Scientific Program

Filter Results:

Show Only CME Accredited Sessions

  • +

    LA01 - IASLC Lectureship Award Session

    • Type: Lectureship Award Session
    • Track:
    • Moderators:
    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      LA01.09 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

  • +

    MA25 - Oligometastasis: Defining, Treating, and Evaluating

    • Type: Mini Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Moderators:
    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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

    • +

      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

    • +

      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

    • +

      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

    • +

      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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

    • +

      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

  • +

    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 not provided

    • +

      MS28.03 - Combinatorial IO + Chemo

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

      • Abstract

      Abstract not provided

    • +

      MS28.04 - Combination with Targeted Therapies

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

      • Abstract

      Abstract not provided

    • +

      MS28.05 - Combining IO with Radiation

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

      • Abstract

      Abstract not provided

    • +

      MS28.06 - Q&A

      14:45 - 15:00

      • Abstract

      Abstract not provided

  • +

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

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

    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

    • +

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

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

      • Abstract

      Abstract not provided

    • +

      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 not provided

    • +

      MS30.05 - Nutritional Management During Radical Radiotherapy

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

      • Abstract

      Abstract not provided

    • +

      MS30.06 - Q&A with Poll Questions

      14:50 - 15:00

      • Abstract

      Abstract not provided

  • +

    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

    • +

      MS31.02 - Clinical Implementation of BAP1 Inhibitors

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

      • Abstract

      Abstract not provided

    • +

      MS31.03 - Targeting the Hippo Pathway

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

      • Abstract

      Abstract not provided

    • +

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

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

      • Abstract

      Abstract not provided

    • +

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

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

      • Abstract

      Abstract not provided

    • +

      MS31.06 - Q&A

      14:45 - 15:00

      • Abstract

      Abstract not provided

  • +

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

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

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

    • Type: Plenary Session
    • Track:
    • Moderators:
    • +

      PL04.01 - Immunotherapy

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

      • Abstract

      Abstract not provided

    • +

      PL04.02 - Biomarkers

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

      • Abstract

      Abstract not provided

    • +

      PL04.03 - Surgery

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

      • Abstract

      Abstract not provided

    • +

      PL04.04 - Radiation Oncology

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

      • Abstract

      Abstract not provided

    • +

      PL04.05 - Clinical Research in Latin America

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

      • Abstract

      Abstract not provided

    • +

      PL04.06 - Targeted Therapy

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

      • Abstract

      Abstract not provided

    • +

      PL04.07 - Discussion and Q&A

      16:15 - 16:25

      • Abstract

      Abstract not provided

    • +

      PL04.08 - Invitation to WCLC 2019 Barcelona, Spain

      16:25 - 16:30

      • Abstract

      Abstract not provided