - 13:45  |  Presenting Author(s): Erin L Stewart  |  Author(s): Michael Cabanero, Vibha Raghavan, Jeffrey Bruce, Paul Guilhamon, Rajat Singhania, Nhu-An Pham, Shu Yi Shen, Tiantian Li, Ming Li, Natasha B Leighl, Frances A Shepherd, Trevor J. Pugh, Daniel De Carvalho, Mathieu Lupien, Geoffrey Liu, Ming Sound Tsao

      • Abstract

      Background

      Sixty to eighty percent of advanced stage lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutated tumors respond to first generation EGFR tyrosine kinase inhibitors (TKIs). However, cure is not yet achievable with any EGFR TKI monotherapy, as patients eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of epigenetically modified drug tolerant cells (DTCs) may be important for tumor cells surviving TKI. We hypothesize that molecularly characterizing DTCs in vivo and comparing them to the untreated tumor in a patient-derived xenograft (PDX) model may delineate mechanisms of tolerance that closely mimic those occurring in patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      DTCs were produced via chronic exposure to erlotinib in a lung adenocarcinoma PDX harbouring an exon 19 deletion. Histological, genomic, transcriptomic (including single-cell RNA-seq), and epigenetic characterizations were performed on DTCs and compared to untreated baseline (BL) tumors.

      4c3880bb027f159e801041b1021e88e8 Result

      Compared to BL, DTCs exhibit decreased levels of proliferation (Ki67 by immunohistochemistry (IHC) and increased expression of senescence/quiescence (p21) and anti-apoptosis (BCL-XL) immunohistochemistry (IHC) markers, while maintaining EGFR pathway signaling (pEGFR, pAKT, pERK, pS6 IHC). Whole exome-sequencing provides evidence that DTCs likely do not represent mutationally distinct subclones from the bulk tumor. Instead, DTCs exhibit a number of differentially expressed genes compared to BL tumors that are involved in cell cycle arrest, senescence/quiescence, differentiation, vesicles, and inflammation. Genes with epigenetic differences (chromatin openness and/or promoter methylation) are involved in similar cellular processes. A minor (<2%) subpopulation of transcriptomically-defined DTC-like cells in the BL tumors are very similar to the DTCs, supporting the hypothesis that DTCs may exist prior to treatment. A number of transcription regulators are found to have differential gene expression and epigenetic regulation as well as DNA-binding motifs found in regions of chromatin uniquely open in DTCs or baseline tumors. These transcription regulators are involved in cell maintenance, proliferation, and differentiation, and may play key roles in promoting DTC phenotype.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this specific EGFR mutant PDX model sensitive to first generation TKIs, DTC-like cells are found in the BL untreated tumors, and its resultant phenotype after exposure to TKI appears to be involved in cell cycle, differentiation, senescence/quiescence, proliferation and maintenance. PDX models may provide insights into therapeutic strategies to target DTCs, and further improve the survival of EGFR-mutated NSCLC patients.

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      MA27.04 - Discussant - MA 27.01, MA 27.02, MA 27.03

      13:45 - 14:00  |  Presenting Author(s): Byoung Chul Cho

      • Abstract

      Abstract not provided

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      MA27.05 - Drug Loaded Mesenchymal Stem Cells for Targeted Lung Cancer Treatment in Mice

      14:00 - 14:05  |  Presenting Author(s): YAOJIONG Wu  |  Author(s): Xusheng Wang

      • Abstract

      Background

      Mesenchymal stem cells (MSCs) are cells residing in many tissues of our body. Due to their low immunogenicity, allogeneic MSCs have been used extensively for immune regulation and many other conditions. Over 90% of culture expanded MSCs are entrapped in the lungs after intravenous infusion. Taking this advantage, in this study, we utilized MSCs as a vehicle for targeted delivery of drugs to the lungs to treat lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      For enhanced cellular uptake, docetaxel (DTX) was loaded in PLGA-PEG nanoparticles (NPs). Lung cancer was induced in KrasG12D mice, who expressed a form of constitutively activated Kras protein in lung cells upon local administration of cre-advenovirus (AdCre) solution. The size of lung cancer was assessed by PET-CT and tissue analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      The amount of DTX uptake by MSCs at 1, 3, 7, 12, and 24 hours was measured by LC-MS, and the result showed that DTX intake reached peak at 12 hours with ~36 μg in 106 MSCs, compared to 15 μg DTX in equal number of fibroblasts, indicating that MSCs had higher NPs-DTX uptake capacity than fibroblasts. To visualize MSCs in vivo, MSCs were labeled with luciferase (Luci). 106 MSCs-Luci loaded with NPs-DTX were injected intravenously in mice. In vivo imaging system (IVIS) analysis showed a predominant accumulation of the cells (drug) in the lungs at 24 hours after injection. The effect of MSCs/NPs/DTX in inhibiting lung cancer development was evaluated in KrasG12D mice. Five days after lung cancer induction, the mice received an intravenous injection of 106 MSCs loaded with NPs-DTX (~25 μg), NPs-DTX (~200 μg) alone, or PBS every 5 days. 30 days after tumor induction, PET-CT analysis detected large masses in the lungs in PBS treated mice, compared to much smaller masses in MSCs/NPs/DTX-treated or NPs-DTX-treated mice. In consistence, the tumor weight was significantly lower in MSCs/NPs/DTX-treated or NPs-DTX-treated animals than PBS-treated mice, and similar reductions in tumor weight were found in MSCs/NPs/DTX-treated or NPs-DTX-treated mice.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Thus our data indicate that MSC loaded with DTX can provide targeted therapy for lung cancer to achieve equal cancer inhibition with much lower doses of DTX thus reducing side effects of the drug. As allogeneic MSCs do not cause obvious immune rejection, our study suggests a novel approach for targeted lung cancer therapy.

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      MA27.06 - Therapeutic Silencing of Oncogenic KRAS With a Mutant-Specific Short Interfering RNA

      14:05 - 14:10  |  Presenting Author(s): Chad Victor Pecot  |  Author(s): Amanda Van Swearingen, Bjoern Papke

      • Abstract

      Background

      Oncogenic mutations in RASgenes are well established drivers of cancer. In particular, lung, pancreatic and colorectal cancers carry high rates of oncogenic mutations in KRAS. Promising preclinical strategies with RNA interference (RNAi) have been developed to target oncogenic RAS function, yet a clinically effective anti-RAS therapy remains to be achieved. While genetic knock-down of mutant KRASwith RNAi is one promising approach, current methods are not selective and also decrease normal RAS, raising concerns about potential normal tissue toxicity.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We took a novel in silico approach to develop a library of siRNAs that are theoretically capble of silencing mutant KRAS sequences yet spare the wild-type sequence. We utilized a 3T3 model system to test our library of siRNAS against various human KRAS G12 and G13 mutations compared with the wild-type sequence. Dose titrations were performed to assess the unique affinity of our lead candidate for mutant v. WT. Using a KRAS mutant orthotopic lung model, we assessed in vivo silencing and therapeutic effects following delivery of our lead candidate when packaged into a nanoliposome.

      4c3880bb027f159e801041b1021e88e8 Result

      Here we describe a custom designed short interfering RNA (siRNA) oligonucleotide (KRAS-m) that displays a higher affinity for the most frequent subsets of oncogenic KRASmRNAs than for wild-type KRASmRNA. Using 3T3 cells stably expressing wild-type or various KRAS mutations, we observed that KRAS-m preferentially suppressed expression of G12C, G12D, G12V and G13D missense mutations compared to wild-type KRAS. Additionally, KRAS-m impaired proliferation of lung cancer cells in 2D as well as 3D spheroids embedded in extracellular matrix. In order to optimize in vivo stability and minimize toxicity, a 2’O-methylation strategy was utilized and several equipotent modifications were found. To overcome future clinical limitations of delivering siRNA to tumors, we evaluated a lipid nanoparticle platform (LNP) clinically-proved to be safe and highly efficient at delivering systemic RNAi. Biodistribution studies in a syngeneic, orthotopic metastasis model of KRAS (G12D) lung adenocarcinoma revealed substantial uptake of LNP-siRNAs in lung tumors and metastasis. Time-kinetic studies in this model revealed a single delivery of LNP-KRAS-m siRNA significantly silenced KRAS protein expression in tumors for at least 3 days. Compared with LNP-control siRNAs, following two deliveries of LNP-KRAS-m siRNAs model led to significant reductions in disease burden.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Taken together, our data indicate a novel strategy to target oncogenic KRAS-driven lung tumors using a mutant-specific siRNA capable of targeting many of the most common KRAS mutations.

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      MA27.07 - Lung Adenocarcinoma Harboring BRAF G469V Mutation is Uniquely Sensitive to EGFR Tyrosine Kinase Inhibitors

      14:10 - 14:15  |  Presenting Author(s): Hirotsugu Notsuda  |  Author(s): Nhu-An Pham, Ming Li, Ni Liu, Vibha Raghavan, Zhenhao Fang, Christopher B Marshall, Nadeem Moghal, Mitsuhiko Ikura, Ming Sound Tsao

      • Abstract

      Background

      BRAF mutations occur in 2-5% of non-small cell lung cancers with ~50% being non-V600E. Previous studies reported that two BRAF G469 mutations, G469V and G469A increase kinase activity and MAPK activation, thus are likely oncogenic. Patients with non-V600E mutations are mostly not sensitive to approved BRAF inhibitors vemurafenib or dabrafenib. We established a lung adenocarcinoma (LUAD) patient derived xenograft (PDX) that is epidermal growth factor receptor (EGFR) wild type and non-amplified, but harbors BRAF G469V mutation, yet is sensitive to gefitinib. We performed functional studies to characterize the oncogenicity and sensitivity of BRAF G469 mutations to EGFR tyrosine kinase inhibitors (TKIs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PDX12 was established in NOD-SCID mice from a resected stage IIIA LUAD. The XDC12 cell line was established from PDX12. NCI-H1395 and -H1755 LUAD cell lines with BRAF G469A mutation were obtained from ATCC. BRAF mutant driver activity was characterized by shRNA knockdown of BRAF in LUAD cell lines and the ability of the mutants to promote IL3-independent growth when expressed in Ba/F3 cells. PDX12 responsiveness to TKIs was evaluated by tumor volume shrinkage while cell line sensitivity was quantified using the MTS assay. Drug effects on signaling were assessed by phospho-immunoblotting. Computational modeling was used to predict how the mutations promote BRAF activation and sensitivity to EGFR-TKIs, while purified BRAF proteins were used to validate predictions.

      4c3880bb027f159e801041b1021e88e8 Result

      Knockdown of BRAF by shRNA inhibited growth of all BRAF mutant cell lines, while ectopic BRAF G469V and G469A expression in Ba/F3 cells promoted IL3-independent MAPK activation and growth, supporting both mutations being oncogenic drivers. The XDC12 cell line was sensitive to EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib), but resistant to the BRAF inhibitor dabrafenib, which correlated with inhibition of MAPK phosphorylation. By contrast, H1395 and H1755 cell lines with BRAF G469A mutations were resistant to both the EGFR-TKIs and the BRAF inhibitor. Similarly, only Ba/F3 cells expressing BRAF G469V, but not G469A, were sensitive to EGFR-TKIs. Consistent with the in vitro data and our initial PDX findings with gefitinib, multiple EGFR-TKIs induced tumor shrinkage in PDX12 in vivo.

      8eea62084ca7e541d918e823422bd82e Conclusion

      BRAF G469V/A mutations are oncogenic drivers but are insensitive to BRAF inhibitors. However, only BRAF G469V, but not G469A mutation, is sensitive to EGFR-TKIs. Thus, two different driver alterations affecting the same BRAF codon can lead to distinct drug sensitivities.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.08 - Discussant - MA 27.05, MA 27.06, MA 27.07

      14:15 - 14:30  |  Presenting Author(s): Gwyn Bebb

      • Abstract

      Abstract not provided

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      MA27.09 - Dual Inhibition of BCL-XL and MCL-1 is Required to Induce Tumour Regression in Lung Squamous Cell Carcinomas Sensitive to FGFR Inhibition

      14:30 - 14:35  |  Presenting Author(s): Marie-Liesse Asselin-Labat  |  Author(s): Clare E Weeden, Casey Ah-Cann, Aliaksei Holik, Delphine Merino, Guillaume Lessene

      • Abstract

      Background

      Fibroblast growth factor receptor 1 (FGFR1) gene amplification has been described in 20% of lung squamous cell carcinoma (SqCC), suggesting that FGFR tyrosine kinase inhibitors may constitute a new therapeutic approach for patients carrying this genetic alteration. However, a recently completed clinical trial reported low response rates to FGFR therapy, indicating the need for refined biomarkers. We have recently described that high levels of FGFR1 RNA expression better predicts response to FGFR inhibitors, yet the treatment results in tumour cell stasis as opposed to cell death. BH3-mimetics are a class of anticancer agents that block the BCL-2 family of pro-survival proteins to induce cell death and were recently approved for clinical use in blood cancers. We therefore hypothesized that combining BH3-mimetics with FGFR-targeted therapy may enhance the killing of SqCC cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We developed patient-derived xenograft models of lung squamous cell carcinoma and evaluated the activity of specific inhibitors of BCL-XL (A1331852), BCL-2 (ABT-199), MCL-1 (S63845) or FGFR (BGJ398) as single agents or in combination in vitro and in vivo. Genetic knockout of BCL-XL was also performed using CRISPR/Cas9. We evaluated compounds synergy in vitro using BLISS assay and in vivo efficacy using mRECIST.

      4c3880bb027f159e801041b1021e88e8 Result

      Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We identified a greater reliance of lung SqCC cells on BCL-XL compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitor alone gives a survival benefit in combination FGFR therapy in vivo. In contrast, triple BCL-XL, MCL-1 and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our work therefore provides a rationale for the simultaneous inhibition of MCL-1, BCL-XL and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.10 - EGFR-Targeted Therapy Alters the Tumor Microenvironment In EGFR-Driven Lung Tumors: Rationale for Combination Therapies

      14:35 - 14:40  |  Presenting Author(s): Yijun Jia  |  Author(s): Tao Jiang, Xuefei Li, Chao Zhao, Caicun Zhou, Sha Zhao

      • Abstract

      Background

      Non-small cell lung cancer patients harboring EGFR mutations have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). However, these patients develop resistance eventually. With the promising implementation of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize this immuneapproach in the context of targeted therapies. Although many clinical trials have attempted to study combining EHGR-TKIs with PD-1/PD-L1 inhibitors in NSCLC cases, the clinical benefit is still undefined. Therefore, we carry out this study to investigate the immune response of EGFR-TKIs in EGFR-driven lung tumors, aiming to explore factors may influence the efficacy of this combination strategy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We investigated the early and long-term antitumor effects of first-generation TKI gefitinib and third-generation TKI osimertinib respectively in mice with EGFRL858R andEGFR19DEL/T790M-driven lung tumors.The changes of immune texture in tumors were dynamically tested in different treatment groups by flow cytometry and immunohistochemistry.

      4c3880bb027f159e801041b1021e88e8 Result

      Upon treatment of gefitinib and osimertinib, we saw significant tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFR19DEL/T790M-driven tumors did not respond to gefitinib, but did show a significant tumor response to third-generation TKI osimertinib treatment. Accompanied with obvious tumor shrinkage, we saw a significant increase of infiltrating CD11b+ myeloid cells and CD3+ lymphocytes throughout treatment. We further analyzed subpopulation of CD11b+ myeloid cells and CD3+ lymphocytes. Results showed that EGFR-TKIs may demonstrated anti-tumor activity by raising cytotoxic CD8+ T cells, activating dendritic cells, eradicating Foxp3+ Tregs and inhibiting M2-like polarization at early stage. However, these immune benefits occurred temporarily and gradually disappeared with treatment went on. On the other hands, the proportion of myeloid-derived suppressor cells(MDSCs), particular mononuclear-MDSCs were consistently elevated responding to sensitive EGFR-TKIs treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Together, results of our study provide novel insights into the immune response to EGFR-TKIs in vivo and provides rationale for potential combinations of EGFR-TKIs and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.And additional therapies aiming to eliminate certain immunosuppressive components should be considered when applying this combination strategy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA27.11 - Genomic Sequencing and Editing Revealed the GRM8 Signaling Pathway as Potential Therapeutic Targets of Squamous Cell Lung Cancer

      14:40 - 14:45  |  Presenting Author(s): Panpan Zhang  |  Author(s): Shaolei Li, Yue Yang

      • Abstract

      Background

      Lung cancer is the leading cause of cancer death worldwide. Squamous cell carcinoma (LUSC) is one subtype of non-small-cell lung cancer (NSCLC), and ranks at the second of lung cancer incidence. Although targeting receptor tyrosine kinases (RTKs) had already brought better clinical outcomes to NSCLC patients carrying corresponding mutations, very few mutated targets had been identified in LUSC subtype, probably because of the lack of mutation hotspot and functional validation of mutated candidate.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The whole exome (WES) and whole genome (WGS) sequencing and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from 11 groups of LUSC primary tumors and corresponding patient-derived xenografts (PDXs).

      4c3880bb027f159e801041b1021e88e8 Result

      The WES data revealed high homologies on the mutation types and signatures among primary tumor and different passages of PDX tumor samples. Nine significant genes carrying single nucleotide variations (SNVs) and three carrying copy number variations (CNVs) were identified as targeting candidates from WES and WGS data based on the mutation frequency and driver gene analysis. The oncogenic or tumor suppressor functions of those 12 candidates were validated through CRISPR-Cas9 loss-of-function system in tumor cells derived from PDX tissues carrying corresponding mutations and in normal bronchial epithelial cell-line. Furthermore, using CRISPRa transcriptionally activating system, one novel candidate, Metabotropic glutamate receptor 8 (GRM8) was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer.

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      MA27.12 - Discussant - MA 27.09, MA 27.10, MA 27.11

      14:45 - 15:00  |  Presenting Author(s): Dave Barbie

      • Abstract

      Abstract not provided

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    MS28 - IO Combinations in Advanced NSCLC

    • Type: Mini Symposium
    • Track: Immunooncology
    • Moderators:
    • +

      MS28.01 - Understanding the Rationale for Combining IO Agents

      13:30 - 13:45  |  Presenting Author(s): Edward B Garon

      • Abstract

      Abstract not provided

    • +

      MS28.02 - Combination IO+IO

      13:45 - 14:00  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract

      Abstract

      Immune checkpoint inhibitors (CPIs) such as anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), anti-programmed death-1 (PD-1), or PD-L1 demonstrated durable response rates across broad range of solid tumors including non-small cell lung cancer (NSCLC), which has revolutionized treatment of solid tumors. In NSCLC, Pembrolizumab monotherapy in patients with high PD-L1 expression showed significant improvement of overall survival (OS) compared with platinum doublets as first-line therapy. For further improvement of efficacy and durable response, several randomized phase III studies of CPIs combined with chemotherapy also demonstrated significant improvement of OS regardless of PD-L1 expression. Given that combination of CTLA-4 inhibitor, ipilimumab with anti-PD1, nivolumab led to significant increase of response rate and survival in malignant melanoma, similar approach has been applied to the treatment of NSCLC. The Checkmate 227 study, a randomized phase 3 trial comparing nivolumab plus ipilimumab (Ipi-Nivo) with standard platinum-based chemotherapy in NSCLC has been conducted. Preplanned co-primary analysis demonstrated significant improvement of progression free survival (PFS) with nivolumab plus ipilimumab in patients with high tumor mutation burden (TMB) of at least 10 mutations per megabase, tested by FoundationOne CDx assay. The median PFS was 7.2 months (95% CI 5.5 to 13.2) versus 5.5 months (HR 0.58, 95% CI 4.4 to 5.8, p<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The incidence of grade 3 or 4 treatment related adverse events was similar between two arms (31.2% with nivolumab plus ipilimumab vs 36.1% with chemotherapy), however, the incidence of discontinuation of drugs is more common in nivolumab plus ipilimumab combination (17% vs 9%). Although overall survival data are not yet mature, these results indicate that TMB is considered an independent predictive marker for selected patients who most likely benefit from the combination of nivolumab and ipilimumab. Recent update of CheckMate 227 study (Part 2) in patients with < 1% of PD-L1 expression was presented. The PFS was significantly improved with combination of nivolumab plus ipilimumab compared with chemotherapy alone (HR=0.74, 95% CI;0.58-0.94), but the benefit from nivolumab plus ipilimumab combination was confined only in patients with TMB 10 mut/Mb suggesting TMB can be considered predictive biomarker for combination of nivolumab plus ipilimumab. In contrast, the MYSTIC study, which compared durvalumab plus tremelimumab with platinum-based chemotherapy, did not meet the primary endpoint of PFS. Final analysis of overall survival is pending. Actually, achievement of 45% of PFS at 1 yr in patients with <1% of PD-L1 expression with combination of nivolumab plus ipilimumab is quite encouraging. However, several issues still remain for use of TMB as a biomarker in clinical practice. TMB can be analyzed by whole exome sequencing, targeted sequencing from tissue or liquid biopsy, where the study platforms are not standardized. Further, the cut-off value of high TMB is quite variable among studies. The tissue availability for TBM test might be another issue and turn-around time also should be improved.

      Immune checkpoints are orchestrated by a set of co-stimulatory and co-inhibitory molecules that regulate the activation and effector functions of T lymphocytes. Until now, combination of ipilimumab with nivolumab showed promising results in NSCLC, but other combination approach of anti-PD1 or anti-PD-L1 with antibodies targeting other co-inhibitory molecules, such TIM-3, BTLA, VISTA, LAG-3, or TIGIT is actively involved in early clinical trial. Similarly, antibodies targeting co-inhibitory molecules, such CD28, OX40, GITR, CD137 or CD27 combined with anti-PD1 or anti-PDL1 are also underway for early clinical trial (Table 1). Most of these combinational approaches have demonstrated synergistic effect in preclinical model, however, it should be further investigated whether these results can be translated into clinical trial, even though several early clinical studies of combination showed tolerable safety profile and response even CPIs refractory patients. Further, it will be long way to go to determine which combination is the most effective among others. Moreover, continuous efforts to search for predictive biomarker for combination approach of CPIs should be elaborated.

      References

      Hellmann, M.D., et al., Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med, 2018

      Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012. 12(4): p. 252-64

      Borghaei H., et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer with <1% tumor PD-L1 expression: Results from CheckMate 227. J Clin Oncol 36,2018 (suppl;abstr 9001)

      Table 1. Ongoing early clinical trials of co-stimulatory of co-inhibitory molecules alone or in combination with anti-PD1 or anti-PD-L1.

      Molecules

      Agents (Company)

      ClinicalTrials.gov identifier

      Co-inhibitory molecules

      CTLA-4

      Ipilimumab (BMS)

      Tremelimumab (AZ)

      MK1308 (Merck)

      Phase III

      Phase III

      NCT03179436

      TIM3-

      MGB453 (Novartis)

      TSR-022 (Tesaro)

      LY3321367 (Lilly)

      NCT02608268

      NCT02817633

      NCT03099109

      VISTA

      JNJ-61610588 (Janssen) *

      NCT02671955

      LAG-3

      BMS986016 (BMS)

      IMP321 (Primo BioMed)

      LAG525 (Novartis)

      TSR033 (Tesaro)

      MGD013 (MacroGenics)

      NCT02966548

      NCT02614833

      NCT03365791

      NCT03250832

      NCT03219268

      TIGIT

      BMS986207 (BMS)

      OMP313M32 (OncoMed)

      MITIG7192A (Genentech)

      MK7684 (Merck)

      NCT02913313

      NCT03119428

      NCT02794571

      NCT02964013

      Co-stimulatory molecules

      OX40

      GSK3174998 (GSK)

      MOXR0916 (Genentech)

      MEDI0562 (Medimmune)

      PF-04518600 (Pfizer)

      NCT02528357

      NCT02219724

      NCT02318394

      NCT02315066

      GITR

      TRX518 (Leap Therapeutics)

      MEDI1873 (Medimmune)

      BMS986156 (BMS)

      NCT01239134

      NCT02583165

      NCT02598960

      CD137

      Urelumab (BMS)

      Utolimumab (Pfizer)

      NCT01471210

      NCT01307267

      CD27

      Varilumab (Celidex Therapeutics)

      NCT01460134

      *terminated

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      MS28.03 - Combinatorial IO + Chemo

      14:00 - 14:15  |  Presenting Author(s): Rosalyn Juergens

      • Abstract

      Abstract not provided

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      MS28.04 - Combination with Targeted Therapies

      14:15 - 14:30  |  Presenting Author(s): Ross Soo

      • Abstract

      Abstract

      Molecular targeted therapy and immunotherapy have transformed the treatment of lung cancer. In oncogene driven lung cancer such as EGFR mutant or EML4-ALK rearranged NSCLC, molecular targeted therapy is associated with high response rates but are usually not durable. Lately, the use of immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) have generated regulatory approvals in the first line and pre-treated setting for advanced NSCLC. Single agent immune checkpoint inhibitors are associated with lower responses but responses are more durable. The combination of targeted therapy and immunotherapy can potentially deliver new opportunities to improve anti-cancer treatments. In this presentation, PD1/PD-L1 inhibitors in combination with targeted therapies will be discussed with a focus on EGFR mutant/ ALK rearranged NSCLC. The areas to be reviewed include: (1) oncogene signalling pathways and PD-L1 expression, (2) the reduced effectiveness of immune checkpoint inhibitors in pre-treated EGFR/ALK +ve NSCLC, (3) mechanisms for an impaired response to immune checkpoint inhibitors, (4) the relationship between PD-L1 expression and response to targeted therapy, (5) the immunological effects of molecular targeted therapy and (6) the efficacy and toxicity outcomes in studies of combination targeted therapy and immune checkpoint inhibitors in oncogene driven tumors.

      In addition, the role of immunotherapy in combination with antiangiogenic agents and EGFR monoclonal antibodies in oncogene negative NSCLC will also be presented. A better understanding of the integration of targeted therapies with immunotherapies will be required to inform on the design of combination strategies and improve outcomes and reduce toxicities in patients.

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      MS28.05 - Combining IO with Radiation

      14:30 - 14:45  |  Presenting Author(s): Corinne Faivre-Finn

      • Abstract

      Abstract

      Lung cancer remains the leading cause of cancer-related death worldwide, with non-small cell lung cancer accounting for 85% of the disease. Over 70% of patients present with locally advanced, non-resectable or metastatic disease and despite improvements in chemo-radiotherapy regimens and the development of molecularly targeted agents, 5 year survival rates remain poor, with acquired resistance to novel targeted therapies becoming a growing concern. Currently there remains an unmet need in effectively treating and inducing durable responses in advanced disease. Targeting the immune system has, however, recently given hope of improving therapeutic outcomes for these patients. The notion that the immune system is capable of recognising and eliminating cancer cells is now a widely accepted phenomenon and growing evidence suggests lung cancer is an attractive target for such intervention. Recent success targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis of immune checkpoint inhibition in stage IV non-small cell lung cancer suggests a major immunotherapeutic advance in treating lung cancer and unheralded opportunity for such approaches to further improve outcome for patients.

      Currently there is considerable interest in combining anti-PD-1 or PD-L1 monoclonal antibodies with established standard of care therapies such as radiotherapy.

      Radiotherapy is known to be immunostimulatory and efforts are underway to combine and augment the efficacy of the immune checkpoint inhibitors further. The combination of radiotherapy with immunotherapy has the potential to augment anti-tumour immune responses. This talk will outline the interaction between lung cancer and the immune system, summarises current evidence supporting the use of monoclonal antibodies targeting the PD-1 axis in lung cancer (including the PACIFIC trial) and will summarise ongoing clinical trials.

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      MS28.06 - Q&A

      14:45 - 15:00

      • Abstract

      Abstract not provided

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    MS29 - Selection into Screening Programs: Interplay of Risk Algorithms, Genetic Markers and Biomarkers

    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Moderators:
    • +

      MS29.00 - Introduction with Poll Slides

      13:30 - 13:35  |  Presenting Author(s): Betty Tong, John R Goffin

      • Abstract

      Abstract not provided

    • +

      MS29.01 - Assessment of Risk Prediction Algorithms for Entry into Screening Programs

      13:35 - 13:50  |  Presenting Author(s): Martin Tammemägi

      • Abstract

      Abstract not provided

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      MS29.02 - Defining Screening Frequency &amp; Duration Using Risk Prediction Algorithms and CT Image Findings

      13:50 - 14:05  |  Presenting Author(s): Kevin ten Haaf

      • Abstract

      Abstract

      Lung cancer screening guidelines generally recommend annual screening, similar to the design of the National Lung Screening Trial.1, 2 However, results from European trials indicate that longer time-intervals between screenings can still yield a stage-shift.3, 4 This has led to discussion on the feasibility of screening programs with longer time-intervals between screenings.

      Findings from trials has led to improvements in interpreting and managing nodules found on CT screens. These findings have been essential in improving nodule management protocols and reducing the number of false-positive results.5, 6 But, the results of CT screens have also been shown to inform an individual’s future lung cancer risk.5, 7, 8

      The NLST showed that individuals with a negative baseline screen had a lower risk of developing lung cancer compared to participants with a positive baseline screen.8 Analyses of the ongoing Dutch-Belgian Lung Cancer Screening Trial (NELSON) indicate that the results of the first three screening rounds were indicative for detection of lung cancer in the fourth screening round.7 In addition, NELSON showed that the characteristics of screen-detected nodules can be used to estimate the two-year risk for developing lung cancer.5

      Risk prediction models have been suggested for selecting individuals for lung cancer screening. Analyses of different risk prediction models have been shown to be superior compared to participant selection based on age and pack-years.9 Combining these models with the information provided by CT screens may allow the personalization of an individual’s screening regimen.

      This session will consider the evidence on the effects of varying time-intervals between screenings. In addition, it will discuss the potential for personalizing the screening regimen based on screening results and other risk factors.

      References

      1. Aberle DR, Adams AM, Berg CD, et al. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. New England Journal of Medicine 2011;365:395-409.

      2. Moyer VA, on behalf of the USPSTF. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine 2014;160:330-338.

      3. Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval. Thorax 2016.

      4. Sverzellati N, Silva M, Calareso G, et al. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen. Eur Radiol 2016;26:3821-3829.

      5. Horeweg N, van Rosmalen J, Heuvelmans MA, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. The Lancet Oncology;15:1332-1341.

      6. Callister MEJ, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules: accredited by NICE. Thorax 2015;70:ii1.

      7. Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Risk stratification based on screening history: the NELSON lung cancer screening study. Thorax 2017.

      8. Patz Jr EF, Greco E, Gatsonis C, et al. Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial. The Lancet Oncology 2016;17:590-599.

      9. ten Haaf K, Jeon J, Tammemägi MC, et al. Risk prediction models for selection of lung cancer screening candidates: A retrospective validation study. PLOS Medicine 2017;14:e1002277.

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      MS29.03 - Polygenic Risk Score for Risk Assessment

      14:05 - 14:20  |  Presenting Author(s): Rayjean J. Hung  |  Author(s): Yonathan Brhane, Nilanjan Chatterjie, David C Christiani, Neil Caporaso, Maria Teresa Landi, Loic Le Marchand, Geoffrey Liu, Stephen Lam, John Kirkpatrick Field, Paul Brennan, Christopher Ian Amos

      • Abstract

      Abstract

      Background: Genome-wide association studies uncovered multiple lung cancer susceptibility genes, and consortium efforts greatly increased our ability to investigate the genetic architecture of histological subtypes. However the clinical utility of these genomic discoveries remains unclear. Method: We therefore constructed a risk prediction model with polygenic risk score (PRS) based on 18,316 lung cancer patients and 14,025 controls with European ancestry, via 10-fold cross-validation with elastic net penalized regression. Model calibration was assessed, and was validated with UK biobank data (N=336,911 unrelated participants with European ancestry). To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (NLST, N=50,772 participants). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. Added value of PRS to the risk prediction model was assessed by Net Reclassification Index. Results: A PRS was constructed based on 128 independent lung cancer variants using regularized penalized regression. The lung cancer ORs for individuals at the bottom 5% and top 5% of the PRS distribution were 0.49 (95%CI=0.43-0.56, P=2.7e-26) and 2.23 (95%CI=1.93-2.58, P=2.3e-27) in the training set, and 0.46 (95%CI=0.34-0.64, P=2.50e-6) and 1.33 (95%CI=1.08-1.64, P=7.10e-3) in the testing set, versus those at 40 to 60% as the referent group. The OR per standard deviation of PRS was 1.43 (95%CI=1.39-1.47. P=7.8e-138) for overall lung cancer risk in the training set and 1.24 (95%CI=1.18-1.30, P=2.59-e19) in the testing set. When considering age as the time scale, PRS separated out the curve of 5-year absolute risk and cumulative risk. When simulating the PRS distribution in the NLST population, we estimated 47.4% of cases occurred in the top 20% of the individuals with highest lifetime cumulative risk. Discussion: Including well-established genomic information in the risk model can contribute to the risk stratification of the population.

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      MS29.04 - LuCID Exhaled Breath Analysis

      14:20 - 14:35  |  Presenting Author(s): Marc Phillipe Van Der Schee  |  Author(s): Edoardo Gaude, Jasper Boschmans, Billy Boyle, Robert Campbell Rintoul, Robert Smith, Anna Battista

      • Abstract

      Abstract

      The Breath Biopsy platform enables the collection and analysis of breath samples, in order to look for volatile organic compound (VOC) biomarkers of disease. The LuCID (lung cancer indicator detection) project is one of the first major deployments of the platform in a research setting, and is currently the largest breath-based trial in the world, recruiting up to 4000 patients. The aim of the LuCID project is to discover VOC biomarkers in breath for early detection of lung cancer, which could improve patient outcomes and save lives. In this talk, we will give an introduction to the LuCID program, then go on to describe the biology underlying the VOC biomarkers, before discussing the inherent challenges associated with breath sampling and analysis. We will conclude by giving an update on the progress of the LuCID trial to date.

      The LuCID Study

      LuCID is an international multi-centre prospective case-control cohort study (ClinicalTrials.gov ID NCT02612532) currently in progress, evaluating breath VOCs in patients with a clinical suspicion of lung cancer. A clinical suspicion is based on symptoms and/or suspicious finding on incidental imaging. Using tidal breathing, patients breathe into the ReCIVA Breath Sampler to collect breath samples on stable sorbent tubes for later analysis by Gas Chromatography-Mass Spectrometry and Field Asymmetric Ion Mobility Spectrometry (FAIMS, Owlstone Medical Ltd). One arm of the study is focused on early detection of lung cancer, with the aim of increasing the number of cases diagnosed at Stages 1 and 2, while an additional arm is currently being initiated looking at differences in breath profiles pre- and post-surgery which has the advantage of allowing the patient to act as their own control.

      The Biology of VOCs

      So why would we believe that VOC biomarkers for lung cancer could be discovered during LuCID? Cancer cells undergo profound changes of their metabolism in order to support high energetic demands of uncontrolled proliferation. Several oncogenic mutations have been shown to affect metabolism of cancer cells by converging to common metabolic pathways linked to cell cycle and anabolic growth. The Warburg effect is among well-established cancer metabolic hallmarks and entails the activation of aerobic glycolysis as main pathway for biosynthetic purposes, as opposed to normal cells that exploit mitochondrial metabolism for their energetic needs. These changes in cellular metabolism favor survival in an oxygen deprived environment and result in altered metabolic intermediates that function as the building blocks for new cells, both enabling the growth of rapidly dividing cancer cells, and also altering the profile of VOCs in breath. As these processes are fundamental to cancer cell survival, such altered metabolism occurs as one of the earliest stages of tumorigenesis, hence VOCs are excellent candidate biomarkers for early detection of cancer.

      Breath Sampling: Challenges and Solutions

      The potential of using breath sampling to identify markers of disease has long been recognised, but has to date seen almost no adoption into clinical practice, with only FeNO and H. pylori breath tests in widespread use. This has largely been due to practical considerations that have made large-scale clinical trials impractical to carry out. Most previous tests have involved collecting breath in bags, which

      - suffer from chemical losses over time

      - are vulnerable to contamination from ambient air if they are reused incorrectly

      - are difficult to transport and store.

      - only allow the collection of smaller volumes, limiting the sensitivity of the analysis.

      In this section, we will discuss how the ReCIVA breath sampler, a key part of the Breath Biopsy platform, allows these problems to be overcome, and we will present data, including VOC washout curves monitoring changes in VOC levels over time following ingestion of a peppermint capsule, that demonstrate how the ReCIVA performs in practice.

      reciva.jpg

      Image 1: The ReCIVA breath sampler

      Current Status of the LuCID trial

      In the concluding section, we will provide an update on the LuCID trial. We have identified some VOCs for which we have observed associations with certain disease processes in our biomarker discovery phase, and we are currently investigating what the mechanisms associating these VOCs with lung cancer initiation and progression might be.

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      MS29.05 - Early Detection Biomarker Development: Is Success on the Horizon?

      14:35 - 14:50  |  Presenting Author(s): Peter Mazzone

      • Abstract

      Abstract

      There is a recognized need for biomarkers capable of assisting with the early diagnosis of lung cancer. We need tools to improve our ability to identify patients at risk of developing cancer; to identify patients with asymptomatic early stage lung cancer; to identify patients who are more likely to die of causes other than lung cancer; to help us characterize the nature of a patient’s lung cancer; and to improve our management of lung nodules (expedite diagnosis, reduce the risks of evaluation, reduce the cost of evaluation).

      To have clinical utility a biomarker result must affect a clinical decision in a manner that leads to improved patient care. Both the benefit of clinical decisions influenced by true positive and negative results and the harms of clinical decisions influenced by false positive and negative results must be considered. In the screening setting a biomarker should lead to fewer lung cancer deaths without substantially increasing harms or expense, or a similar number of lung cancer deaths with fewer harms or less expense. When used to characterize a lung nodule a biomarker should lead to earlier diagnosis of malignant nodules without substantially increasing the number of procedures performed on patients with benign nodules or fewer procedures for patients with benign nodules without substantially delaying the diagnosis of cancer in patients with malignant nodules.(1)

      Biomarker development moves through a series of phases. In the discovery phase, a molecule or pattern of molecules are found to be associated with the presence or absence of the condition in question. If the association appears to be strong enough the biomarker may be taken to validation stages. Technical validation refers to the assessment of the accuracy (precision, reproducibility) of the assay that will measure the biomarker. Clinical validation refers to determining the accuracy (sensitivity, specificity, AUC, NRI) of a biomarker, with a fixed threshold for result interpretation, when applied to the intended use population. Through each phase of development standard operating procedures that include pre-analytical, analytical, and post-analytical processes, must be in place. Even accurate biomarkers may not be clinically useful. Prior to clinical use, it is important that the validated biomarker move through the clinical utility phase of assessment.

      To determine if the accuracy of a validated biomarker is high enough to invest in a clinical utility study one must consider the potential impact of true and false positive and negative results. In a screening context true positive results may lead to individuals with lung cancer being identified at curable stages while false positive results may lead to individuals without lung cancer (or at low risk of developing lung cancer) being enrolled in screening programs where they will be exposed to the associated harms of screening. True negative results could lead to individuals without lung cancer (or at low risk of developing lung cancer) avoiding the harms associated with low-dose CT screening while false negative results could prevent individuals with (or who will develop) lung cancer from being enrolled in a low-dose CT based lung cancer screening program, and thus not have an opportunity to benefit.

      A judgment about an acceptable tradeoff of benefit and harm from using the biomarker will have to be made. The biomarker should be more accurate at identifying patients with (or who will develop) potentially curable lung cancer than current eligibility criteria and available clinical risk prediction calculators, alone or in combination. What is considered an acceptable tradeoff in a screening context is likely to vary based on whether the biomarker is being applied to a cohort already eligible for LDCT screening or to a cohort that is currently not eligible for LDCT screening. In the former it is most important that patients with lung cancer are not excluded from being screened (rule out test) while in the latter it may be more important not to screen individuals without lung cancer (rule in test). Calculations exist that use currently accepted benefit:harm ratios when available (e.g. the currently eligible cohort for screening had an incidence of lung cancer of 0.83% in the NLST trial) to help determine if the validated accuracy supports pursuit of clinical utility studies.(2) Biomarker-stratified, enrichment, and biomarker-strategy study designs are acceptable approaches to determine clinical utility.

      Ongoing research trials are moving potential biomarkers through the phases of development. A handful of biomarkers have completed discovery level work and are working on, or have published or presented clinical validation study results. Others continue discovery level work. Few have entered formal clinical utility testing. Oncimmune’s panel of autodantibodies, the EarlyCDT-Lung test, is being assessed as part of a 12,000 person randomized controlled screening study (the ECLS study). An exciting amount of high quality discovery and clinical validation work is ongoing. Some companies are in the process of planning true clinical utility studies for early lung cancer detection (Table).

      Company

      Biomarker

      Target

      Completed

      Ongoing

      Plans

      ANCON

      VOC – NBT

      N/A

      N/A

      Discovery

      N/A

      bioAffinity

      Sputum flow cytometry

      N/A

      N/A

      Discovery

      N/A

      Exact Sciences

      DNA methylation

      Nodule

      N/A

      Discovery

      Clinical Validation

      Genesys

      Antigens, Auto-antibody

      Screening

      Clinical Validation

      N/A

      N/A

      GRAIL

      cfDNA assays

      Screening

      N/A

      Discovery

      Clinical Validation

      InDi

      2 proteins + clinical

      Nodule

      Clinical Validation

      N/A

      Clinical Utility

      MagArray

      Antigens and Autoantibodies

      Nodule

      Discovery

      Clinical Validation

      Clinical Utility

      Nucleix

      DNA methylation

      Screening

      Discovery

      N/A

      Clinical Validation

      Oncimmune

      Autoantibodies

      Nodule, Screening

      Clinical Validation

      ECLS study

      Clinical Utility

      Oncocyte

      mRNA + size

      Nodule

      Discovery

      Clinical Validation

      Clinical Utility

      Owlstone

      VOC - FAIMS

      N/A

      N/A

      Discovery

      N/A

      Synergenz

      SNPs + clinical

      Screening

      Clinical Validation

      N/A

      N/A

      Veracyte

      Airway genome signature

      Nodule

      Clinical Validation

      Registry study

      Discovery

      Mazzone PJ, Sears CR, Arenberg DA, Gaga M, Gould MK, Massion PP, Nair VS, Powell CA, Silvestri GA, Vachani A, Wiener RS. Evaluating molecular biomarkers for the early detection of lung cancer: When is a biomarker ready for clinical use? An official American Thoracic Society policy statement: Executive summary. Am J Respir Crit Care Med 2017;196(7):911-919.

      Pepe MS, Janes H, Li CI, Bossuyt PM, Feng Z, Hilden J. Early-phase studies of biomarkers: what target sensitivity and specificity values might confer clinical utility? Clin Chem 2016;62:737–742.

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      MS29.06 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

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    MS30 - Modern Day RT in LA NSCLC: Where Is the Evidence?

    • Type: Mini Symposium
    • Track: Treatment of Locoregional Disease - NSCLC
    • Moderators:
    • +

      MS30.01 - Introduction with Poll Questions

      13:30 - 13:35  |  Presenting Author(s): Fiona Hegi-Johnson, Yuko Nakayama

      • Abstract

      Abstract not provided

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      MS30.01 - Overview of RT Technology in LA NSCLC (IMRT, VMAT, IGRT)

      13:35 - 13:50  |  Presenting Author(s): Gerard G Hanna

      • Abstract

      Abstract

      External bean radiotherapy remains the key treatment modality for the radical treatment of inoperable locally advanced non-small cell lung cancer (LA-NSCLC). Outcomes remain poor with a median overall survival of approximately 25–29 months in those patients who have received combined modality therapy [1,2]. In radiotherapy treatment the aim of radical treatment is to achieve an optimal therapeutic benefit with the highest probability of tumour control but with minimal associated toxicity. The Radiation Therapy Oncology Group (RTOG) randomised phase III 0617 study comparing standard dose (60 Gy) to dose escalated radiotherapy (74 Gy) given with concomitant systemic therapy has highlighted in the modern era the importance of the dose received by normal tissues and toxicity in relation to overall survival. In this study the maximum grade of oesophageal toxicity and the proportion of heart receiving radiation dose were both factors associated with poorer survival [2].

      The last two decades have seen many technical advances in radiotherapy delivery techniques. For treatment planning, the objective is to attain conformity of the planned dose to the target volume within minimal dose to adjacent normal tissues. There have been significant advances in radiotherapy treatment planning with improved accuracy of modelling how radiotherapy treatment beams interact with inhomogeneous structures such as the lung. This coupled with improved computing power, permits the accurate and fast generation of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans. Both IMRT and VMAT delivery improves of the sparing of normal tissues but may increase low dose radiotherapy exposures to the lung. The impact of this low dose exposure remains uncertain.

      There have been important advances in assessment and management of target and organ motion within the thorax and use of techniques to individualise treatment based on the motion to improve the treatment accuracy [3,4]. For radiotherapy delivery over the course of treatment, the objective is consistency between the planned and delivered dose distributions. With recent widespread availability of cone-beam computerised tomography (CBCT) it is now possible to use these images to assess of the shape and position of the radiotherapy target in relation to the planned dose delivery prior to treatment, image guided radiotherapy (IGRT), to improve accuracy of treatment delivery and where necessary to use this information to adapt treatment based, image guided adaptive radiotherapy (IGART) [5]. It is hoped that emerging technologies such MR-Linac, which combines a magnetic reasonance imaging unit with linear accelerator, will further develop IGRT and IGART delivery.

      Establishing the clinical benefit and cost-effectiveness of these technological advances is challenging. The improved median survival in the standard arm of recent randomised trials [1,2] compared to historical trials suggests that technical advances may improve survival outcomes. Additionally, there are retrospective data from a large series that suggest IMRT in particular may be associated with improved outcome in stage III NSCLC with T3 and T4 tumours [6] and a recent secondary analysis of the RTOG 0617 trial suggests use of IMRT compared to 3D conformal techniques is associated with lower severe lung toxicity and lower cardiac doses [7]. Finally, it is hoped that the use of these advanced techniques will permit radiotherapy treatment intensification either through alter radiotherapy dose delivery or the combination with systemic therapy.

      References:

      [1] S. Senan, A. Brade, L.H. Wang, J. et al., PROCLAIM: randomized Phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 2016;34(9):953–962.

      [2] J.D. Bradley, R. Paulus, R. Komaki, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187–199.

      [3] J. Cole, G.G. Hanna, S. Jain, et al. Motion management for radical radiotherapy in non-small cell lung cancer, Clin. Oncol. (R. Coll. Radiol.) 2013;26(2):67–80.

      [4] J.W.H. Wolthaus, J.-J. Sonke, M. van Herk, et al. Comparison of different strategies to use four-dimensional computed tomography in treatment planning for lung cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 2008;70 (4):1138–1229.

      [5] M. Kwint, S. Conijn, E. Schaake, et al. Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy, Radiother. Oncol. 2014; 113(3): 392–397.

      [6] N. Jegadeesh, Y. Liu, T. Gillespie, F. et al. Evaluating intensity-Modulated radiation therapy in locally advanced non-small-cell lung cancer: results from the national cancer data base. Clin. Lung Cancer 2016;17(5):398-405.

      [7] S.G. Chun, C. Hu, H. Choy, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial, J. Clin. Oncol. 2017 Jan;35(1):56-62.

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      MS30.02 - What Evidence Is Available to Support RT Technology in LA NSCLC (including Protons)?

      13:50 - 14:05  |  Presenting Author(s): Yong Chan Ahn

      • Abstract

      Abstract not provided

    • +

      MS30.03 - What Evidence Is Available to Support RT Treatment Intensification in LA NSCLC?

      14:05 - 14:20  |  Presenting Author(s): Jeffrey Bradley

      • Abstract

      Abstract not provided

    • +

      MS30.04 - Perspective

      14:20 - 14:35  |  Presenting Author(s): Maria Werner-Wasik

      • Abstract

      Abstract

      Radiation therapy (RT) in locally advanced non-small cell lung cancer (LA-NSCLC) has not changed in its essence over many decades. The refinements in “standard-of-care” RT followed the general advancements applicable to many other malignancies, such as introduction of IMRT (including VMAT) and IGRT. Tumor motion appears more relevant in lung tumors than in other disease sites, and lung-tumor interface allows for a measurable and intuitively observable movement, therefore enabling motion management in the lung to be more advanced, such as 4D CT for planning and tumor tracking (CyberKnife) or gating in daily practice.

      Nevertheless, the median survival time (MST) for good performance unresectable Stage II/III patients with NSCLC, treated with concurrent chemoradiotherapy (chemo-RT) has improved significantly over last quarter century, from MST of 17.1 mo (RTOG 9410) to MST of 28.7 mo (RTOG 0617). Since the agents used in concurrent chemotherapy are not significantly different, other causes, mostly widespread use of PET scans for staging, as well as improved RT techniques, likely play a role. Use of CT simulation is associated with improved MST, even when adjusted for other variables, such as chemotherapy use, comorbidities or urban location. Volumetric (rather than 2D) dose prescription; use of lower energy photons and heterogeneity correction; accounting for tumor motion with a 4D CT simulation and IGRT; better understanding of normal tissue tolerance (lung V20) and of the need to limit RT course breaks, all add incremental benefits for a more favorable outcome.

      In addition, factors such as RT center’s experience and volume of treated patients, as well as any protocol deviations in clinical trials, have been found to have a major impact in clinical practice, raising the possibility that strict adherence to RT planning guidelines might benefit all cancer patients treated with RT. Those factors have not yet been accounted for as eligibility/stratification factors in studies.

      Some much touted newer technologies, as particle RT (protons) have not so far demonstrated a verifiable superiority over photons. The Phase II randomized MDACC trial of photon vs. proton-based chemoradiotherapy for patients with Stage III or oligometastatic NSCLC did not show a difference in radiation pneumonitis rates between the arms and no improvement in local control in the proton arm. However, a steep learning curve in using proton RT was discovered, with lower pneumonitis rates in those patients in the proton group who were treated in the latter half of the study vs. those treated in its early phase.

      The ongoing NRG Oncology/RTOG 1308 Phase III randomized trial of photon vs. proton chemo-RT (70 Gy, but not lower than 60 Gy) has had a slow accrual, partially due to the paucity of participating centers, since proton technology is not widespread yet; also, a high percentage of patients not being able to enroll due to medical insurance coverage denial for protons, as well as possible perceptions of the superiority of protons. That study’s design has been modified recently to allow for a faster study’s completion. The original primary endpoint was overall survival, in contrast to the MDACC trial, where pneumonitis and local failure rate were co-endpoints. In order to complete the RTOG 1308 trial sooner by lowering its target accrual, the current primary hypothesis is that the MST in the proton arm is non-inferior to the photon arm (i.e. 28 mo), and major cardiac toxicity and grade 4 or higher lymphopenia is better in the proton vs. photon arm. Additionally, the Quality of Life hypothesis is that, compared with patients receiving photon therapy, patients on the proton arm will have less severe shortness of breath 6 months after the end of concurrent chemor-RT (representing late adverse response to therapy), and that the differences in symptom ratings (based on MDASI shortness of breath item) between arms will be clinically meaningful.

      The recent availability of Magnetic Resonance (MR)-Guided RT may open a new era in lung cancer RT, allowing for the real-time intrafractional tumor tracking and “on the fly” adaptive RT, both likely to allow smaller tumor target volumes and a rigorous evaluation of doses delivered to the normal structures, therefore lowering toxicity and potentially opening the door to reassessment of RT dose intensification.

      Finally, with the explosion of evidence-based applications of immunotherapy in metastatic lung cancer and the demonstration of an impressive survival prolongation in the Phase III randomized PACIFIC trial with the addition of maintenance durvalumab following chemo-RT, the role of chemotherapy may be eventually challenged and reevaluated in Stage III NSCLC, to be possibly replaced by concurrent immunotherapy or a chemo-immunotherapy combination.

      References:

      Curran WJ, Paulus R, Langer C et al, JNCI 2011

      Bradley J, Paulus R, Komaki R et al, Lancet Oncology 2015

      Chee KG, Nguyen DW, Brown M et al, Arch Internal Medicine 2008

      Ohri N, Shen X, Dicker AP et al, JNCI 2013

      Chen AB, Neville BA, Sher DJ et al, JCO 2011

      Eaton BR, Pugh SL, Bradley JD et al, JNCI 2016

      Liao Z, Lee JJ, Komaki R et al, JCO 2018

      Antonia SJ, Villegas A, Daniel D et al, NEJM 2017

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      MS30.05 - Nutritional Management During Radical Radiotherapy

      14:35 - 14:50  |  Presenting Author(s): Rhys White

      • Abstract

      Abstract

      Curative intent fractionated external beam radiotherapy (RT) with or without chemotherapy is used to treat locally advanced non-small cell cancer (NSCLC) and common side effects include anorexia, oesophagitis and fatigue, all of which can all impact on nutritional status. Previous research has shown that up to one third of lung cancer patients treated with RT experience clinically significant weight loss1 while one third of lung cancer patients present with malnutrition prior to even commencing RT 2. The negative impact of weight loss and malnutrition on patient and clinical outcomes is well established across all modes of cancer treatment including chemoradiotherpy3.

      There is limited evidence available relating to effective nutritional support strategies to prevent or treat weight loss and malnutrition in lung cancer4. There may be a role for enteral feeding where severe oesophagitis occurs in order to support patients through radical radiotherapy and its recovery1. The nutrition intervention demonstrated to be most effective in other tumours undergoing radiotherapy treatment is intensive individualised dietary counselling5 and the presence of dedicated dietetic services to head and neck and oesophageal cancer patients is well established in the U.K with dietitians identified as core members of the multi-disciplinary team.

      This session will explore the impact of a worsening nutritional status on clinical and patient outcomes and discuss the nutritional interventions that may be of benefit. It will also consider the role of a dedicated lung cancer dietitian and the impact this can have on patients with lung cancer.

      References:

      1. Kiss, N., Isenring, E., Gough, K. et al (2014) The prevalence of weight loss during (chemo)radiotherapy treatment for lung cancer associated patient- and treatment-related factors. Clin Nutr, 33: 1074-1080

      2. Unsal, D., Bulent, M., Akmansu, M. et al (2006) Evaluation of nutritional status in cancer patients receiving radiotherapy. Am J Clin Oncol 29: 183-188

      3. Sanders, K., Hendricks, L., Troost. et al. (2016) Early weight loss during chemoradiotherapy has a detrimental impact on outcome in NSCLC. J Thor Oncol, 11: 873-879

      4. Kiss, N., Krishnasamy, M. and Iserning, E. (2013) The effects of nutrition intervention in lung cancer patients undergoing chemotherapy and/or radiotherapy: a systematic review. Nutr Cancer, 66: 47-56

      5. Lee, J., Leong L. and Lim, S. (2016) Nutrition intervention approaches to reduce malnutrition in oncology patients: a systematic review. Support Care Cancer, 24: 469-480

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      MS30.06 - Q&A with Poll Questions

      14:50 - 15:00

      • Abstract

      Abstract not provided

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    MS31 - Clinical Science in Mesothelioma

    • Type: Mini Symposium
    • Track: Mesothelioma
    • Moderators:
    • +

      MS31.01 - Mechanisms and Targets for BAP1 Activity

      13:30 - 13:45  |  Presenting Author(s): Michele Carbone

      • Abstract

      Abstract not provided

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      MS31.02 - Clinical Implementation of BAP1 Inhibitors

      13:45 - 14:00  |  Presenting Author(s): Paul Baas  |  Author(s): Laurel Schunselaar

      • Abstract

      Abstract

      Over the last few years BRCA associated protein 1 (BAP1) has attracted attention in the development of cancer[1-2].
      BAP1 is one of the molecular targets that has been identified as a novel target in this disease. The function of BAP1 is mainly regulatory, including its function as deubiquitinating enzyme (DUB) of H2A. Through its deubiquitinase activity and the effects on transcription, BAP1 functions as a tumor suppressor gene. It regulates transcription, cell cycle control, DNA damage repair and cellular differentiation [1-4].

      Patients with a BAP1 germline mutation often presents with skin disorders including skin tumors and uveal melanomas and are often diagnosed at an early age. BAP1 germline mutation in patients with mesothelioma was first reported in 2011 [5]. In these cases, prognosis seems to be better with a 5-year survival rate of 47%, as compared to 6,7% for patients who did not have the mutation [6].

      Although germline mutations are rare in mesothelioma [7], somatic BAP1 aberrations are more common in mesothelioma tumors. Studies showed that 47-67% of the mesothelioma tumors contain a BAP1 genetic aberration. BAP1 somatic mutations are more frequent in the epithelioid subtype than in the sarcomatoid subtype. Besides single point mutations in the BAP1 gene, copy number loss, rearrangements and multiple alterations have been reported. The somatic BAP1 mutation can easily be identified with immunohistochemistry.

      BAP1 as a drug target in mesothelioma

      The regulation of histones by BAP1 suggests that an interaction with histone deacetylase (HDAC) inhibitors could be beneficial. In mesothelioma, the effect of HDAC inhibitors on H2A is not known, but BAP1 knockdown in mesothelioma cell lines increases the sensitivity for HDAC inhibitors leading to cell death, a process known as synthetic lethality. In the VANTAGE 014 study, a phase III trial including 661 patients, the HDAC inhibitor vorinostat did not improve overall survival in an unselected group of patients compared to placebo [8].

      Enhancer of zeste homolog 2 (EZH2) is upregulated in mesothelioma and preclinical models have identified a possible association between BAP1 loss and EZH2 upregulation. Specific EZH2 inhibitors decreased cell proliferation, reduced invasion and reduced clonogenicity in mesothelioma cell lines and tumor bearing mice. Importantly, BAP1 mutant mice were more responsive to the EZH2 treatment compared to wild type mice. In different tumor types, phase I studies with EZH2 inhibitors showed promising results [9]. Currently a study in mesothelioma patients with the EZH2 inhibitor tazemetostat is ongoing (NCT02860286).

      Another interaction partner of BAP1 is host cell factor 1 (HCF1). This protein has a role in cell cycle progression by activating transcription of promotors bound by the E2F (transcription) family. BAP1 deubiquitinates HCF1 and recently multiple groups showed that BAP1 mutation results in increased HCF1 ubiquitination, impairing E2F activation. Decreased activation of E2F causes problems in cell cycle progression and results in the inhibition of cell growth. Although there are no drugs yet available to inhibit E2F, these interaction partners may provide options for new therapeutic interventions.

      Synthetic lethality.
      Due to its regulatory function in DNA repair damage, it is expected that in BAP1 mutated cases the homologous recombination (HR) DNA repair system is impaired. The use of PARP1 inhibitors could therefore be promising as is shown in ovarian and mammary carcinoma. Preclinical studies of nirapanib and olaparib in mesothelioma cell lines proved to inhibit the cell growth, but this effect was independent of the BAP1 mutation status [10]. Therefore it is expected that other pathways are more important in this approach.

      Conclusions.

      For the treatment of tumors with BAP1 protein loss, it is important to identify therapeutic agents that reverse the phenotypic effects. Multiple interaction partners and proteins under influence of BAP1 are reported and (pre)clinical data of new inhibitors targeting these partners is promising. Further research on BAP1 action is required before we define an optimal treatment plan. Due to the many interaction partners and different functions of BAP1 the future we will probably end up with a combination of agents to reverse the phenotypic effect of BAP1 protein loss.

      Reference

      1. Wang, A., et al., Gene of the month: BAP1. J Clin Pathol, 2016. 69(9): p. 750-3.

      2. Bononi, A., et al., Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies. Expert Rev Respir Med, 2015. 9(5): p. 633-54.

      3. Misaghi, S., et al., Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol, 2009. 29(8): p. 2181-92.

      4. Scheuermann, J.C., et al., Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature, 2010. 465(7295): p. 243-7.

      5. Testa, J.R., et al., Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet, 2011. 43(10): p. 1022-5.

      6. Baumann, F., et al., Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis, 2015. 36(1): p. 76-81.

      7. Sneddon, S., et al., Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma. Gene, 2015. 563(1): p. 103-5.

      8. Krug, L.M., et al., Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol, 2015. 16(4): p. 447-56.

      9. Kim, K.H. and C.W. Roberts, Targeting EZH2 in cancer. Nat Med, 2016. 22(2): p. 128-34.

      10. Gayathri Srinivasan et al. Synthetic lethality in malignant pleural mesothelioma with PARP1
      inhibition.
      Cancer Chemother Pharmacol. 2017; 80(4): 861–867.

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      MS31.03 - Targeting the Hippo Pathway

      14:00 - 14:15  |  Presenting Author(s): David Mark Jablons  |  Author(s): Gavitt A. Woodard

      • Abstract

      Abstract

      The prognosis for malignant pleural mesothelioma (MPM) remains poor and many anticipated advances in MPM treatment have been disappointing. One reason for the failure of conventional cytotoxic drugs is that they do not address the cancer stem cell population or the stem cell pathways that drive tumor resistance and resurgence following treatment. Cancer stem cells are defined by their properties of self-renewal, pluripotency, a high proliferative capacity and the ability to resist standard chemotherapy and radiation. Among the stem cell pathways, Hippo has proven to be critical to driving growth in MPM with mutations along this pathway implicated in the majority of MPM tumors.

      The Hippo pathway is a highly conserved regulator of organ size by regulating contact inhibition and of stem cell proliferation and maintenance.(1) The largest and most comprehensive genomic analysis to date of transcriptomes, whole exomes and targeted exomes from 216 MPM samples found Hippo pathway signaling to be the number one most significantly mutated pathway in mesothelioma with a Q-value of 1.70E-17, driven by mutations, copy number variations and fusions in NF2, LATS1, LATS2 and MST1.(2) One of the most frequently mutated genes in MPM is Neurofibromatosis type 2 (NF2) tumor suppressor, located at chromosome 22q12, and is detected in 40% to 50% of MPM tumors.(3) Large tumor suppressor homolog 2 (LAST2) gene, which is located at chromosome 13q12, is another frequently inactivated gene that is detected in 13% of MPM tumors. (3, 4) Inactivation of NF2 and LATS2 by deletion and/or mutation often contribute to dysregulation of Hippo pathway.(5) In addition to LATS2, its closest gene family member LATS1 another Hippo pathway gene, has also recently been identified to be dysregulated in MPM, though less commonly than LATS2. LATS1 is located on chromosome 6 and changes in copy number variation and fusions to Presenilin 1 (PSEN1) on chromosome 14 have been observed in MPM.(2, 3) Mammalian sterile-20 like kinase 1 (MST1) is an important upstream kinase in the Hippo pathway that has also been found to be dysregulated in MPM.(2) Given the high frequency of mutations and dysregulation in the Hippo pathway, it is a promising potential area of drug development.

      One specific target along the Hippo pathway is blocking Yes-associated protein (YAP) activity. In normal cells, Merlin, a protein encoded by NF2, and LATS2 contribute to the phosphorylation of the transcription factor YAP at S127,(6) resulting in YAP ubiquitination and activation of Hippo pathway to control cell proliferation. In MPM tumor cells, inactivation of NF2 and LATS2 prevent the phosphorylation of YAP at S127, which results in YAP relocation from the cytosol to nucleus where it interacts with TEA domain transcription factors (TEAD). In addition, constitutively activation of YAP has been identified in over 70% of primary MPM tumors, (3, 5, 7) and YAP activation leads to Hippo signaling attenuation and transcription of downstream target genes, such as connective tissue growth factor (CTGF) and Cyr61.(8) Low Merlin expression (NF2), results in YAP1 activation, and has been shown to be associated with worse clinical outcomes with shorter times to recurrence and shorter overall survival times in patients with MPM.(9) Blocking YAP activity, either via upstream inhibition of one of the several pathways that regulate YAP and Hippo or via direct YAP/TEAD inhibition is an area of active interest.(10) Several novel small molecule YAP inhibitors are in preclinical development with promising results and may enter clinical trials in the near future.

      FIGURE: Hippo Pathway Potential Drug Targets

      figure.jpg

      References

      1. Ramos A, Camargo FD. The Hippo signaling pathway and stem cell biology. Trends in cell biology. 2012;22(7):339-46.

      2. Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nature genetics. 2016;48(4):407-16.

      3. Miyanaga A, Masuda M, Tsuta K, Kawasaki K, Nakamura Y, Sakuma T, et al. Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015;10(5):844-51.

      4. Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer research. 2011;71(3):873-83.

      5. Felley-Bosco E, Stahel R. Hippo/YAP pathway for targeted therapy. Translational lung cancer research. 2014;3(2):75-83.

      6. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & development. 2007;21(21):2747-61.

      7. Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer science. 2010;101(5):1279-85.

      8. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nature reviews Cancer. 2013;13(4):246-57.

      9. Meerang M, Berard K, Friess M, Bitanihirwe BK, Soltermann A, Vrugt B, et al. Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma. Molecular oncology. 2016;10(8):1255-65.

      10. Woodard GA, Yang YL, You L, Jablons DM. Drug development against the hippo pathway in mesothelioma. Transl Lung Cancer Res. 2017 Jun;6(3):335-342.

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      MS31.04 - CAR-T and ADC's in MPM

      14:15 - 14:30  |  Presenting Author(s): Prasad S. Adusumilli

      • Abstract

      Abstract

      Novel immunotherapies for malignant pleural mesothelioma (MPM) include Antibody-drug conjugates (ADCs) and Chimeric antigen receptor (CAR) T cells, both of which are in early-phase clinical trials with promising results. CAR T cells are patient T cells that are transduced with genetically engineered synthetic receptors to target a cancer cell surface antigen. The remarkable clinical response rates achieved by adoptive transfer of T cells that target CD19 in patients with leukemia and lymphoma have led to a growing number of clinical trials exploring CAR T-cell therapy for solid tumors including in MPM. Herein, I will review the evolution of ADCs and adoptive T-cell therapy; highlight advances in CAR T-cell therapy for MPM; and summarize the antigen targets being investigated in clinical trials. I will further discuss the barriers to successfully translating ADCs and CAR T-cell therapy for solid tumors and present strategies that have been investigated to overcome these hurdles.

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      MS31.05 - Vaccination and Antibody-Based Therapy in Mesothelioma

      14:30 - 14:45  |  Presenting Author(s): Joachim G.J.V. Aerts

      • Abstract

      Abstract

      The concept of antibody based therapy hints on two concepts, on the one hand precluding the function of the ligand it binds to, which is for instance the case in VEGF targeting antibodies. And on the other hand the induction of antibody dependent cellular toxicity (ADCC) which may be induced by these antibodies. The latter is caused by activation of the immune system after an antibody binds to its ligand. Here I will focus on the role of antibodies targeting the immune checkpoints.

      Immunotherapy is now considered a standard treatment in many malignancies. Also in mesothelioma, different antibodies are now being explored [Yap 2017]. The most clinically used type of immunotherapy in oncology are checkpoint inhibitors, mostly PD-(l)1 and CTLA-4 directed antibodies. Concerning the latter, a recently published randomised trial failed to show an benefit of the anti-CTLA-4 antibody tremilimumab, compared to placebo in second and third line treatment in mesothelioma [Maio 2017]. Small and single arm studies on PD-(l)1 have been presented and did show clinical meaningful responses in patients. However this was only present in a minority of patients [Lievense 2017]. The role of ADCC in the functioning of the antibodies is not well established nor investigated, but for instance a regulatory T-cell depletion due to CTLA-4 antibodies has been described.

      The lack of benefit in the majority of patients is ascribed to the absence of a tumor directed T-cell response present in the majority of mesothelioma patients [Aerts 2013, Yap 2017]. This lack of tumor directed T-cells is related to the immunosuppressive environment caused by mesothelioma. One way of increasing the tumor directed T-cell responses is via vaccination. However in thoracic malignancies the effects of peptide vaccinations were found to be rather limited again due to the immunosuppressive environment created by the tumor. Cellular vaccinations were found to be more effective in this setting [Dammeijer 2016].

      In mesothelioma studies on cellular vaccination with dendritic cell vaccination have indeed shown that an increase in tumor directed T-cells can be achieved with clinically relevant responses [Le 2012, Peikert 2016, Aerts 2018]. This concept is now taken forward in a large randomised trial comparing dendritic cell vaccination with best supportive care as maintenance treatment after chemotherapy in patients with mesothelioma.

      In conclusion antibody based therapy and vaccination hold promise in mesothelioma, and given the dismal prognosis of these patients these options should be investigated and explored further.

      Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Maio M, Scherpereel A, Calabrò L, Aerts J, Cedres Perez S, Bearz A, Nackaerts K, Fennell DA, Kowalski D, Tsao AS, Taylor P, Grosso F, Antonia SJ, Nowak AK, Taboada M, Puglisi M, Stockman PK, Kindler HL. Lancet Oncol. 2017 Sep;18(9):1261-1273

      A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Le DT, Brockstedt DG, Nir-Paz R, Hampl J, Mathur S, Nemunaitis J, Sterman DH, Hassan R, Lutz E, Moyer B, Giedlin M, Louis JL, Sugar EA, Pons A, Cox AL, Levine J, Murphy AL, Illei P, Dubensky TW Jr, Eiden JE, Jaffee EM, Laheru DA.Clin Cancer Res. 2012 Feb 1;18(3):858-68.

      Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human. Aerts JGJV, de Goeje PL, Cornelissen R, Kaijen-Lambers MEH, Bezemer K, van der Leest CH, Mahaweni NM, Kunert A, Eskens FALM, Waasdorp C, Braakman E, van der Holt B, Vulto AG, Hendriks RW, Hegmans JPJJ, Hoogsteden HC. Clin Cancer Res. 2018 Feb 15;24(4):766-776

      Checkpoint Blockade in Lung Cancer and Mesothelioma.Lievense LA, Sterman DH, Cornelissen R, Aerts JG. Am J Respir Crit Care Med. 2017 Aug 1;196(3):274-282.

      Efficacy of Tumor Vaccines and Cellular Immunotherapies in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Dammeijer F, Lievense LA, Veerman GD, Hoogsteden HC, Hegmans JP, Arends LR, Aerts JG. J Clin Oncol. 2016 Sep 10;34(26):3204-12.

      Harnessing the Power of the Host: Improving Dendritic Cell Vaccines for Malignant Pleural Mesothelioma. Peikert T, Sterman DH.

      Am J Respir Crit Care Med. 2016 May 1;193(9):943-5

      Novel insights into mesothelioma biology and implications for therapy. Yap TA, Aerts JG, Popat S, Fennell DA. Nat Rev Cancer. 2017 Jul 25;17(8):475-488.

      Tumor-specific cytotoxic T cells are crucial for efficacy of immunomodulatory antibodies in patients with lung cancer.

      Aerts JG, Hegmans JP. Cancer Res. 2013 Apr 15;73(8):2381-2382

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      MS31.06 - Q&A

      14:45 - 15:00

      • Abstract

      Abstract not provided

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    MS32 - SCLC - From Benchside to Bedside - Clinical Science Session

    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Moderators:
      • Abstract

      Abstract

      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor that has historically been treated as a single disease. Loss of the tumor suppressors RB1 and TP53, and amplifications inMYCfamily members, are frequent events in SCLC. We show that Myc expression cooperates withRb1 andTrp53loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low ‘‘variant’’ subset of SCLC with low ASCL1 and high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival (Mollaoglu et al, Cancer Cell, 2017; Cardnell et al, Oncotarget, 2017). These findings were recently recapitulated in clinical trials where patients with relapsed SCLC exhibited significantly longer survival when treated with an Aurora kinase inhibitor specifically if tumors were high for MYC. More recently, our work and others suggests that MYC-high SCLC is also vulnerable to CHK1 inhibition. These data identify molecular features for patient stratification of SCLC and uncover a potential targeted treatment approach for MYC-driven SCLC.

      More recently, we have performed unbiased metabolic profiling of MYC-driven SCLC cell lines and murine tumors compared to MYCL and MYCN-driven samples. We find that MYC-driven SCLC is metabolically distinct in vitro and in vivo.Our findings reveal that guanosine nucleotides and biosynthetic enzyme Inosine Monophosphate Dehydrogenase-1 and -2 (IMPDH1 and IMPDH2) are elevated in MYC-high/ASCL1-low tumors and cell lines. IMPDH inhibition using Mizoribine selectively impeded the growth of MYC-high/ASCL1-low xenografts, and combined with chemotherapy to improve survival in MYC-driven genetically engineered mouse models (Huang et al, Cell Metabolism, In Press). These data strongly suggest that SCLC is composed of unique molecular subtypes with specific vulnerabilities to targeted therapy that should be considered in basic studies and clinical trial design.

      References:

      Cardnell RJ, Li L, Sen T, Bara R, Tong P, Fujimoto J, Ireland AS, Guthrie MR, Bheddah S, Banerjee U, Kalu NN, Fan YH, Dylla SJ, Johnson FM, Wistuba II, Oliver TG, Heymach JV, Glisson BS, Wang J, Byers LA (2017). Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies. Oncotarget, 8(43), 73419-73432.

      Huang F, Ni M, Chalishazar MD, Huffman KE, Kim J, Cai L, Shi X, Zacharias LG, Cai F, Gu W, Ireland AS, Gazdar AF, Oliver TG, Minna JD, Hu Z, and DeBerardinis RJ (In Press). Inosine monophosphate dehydrogenase dependence in a subset of small cell lung cancers. Cell Metab, 2018.

      Mollaoglu G, Guthrie MR, Bohm S, Bragelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG (2017). MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell, 31(2), 270-285.

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      MS32.02 - Patient Derived Models (PDX &amp; CTC-Derived)

      13:45 - 14:00  |  Presenting Author(s): Anna F. Farago

      • Abstract

      Abstract

      Patient-derived xenograft (PDX) models are a powerful preclinical tool for studying small cell lung cancer (SCLC) biology and therapeutic vulnerabilities. SCLC PDX models can be generated from biopsies or circulating tumor cells (CTCs), though these approaches can be limited by scarcity of tissue and low efficiency of tumor growth. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we have generated over 40 PDX models. In a 24-month period, we initiated 17 biopsy-derived PDXs and 17 CTC-derived PDXs, at 89% and 38% efficiency, respectively (Drapkin et al., Cancer Discovery 2018). Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. We have standardized quantitative measurements of efficacy of in vivo treatments, utilizing both depth of tumor shrinkage (response) and time to tumor volume doubling (time to progression). With these approaches, we have assessed responses to both standard of care and experimental therapies across a large panel of mice. We find that sensitivity to etoposide and platinum (EP) corresponds with the treatment history of patients, and that resistance to EP corresponded to increased expression of a MYC gene signature. Similarly, responses of the PDXs to an experimental combination, olaparib and temozolomide, mirrors the responses seen in patients treated on a clinical trial (Farago et al., ASCO 2018). Biomarker analysis in this panel reveals that basal PARylation is a highly sensitive and specific predictor of response to olaparib and temozolomide. Collectively, this experience highlights the utility of PDX models in SCLC for biomarker discovery and assessment of novel therapeutic strategies.

      References:

      1. Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zong J, Igo P, Hazar-Rethinam MH, Licausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Buttner R, Haas S, Sequist LV, Shaw AT, Wong K-K, Hata A, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, Farago AF. Genomic and functional fidelity of small cell lung cancer patient-derived xenografts. Cancer Discovery 2018 May 8(5):600-615. PMID: 29483136

      2. Farago AF, Drapkin BJ, Charles A, Yeap B, Heist RS, Azzoli CG, Jackman D, Marcoux P, Barbie D, Myers DT, Phat S, Zhong J, Grinnell JB, Sequist LV, Mino-Kenudson M, Maheswaran S, Haber D, Hata A, Dyson N, Shaw AT. Safety and efficacy of combination olaparib (O) and temozolomide (T) in small cell lung cancer (SCLC). American Society of Clinical Oncology Annual Meeting, June 1-5 2018. Poster presentation

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      MS32.03 - Liquid Biopsies for Drug Development in SCLC

      14:00 - 14:15  |  Presenting Author(s): Caroline Dive  |  Author(s): Ged Brady, Dominic Rothwell, Kristopher Frese, Kathryn Simpson, Jacqueline Pierce, Elaine Kilgour, Fiona Blackhall

      • Abstract

      Abstract

      The progress in recent years in understanding SCLC biology and phenotypic heterogeneity has led to a number of rational drug development opportunities being evaluated in early clinical trials. Historically clinical trials in SCLC have not included predictive or pharmacodynamics biomarkers because of a lack of understanding of what to measure and the difficulty of obtaining tumour specimens in which to evaluate them, particularly longitudinally.

      SCLC patients have prevalent circulating tumour cells (CTCs) that express EpCAM and are thus detectable using the CellSearch (CS) platform. CS CTC number is prognostic at baseline, has a wide dynamic range making it useful as a pharmacodynamic biomarker, and also acts as a surrogate of tumour response to chemotherapy (1). The prevalence of CS CTCs also allows CTC-based predictive biomarker assay development. In this regard we showed that a single CTC-based copy number alteration (CNA) signature can predict pre-treatment whether a SCLC patient will be chemorefractory (progress within 90 days of chemotherapy treatment) or initially chemosensitive (2). We have also recently shown using global CNA metrics and a panel of 110 SCLC associated genes that ctDNA was detectable in >90% of a cohort of both limited and extensive stage SCLC patients making it a highly suitable tool for patient monitoring.

      In 2014 we pioneered the development of CTC derived patient explant (CDX) models in immune compromised mice (3) which faithfully recapitulate the donor patients’ tumour morphology and genomic landscape, and mimic their response to cisplatin-based chemotherapy. The models also display patient-relevant metastatic tissue tropism and cell subpopulations are competent for vasculogenic mimicry (4). We are currently interrogating phenotypic heterogeneity in our panel of 45 CDX models and using them to test novel drug combinations including DNA damage repair and cell cycle checkpoint inhibitors (5). CDX cells can be cultured ex vivo for short periods, genetically manipulated and re-implanted in vivo for hypothesis testing studies (6) and most recently we have witnessed progress in culturing CTCs directly from patients' blood samples. These ex vivo approaches allow therapy screening (CDX cultures) or real time viability assays tailored to small cell numbers (CTC cultures) that ultimately may be able to inform patient treatment. All of the aforementioned applications of liquid biopsies in SCLC will be discussed and reviewed.

      References

      1. Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30(5):525-32.

      2. Carter L, Rothwell DG, Mesquita B, Smowton C, Leong HS, Fernandez-Gutierrez F, et al. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat Med. 2017;23(1):114-9.

      3. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014;20(8):897-903.

      4. Williamson SC, Metcalf RL, Trapani F, Mohan S, Antonello J, Abbott B, et al. Vasculogenic mimicry in small cell lung cancer. Nat Commun. 2016;7:13322.

      5. Lallo A, Frese KK, Morrow CJ, Sloane R, Gulati S, Schenk MW, et al. The combination of the PARP inhibitor olaparib and the Wee1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer Clin Cancer Res. in press.

      6. Lallo A, Warpman Berglund U, Frese KK, Potter DS, Helleday T, Dive C. Ex vivo culture of circulating tumour cell derived explants to facilitate rapid therapy testing in small cell lung cancer. European Association for Cancer Research Annual Conference; Manchester, U.K.2016.

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      MS32.04 - Molecular Phenotypes of SCLC

      14:15 - 14:30  |  Presenting Author(s): Adi Gazdar

      • Abstract

      Abstract

      Heterogeneity of neuroendocrine (NE) differentiation in small cell lung cancer (SCLC) determines very different molecular phenotypes

      Background and Purpose: SCLC is usually regarded as a homogenous tumor treated in a standard fashion. We have established and validated a 50 gene expression quantitative scoring system for NE lung tumors, consisting of both positive and negative scores [1]. While almost all carcinoid tumors have positive scores, SCLC and large cell neuroendocrine carcinomas have positive and negative subpopulations.

      Methodology: We utilized the NE gene expression score to demonstrate intertumor heterogeneity of gene expression patterns and their relationship to signaling pathways and to immune and inflammatory response. We used cluster analysis to divide the SCLC samples into high and low NE subtypes. We studied two public SCLC tumor data sets (n = 140) as well as 70 cell lines established by us and a pair of high/low sublines established from a single SCLC cell line.

      Results: The NE score cluster analysis indicated that ~10% of cell lines and ~20 of SCLC tumors were of the low NE subtype. The low NE subtype samples had RB1 mutations or low or absent RB1 expression, confirming their SCLC origin. Differences between the high and low subtypes were divided into those common to tumors and cell lines and those largely or entirely limited to tumors.

      Differences common to tumors and cell lines. At least three different lineage specific transcription factors were expressed by SCLC tumors and cell lines. Most NE high cells expressed ASCL1 in conjunction with NKX2-1. NEUROD1, occasionally with ASCL1, was expressed by a smaller subset of NE high and occasionally by NE low cells. POU2F3 was expressed by most of the NE low subtypes, and about half of these also expressed ASCL2. However, about 4% of tumors and cell lines (all belonging to the NE low subtype) lacked an identified lineage specific transcription factor. The NE high subtype expressed all of the classic NE markers, as well as numerous neural markers covering neural and glial differentiation. In addition they selectively expressed markers for DNA damage, the FGFR pathway, calcium signaling and Notch inhibitors. The NE low subtype lacked all or most of the NE cell program, NKX2-1 and DLL3 expression, while MYC and REST expression, the Hippo, TGFb and Notch pathways and EMT were greatly upregulated. These and other findings were predicted to impact on the potential responses of the two subtypes to chemotherapy, radiotherapy, and multiple targeted therapies.

      Differences limited to tumors and absent in cell lines: Despite having a high mutational burden, SCLC is considered to be an “immunological desert”, with few infiltrating immune or inflammatory cells, low or absent PDL-1 expression, and modest responses to PD-1 blockade. While the high NE tumors fitted this description most of the low NE tumors had strands of fibrosis encircling tumor islets, with varying numbers of inflammatory cells in the fibrous strands. Major differences at multiple steps were present in the low NE subtype involving the over 200 genes regulating the Cancer-Immunity Cycle, including the major cytokine families, toll like receptors, the inflammasome pathway, the JAK/STAT pathway, HLA antigens, CD47 antigen, perforin and granzymes. These changes were accompanied by highly significant increases in the relative numbers of multiple types of infiltrating immune and inflammatory cells. In addition, the low NE subtype had increased expression of PDL-1 and the interferon gamma signature, suggesting enhanced responses to immunotherapy.

      Conclusions: SCLC tumors and cell lines can be divided into high and low NE subtypes and these subtypes have major differences in lineage specific transcription factors, expression of the NE program, as well as some oncogenes and pathways, predicting them to respond very differently to conventional and targeted therapies. In addition, very different infiltrating cellular and gene expression patterns of immune responses were present in the low NE tumors, involving multiple aspects of Innate and Adaptive Immunity, and predicting that the low NE subtype tumors are more likely to respond to immunotherapy. In addition, several possibilities of combining cytotoxic, targeted and immunotherapies are suggested from our findings.

      I thank my collaborators for their invaluable contributions: Ling Cai, Tao Wang, Guanghua Xiao, Luc Girard and John Minna.

      1. Zhang W, Girard L, Zhang YA, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 2018;7(1):32-49.

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      MS32.05 - Targeting DNA Damage and Repair

      14:30 - 14:45  |  Presenting Author(s): Lauren Byers

      • Abstract

      Abstract

      Small cell lung cancer (SCLC) remains one of the most recalcitrant cancer types, with a 5 year survival less than 10% across all stages. At the genomic level, SCLC is characterized by loss of p53 and RB1 function and frequent amplification or overexpression of MYC family members1. These molecular hallmarks of SCLC contribute to high rates of replication stress and genomic instability which, in turn, may make SCLC tumors more susceptible to drugs targeting DNA damage response (DDR).

      Previously, we found that PARP1, Chk1, Wee1, and other proteins regulating DNA repair are highly expressed in SCLC, as compared to other lung cancers2. Based on this finding, several DDR inhibitors have now been tested in SCLC models as single agents or in combination with other DDR inhibitors or chemotherapy. Pharmacologic inhibitors of PARP, Chk1, Wee1, and ATR (alone or in combination) have shown promising activity in SCLC cell lines and mouse models (as reviewed in Sen, Gay, and Byers, TLCR 2018)3.

      Interestingly, in SCLC, response to PARP inhibitors and other DDR inhibitors has not been associated with mutations in BRCA1/2, other gene defects in homologous recombination (HR), or with higher HR deficiency scores. Rather, several novel biomarkers have been identified that define subsets of SCLC with enhanced sensitivity to specific DDR inhibitors. These include high SLFN11 expression as a predictor of PARP inhibitor sensitivity and MYC amplification or overexpression as a predictor for Chk1 and aurora kinase targeting. Many of these biomarkers are associated with pathways that contribute to replication stress (e.g., high MYC activity) or that promote replication arrest following DNA damage (e.g., high SLFN11)4,5. This supports the hypothesis that SCLC tumors under greater replication stress may be more susceptible to DDR inhibitors.

      Several PARP inhibitors (e.g., olaparib, rucaparib, niraparib) are now approved for the treatment of breast and ovarian cancer and inhibitors that hit other DDR targets are in various stages of clinical development. The availability of these agents – together with the preclinical data – has led to several clinical trials investigating DDR inhibitor targeting in SCLC. Results from a recently published randomized Phase 2 trial of temozolomide (TMZ) with either veliparib (PARP inhibitor) or placebo in 104 relapsed SCLC patients did not meet its primary endpoint of 4-month progression free survival (PFS)6. However, response rates were three times as high in the veliparib-treated patients (39% TMZ/veliparib vs. 19% TMZ/placebo, p=0.016). Furthermore, when patients were stratified by biomarker status, those patients with SLFN11-positive tumors (as measured by IHC) who received the PARP inhibitor had significantly higher PFS and overall survival (OS) than biomarker-negative patients (interaction p-value 0.009). For example, SLFN11-positive patients treated with TMZ/veliparib had a median OS of 12.5 months as compared to 7.5 months in SLFN11-negative patients (p=0.014). In contrast, there was no difference in PFS or OS based on biomarker status in patients in the placebo (TMZ only) arm, supporting that the biomarker was in fact predictive of benefit from PARP inhibitor treatment.

      An ongoing study combining the PARP inhibitor olaparib with TMZ is further exploring this combination in relapsed SCLC patients (NCT02446704). In addition, two trials have now been conducted investigating veliparib in combination with frontline platinum-etoposide chemotherapy (NCT01642251 and NCT02289690). SLFN11 biomarker analysis from the first of these studies will be presented at this meeting. Other DDR inhibitors in clinical investigation include the Chk1 inhibitor prexasertib and the Wee1 inhibitor AZD1775 (alone or in combination with other DDR inhibitor or chemotherapy).

      DDR targeting may also potentiate the effect of immunotherapy. In other cancer types, recent reports describe enhanced activity of immune checkpoint inhibitors in cancers with inherent DDR deficiencies such as BRCA1 mutations. Clinical trials in multiple tumor types including lung cancer are underway investigating whether treatment with a DDR inhibitor could enhance response to immunotherapy. Emerging preclinical data suggests activity of DDR-immune targeting in SCLC.

      REFERENCES

      1. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53.

      2. Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov 2012;2:798-811.

      3. Sen T, Gay CM, Byers LA. Targeting DNA damage repair in small cell lung cancer and the biomarker landscape. Transl Lung Cancer Res 2018;7:50-68.

      4. Sen T, Tong P, Stewart CA, et al. CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res 2017;77:3870-84.

      5. Steward, AC, Tong P, Cardnell RJ, et al. Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer. Oncotarget 2017;8:28575-87.

      6. Pietanza MC, Waqar SN, Krug LM, et al. Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer. J Clin Oncol 2018:JCO2018777672.

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      MS32.06 - Epigenetic Targets

      14:45 - 15:00  |  Presenting Author(s): John Poirier

      • Abstract

      Abstract

      Lung cancer remains the most common cause of death in men and women, responsible for more deaths than colon, breast and prostate cancer combined. Lung adenocarcinoma (a type of NSCLC) and small cell lung cancer (SCLC) comprise two of the major subgroups within lung cancer and collectively contribute to a high degree of cancer mortality year after year. Despite recent success in developing and implementing targeted therapeutics for several prominent driver oncogenes in NSCLC, SCLC remains a critical unmet medical need in the cancer field, in part due to a relative paucity of actionable mutations and well-defined biomarker-directed therapies. New therapeutic strategies are desperately needed to improve clinical outcomes for patients with SCLC.

      Despite lacking known driver oncogenes, such solid tumors have been shown to have frequent inactivating mutations in epigenetic remodeling enzymes – the “reader” and “writers” of the epigenome – which collectively play a role in the regulation of transcription, cellular plasticity and the ability of cancer to adapt or resist therapeutic interventions. Known to be central to the role in regulation of gene expression are the SWI/SNF family of chromatin remodeling enzymes (also know as “BAF”), the Polycomb Repressive Complexes (PRC1/2), the p300-CBP transcriptional coactivator family, BRD4, LSD1-NuRD, MLL and others. These transcriptional rheostats have a central role in dynamic process of opening and closing chromatin to the access of transcription and elongation factors. It is increasingly appreciated that SCLC is particularly sensitive to perturbations in transcription. Small molecules now exist to target the catalytic function of many of these epigenetic targets and are proceeding to clinical testing for patients with molecularly defined cancers, offering a therapeutic opportunity in an otherwise barren space.

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    PL04 - Take Action - Key Messages from WCLC 2018 and Goals for 2019

    • Type: Plenary Session
    • Track:
    • Moderators:
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      PL04.01 - Immunotherapy

      15:15 - 15:25  |  Presenting Author(s): David R. Gandara

      • Abstract

      Abstract not provided

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      PL04.02 - Biomarkers

      15:25 - 15:35  |  Presenting Author(s): Ming Sound Tsao

      • Abstract

      Abstract not provided

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      PL04.03 - Surgery

      15:35 - 15:45  |  Presenting Author(s): Ramon Rami-Porta

      • Abstract

      Abstract not provided

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      PL04.04 - Radiation Oncology

      15:45 - 15:55  |  Presenting Author(s): Jose Belderbos

      • Abstract

      Abstract not provided

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      PL04.05 - Clinical Research in Latin America

      15:55 - 16:05  |  Presenting Author(s): Clarissa Mathias

      • Abstract

      Abstract not provided

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      PL04.06 - Targeted Therapy

      16:05 - 16:15  |  Presenting Author(s): Michael Boyer

      • Abstract

      Abstract not provided

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      PL04.07 - Discussion and Q&A

      16:15 - 16:25

      • Abstract

      Abstract not provided

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      PL04.08 - Invitation to WCLC 2019 Barcelona, Spain

      16:25 - 16:30

      • Abstract

      Abstract not provided