Virtual Library

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    ISS01 - Symposium Supported by Takeda: New Insights and Clinical Implications for the Treatment of ALK+ NSCLC (Not IASLC CME Accredited) (ID 854)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 6
    • Moderators:
    • Coordinates: 9/23/2018, 09:45 - 11:15, Room 105
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      Welcome and Introductions (ID 12155)

      09:45 - 09:52  |  Presenting Author(s): Natasha B Leighl

      • Abstract

      Abstract not provided

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      Insights Into Mechanisms of Resistance and Characterizing Oncogenic Drivers in ALK+ NSCLC (ID 14794)

      09:52 - 10:14  |  Presenting Author(s): Robert C. Doebele

      • Abstract

      Abstract not provided

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      Current Landscape of ALK Inhibitors and Key Data (ID 14795)

      10:14 - 10:36  |  Presenting Author(s): Karen L. Reckamp

      • Abstract

      Abstract not provided

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      How to Integrate New Agents and Disease Monitoring Practices Into Optimal Patient Care (ID 14796)

      10:36 - 10:58  |  Presenting Author(s): Luis Paz-Ares

      • Abstract

      Abstract not provided

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      Panel Discussion (ID 14797)

      10:58 - 11:13  |  Presenting Author(s): Natasha B Leighl, Robert C. Doebele, Luis Paz-Ares, Karen L. Reckamp

      • Abstract

      Abstract not provided

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      Conclusion (ID 14798)

      11:13 - 11:15  |  Presenting Author(s): Natasha B Leighl

      • Abstract

      Abstract not provided

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    ISS04 - Symposium Supported by Bristol-Myers Squibb: Refining the Focus in Lung Cancer: New Data and Emerging Biomarkers (Not IASLC CME Accredited) (ID 857)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/23/2018, 14:30 - 16:00, Room 105
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    ISS11 - Symposium Supported by Pfizer: Future Options for ALK+ Metastatic NSCLC (Not IASLC CME Accredited) (ID 865)

    • Event: WCLC 2018
    • Type: Industry Supported Symposia
    • Track:
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 105
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      Welcome and Introduction (ID 12168)

      07:00 - 08:00  |  Presenting Author(s): Geoffrey Liu

      • Abstract
      • Slides

      Abstract not provided

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      Recent advances in treating ALK+ NSCLC: An evolving landscape (ID 14833)

      08:00 - 08:00  |  Presenting Author(s): Ben J Solomon

      • Abstract

      Abstract not provided

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      Navigating the spectrum of resistance mutations in ALK+ NSCLC: How to identify and treat them (ID 14834)

      08:00 - 08:00  |  Presenting Author(s): Alice T. Shaw

      • Abstract

      Abstract not provided

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      Panel Q&A (ID 14835)

      08:00 - 08:00  |  Presenting Author(s): Geoffrey Liu, Ben J Solomon, Alice T. Shaw

      • Abstract

      Abstract not provided

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    LA01 - IASLC Lectureship Award Session (ID 989)

    • Event: WCLC 2018
    • Type: Lectureship Award Session
    • Track:
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 105
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      LA01.01 - Clifton F. Mountain Lectureship Award for Staging - Is There Still a Stage for Improvements in Staging? (Now Available) (ID 14697)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (ID 14723)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (ID 14724)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      LA01.04 - Adi F. Gazdar Lectureship Award for Translational Research - Genomic Alterations in Human Lung Cancers (Now Available) (ID 14725)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (ID 14726)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      LA01.06 - Daniel C. Ihde Lectureship Award for Medical Oncology - The Intersection of Science and Medicine (Now Available) (ID 14727)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      LA01.07 - Robert J. Ginsberg Lectureship Award for Surgery - Honoring the Tradition of Surgically-Based Clinical Trials (Now Available) (ID 14728)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (ID 14729)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA05 - Improving Outcomes in Locoregional NSCLC II (ID 901)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 105
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      MA05.01 - E6508: Phase II Study of Immunotherapy with Tecemotide and Bevacizumab after Chemoradiation in Unresectable Stage III NS-NSCLC (Now Available) (ID 13853)

      13:30 - 13:35  |  Presenting Author(s): Jyoti Patel  |  Author(s): Ju-Whei Lee, Henry Wagner Jr, David P Carbone, Anil Shanker, Leora Horn, Melissa L. Johnson, David E Gerber, Jane Jijun Liu, Millie S Das, Mohammad Ali Al-Nsour, Christopher S R Dakhil, Suresh S. Ramalingam, Joan Schiller

      • Abstract
      • Presentation
      • Slides

      Background

      Chemoradiation (CRT) is standard of care for unresectable stage III NSCLC. Tecemotide is a MUC1 antigen-specific cancer immunotherapy. Bevacizumab is considered to have a significant role in immune modulation. Immunotherapy in combination with VEGF blockade was tested in this phase II trial combining tecemotide and bevacizumab in patients with stage III NS- NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Subjects with stage III NS- NSCLC suitable for definitive CRT received carboplatin(C) AUC 2 + paclitaxel(P) 45 mg/m2 weekly + 66 Gy/33fx/6.5wk and consolidation C AUC 6 + P 225 mg/m2 q21 days x 2. Patients with CR/PR/SD were then registered onto Step 2 (S2). S2 was 6 weekly tecemotide injections followed by q6 weekly injections and bevacizumab 15 mg/kg q3 weeks for up to 34 doses. The primary endpoint was safety of tecemotide and bevacizumab after CRT and consolidation. The proportion of circulating dendritic cells and their expression of CD40, HLA-DR and CD123 (IL-3R) were analyzed by flow cytometry at various time points.

      4c3880bb027f159e801041b1021e88e8 Result

      70 patients were enrolled from Dec 2010 to Oct 2014; 68 started therapy, and 39 completed CRT and consolidation therapy. Reasons for discontinuation included progression (11) and toxicity (10). 33 patients were registered to S2. The median number of S2 cycles was 12 (range 2-34). S2 toxicity: gr 3 N=9 (6 hypertension), gr 4 N=1, gr 5 N=1. Among the treated and eligible patients (n=31), from study entry, the median PFS was 14.3 (95% CI 11.0-22.2), OS was 40.1 (95% CI 21.7-NA) months. A correlative trend of increased expression of CD40 and HLA-DR on CD11c+ cells was observed at cycle 7 (week 21) of S2.

      e6508.patel.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      This cooperative group trial met its endpoint, demonstrating tolerability of tecemotide and bevacizumab after CRT and consolidation in NS-NSCLC pts. In this select group of patients, therapy with tecemotide and bevacizumab was associated with encouraging PFS and OS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.02 - PACIFIC Subgroup Analysis: Pneumonitis in Stage III, Unresectable NSCLC Patients Treated with Durvalumab vs. Placebo After CRT (Now Available) (ID 13876)

      13:35 - 13:40  |  Presenting Author(s): Johan F. Vansteenkiste  |  Author(s): Jarushka Naidoo, Corinne Faivre-Finn, Mustafa Özgüroğlu, Augusto Villegas, Davey Daniel, Shuji Murakami, Rina Hui, Ki Hyeong Lee, Byoung Chul Cho, Kaoru Kubota, Lynne Poole, Catherine Wadsworth, Phillip A. Dennis, Scott J Antonia

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (cCRT), on-treatment pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in both arms with similar rates of grade 3/4 pneumonitis (durvalumab, 3.4%; placebo, 2.6%). We performed exploratory analyses to further characterize time to onset and duration of pneumonitis and examine its relationship with underlying risk factors, including patient characteristics and prior CRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a randomized, double-blind study of patients with WHO PS 0/1 without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after completing cCRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Potential associations between the presence of the AE pneumonitis (investigator assessed with review/adjudication by study sponsor) and baseline characteristics or patient disposition were investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Feb 13, 2017, 709 patients had received treatment; 33.6% on durvalumab and 24.9% on placebo had any-grade pneumonitis. Treatment exposure was similar in patients with or without pneumonitis across both arms. Median time to onset of pneumonitis from treatment start was the same for both durvalumab and placebo, 55.0 days (73.0 and 76.5 days from RT completion). Pneumonitis was self-limited, with median durations of 64.0 and 57.0 days, respectively. Patients with pneumonitis were more likely to be Asian (47.9% vs 17.6%) or have EGFR mutations (11.0% vs 3.8%); however, the proportions of patients with pneumonitis and these risk factors were numerically lower with durvalumab than with placebo (Asian: 44.4% [71/160] vs 57.6% [34/59]; EGFRm: 10.6% [17/160] vs 11.9% [7/59]), suggesting no apparent interaction with treatment. There were no apparent associations of pneumonitis with baseline respiratory disorders, prior RT dose, or prior cisplatin or carboplatin use. Previous induction CT was more commonly associated with the absence of pneumonitis in both treatment arms (durvalumab: 30.1% vs 17.5%; placebo: 31.5% vs 20.3%). The presence of pneumonitis was associated with greater discontinuation due to AEs (durvalumab: 25.6% vs 10.2%; placebo: 18.6% vs 6.8%) regardless of treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Rates of pneumonitis were higher in Asian patients and those with EGFRm, as previously reported. Durvalumab did not increase pneumonitis in patients with these risk factors. There were no differences in treatment exposure in patients based on the presence/absence of pneumonitis. Multivariate analyses may further assist in the discernment of etiologic risks.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.03 - Immune Microenvironment and its Association with Adjuvant Chemotherapy Benefit in Locoregionally Advanced Lung Adenocarcinoma (Now Available) (ID 12999)

      13:40 - 13:45  |  Presenting Author(s): Raj Ghanshyam Vaghjiani  |  Author(s): Takashi Eguchi, Navin Chintala, Xiaoyu Li, Rania G Aly, Katsura Emoto, Kay See Tan, David R. Jones, Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      The impact of the tumor immune microenvironment on the effectiveness of platinum-based adjuvant chemotherapy (ACT) in locoregionally advanced (stage II-III) lung adenocarcinoma (ADC) is unknown. We performed an analysis of the cellular components of the tumoral and tumor-associated stromal immune environment in stage II-III lung ADC and examined their association with ACT benefit.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue microarrays (6 tumor and 3 stromal cores from each tumor) were constructed using resected tissue from patients with pT2-T4N1 lung ADC (n=500, 2000-2012) who did (n=225) and did not (n=214) receive ACT. Multiplex immunofluorescence was used to determine the quantity, localization, and colocalization of 21 types of immune cells and markers (including PD-1, PD-L1, CD3, CD20, CD68, CD163, MPO, and PanCK). The association between immune cell infiltration and recurrence free probability (RFP) was compared using Kaplan-Meier methods, and benefit from ACT by unsupervised hierarchical cluster modeling.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, increased tumoral infiltration of CD20+ B-cells and CD3+ and CD4+ T-cells was associated with an improvement in 5-yr RFP (CD20+ low vs high: 37% vs 49%, p=.03; CD3+: 39% vs 48%, p=.003; and CD4+: 39% vs 47%, p=.02, respectively) whereas increased stromal MPO+ neutrophil infiltration was associated with a worse 5-yr RFP (low vs high: 50% vs 38%, p=.003). Among patients who received ACT, cluster modeling revealed 5 risk groups (Groups A-E; Figure) with immune signatures including tumoral B-cells and CD163+PD-1+ macrophages as well as stromal CD57+ NK-cells and CD163+PD-L1+ macrophages that provided a progressive stratification of RFP following adjuvant treatment.

      vaghjiani.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Immune infiltration analysis can predict benefit from ACT and thereby provide a rationale to select patients for either chemotherapy, immunotherapy, or combination therapy following surgical resection.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.04 - Discussant - MA 05.01, MA 05.02, MA 05.03 (Now Available) (ID 14590)

      13:45 - 14:00  |  Presenting Author(s): Scott N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA05.05 - Photon-Based Cardiac Sparing Via Volumetric Modulated Arc Therapy in Thoracic Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer (Now Available) (ID 13419)

      14:00 - 14:05  |  Presenting Author(s): Matthew J Ferris  |  Author(s): Katherine Sykes, Oluwatosin A Kayode, Jonathan Wolf, Robert H Press, Jeffrey M Switchenko, Walter John Curran, Jr., Kristin A Higgins

      • Abstract
      • Presentation
      • Slides

      Background

      Increasing radiation dose to the heart is associated with worse survival in stage III non-small cell lung cancer. Techniques to reduce the dose to the heart, including proton beam therapy (PBT), are being evaluated in ongoing clinical trials. However, advanced technologies such as PBT are not readily accessible for most patients. We therefore sought to evaluate the efficacy of volumetric modulated arc therapy (VMAT), a readily available technology in the United States, to spare cardiac substructures and determine how a cardiac optimization treatment planning algorithm influences dose distribution to other thoracic organs at risk (OARs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We selected stage III non-small cell lung cancer patients who were treated at our institution with VMAT to 60 Gy in 2 Gy fractions. Cardiac substructures were retrospectively contoured, and included: valves, atrioventricular node (AVN), coronary arteries (CA), chambers, and great vessels. New radiation treatment plans were created to spare these structures while preserving planning target volume (PTV) coverage and maintaining standard dose constraints to OARs. Dosimetry variables—maximum dose (Dmax), mean dose (Dmean), and common clinically relevant dose-volume relationships—for the new cardiac-sparing radiation treatment plans were compared via paired t-test to the original radiation treatment plans.

      4c3880bb027f159e801041b1021e88e8 Result

      Twenty-six patients, treated from July 2013 to September 2017, were included. Statistically significant improvements were demonstrated for all cardiac structures for the new cardiac-sparing plans compared to the original plans, while maintaining appropriate lung, esophagus, and spinal cord constraints, and PTV coverage goals, as demonstrated in Table 1 (significant P-values in bold).

      Table 1

      Dosimetry variable

      Cardiac-sparing plan (mean)

      Original plan (mean)

      P-value*

      Cardiac parameters

      Heart Dmax

      64.9 Gy

      63.6 Gy

      0.928

      Heart Dmean

      12.3

      16.1

      < 0.001

      Heart V5Gy

      55.4

      64.1

      0.003

      Heart V30Gy

      12.5

      18.7

      < 0.001

      Heart V40Gy

      7.9

      11.5

      < 0.001

      Heart V45Gy

      6.5

      11.5

      < 0.001

      Heart V60Gy

      2.7

      3.4

      0.001

      Aortic valve Dmax

      22.9

      31.7

      < 0.001

      Aortic valve Dmean

      11.4

      31.7

      < 0.001

      Mitral valve Dmax

      24.6

      29.4

      0.002

      Mitral valve Dmean

      11.2

      16.7

      < 0.001

      Pulmonic valve Dmax

      26.8

      35.4

      < 0.001

      Pulmonic valve Dmean

      14.1

      25.1

      < 0.001

      Tricuspid valve Dmax

      9.7

      16.6

      < 0.001

      Tricuspid valve Dmean

      5.6

      10.3

      < 0.001

      AVN Dmax

      13.4

      20.4

      < 0.001

      AVN Dmean

      8.1

      14.0

      < 0.001

      Left main CA Dmax

      26.4

      38.8

      < 0.001

      Left main CA Dmean

      16.4

      30.2

      < 0.001

      Left anterior descending CA Dmax

      27.4

      34.8

      < 0.001

      Left anterior descending CA Dmean

      14.4

      22.6

      < 0.001

      Left circumflex CA Dmean

      32.6

      36.8

      0.001

      Left circumflex CA Dmean

      19.3

      26.9

      < 0.001

      Right CA Dmax

      18.1

      26.1

      < 0.001

      Right CA Dmean

      9.4

      15.7

      < 0.001

      Left atrium Dmax

      51.8

      54.8

      0.091

      Left atrium Dmean

      17.5

      21.0

      < 0.001

      Left ventricle Dmax

      35.7

      40.1

      < 0.001

      Left ventricle Dmean

      8.3

      11.3

      < 0.001

      Right atrium Dmax

      31.4

      36.1

      0.004

      Right atrium Dmean

      11.1

      13.9

      < 0.001

      Right ventricle Dmax

      23.7

      33.2

      < 0.001

      Right ventricle Dmean

      6.9

      12.2

      < 0.001

      Aorta Dmax

      50.8

      55.3

      0.001

      Aorta Dmean

      20.4

      27.9

      < 0.001

      Pulmonary artery Dmax

      65.2

      65.1

      0.895

      Pulmonary artery Dmean

      32.3

      37.9

      < 0.001

      Superior vena cava Dmax

      47.4

      51.7

      0.002

      Superior vena cava Dmean

      29.4

      33.1

      0.006

      Other OAR parameters

      Lungs V5Gy

      56.5

      58.2

      0.121

      Lungs V20

      22.4

      23.3

      0.083

      Lungs Dmean

      13.6

      14.8

      0.012

      Spinal cord Dmax

      28.0

      31.1

      0.013

      Esophagus Dmean

      21.2

      22.1

      0.023

      PTV coverage parameters

      PTV Dmax

      65.5

      67.2

      0.189

      PTV minimum dose

      51.2

      52.7

      0.019

      PTV V100%

      95.2%

      95.4%

      0.195

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dose to the heart and cardiac substructures can be substantially lowered using a cardiac-sparing optimization algorithm with VMAT, without increasing radiation dose other thoracic OARs or compromising PTV coverage. Though time-consuming, delineation of the full complement of cardiac substructures provides an effective means of improving the quality of radiation treatment plans with readily available technologies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA05.06 - Locally Advanced Lung Cancer Radiotherapy in Deep Inspiration Breath Hold: Dosimetric Benefits from a Prospective Trial (Now Available) (ID 12465)

      14:05 - 14:10  |  Presenting Author(s): Mirjana Josipovic  |  Author(s): Marianne C Aznar, Jonas Scherman Rydhög, Jakob Borup Thomsen, Sidsel Marie Skov Damkjaer, Lotte Nygård, Mette Pøhl, Seppo W Langer, Lena Specht, Gitte Fredberg Persson

      • Abstract
      • Presentation
      • Slides

      Background

      Radiotherapy for locally advanced non-small cell lung (NSCLC) cancer is often complicated by treatment-related toxicity. A toxicity-reducing technique is deep inspiration breath hold (DIBH), where the lungs inflate and the heart is pushed downwards. DIBH is widely applied in breast radiotherapy, but only sporadically in NSCLC. We initiated the INHALE trial, investigating compliance and benefits of DIBH for NSCLC at a single academic institution.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients referred for definitive radiotherapy of locally advanced NSCLC (66Gy/33 fractions) were included from May 2015-Dec 2017. All patients underwent respiratory coaching for voluntary visually guided DIBH and were imaged with PET/CT, 4D-CT and DIBH-CT. Target volumes were defined according to national guidelines. PTV margins were patient- and modality-specific. For all patients, FB and DIBH plans were made with volumetric modulated arc therapy, with equal PTV coverage. The plan with the lowest lung and/or heart dose was chosen for treatment. Normal tissue complication probability for pneumonitis was calculated retrospectively based on a logistic dose response model.

      4c3880bb027f159e801041b1021e88e8 Result

      The treatment intent was maintained in 69 of included 88 patients (2 were downstaged, 12 upstaged, 2 withdrew consent, other causes in 3). 62/69 were DIBH compliant and in 61 patients a FB and a DIBH plan were made (in one patient, 4DCT image quality was not sufficient). In 54/61 patients, the DIBH plan was chosen for treatment. 3/54 patients lost DIBH compliance within the first few fractions.

      All data is presented as median (range), with p<0.001 (Wilcoxon signed rank). Lung volume increased in DIBH by 55% (20-168%). Compared to FB, DIBH reduced mean lung dose from 14.4Gy (1.2-25.3Gy) to 11.8Gy (1.0-20.4Gy), and lung V20 from 23.7% (1.5-47.8%) to 20.8% (1.2-39.7%). Reduced lung dose translated to reduced pneumonitis risk: from 8.6% (2.3-23.3%) to 6.5% (2.2-14.4%). Lung dose constraints were violated in 5/62 patients in FB and 1/62 patients in DIBH.

      Mean heart dose was reduced from 3.6Gy (0.1-25.8Gy) in FB to 2.4Gy (0.1-25.3Gy) in DIBH. DIBH reduced mean heart dose in 44/61 patients. The differences between FB and DIBH varied between – 6.6Gy and 8.9Gy, stressing the influence of tumour location on the potential of reducing heart dose with DIBH.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Benefits of changed anatomy with DIBH were reduced dose to lungs and, for most patients, to the heart. Curative treatment intent could be maintained in more patients. Risk of developing radiation pneumonitis was reduced. Continuous follow up of INHALE patients will reveal how the reduced risk is manifested clinically.

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      MA05.07 - Dose Escalated Chemo-RT to 84 Gy in Stage III NSCLC Appears Excessively Toxic: Results from a Randomized Phase II Trial (Now Available) (ID 11966)

      14:10 - 14:15  |  Presenting Author(s): Jan Nyman  |  Author(s): Stefan Bergström, Hedvig Björkestrand, Anna-Maja Svärd, Simon Ekman, Erik Lundin, Erik Holmberg, Mikael Johansson, Signe Friesland, Andreas Hallqvist

      • Abstract
      • Presentation
      • Slides

      Background

      Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease, however, with a rather high probability of locoregional and metastatic recurrence further treatment optimization is warranted. Based on previous one-armed trials with dose escalated radiotherapy, showing feasibility, the Swedish Lung Cancer Study Group aimed to investigate whether dose escalation based on individual normal tissue constraints could improve outcome in this randomized phase II trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NSCLC patients with stage III disease, good performance status (0-1), adequate lung function (FEV1 > 1.0 L and CO diff. > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. The radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to a total dose of 68 Gy (standard arm A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week while keeping the total treatment time constant at seven weeks with the same dose to involved nodes and primary tumor.

      4c3880bb027f159e801041b1021e88e8 Result

      A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in the dose escalated group compared to 28 and 45 months in the standard group. The 1-, 3- and 5-year survival rates were 56%, 33% and 17% in the escalated arm and 72%, 61% and 34% in the standard arm. There were four toxicity-related deaths due to esophageal perforations (one in arm A and three in arm B) and three deaths due to pneumonitis (one in arm A and two in arm B).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 5-year survival of 34%. A possible step forward will be to improve systemic therapy, but future approaches with escalated radiotherapy may include boost techniques to remaining PET positive areas or different escalation schedules to the primary tumor and mediastinal nodes.

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      MA05.08 - Discussant - MA 05.05, MA 05.06, MA 05.07 (Now Available) (ID 14591)

      14:15 - 14:30  |  Presenting Author(s): Benjamin H Lok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA05.09 - PFS and Cardiac-Toxicity-Adjusted-PFS As Predictors of OS in Locally Advanced NSCLC Treated with Concurrent Chemoradiation (Now Available) (ID 12391)

      14:30 - 14:35  |  Presenting Author(s): Chen Hu  |  Author(s): Mitchell Machtay, James Dignam, Rebecca Paulus, Jeffrey Bradley

      • Abstract
      • Presentation
      • Slides

      Background

      Overall survival (OS) is the gold standard for LA-NSCLC with chemoradiation (CCRT), while the complex relationships among RT dosimetry, systemic therapies, cardiopulmonary toxicity, progression (PD) and OS are also of increasing scientific and clinical interest.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NRG Oncology RTOG 0617 (NCT00533949) was a randomized phase 3 trial comparing standard (SD, 60 Gy) versus high-dose (HD, 74 Gy) CCRT +/- cetuximab from 11/07-06/11. This secondary analysis includes 469 patients (pts) given ≥50 Gy. A PFS event was defined as the first occurrence of local, regional, distant PD or death w/o documented PD. A CTA-PFS event was the first occurrence of grade 2+ treatment-related cardiac toxicity event or a PFS event. Landmark analyses at 6mo and 12mo were used to minimize the immortal time bias. Cox model with PD or CT/PD as a time-dependent covariate was used to evaluate their predictive roles. Median f/u time for surviving pts was 5.1 years.

      4c3880bb027f159e801041b1021e88e8 Result

      As previously reported, pts treated with HD had significantly lower OS rates (HR=1.28, 95%CI: 1.04-1.58, p=0.018) and CTA-PFS rates (HR=1.24, 95%CI: 1.02-1.51, p=0.035), and marginally lower PFS rates (HR=1.21, 95%CI: 0.99-1.47, p=0.06) than pts treated with SD. Median survival time (MST) among pts having PD within 6mo versus not were 13.4mo (95%CI: 10.0-19.0mo) and 30.7mo (95%CI: 28.0-37.0mo) (p<0.001). MST for pts having PD within 12mo versus not were 20.6mo (95%CI: 18.8-25.0mo) and 60mo (95%CI: 47.6-74.5mo)(p<0.001). Results are similar when using CTA-PFS with 6mo or 12mo cutoff (p<0.001). RT dose was no longer significantly associated with OS (p=0.08 or p=0.15) when PD or CT/PD was included in multivariable analysis (p<0.001), suggesting OS differences in HD/SD may be partially captured by PFS or CTA-PFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Long-term survival results from RTOG 0617 suggest that PFS (or CTA-PFS) status at 6mo or 12mo predicts long-term OS, and may potentially be considered as a surrogate endpoint of OS in clinical trials. Pts who were progression-free at 12mo had a MST of 5 years. Further validation on external datasets and in the modern era of immunotherapy are needed.

      Funding: This project was supported by grants NCORP (UG1CA189867), NRG Operations (U10CA180868), NRG SDMC (U10CA180822), IROC (U24CA180803), and CTEP from the National Cancer Institute (NCI).

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      MA05.10 - The Pathologic Response of Locally Advanced NSCLC Treated with Concomitant Chemoradiation to 60 Gy in Image Guided Radiation Therapy (IGRT) (Now Available) (ID 13758)

      14:35 - 14:40  |  Presenting Author(s): Sarit Appel  |  Author(s): Jair Bar, Damien Urban, Amir Onn, Marina Perelman, Yaacov Richard Lawrence, Alon Ben-Nun, Ory Haisraely, Zvi Symon, Tatiana Rabin El Ezra, Edith Marom, Sivan Liberman, Efrat Ofek

      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant concomitant chemoradiation (NACCRT) was historically limited to 45 Gy. We recently published data on the safety of a higher radiation dose in this setting. Here we evaluate the pathologic response of locally advanced non small cell lung cancer (LANSCLC) treated with 60Gy NACCRT combined with modern IGRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our cohort comprised patients that underwent NACCRT followed by surgery during August 2012-December 2017 at our institution. We retrospectively collected the demographic, stage, histology, and treatment details. Radiation was planned using eclipse system to deliver 2 Gy per fraction to a total of 60 Gy

      Treatment effect was determined from the pathologic specimen in accordance with College of American Pathologists recommendations, based on the modified tumor regression grading: Favorable pathologic responses included major tumor regression (MTR); we also evaluated the average percent of the residual tumor cells seen in the specimen. Statistical analysis was performed to analyze treatment effect on the pathologic response using spearman correlation and Kruskal-Wallis test with SPSS software v.24.

      4c3880bb027f159e801041b1021e88e8 Result

      Our cohort included 70 patients. Mean age was 63 years (range 45–79.7), men n=49 (70%), smoking status: never smokers n=11 (16.2%), past smokers n=10 (14.7%), current smokers n=47 (69.1%). Histology consisted adenocarcinoma n=42 (60%), squamous n=21 (30%) and other n=7 (10). Stage 2 were n=65 (78.3%) and stage 3 n=15 (21.4%). Chemotherapy consisted of platinum-doublet administered to 69 patients (98.5%). A mean radiation dose of 59 Gy (range 46-72 Gy) was delivered with IGRT prior to each fraction. Five patients received lower radiation doses due to toxicity or dose constraints. Surgery comprised of lobectomy n=50 (71.4%), chest wall resection n=9 (12.9%) or pneumonectomy n=11 (15.7%). Negative surgical margins were achieved in n=63 (90%) and positive margins in n=7 (10%). 30-day mortality was n=2 (2.8%) both cases after Right-sided pneumonectomy.

      MTR was observed in 45 cases (64.3%) including a pathological complete response in 25 (35.7%) and < 10% residual tumor in 20 cases (28.5%). The mean percent of residual tumor cells was 16% and the median 6.5%. Percent of residual tumor cells did not correlate to radiation dose (Rs=0.092), and not to the histology (p= 0.165), and not to type of chemotherapy (p=0.35).

      8eea62084ca7e541d918e823422bd82e Conclusion

      NACCRT delivered to 60 Gy with modern image-guided radiation therapy is safe. Two thirds of such patients achieve major tumor regression.

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      MA05.11 - Radiomics Analysis Using SVM Predicts Mediastinal Lymph Nodes Status of Squamous Cell Lung Cancer by Pre-Treatment Chest CT Scan (Now Available) (ID 12033)

      14:40 - 14:45  |  Presenting Author(s): Xing Wang, Wu Nan  |  Author(s): Shi Yan, Quanzheng Li, Ning Guo, Zhe Guo

      • Abstract
      • Presentation
      • Slides

      Background

      Assessment of mediastinal lymph nodes (N2 station) is essential in staging patients with Non-small-cell lung cancer (NSCLC), for patients with preoperative confirmed N2 status should follow neoadjuvant therapy before surgery, and occult N2 status should be avoided. There are several invasive and non-invasive exams available for preoperative N staging, like EBUS-TBNA and PET-CT scan. Chest CT scan was the basic examination of every patient, while only the length of minor axis could be used to predict lymph node involvement, and the potential value of CT might be underestimated. In this study we aimed to explore the value of radiomics analysis with machine learning in differentiating N2 from N1/N0 subjects using pre-treatment chest CT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Ninety-three patients with squamous cell lung cancer, who underwent pre-treatment CT scans were included in this study. By use of Laplacian of Gaussian (LoG) filter and matrix based radiomics models (e.g. gray-level co-occurrence matrix), comprehensive radiomics features were extracted from the regions of interest which were manually delineated on primary tumors. We performed radiomics analysis using support vector machine (SVM) to test texture and heterogeneity features derived from pre-treatment CT images as indicators for the staging of lymph node metastasis, especially N2. The gold standard of N staging is confirmed pathologically after systematic mediastinal lymphadenectomy (N2 subjects=31).

      4c3880bb027f159e801041b1021e88e8 Result

      For the performance evaluation of single image feature, there are 16 features able to differentiate N2 subjects from others (N0 and N1) with p value <0.05. Furthermore, SVM training and classification were performed using 5-feature combinations as inputs. With feature selection, the best performance of N2 prediction is 83% accuracy with 87% sensitivity and 81% specificity.

      figure.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Radiomics analysis using SVM training can successfully predict N staging by pre-treatment chest CT scan for NSCLC patients, which could diminish the odds of occult N2 status and provide unique information preoperatively for treatment planning.

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      MA05.12 - Discussant - MA 05.09, MA 05.10, MA 05.11 (Now Available) (ID 14592)

      14:45 - 15:00  |  Presenting Author(s): Matthew Hatton

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA10 - Considerations in Immunotherapy / Real World (ID 911)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 11
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 105
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      MA10.01 - Antibiotic Use and PD-1 Inhibitors: Shorter Survival in Lung Cancer, Especially When Given Intravenously. Type of Infection Also Matters (Now Available) (ID 13542)

      10:30 - 10:35  |  Presenting Author(s): Xabier Mielgo-Rubio  |  Author(s): Luis Enrique Chara, Miguel Jhonatan Sotelo-Lezama, Rafael Lopez Castro, Judit Rubio-Martínez, Alejandro Velastegui, Clara Olier-Garate, Sandra Falagan, Isabel Gómez-Barreda, Pilar Bautista-Sanz, Jorge Silva-Ruiz, Juan Moreno Rubio, Cynthia López, Ana Cardeña-Gutiérrez, Elia Pérez-Fernández, María Sereno Moyano

      • Abstract
      • Presentation
      • Slides

      Background

      Some studies found that cancer patients treated with PD-1 immune checkpoint inhibitors (ICI) who receive antibiotics (ATB) had worse efficacy outcomes because ATB can dysregulate gut microbiota. AvaiIable data in NSCLC are contradictory. In addition it’s unknow whether route of administration, type of the ATB and reason for its use, can affect survival outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a multicenter retrospective study. We included consecutive patients with advanced non-small-cell lung cancer (NSCLC) treated with nivolumab or pembrolizumab in second line or beyond between March 2015 and April 2018, from 7 hospitals in Spain. The aim of the study was to evaluate if patients taking ATB 2 months before or within the first month after starting ICI had worse OS, and if OS was affected by the route of administration, type of ATB, and the reason for its use.

      4c3880bb027f159e801041b1021e88e8 Result

      168 patients were evaluated. Median age was 65 years (39-85). 134(79,8%) were male and 121 (72%) had PS>=1. Predominant histologies were adenocarcinoma (50%) and squamous-cell carcinoma (42,9%). 92,3% received nivolumab and 7,7% pembrolizumab. The median number of prior lines was 1 (1-5), median number of cycles 11 (1-68). Median follow: 6,3m. Most were current or former smokers (94,6%). Only 2,9% had driver mutations. PD-L1 was available in 25% (<1%: 36,6%; 1-49%: 39%; >=50%: 24,4%). Response rate (RR) was 30,4%. 47,9% received ATB, 30% of them intravenously and 70% orally. Median PFS and OS were 5,6 months (m) (95%CI, 3,9-7,3) and 11,4 m (95%CI, 9,4-13,5). Patients who received ATB had shorter OS (8,1m (95%CI, 3,6-12,5) vs 11,9m (95%CI 9,1-14,7); p=0,026) and PFS (5m (95%CI,3,1-6,9) vs 7,3m (95%CI,2-12);p=0,028). Those patients receiving ATB intravenously had shorter OS than orally (2,9m (95%CI, 1,6-4,1) vs 14,2m (95%CI, 7,9-20,6); p=0,0001) and shorter PFS (2,2m (95%CI,0,6-3,7) vs 5,9m (95%CI,3,9-8); p=0,001). Patients treated for a lower respiratory tract infection (LRTI) and urinary infection had significantly shorter OS (6m (95%CI2,2-9,7) vs 26m (95%CI, 7,9-44); p=0,006).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that use of antibiotics (mainly intravenously) has a negative impact on survival outcomes in patients with pretreated advanced NSCLC receiving ICI. To our knowledge, this is the biggest retrospective study evaluating the impact of ATB on the efficacy of ICI in NSCLC patients and the first one evaluating route of administration of ATB. We also found worse outcomes when ATB were administered for low respiratory or urinary tract infection.

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      MA10.02 - Impact of Antibiotics on Outcome of Metastatic Non Small Cell Lung Cancer Patients Treated with Immunotherapy (Now Available) (ID 14021)

      10:35 - 10:40  |  Presenting Author(s): Giulia Galli  |  Author(s): Marta Poggi, Giovanni Fucà, Martina Imbimbo, Claudia Proto, Diego Signorelli, Milena Vitali, Nicoletta Zilembo, Monica Ganzinelli, Filippo De Braud, Marina Chiara Garassino, Giuseppe Lo Russo

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy (IO) is effective against metastatic non small cell lung cancer (mNSCLC). Gut microbioma has a strong impact on immune functions and its imbalance due to antibiotics (atbs) may impair the efficacy of IO. Recent works on other malignancies supported this evidence, but data are still lacking. We studied this topic in a case series of mNSCLC patients (pts) treated with IO.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data about all consecutive pts with mNSCLC treated with IO at Istituto Nazionale dei Tumori, Milan, Italy, between 04/2013 and 01/2018 were retrospectively collected. Pts were stratified according to atb use between 1 month (mo) before and 3 mos after the beginning of IO, and to atb exposure (AEx) defined as the ratio “days under atb/days under IO”. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analysis was performed with Cox proportional model.

      4c3880bb027f159e801041b1021e88e8 Result

      One hundred fifty-seven pts were analyzed, for a median follow-up of 28.6 mos. IO consisted in an anti-PD1 agent in 62.4% of cases, in an anti-PDL1 agent in 32.5% of cases, in a combination anti-PDL1+anti-CTLA4 in 5.1% of cases. First-line IO was administered in 25 cases, second-line IO in 66 cases, third- or more advanced-line IO in 66 cases. Twenty-seven pts received atbs. The 3 most commonly used atbs were levofloxacin (55.6%), amoxicillin/clavulanate (25.9%), and ceftriaxone (14.8%). No differences in either response rate, progression free survival (PFS) and overall survival (OS) were observed between the subgroups defined by atb use (p .14, .18 and .24, respectively). Median AEx of the treated pts was 5%. The pts with an AEx longer than the median one had significantly worse PFS (2.2 vs 7.7 mos, p<.0001) and OS (4.9 vs 16.3 mos, p .0004) than the others. This result maintained significance after correction for IO line (p .0003) and performance status (p .0002), which were the only other variables influencing PFS and OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Though no differences in outcome could be observed in our population according to simple atb use, a significant disadvantage in PFS and OS became evident for pts with a higher AEx. If confirmed, these data may suggest to carefully weigh the prescription of atbs to mNSCLC pts treated with IO.

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      MA10.03 - Plasmatic Evaluation of the Intestinal Barrier and Blood Microbiota, and Antibiotic Use in Non-Small Cell Lung Cancer Patients Treated with Nivolumab (Now Available) (ID 13863)

      10:40 - 10:45  |  Presenting Author(s): Etienne Giroux Leprieur  |  Author(s): Julia Ouaknine, Pierre Helly De Tauriers, Coraline Dumenil, Nathalie Neveux, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Julie Tisserand, Jean-François Emile, Thierry Chinet

      • Abstract
      • Presentation
      • Slides

      Background

      Recent data suggest that gut microbiota and antibiotic use affect the efficacy of immune checkpoint inhibitors. We aimed to evaluate the predictive role of blood microbiota, plasma citrulline (marker of the intestinal barrier), and the impact of early (from 2 months before until 1 month after beginning of nivolumab) and late (after 1 month of nivolumab) antibiotic use on nivolumab efficacy in NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We included consecutive patients with advanced NSCLC treated with nivolumab between July 2014 and December 2017. Plasma tests were taken prospectively during treatment. The microbial population present in the plasma samples was determined using sequencing of variable regions of the 16S rRNA bacterial gene at M0. Plasma citrulline concentrations were evaluated by ion exchange chromatography at month (M) 0, M2, M4 and M6 of nivolumab.

      4c3880bb027f159e801041b1021e88e8 Result

      Seventy-two patients were included (male: 62%; smokers: 87%; adenocarcinoma: 63%). Early use of antibiotics (EUA) (n=28/72) was associated with poor overall survival (OS) (median 5.1 months, versus 13.4 months without EUA, p=0.03), whereas later use of antibiotic during treatment had no significant effect. Thirty-six patients (50%) had serial plasma samples available for analyses. The composition of blood microbiota at M0 was associated with tumor response and long-term benefit of nivolumab, with a significant impact of Paludibacilum, Gemmatimonadaceae and Nocardioides. Patients with long-term benefit of nivolumab had significantly higher plasma citrulline concentrations than other patients, at M0, M2 and M4, and maintained high citrulline concentrations at M6. Median progression-free survival (PFS) and OS for patients with citrulline ≥20µM at M0 were 7.9 months and not reached, versus 1.6 months (p<0.0001) and 2.2 months (p<0.0001) for patients with citrulline <20µM, respectively. Patients with EUA had lower median citrulline concentrations at M0 (17µM [IQR 15-30] versus 31µM [IQR 21.3-40.5]; p=0.06).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study confirms the negative impact of EUA during nivolumab treatment, and suggests that plasma evaluation of the intestinal barrier and blood microbiota may help to predict the outcome of NSCLC patients treated with nivolumab.

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      MA10.04 - Discussant - MA 10.01, MA 10.02, MA 10.03 (Now Available) (ID 14611)

      10:45 - 11:00  |  Presenting Author(s): Bertrand Routy

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA10.05 - Effect of Early Steroids use in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 14163)

      11:00 - 11:05  |  Presenting Author(s): Giovanni Fucà  |  Author(s): Marta Poggi, Giulia Galli, Martina Imbimbo, Giuseppe Lo Russo, Claudia Proto, Milena Vitali, Monica Ganzinelli, Nicoletta Zilembo, Filippo De Braud, Marina Chiara Garassino, Diego Signorelli

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy (IO) radically improved patients (pts) outcomes in advanced non-small cell lung cancer (NSCLC). Because of their immunosuppressive activity, the use of steroids as supportive care medications or for mild adverse events, even if at anti-inflammatory dosage, is debatable. In this study we assessed the effect of early steroids use on clinical outcomes of pts with advanced NSCLC treated with IO.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected demographics, clinical and pathological data of pts with advanced NSCLC treated with IO at our institution with at least one instrumental response assessment. Early use of steroids was defined as the use of a daily prednisone-equivalent dose 10 mg for at least 1 day within 28 days from the start of IO. Chi-square test or Fisher's exact test were used to analyze the association of early use of steroids with pts’ characteristics. The Kaplan-Meier method and the Cox proportional-hazards model were used for survival analyses while the reverse Kaplan-Meier method was used for follow-up quantification.

      4c3880bb027f159e801041b1021e88e8 Result

      We included 151 pts, 35 (23 %) of whom recurred to an early use of steroids. Six pts (4%) received combinatorial PD-L1+CTLA-4 blockade while 145 (96%) received single agent anti PD-1/PD-L1. Early use of steroids was positively associated with ≥2 metastatic sites (OR 3,08, 95% CI 1.33-7.89; P = .01) and ECOG PS 2 (OR 4.57; 95% CI 1.10-20.37; P = .03) and negatively associated with disease control (OR 0,32; 95% CI 0.14-0.71, P = .006). With a median follow-up of 28.61 months, early use of steroids characterized a poorer median OS (4.86 vs 15.14 months; HR 2.60; 95% CI 1.70-4.10; P < .0001). In the multivariable model including the only other covariate significantly associated with survival (ECOG PS), the early use of steroids was confirmed to independently worsen OS (HR 2.38; 95% CI 1.49-3.81; P = .0003). Early use of steroids was also associated with a poorer median progression-free survival (PFS) (1.98 vs 3.94 months; HR 1.80; 95% CI 1.20-2.80; P = .003).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In our analysis, the early use of steroids significantly affected disease control, PFS and OS in advanced NSCLC patients treated with IO. If our findings will be further prospectively confirmed, early use of steroids should be avoided in this setting.

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      MA10.06 - Impact of Immune-Related Adverse Events on Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Nivolumab (Now Available) (ID 13039)

      11:05 - 11:10  |  Presenting Author(s): Biagio Ricciuti  |  Author(s): Carlo Genova, Andrea De Giglio, Marta Brambilla, Maria Bassanelli, Maria Giovanna Dal Bello, Sara Baglivo, Giulio Metro, Francesco Grossi, Rita Chiari

      • Abstract
      • Presentation
      • Slides

      Background

      Anti PD1 and anti PD-L1 monoclonal antibodies represent the standard of care for platinum-pretreated advanced non-small cell lung cancer (NSCLC) patients, having shown to prolong survival compared to chemotherapy in second-line setting in phase III clinical trials. Patients treated with these drugs not infrequently experience immune-related adverse events (irAEs), which we hypothesize might reflect antitumor response. In this study we investigated whether the development of irAEs was associated with nivolumab efficacy in patients with advanced NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a multicenter retrospective study of patients with advanced NSCLC treated with nivolumab between October 2013 and September 2017. IrAEs were defined as AEs having immunological basis that required intensive monitoring and interventions. We evaluated nivolumab efficacy according to the development of irAEs.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 195 patients (median [range] age, 63 [30-40] years; 128 men [65.6%], 67 women [34.4%]), irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events. Median PFS was 5.7 months in patients with irAEs compared to 2 months of those without irAEs (P < 0.0001). Median OS was 17.8 months compared to 4.04 months of no-irAEs group (P < 0.0001). The survival benefit of irAEs was consistent also in 12- and 6-weeks landmark analysis. Patients who developed ≥ 2 irAEs (n: 37) had a significantly longer median PFS and OS compared to those with one AE (n: 48) or none (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2, P < 0.0001; OS: 26.8 months vs. 11.9 vs. 4, P < 0.0001). Multivariable analysis revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.48 (95%CI, 0.34-0.77; P < 0.0001) for PFS and 0.38 (95%CI, 0.26-0.56; P < 0.0001) for OS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the largest study conducted to date aimed to evaluate whether the development of irAEs is predictive of nivolumab efficacy in pre-treated NSCLC patients. In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients who had received nivolumab in ≥ 2 line setting. This data was consistent in the 12- and 6-weeks landmark analysis, suggesting that an early onset of irAEs might be predictive of durable clinical benefit in NSCLC patients treated with nivolumab. Moreover, patients who experienced ≥ 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE. Further studies are required to investigate the molecular mechanisms underlying this association.

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      MA10.07 - Discussant - MA 10.05, MA 10.06 (Now Available) (ID 14614)

      11:10 - 11:25  |  Presenting Author(s): Kenneth O’byrne

      • Abstract
      • Presentation
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      Abstract not provided

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      MA10.08 - Choice of Taxane and Outcomes in the KEYNOTE-407 Study of Pembrolizumab Plus Chemotherapy for Metastatic Squamous NSCLC (Now Available) (ID 14698)

      11:25 - 11:30  |  Presenting Author(s): Balazs Halmos  |  Author(s): Alexander V Luft, Margarita Majem, Rina Hui, Romain Corre, Mahmut Gümüş, Konstantin Laktionov, Barbara Hermes, İrfan Çiçin, Andrew G Robinson, Terufumi Kato, Ying Cheng, Dariusz Kowalski, Xiaodong Li, Gregory M Lubiniecki, Bilal Piperdi, Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      In the randomized, double-blind, phase 3 KEYNOTE-407 study (NCT02775435), pembrolizumab plus chemotherapy with carboplatin and paclitaxel or nab-paclitaxel significantly prolonged OS (HR 0.64, 95% CI 0.49-0.85, P=0.0008) and PFS (HR 0.56, 95% CI 0.45-0.70, P<0.0001) compared with placebo plus chemotherapy in patients with previously untreated, metastatic squamous NSCLC. The benefit of pembrolizumab plus chemotherapy was observed irrespective of PD-L1 TPS. Pembrolizumab plus chemotherapy also had a manageable safety profile. We performed an exploratory analysis of outcomes by investigator’s choice of paclitaxel or nab-paclitaxel, which was a randomization stratification factor.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      559 eligible patients were randomized 1:1 to pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus 4 cycles of carboplatin AUC 6 mg/mL/min Q3W and investigator’s choice of paclitaxel 200 mg/m2 Q3W or nab-paclitaxel 100 mg/m2 QW. Primary end points were OS and PFS; ORR and safety were secondary.

      4c3880bb027f159e801041b1021e88e8 Result

      Paclitaxel was the chosen taxane in 60% of patients. The addition of pembrolizumab to chemotherapy improved OS, PFS, and ORR regardless of choice of carboplatin and paclitaxel or carboplatin and nab-paclitaxel (Table). Incidence of grade 3-5 AEs in the pembrolizumab plus chemotherapy arm vs placebo plus chemotherapy arm was 63.9% vs 59.3% in paclitaxel recipients and 78.9% vs 81.4% in nab-paclitaxel recipients. AEs led to discontinuation of all treatment in 13.6% vs 8.4% of paclitaxel recipients and 12.8% vs 3.5% of nab-paclitaxel recipients and led to discontinuation of any treatment in 19.5% vs 13.2% and 29.4% vs 9.7%, respectively. Immune-mediated AEs occurred in 29.6% vs 9.6% of paclitaxel recipients and 27.5% vs 7.1% of nab-paclitaxel recipients.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Adding pembrolizumab to chemotherapy with carboplatin and a taxane improved efficacy and was generally tolerable compared with chemotherapy alone as first-line therapy in patients with metastatic squamous NSCLC regardless of whether paclitaxel or nab-paclitaxel was the chosen taxane.

      Carboplatin plus Paclitaxel Carboplatin plus Nab-Paclitaxel

      Pembrolizumab + Chemotherapy

      N = 169

      Placebo + Chemotherapy

      N = 167

      Pembrolizumab + Chemotherapy

      N = 109

      Placebo + Chemotherapy

      N = 114

      OS, median

      (95% CI), mo

      14.0 (12.6-16.6) 10.3 (8.2-14.8) NR (NE-NE) 12.6 (9.6-NE)
      HR (95% CI)a 0.67 (0.48-0.93) 0.59 (0.36-0.98)

      PFS, median

      (95% CI), mo

      6.4 (6.0-8.3) 4.4 (4.2-5.1) 6.5 (6.2-8.5) 5.9 (4.4-6.9)
      HR (95% CI)a 0.52 (0.40-0.68) 0.65 (0.45-0.94)
      ORR, % (95% CI) 57.4 (49.6-65.0) 37.7 (30.4-45.5) 58.7 (48.9-68.1) 39.5 (30.4-49.1)
      aBased on a Cox regression model with treatment as a covariate.

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      MA10.09 - NECPAL 2: A Multicentre Descriptive Study of Primary and Continuous Attention in Palliative Care in Argentina: Lung Cancer Cohort (Now Available) (ID 12928)

      11:30 - 11:35  |  Presenting Author(s): Carolina Gabay  |  Author(s): Mara Bonet, Monica Castro, Romina Tranier, Sol Sandijian, Silvina De Lellis, Alvaro Sauri, Vilma Tripodoro, Gustavo De Simone

      • Abstract
      • Presentation
      • Slides

      Background

      In Argentina Lung cancer is the most deadly neoplasm (9230 annuals death). Early identification of palliative care (PC) needs has proven benefits in terms of quality of life, survival, and decision making in Lung cancer patients. The NECPAL CCOMS-ICO© tool is face and content-validated instrument to identify patients likely in need of PC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To implement and evaluate a demonstration multicenter program for early and continuous PC for Lung cancer patients in Buenos Aires using the NECPAL-CCOMS-ICO© tool (multifactorial assessment) in every level of attention. We reported the results of one University Cancer center lung cancer cohort (2016-2018).

      We categorized patients as surprise question positive (SQ+), (Would you be surprised if this patient were to die in the next 12 month?). If the healthcare professional answered ‘NO’, the patient was considered SQ+ and they were also considered NECPAL+ when they presented at least one additional parameter from the NECPAL tool. All patients classified as NECPAL+ were considered to be in need of PC. Then using a Cox regression model analyzed predictors for overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      82 patients out of 206 were SQ+ and NECPAL +. Median age 64 (35-82). 46 % had stage IVB (8th ) ,18 % IVA , 19.5% locally advanced, and 7 ptes early stage. 6 ptes presented SCLC . Male were 59%. 78 ptes were analyzed for overall survival; n=4 were excluded due lost of follow up. 56% had died with a Median OS of 11 months (7.2-14.7). 5/82 ptes did not receive any kind of oncology treatment due ECOG, comorbidities or patients’ choice. Median OS was 17 months (10.5-23.4) for men and 10 months (3.7-16.2) for females (p=0.08).

      In the univariate analyses, only metastasis in vital organs (nervous central system, liver, massive lung) was predicted of survival (17 vs 8 months; p=0.035). The other NECPAL indicators did not met the criteria for significance.

      The multivariate analysis, did not find a statistically significant combination of predictors for overall survival except metastasis in vital organs. It was noted an small number of low PPS score (11/78), as well as nutritional (14/78) or severe functional deterioration (5/78), in spite of the majority of the cohort had advanced disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This Program adds a prospective direct method of measuring prevalence of PC needs including a Palliative approach. The results presented support consideration of the NECPAL tool as a prognostic tool in our setting.

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      MA10.10 - Lung Cancer Stigma: A Ten-Year View of Patient, Provider, and Public Attitudes About Lung Cancer. (Now Available) (ID 13413)

      11:35 - 11:40  |  Presenting Author(s): Jennifer C King  |  Author(s): Maureen Rigney, Lisa Carter-Harris

      • Abstract
      • Presentation
      • Slides

      Background

      The presence of lung cancer stigma is well documented (Chapple, 2004; Chambers, 2012; Marlow, 2015) and impacts the care and treatment of lung cancer survivors (Tod, 2008; Carter-Harris, 2014). In 2008, a large survey of patients, oncologists, and general public revealed that most participants felt lung cancer was principally caused by external factors, was preventable, and lung cancer patients were partly to blame for their illness (Weiss 2014; 2017). We replicated the survey to understand whether perceptions have changed over the last decade.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      1001 members of the general public, 208 lung cancer patients, and 205 oncologists who treat lung cancer were surveyed with the identical instrument as 2008 plus 3-11 questions at the end including Cataldo Lung Cancer Stigma Scale (Cataldo, 2011) strongest-loaded items for the patient survey. The survey was administered by phone and online during summer 2018.

      4c3880bb027f159e801041b1021e88e8 Result

      General lung cancer awareness has significantly improved in a decade with 94% of the public reporting familiarity with lung cancer, every segment reporting increased media visibility (65%, 78%, 85% for public, patients, and oncologists, respectively), and patients reporting significantly increased use of advocacy organizations (39% vs 18%, p<.05). Additionally, significantly more oncologists reported having adequate treatment options to prolong patients’ lives (52% vs 31%, p<.05) and most patients reported satisfaction with medical care (87%) and treatment options (71%).

      Despite these advances, stigma remains a critical problem. In 2018, significantly more of the public believed lung cancer patients are viewed/treated differently than other cancer patients (37% vs 31%, p<.05) and a similar proportion (56%) felt patients are partly to blame for their illness. Oncologists continue to believe there is stigma associated with lung cancer (68%) although more felt stigma was lower for never-smokers. More oncologists indicated patients blame themselves (67% vs 57%). Patients reported significant increases (p<.05) in presence of stigma associated with lung cancer (70% vs. 54%), lung cancer patients being treated differently by society (63% vs. 45%), having personally been treated different by society (43% vs 25%), and loved ones would be more supportive if they had a different type of cancer (25% vs. 11%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      After a decade of lung cancer research progress, results indicate considerably elevated awareness. Unfortunately, disease stigma remains. Interestingly, stigma is reported more frequently by lung cancer patients and may be felt more acutely, perhaps due to increased awareness and empowerment. This work underscores the need to address stigma with proactive multilevel approaches (Hamann, 2018).

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      MA10.11 - Discussant - MA 10.08, MA 10.09, MA 10.10 (Now Available) (ID 14616)

      11:40 - 11:55  |  Presenting Author(s): Antoinette Wozniak

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA23 - Early Stage Lung Cancer: Present and Future (ID 926)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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      MA23.01 - Buffy Coat Immunooncologic Diagnosis and Prognosis of pStage I Lung Adenocarcinoma (Now Available) (ID 12453)

      10:30 - 10:35  |  Presenting Author(s): Harvey Pass  |  Author(s): Wenjie Xu, Chandra Goparaju

      • Abstract
      • Presentation
      • Slides

      Background

      Accurate diagnosis of CT detected pulmonary nodules is crucial to decrease futile minimally invasive resections. We hypothesize that the circulating cellular microenvironment (buffy coat [BC]) containing granulocytes, mononuclear cells, and platelets presents immunologic transcriptional profiles for distinguishing adenocarcinoma from granulomas, and can prognosticate pStage I adenocarcinomas.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      BC total RNA was extracted from 48 pStage I adenocarcinomas having R0 resection and 23 granuloma patients found at surgery. Of the cancers, 23 did not recur either systemically or locoregionally and were matched by age, gender, and pack-years to progressors. RNA was profiled using Nanostring PanImmune Oncology panel for 770 immune genes and cytokines. A machine learning algorithm based on Elastic Net using 1000 loops of cross validation was run to estimate AUC, and logistic regression models used for prognostic classification.

      4c3880bb027f159e801041b1021e88e8 Result

      wclc 18 final.pngThe figure depicts the results of the diagnostic profiling in the upper panel (A-C), and prognostication in lower panel (D-F). Unsupervised heat map separated adenocarcinomas (grey) from granulomas, and among the gene set analysis, differences in interleukins, microglial function, antigen processing, cytokines and macrophage functions were the most significant for cohort discrimination. A 33 gene set signature was able to separate granuloma from cancer with mean AUCs of 0.982. Expresion of BC immune related genes were remarkably different between the patients who recurred, and there were differences in profiles of locoregional recurrences compared to systemic recurrences (data not shown).Patients with elevated T-regs but decreased T-cells were characterized by distant progression, while decreased mast cells and increased CD-8 and total T-cells were associated with local recurrence. A three step prognostication index using 19 genes could stratify these patients by time to progression (E,F).

      8eea62084ca7e541d918e823422bd82e Conclusion

      These encouraging data offer the potential for immune transcriptional signatures to better select patients for diagnosis/management of early stage adenocarcinoma. Further validation studies are underway for possible presentation at WCLC18.

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      MA23.02 - Circulating Tumor DNA Analysis with a Novel Variant Classifier for Recurrence Detection in Resected, Early-Stage Lung Cancer (Now Available) (ID 13498)

      10:35 - 10:40  |  Presenting Author(s): Vincent K Lam  |  Author(s): Hai T Tran, Mayra E Vasquez, Kitty Li, Kenneth Yuen, Feng Vang, Ariel Jaimovich, Drew Kennedy, Justin Odegaard, Stefanie Mortimer, Steven R. Olsen, Victoria M. Raymond, Ara A Vaporciyan, Mara B Antonoff, Garrett L Walsh, Emily Roarty, Lara Lacerda, Jack A Roth, Stephen Swisher, Chantale Bernatchez, Boris Sepesi, Don Lynn Gibbons, Jianjun Zhang, John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, data regarding feasibility are limited, especially for stage I-II disease.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed longitudinal plasma ctDNA profiling of early-stage lung cancer patients (pts) that underwent resection at MD Anderson Cancer Center from Apr 2016 to Jan 2017. Plasma ctDNA was analyzed from pre-operative and multiple post-operative time points until disease recurrence. ctDNA profiling was performed using a 30kb Digital Sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes that are commonly present in lung cancer. ctDNA profiles from ~30,000 lung cancer pts were used to train a classifier to exclude non-tumor related mutations.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 40 pts were included in this analysis, comprised of the first 17 pts with recurrence in the longitudinal study and 23 consecutive pts without recurrence. This cohort was primarily stage I and II (15 [38%], 16 [40%]). Histology included adenocarcinoma (29 [73%]), SCC (6 [15%]), and SCLC (2 [5%]). 58% had adjuvant therapy. Median follow-up was 17.7 (3.4 – 24.5) months and median time to recurrence was 7.1 (3.4 – 16.5) months in this selected cohort. At least one ctDNA alteration was detected in 55% (21/38) of pts with evaluable pre-op samples and in 22% (8/37) of pts at 4 weeks post-op. Presence of ctDNA at 4 weeks post-op heralded eventual recurrence with 43% sensitivity and 91% specificity (75% PPV, 73% NPV) and was significantly associated with worse recurrence free survival (p=0.022, HR 6.52; 95% CI 1.3 – 32.6), while also accounting for stage. In the absence of the variant classifier, an additional 7/37 pts had non-tumor alterations detected at 4 weeks post-op with a recurrence sensitivity and specificity of 57.1% and 69.6%. ctDNA was identified in 76% (13/17) of pts prior to or at the time of recurrence. The median interval between ctDNA detection and radiographic recurrence was 91 days.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Detection of post-op ctDNA, as early as 4 weeks after resection of early-stage lung cancer, is associated with significantly increased risk of recurrence. Accurate detection of ctDNA in this MRD setting is enabled by a highly sensitive sequencing platform that incorporates a novel variant classifier to enhance clinical specificity.

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      MA23.03 - Risk Assessment for Indeterminate Pulmonary Nodules Using a Novel, Plasma-Protein Based Biomarker Assay (Now Available) (ID 13873)

      10:40 - 10:45  |  Presenting Author(s): Anil Vachani  |  Author(s): Amanda L Fish, Mike Beggs, Luis Carbonell, Zaid Haddad, Alice Juang, Sandy Kamer, Bhavin Patel, Heng Yu, Alan Wu, Pierre P Massion, Mehrdad Arjomandi, James Brown, Neil Trivedi, Tess Rubenstein

      • Abstract
      • Presentation
      • Slides

      Background

      To reduce overdiagnosis and overtreatment of non-cancerous pulmonary nodules found on CT scans, a noninvasive and easily administered test is needed to assess clinically significant disease risk. Such an assay should also accurately inform whether additional aggressive evaluation, including lung biopsy or thoracic surgery, is warranted.

      Objective: To determine the performance of a novel, plasma-based multiplexed protein test model when compared to the Veterans Affairs Clinical Factors Model (VA model) for discriminating between a lung cancer diagnosis established pathologically and an Indeterminate Pulmonary Nodule (IPN) found to be clinically and radiographically stable for at least one year.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The protein biomarker-based risk model had been trained and tested with a cohort of 277 subjects at high risk of lung cancer, aged 25-85, who were current smokers with an indeterminate lung nodule 4-30mm in diameter (121 subject training set; 59 subject test set) from eight medical centers across the US. Using retrospective plasma samples, we compared the protein biomarker model results with the malignant or benign outcomes in an independent validation cohort comprised of 97 subjects from the Vanderbilt University medical center.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 97 validation study subjects (average age 60.1 years, range 42-83; average nodule size 16.1mm), the protein biomarker model correctly identified as benign or malignant an additional 44 of the 68 (65%) indeterminate pulmonary nodules classified as having intermediate risk by the VA model. Negative predictive value was 0.94. Only three patients with malignant disease were missed (94% sensitivity) while an additional 28 intermediate risk samples (41%) were properly classified as true positive, thus potentially avoiding aggressive interventions in those subjects with benign disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study evaluated a novel plasma protein biomarker assay model as a noninvasive risk assessment aid for characterizing indeterminate pulmonary nodules. When the model results are combined with the VA model, risk stratification for benign nodules is improved compared to current methods in clinical practice. We hypothesize patients with benign disease may benefit the most from this assay by avoiding unnecessary lung biopsy and subsequent overtreatment, while improving patient quality of care and reducing risks from these procedures. Providers and their patients in whom they suspect lung cancer may consider using this novel assay prior to proceeding with more aggressive interventions.

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      MA23.04 - Discussant - MA 23.01, MA 23.02, MA 23.03 (Now Available) (ID 14612)

      10:45 - 11:00  |  Presenting Author(s): Scott Bratman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA23.05 - Post-Operative Radiation Improves Overall Survival in Patients with Node-Positive Non-Small Cell Lung Cancer Undergoing Sublobar Resections (Now Available) (ID 14350)

      11:00 - 11:05  |  Presenting Author(s): Karl Fabian Lim Uy  |  Author(s): Rickie P Voland, John Michael Varlotto, Malcolm Decamp, Kerri McKie, Debra Maddox, Paul Rava, TJ Fitzgerald, Jennifer Toth, Paulo Oliveira, Michael F Reed, Chandra Belani, Jennifer Baima, Jianying Zhang, William Vincent Walsh, Monali Patel, Max Rosen, Lacey McIntosh, Negar Rassaei, John Flickinger

      • Abstract
      • Presentation
      • Slides

      Background

      The incidence and prognosis associated with patients undergoing sub-lobar resections and having positive lymph nodes(PLN) has been rarely studied. Our investigation will retrospectively review this topic.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The National Cancer Database(NCDB) was queried during the years 2004-2014 to assess patients undergoing sub-lobar resection (wedge, segmentectomy, and sub-lobar-NOS, N = 38,599) and specifically the patients with PLN (N = 5484). Patients were excluded who had any pre-op chemotherapy and/or radiation, had follow-up of less than 3 months, had stage IV disease or >1 tumor nodule. Multi-variable modeling(MVA) was used to determine factors for overall survival (OS). Propensity score matching(PSM) was used to determine pre-operative risk factors for PLN in patients having at least one node examined(N=22712) (matched by median number of nodes examined) and to assess the role of radiation in those patients with node positive disease (matched by age, sex, stage, chemotherapy, and number of nodes positive).

      4c3880bb027f159e801041b1021e88e8 Result

      The incidence of PLN decreased progressively during our study from 17.9% in 2004 to 9.4% in 2014 (N1 8.3-5.0% and N2 9.6-4.4%). A lower risk of PLN was noted for squamous cell carcinomas, bronchoalveolar (minimally invasive) adenocarcinomas, and right upper lobe locations; but the risk increased with age, tumor size and clinical stage. In the node positive group, MVA demonstrated that OS was worse with males, older ages, non-Hispanic Whites (compared to Asian and Hispanic Whites), lowest income quartile, Charlson co-morbidity > 0, grade, tumor size, number of positive nodes, positive surgical margins, length of stay, and not receiving chemotherapy or radiation. PSM demonstrated that radiation increased OS in patients having PLN regardless of margin status or N level involvement.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The incidence of node positive sub-lobar resections has decreased during the years of our study, but still can be found in nearly 10%. In both MVA and PSM, post-operative radiation improves OS.

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      MA23.06 - Small Residual Setup Errors After Image-Guided Radiotherapy Affect Heart Dose and Are Linked to Overall Survival (Now Available) (ID 13785)

      11:05 - 11:10  |  Presenting Author(s): Alan McWilliam  |  Author(s): Corinne Johnson, Gareth Price, Corinne Faivre-Finn, Marcel Van Herk

      • Abstract
      • Presentation
      • Slides

      Background

      There is limited evidence of the effect of radiotherapy image guidance on survival. This work investigates the relationship between small residual set-up errors following IGRT and overall survival in lung cancer patients (mostly with significant comorbidities), and explores which anatomy may be responsible for observed differences.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Residual setup errors of 546 NSCLC patients treated with an off-line 5mm action threshold correction protocol for bony anatomy were summarized per patient as the mean and standard deviation for each axis, as well as the vector magnitude in a direction from tumour towards the heart, and included in multivariate Cox regression. Delivered dose distributions including residual setup errors were estimated and the difference between the delivered and planned dose was compared for patients who did/did not survive longer than 1 year. Permutation testing (n=1000) assessed significance.

      4c3880bb027f159e801041b1021e88e8 Result

      Residual setup errors were not correlated with any pre-treatment clinical variable. Patients with a residual shift towards the heart (mean ~2 mm, max 5mm) have significantly worse overall survival (hazard ratio 1.310, p = 0.001). The average dose in the heart region changes linearly with the residual shift magnitude towards the heart (~0.8Gy/mm). A higher delivered dose than planned in a region at the heart base (Figure 1, arrow) is associated with poorer survival in multivariate analysis (hazard ratio 1.214/Gy, p<0.001).

      figure1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Small residual shifts after IGRT are strongly associated with overall survival in NSCLC patients, with shifts of the high dose region towards the heart leading to worse survival. The most likely cause of shorter survival is a corresponding increase in dose to the heart base. This analysis provides direct evidence of the importance of accurate patient positioning and highlights the significance of the heart base as a dose sensitive organ in thoracic radiotherapy patients with early effects on survival.

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      MA23.07 - Defining the Role of Adjuvant Therapy for Early Stage Large Cell Neuroendocrine Lung Cancer (Now Available) (ID 12814)

      11:10 - 11:15  |  Presenting Author(s): Elliot Wakeam  |  Author(s): Sean Stokes, Alexander Adibfar, Natasha B Leighl, Meredith Giuliani, Thomas K. Varghese, Gail Elizabeth Darling

      • Abstract
      • Presentation
      • Slides

      Background

      Large cell neuroendocrine lung cancer (LC-NEC) is a rare, high-grade neuroendocrine tumor. Patterns of adjuvant treatment after surgical resection have not been well defined.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with a pathologic diagnosis of LC-NEC were identified in the National Cancer Database 2004-2014. Patient demographics, tumor and treatment characteristics were examined. Survival differences in patients receiving chemotherapy were evaluated using Kaplan-Meier curves, and multivariate hierarchical Cox models were constructed to evaluate the impact of patient, histologic, tumor, treatment and hospital characteristics on overall survival (OS). A conditional landmark of 90-day postoperative survival was used to address immortal time bias and propensity-matching was used to address imbalance in covariates between groups.

      4c3880bb027f159e801041b1021e88e8 Result

      1,793 patients were identified with pathologically stage I LC-NEC, of which 482 (26.9%) received adjuvant chemotherapy. Use of adjuvant chemotherapy remained similar across the study period. Patients receiving adjuvant chemo were younger, less comorbid and more likely to have T2 tumors. Significantly longer survival was observed with the receipt of adjuvant chemotherapy (5-year OS 59.2% vs. 45.3%), which persisted after adjustment in multivariable Cox models (HR 0.69, 95%CI0.58 – 0.82, p<0.0001). Adjuvant chemotherapy was associated with longer survival in patients with tumors 2-3cm (60.4% vs. 41.8%; HR 0.64, 95%CI 0.46-0.89, p<0.0001), and T2 tumors (59.8% vs. 42.1%; HR 0.63, 95%CI 0.50-0.81, p<0.0001), but no differences were observed for LC-NEC patients with tumor size <2cm. Adjuvant chest radiotherapy was not associated with improved survival. T-stage specific propensity-matching confirmed these findings, however the association between survival and adjuvant chemotherapy for patients with tumors 2-3cm was no longer significant.

      slide1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this national study of LC-NEC, adjuvant chemotherapy was associated with significantly longer survival in Stage I tumors greater than 2cm. Adjuvant radiation was not associated with survival. A randomized trial of stage T2-4N0 LCNEC is needed to clarify the role of adjuvant chemotherapy in this population.

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      MA23.08 - Discussant - MA 23.05, MA 23.06, MA 23.07 (Now Available) (ID 14613)

      11:15 - 11:30  |  Presenting Author(s): Kevin Franks

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA23.09 - Minimally Invasive Approaches Do Not Compromise Outcomes for Pneumonectomy, a Comparison Utilizing the National Cancer Database (Now Available) (ID 12073)

      11:30 - 11:35  |  Presenting Author(s): Mark Hennon  |  Author(s): Abhinav Kumar, Harshita Devisetty, Thomas A. D'Amico, Todd Demmy, Adrienne Groman, Sai Yendamuri

      • Abstract
      • Presentation
      • Slides

      Background

      Minimally invasive approaches are increasingly being used for the conduct of complex surgical procedures. Whether the benefits of minimally invasive approaches compared to thoracotomy for sublobar and lobar lung resection for nonsmall cell lung carcinoma are realized for patients undergoing pneumonectomy is not clear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The National Cancer Database was queried for patients who underwent pneumonectomy for NSCLC from 2010-2014. Those who underwent resection by a minimally invasive approach (MIS) were compared with those who were done by thoracotomy (Open) in an intent-to-treat analysis. Associations between potential covariates and treatment were analyzed using the Pearson Chi-square test for categorical variables and Wilcoxon Rank Sum test for continuous variables. Univariable and multivariable logistic models and proportional hazards model were used to assess the effect of surgical approach on 30 day and 90 day mortality and overall survival. Relative prognosis was summarized using odds ratios (OR) and hazards ratios (HR) estimates and 95% confidence limits.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 4,938 patients underwent pneumonectomy during the study period, of which 755 (15.3%) were completed by minimally invasive approaches (MIS). No difference was noted in 30 and 90-day mortality rates for MIS compared to Open approaches (6.8% and 12.3% vs 6.7% and 11.9% respectively, p = 0.9 and 0.86). Tumor histology and stage characteristics were similar between the two groups. Mean lymph nodes examined was higher in the MIS group compared to Open (17.1± 0.4 vs 16.1 ± 0.2, p=0.034). Surgical approach was not associated with any difference in perioperative mortality with univariable or multivariable analysis. MIS was associated with improved overall survival on univariable analysis, but this was not evident with multivariable analysis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pneumonectomy performed by minimally invasive approaches does not compromise perioperative mortality or long term outcomes. Further investigation into the impact of minimally invasive approaches on perioperative outcomes for whole lung resection is warranted.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA23.10 - Cone-Beam Computed Tomography-Guided Microcoil Localization of Pulmonary Nodules During Video-Assisted Thoracic Surgery (Now Available) (ID 13345)

      11:35 - 11:40  |  Presenting Author(s): Hideki Ujiie  |  Author(s): Alexander Gregor, Tomonari Kinoshita, Kosuke Fujino, Chang Young Lee, Yamato Motooka, Terunaga Inage, Tatsuya Kato, Elsie Nguyen, Kazuhiro Yasufuku

      • Abstract
      • Presentation
      • Slides

      Background

      The standard procedure at our institution for intraoperative localization of non-palpable small lung nodules is computed tomography (CT)-guided microcoil placement prior to video-assisted thoracic surgery (VATS). Typically, microcoil placement is performed in the radiology suite followed by transfer to the operation room (OR). Our institution has built the Guided Therapeutics (GTx) OR, which includes a robotic cone-beam CT (CBCT). The GTx OR allows imaging and therapy to occur in one location. This can improve workflow and reduce patient transportation, which may increase the risk for microcoil dislodgement or the development of pneumothorax/hemothorax. Our objective was to determine the safety and efficacy of CBCT-guided microcoil placement for nodule localization during VATS.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This is a single center phase I clinical trial (NCT02496624). Patients with small lung nodules who were candidates for standard CT-guided microcoil localization were enrolled. CBCT was used to generate a 3D reconstruction. The lesion was then segmented using Syngo iGuide software. This reconstruction was next integrated into the digital workspace and automatically registered onto the fluoroscopic images, creating ‘augmented fluoroscopy’. The microcoil was placed percutaneously using ‘augmented’ guidance, proximal to the lesion, using local anesthetic. Patients were subsequently induced into general anesthesia, intubated, and positioned for VATS. Minimally invasive resection of the nodule together with the microcoil was performed under standard fluoroscopic guidance.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 11 patients were enrolled (mean age 70 ± 11SD). The average tumor size on CT was 1.3 cm (range 0.9-1.7). The average deepest depth from the pleural surface was 2.3 cm (1.3-3.8). The average CBCT-guided intervention time was 39 minutes (25-54), and VATS procedural time was 54 minutes (14-78). We were able to detect and successfully resect all nodules. Average total radiation dose was in an acceptable low range (8307 μGy*m2, range, 2402–18,371). There were no intraoperative complications. Average post-operative length of stay was 1.8 days. A pathological diagnosis was made for all patients: 8 primary lung cancers and 3 lung metastases. All surgical margins were negative on final pathology.

      8eea62084ca7e541d918e823422bd82e Conclusion

      CBCT-guided microcoil insertion followed by VATS was safe, with short operative times, short length of stay and 100% diagnostic yield. With the GTx OR’s real-time guidance capabilities, surgeons can operate with increased confidence of finding and removing the target lesion. This technique will become increasingly important in the future with growing numbers of small nodules being detected on CT by lung cancer screening programs.

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      MA23.11 - Lobe-Specific Nodal Dissection for Clinical Stage I and II Non-Small Cell Lung Cancer: Japanese Multi-Institutional Retrospective Study (Now Available) (ID 13741)

      11:40 - 11:45  |  Presenting Author(s): Tomoyuki Hishida  |  Author(s): Etsuo Miyaoka, Kohei Yokoi, Hisao Asamura, Katsuyuki Kiura, Kazuhisa Takahashi, Hirotoshi Dosaka-Akita, Hideo Kobayashi, Hiroshi Date, Hirohito Tada, Meinoshin Okumura, Ichiro Yoshino

      • Abstract
      • Presentation
      • Slides

      Background

      Systematic nodal dissection (SND) is an international standard of lymph node dissection for non-small cell lung cancer (NSCLC). Recently, lobe-specific patterns of mediastinal lymph node metastases have been recognized, and lobe-specific nodal dissection (LSD) has been proposed for early-stage NSCLC. The purpose of this study was to assess the surgical outcomes according to the extent of mediastinal lymph node dissection for patients with NSCLC by using a nationwide registry database.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From among 11,663 patients in a Japanese lung cancer registry study for 2004, 5392 patients with clinical stage (c-stage) I or II NSCLC that was completely resected by lobectomy and either SND or LSD were enrolled. Patients who received preoperative therapy or had middle lobe tumor were excluded. In the LSD group, inferior mediastinal (subcarinal) nodes were not dissected for upper lobe tumors, and superior mediastinal nodes were not dissected for lower lobe tumors. To reduce the selection bias, an inverse probability of treatment weighting (IPTW) method using a propensity score was implemented.

      4c3880bb027f159e801041b1021e88e8 Result

      LSD and SND were performed in 1,268 (23.5%) and 4,124 (76.5%) patients, respectively. LSD group included more c-IA and upper lobe tumors relative to SND group, although there was no significant differences in age and preoperative comorbidity. There was no significant difference in postoperative morbidity and mortality between 2 groups. Extended pathological N2 disease outside LSD area was found in 3.2% of the SND group, but recurrences were not different between 2 groups (all recurrences: 22.0% in LSD, 26.9% in SND; local recurrence: 6.1% in LSD, 7.7% in SND; p=0.788). The 5-year overall survival (OS) was 81.5% in LSD and SND in 75.9%. An IPTW–adjusted Cox model showed that LSD did not have a negative prognostic impact and instead was associated with favorable survival (hazard ratio: 0.68, 95% confidence interval: 0.60-0.77).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This retrospective registry study suggested that LSD is an alternative to SND for selected patients with c-stage I or II NSCLC. Future prospective studies are warranted to determine whether LSD is applicable and provides clinical benefit for the general population of patients with cstage I or II NSCLC.

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      MA23.12 - Discussant - MA 23.09, MA 23.10, MA 23.11 (Now Available) (ID 14615)

      11:45 - 12:00  |  Presenting Author(s): Giulia Veronesi

      • Abstract
      • Presentation
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      Abstract not provided

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    MS12 - Immunotherapy and RT (ID 791)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 105
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      MS12.01 - Biology IO+RT (Now Available) (ID 11449)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

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

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

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

      e353dbe42c8654f33588d4da0b517469

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      MS12.02 - Clinical Data Available (Now Available) (ID 11450)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

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

      e353dbe42c8654f33588d4da0b517469

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      MS12.03 - Ongoing Studies (Now Available) (ID 11451)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS12.04 - Implications for Routine Practice (Now Available) (ID 11452)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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    MS21 - Giants in Thoracic Oncology (ID 869)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track:
    • Presentations: 8
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 17:00, Room 105
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      MS21.01 - Surgery and its Evolution (Now Available) (ID 13372)

      15:15 - 15:25  |  Presenting Author(s): Paul Emile Van Schil

      • Abstract
      • Presentation
      • Slides

      Abstract

      Slow rise

      Surgery would not be possible without detailed knowledge of human anatomy. In the 16th century Andreas Vesalius published his “De humani corporis fabrica”, providing very detailed anatomy of the human body. He also understood the importance of teaching, already internationally, and performed the first endotracheal intubation in pigs. William Harvey described the anatomy of the cardiovascular circulation. Ambroise Paré rediscovered blood vessel ligation, applied specific wound dressings and already designed rudimentary limb prostheses. General surgical interventions quickly developed (1). Thoracic surgery only developed very late due to the fact that opening of the chest resulted in collapse of the lung and pneumothorax (2). Opposing views ensued whether the thoracic interventions should be performed by “Unterdruck” or “Überdruck” (negative versus positive pressure). Gotthard Bülau introduced closed water seal drainage to re-expand the lung. After experimental studies, Ferdinand Sauerbruch designed a negative pressure chamber to perform thoracic interventions, principle of which was also used in the “iron lungs” during the polio epidemic. However, its use was not quite practical and finally, positive pressure became the preferred option after development of a positive pressure apparatus by Ludolph Bauer.

      Tuberculosis: start of thoracic surgery

      After introduction of endotracheal intubation and intratracheal anesthesia, thoracic surgery developed as a separate specialty from general surgery. Pulmonary tuberculosis became a wide-spread problem and specific tuberculosis centers (sanatoria) were created with multidisciplinary medico-surgical cooperation “avant la lettre”. This provided a clear impetus towards further development of thoracic surgery. Devastating infections were encountered necessitating a variety of special procedures as extrapleural dissection, rib resection, cavernostomy with open drainage, and sometimes an extensive thoracoplasty. Théodore Tuffier is credited for performing the first successful lung resection for tuberculosis in 1891, putting a clamp on the apex after extrapleural dissection followed by resection of diseased lung parenchyma and closure of the lung surface by a continuous suture.

      Lung resection: pneumonectomy

      Alexis Carrel who won the Nobel prize In 1912, contributed enormously to further development of surgical techniques by providing detailed description of vascular sutures, organ transplantation and even extracorporeal circulation. Thoracic surgical oncology started to develop with Evarts A. Graham performing the first one-stage pneumonectomy for lung cancer in 1933. Patient was a 48-year-old gynecologist who resumed practice afterwards and died at the age of 78 years. In the era before computed tomography, pneumonectomy became a standard procedure for lung cancer to obtain a complete resection.

      Lung resection: less than pneumonectomy

      Surgical principles of lobectomy developed somewhat later, although Arthur Tudor Eduards performed the first lobectomy for tumor in 1928 but this case was only published ten years later. Initially a mass-suture ligation technique was used for which a lobectomy tourniquet was developed. Later on, individual dissection with ligature or suture of hilar structures was introduced. William Rienhof described the modern technique of bronchial suture with interrupted silk sutures. He already advocated an atraumatic dissection, preservation of blood supply and covering of the bronchial stump.

      Lung resection: less than lobectomy

      Elective resection of pulmonary segments was described by Edward D. Churchill who performed the first anatomical lingulectomy in 1939. Especially for tuberculosis and bronchiectasis, segmentectomies were performed. With the introduction of the new WHO and 8th TNM classifications of lung tumors, there is currently an ongoing discussion whether sublobar resection comprising an anatomical segmentectomy and wide wedge excision for small (< 2 cm) early-stage lung cancer, provides similar results as lobectomy (3). The results of randomized trials are eagerly awaited for.

      Bronchoplastic and tracheoplastic surgery

      Not only resection of lung parenchyma became common practice but also reconstruction of the bronchus and trachea in selected patients with central lung tumors. Although initially considered “impossible surgery”, Paul Gebauer in 1948 described bronchial excision and reconstruction by a wire-supported dermal graft. The first sleeve lobectomy was performed in 1947 by Sir Clement Price Thomas in a Royal Air Force cadet as an alternative to pneumonectomy which would have made an end to his career as military pilot. Tracheal surgery was further developed by Griffith Pearson and Hermes Grillo who both obtained an extensive experience with tracheal resection and reconstruction for non-malignant and malignant diseases.

      Minimally invasive surgery

      Although generally, the principles of surgical resection of lung, mediastinal and pleural tumors have been well-established, the approach still remains controversial. Initially, for extensive disease posterolateral thoracotomy and sternotomy were routinely used. With better imaging techniques, especially computed tomography and later on, positron emission tomography, and new technical developments, minimally invasive procedures were introduced from 1990 on. There was a slow transition from muscle-sparing thoracotomies to minimally invasive approaches by video-assisted thoracic surgery (VATS) or more recently, to robotic-assisted thoracic surgery (RATS). VATS can be performed by multiple ports, a single port without rib spreading, and more recently, by a subxiphoid approach. The relative contribution of each technique has not been clearly established but medium-term results seem to be similar to open techniques on the condition that oncological principles are not compromised. Complete resection including systematic lymph node dissection for lung cancer still remains the most important prognostic factor. Undoubtedly, minimally invasive techniques will be refined in the near future making thoracic surgery a fascinating specialty.

      References

      1. Naef A. P. The story of thoracic surgery. Hogrefe & Huber Publishers, Toronto, 1990

      2. Naef A.P., von Segesser L.K. (eds). Thoracic and Cardio-vascular Surgery. From the magic mountain to rocket science. European Association for Cardio-thoracic Surgery, Windsor, 2010

      3. Sihoe A., Van Schil P. Non-Small cell lung cancer: when to offer sublobar resection? Lung Cancer 2014; 86: 115-120

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      MS21.02 - Chemotherapy through the 21st Century (Now Available) (ID 13373)

      15:25 - 15:35  |  Presenting Author(s): David H Johnson

      • Abstract
      • Presentation
      • Slides

      Abstract

      The development of systemic therapies for lung cancer can be divided into three phases starting with the application of cytotoxic agents in the mid-20th century, followed by the arrival of molecularly targeted therapies at the beginning of the 21st century and more recently the emergence (or reemergence) of immunotherapy. The first of these phases dates to 1948 when Karnofsky and colleagues reported on the activity of nitrogen mustard (HN2) in bronchogenic carcinoma. The impetus for their study derived in part from a “remarkable temporary remission” they had observed in a patient with an “anaplastic carcinoma of the lung” coupled with prior reports detailing the use of HN2 in the “palliative treatment of Hodgkin’s disease, lymphosarcoma, leukemia, and allied disorders”. This seminal study involved 35 patients with a mixture of tumor histologies (mostly squamous carcinomas) all but one of whom were male. Tumor shrinkage was noted in nearly 50% of patients with an average response duration of approximately three weeks. Notably, HN2 also produced a rapid improvement in tumor-related symptoms in nearly three-quarters of the study population. This symptomatic relief was considered the “most important and striking effect” and was “usually evident within four to seven days”. Although the authors concluded that HN2 was a “feeble therapeutic agent in carcinoma of the lung”, this proved to be a landmark study for the following reasons: 1) it helped established standards for the rigorous clinical testing of cytotoxic agents in for what was then considered an “untreatable” disease; 2) it pioneered the use of performance status (i.e. Karnofsky scale) as a useful tool for classifying the clinical condition of individual patients, and 3) because it was the first to use of quality of life analysis and assessment of tumor-related symptom control as important endpoints of drug efficacy in lung cancer.

      Over the ensuing seven decades thoracic oncologists doggedly pursued the development of effective cytotoxic agents in NSCLC with the time-honored goals of improving overall survival, reducing tumor-related symptoms and, where possible, effecting a cure. Though the pace of progress was at times painfully slow, these determined efforts eventually paid off initially with the recognition that cisplatin-based drug combinations could produce higher response rates than non-platinum-containing regimens and later with the recognition that these regimens also improved survival compared to supportive care alone. Today platinum-based doublet therapy is considered standard first-line treatment for patients with advanced stage NSCLC and good performance status lacking an actionable genomic abnormality. The most commonly used regimens appear comparable with respect to toxicities and outcome with the possible exception of platinum-pemetrexed, which is less effective in squamous carcinomas. Maintenance therapy is an option in patients with non-squamous carcinomas whose disease has not progressed after 4-6 six cycles of initial platinum-based chemotherapy. Likewise, the addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), yields a modest improvement in survival in selected patients with non-squamous carcinomas albeit at the cost of additional toxicities. In patients with squamous carcinomas adding necitumumab, an antibody against EGFR, modestly improves overall survival. In the second-line setting, docetaxel (± ramucirumab) yields a modest survival benefit over supportive care. Similar results have been achieved with pemetrexed. Symptom improvement also can be achieved with chemotherapy, usually occurs early in the courses of treatment and may occur in the absence of objective tumor regression. Finally, in early stage and locally advanced disease, chemotherapy modestly increases rates of cure when administered before or after surgery and/or radiotherapy.

      Enthusiasm for cytotoxic therapy waned in the early 2000s with the recognition that gefitinib, an EGFR tyrosine kinase inhibitor, produced marked tumor regression in selected patients whose tumors harbored either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. This milestone discovery spurred further studies that identified additional genomic abnormalities that could serve as therapeutic targets (e.g., ALK translocations, HER2 and BRAF mutations, etc.). Drugs that specifically target these genomic abnormalities became the major focus of much of the cancer drug development of the past 15 years and are now considered a cornerstone of genomic or precision medicine. In more recent years much attention has shifted to application of immunotherapeutic agents in solid tumors including NSCLC (and SCLC) seemingly pushing cytotoxic agents further into the background. Indeed, immune checkpoint inhibitors already have changed (& are changing) the treatment paradigm for NSCLC patients with advanced and locally advanced disease. Moreover, we are witnessing dramatic advances in the combined use of immunotherapy and chemotherapy potentially heralding a new phase of systemic therapy for lung cancer – viz. the routine use of chemotherapy integrated with targeted therapy and/or immunotherapy. However, despite the transformational successes of genomic medicine it is important to remember that only a small percentage of NSCLC patients actually derive benefit. Accordingly, further progress in the management of NSCLC will require the use of all the therapeutic tools at our disposal in the most thoughtful manner possible informed by both basic science and clinical observations. In short, in spite of its prosaic nature, chemotherapy will remain a key component of the management of lung cancer for the foreseeable future.

      Hellmann MD, Li BT, Chaft JE, Kris MG. Chemotherapy remains an essential element of personalized care for persons with lung cancers. Ann Oncol. 2016;27(10):1829-35.

      Doroshow DB, Herbst RS. Treatment of advanced non–small cell lung cancer in 2018. JAMA Oncol. 2018;4(4):569-70.

      Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446-54.

      Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the pallative treatment of carcinoma. With particular reference to bronchogenic carcinoma. Cancer. 1948;1:634-11.

      Ihde DC. Chemotherapy of lung cancer. N Engl J Med. 1992;327(20):1434-41.

      Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. J Clin Oncol. 1988;6(4):633-41.

      Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311(7010):899-909.

      Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-50.

      Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-92.

      Tannock IF, Hickman JA. Limits to personalized cancer medicine. N Engl J Med. 2016;375(13):1289-94.

      Gotwals P, Cameron S, Cipolletta D, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. 2017;17(5):286-301.

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      MS21.03 - Revolution in Radiation (Now Available) (ID 13374)

      15:35 - 15:45  |  Presenting Author(s): Ben Slotman

      • Abstract
      • Presentation
      • Slides

      Abstract

      In the past few decades, there have been many changes in the field of radiotherapy. These include better imaging, better motion management, improvements in treatment planning, better position verification and more precise treatment delivery. This has led to an increased use of radiotherapy and to significant improvements in clinical outcome.

      Stereotactic body radiotherapy (SBRT, aka SABR) is currently the standard of care for patients with medically inoperable stage I NSCLC. The technique is now safely used for more centrally located, larger and multiple lesions as well. SBRT is increasingly being considered as an alternative to surgery in operable patients. The results of two randomized clinical trials which were closed prematurely due to poor accrual, suggest equivalence between SBRT and surgery. Comparative effectiveness studies point in the same direction. New randomized trials on this topic are currently recruiting.

      In stage III NSCLC, radiotherapy can also be delivered with increased precision. Although the use of much higher dose has not (yet) led to better outcomes, the newer radiation techniques are associated with less toxicity and over the years, there has been a steady improvement in control and survival rates. The use of immunotherapy in combination with radiotherapy holds many promises. The role of proton therapy is still investigational.

      For patients with oligometastatic disease or oligoprogression, local treatments including radiotherapy can be highly effective and may lead to long term control and improvements in survival. We are awaiting the results of randomized studies to unequivocally show this benefit.

      In LS-SCLC, there is still discussion on the schemes for thoracic radiotherapy (BID or QD). The improvement in median survival in both arms of the recent CONVERT trial compared to earlier studies are probably exemplary for the general improvements in radiotherapy techniques. In ES-SCLC patients, thoracic radiotherapy is advocated for those patients with a response after chemotherapy but with residual disease in their chest. In ES-SCLC, prophylactic cranial irradiation is nowadays sometimes replaced with MRI-surveillance. Delayed cranial irradiation is than used in about two out of three patients.

      An important breakthrough in radiotherapy is the introduction of MRI guidance on the linear accelerator. This not only provides better soft-tissue imaging, but also for the first time, continuous imaging during the delivery of the treatment. The anatomical information from the MRI made daily with the patient on the treatment couch can be used to daily adapt the treatment plan. This allows for the use of smaller margins and early results demonstrate important benefits, especially in high-risk patients.

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      MS21.04 - Targeted Therapy - The Second Revolution (Now Available) (ID 13375)

      15:45 - 15:55  |  Presenting Author(s): Frances A Shepherd

      • Abstract
      • Presentation
      • Slides

      Abstract

      Over the last 15 years we have witnessed a revolution in the development of molecularly targeted therapy for non-small cell lung cancer (NSCLC). At the same time, there has been an unprecedented evolution in the techniques available to detect molecular changes in tumours. The technology has evolved from single gene assessment in frozen tissues by Sanger sequencing to broad molecular profiling platforms that are able to sequence large panels of mutations using only circulating tumour DNA from peripheral blood samples.

      The revolution started in the late 1990s when monoclonal antibodies and oral tyrosine kinase inhibiters were being developed to target the epidermal growth factor (EGFR) pathway of NSCLC. At that time, assessment of EGFR was limited to immunohistochemical assessment of EGFR protein, or copy number. However in 2003, dramatic responses seen in a small subset of patients led to deep sequencing of these patients’ tumours and the identification of two driver mutations in the tyrosine kinase domain of the EGFR gene. Testing for these mutations on Exons 19 and 21, now has become standard of care and should be reflex for all cases of adenocarcinoma of the lung.

      Several trials comparing first-line chemotherapy to first or second generation EGFR TKIs have now shown conclusively that TKI therapy is superior to chemotherapy, and for a decade now, first or second generation EGFR TKIs, including gefitinib, erlotinib and afatinib are now the standard of care world-wide. However, all patients relapse usually within months to a short number of years, and considerable research has shown that there are several possible mechanisms of resistance. The most frequent (50-60%) is emergence of the T790M resistance mutation, and several TKIs specifically targeting this mutation have been developed. Osimertinib, a third generation TKI has been approved for second-line treatment of T790M mutant NSCLC, and recently a trial comparing osimertinib to gefitinib or erlotinib in the first-line setting has demonstrated its superiority for both progression-free and overall survival. Other mechanisms of resistance include emergence of other mutations, MET amplification, and for a small percentage of patients, small cell transformation.

      ALK mutations were discovered when a single patient had a dramatic and unexpected response to crizotinib, which was being evaluated at that time as a MET inhibitor; sequencing identified the first ALK fusion in a lung cancer tumour. This led rapidly to focused screening and expansion of the Phase I/II trial specifically for patients with ALK mutated tumours. As was the case with EGFR TKIs, numerous second-line and then first-line studies confirmed the superiority of crizotinib over chemotherapy, and ALK TKIs are now the first-line standard of care. Second and third generation ALK inhibitors have been developed rapidly including ceritinib, alectinib, brigatinib and lorlatinib. While ALK mutations may be comprised of several different fusion partners, for the most part, TKI selection has not been based on the fusion variant. Recently, resistance point mutations in the TK domain also have been reported, of which the G1202R mutation appears to confer the greatest resistance.

      ROS1 is another fusion variant that has demonstrated excellent response to crizotinib and other ALK TKIs.

      Less frequent lung cancer mutations for which targeted therapy is available in other cancers include HER2, BRAF, RET mutations, The MET exon 14 skipping mutation is seen in sarcomatoid lung cancer variants, and it also is responsive to crizotinib.

      Mutation testing for lung cancer should now be reflex at the time of diagnosis. In general, at a minimum, all patients should have testing with a multiplexed targeted panel that includes all the mutations for which targeted therapies are available. Screen by immunohistochemistry for ALK and ROS1 (and pDL-1) also are recommended. The next generation hybrid capture platforms are not yet widely in use, but in limited centres have been shown to be a reliable test for fusion variants including ALK and ROS.

      Molecular testing technology has advanced so much and so rapidly that it is now possible to identify mutations through testing of ctDNA in peripheral blood. Several techniques and platforms have been developed that have shown high sensitivity and specificity in particular for T790M detection. Now in many centres, routine blood testing is now preferred over invasive biopsies to look for this resistance mutation when progression is suspected. Multiplexed targeted panels evaluating many mutations and even tumour mutation burden in peripheral blood also are now available, but the true role of these panels in clinical care has yet to be determined.

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      MS21.05 - Quality of Life - Are we Paying Enough Attention? (Now Available) (ID 13378)

      15:55 - 16:05  |  Presenting Author(s): Richard J Gralla

      • Abstract
      • Presentation
      • Slides

      Abstract

      The greatest challenge facing quality of life, symptom and patient reported outcome evaluation in advanced lung cancer is the incorporation of the measurement of these parameters into daily clinical practice. While all oncologists embrace the significant basic science and survival improvements of recent years, we must acknowledge that these benefits are still only measured in months of additional life for the average patient, and treatments continue to have significant risks. Are we meeting the goals and needs of patients receiving systemic therapy?

      There are several issues key to understanding the practicality and value of PRO evaluation. Recent studies have addressed these questions. How much do patients value and agree with the monitoring of quality of life? Are PRO issues accurately and reproducibly measured? Can we conduct PRO evaluation in clinical research and in daily practice in a practical fashion that can allow inclusion into all clinical settings? Most importantly, beyond demonstrating that oncologists wish to listen to the patient’s voice, does the measurement of PROs give guidance in daily practice that results in better patient care, economic benefit, and aids in better decision making?

      There can be no doubt that patients with advanced lung cancer place aspects of quality of life at the top of their concerns and goals in their management. Over 95% of patients stated that quality of life was a key concept for them in a survey of 660 patients with lung cancer (1), and a similar percentage of 148 patients endorsed serial evaluation of quality of life and lung cancer symptoms (2). Today we have valid measures designed for lung cancer and mesothelioma with tested, published, and acceptable psychometrics. Such testing establishes feasibility, acceptability, reliability and validity. These measures, including the EORTC-QLQ-30, the FACT-L, the LCSS and the LCSS-meso, all meet high standards and are available in over 50 languages (3).

      Using electronic assistance makes the evaluation of PROs more practical in both clinical trials and daily practice. A trial using the electronic form of the LCSS placed on a tablet-like device (called the “eLCSS-QL”) demonstrated high patient, nurse and physician acceptance. The electronic format correlated very highly with the paper and took only about two minutes to complete (2). Other major advantages of using computer assistance is that results over time can immediately be displayed graphically, the data can be filed without transcription, and the device can interpret the results. All of these features make evaluating PROs easy to incorporate into busy clinical practices and into research trials.

      To date, the greatest use of quality of life and PRO evaluation in patients with thoracic malignancies has been in clinical trials. Typically, these assessments have been used to determine whether or not a new treatment which influences survival or PFS or response also affects quality of life. These results are generally used as secondary or tertiary endpoints in new agent approval. Shortcomings in PRO assessment are common in these trials, most frequently seen as failure to include all patients and in low percentages of patients with sufficient follow up. With high patient acceptance and available feasible questionnaires, the fault lies with the study design or the conduct of the investigators, and not with the patients.

      We recently completed a study which investigated several endpoints through the use of electronically conducted PRO evaluation, with the eLCSS-QL. 164 patients completed the eLCSS-QL every 3 weeks; all endpoints were evaluable in over 90% of patients. Specifically, we evaluated whether just 3 items (quality of life, distress, activity level, called the 3-Item Global Index or “3-IGI”) of the 9 included in the LCSS could: 1) more accurately predict survival at baseline than performance status; 2) could predict risk groups for hospitalization; 3) identify those at greater risk for regret; and most importantly 4) indicate by change in the 3-IGI after just 2 treatment cycles which patients are likely or unlikely to benefit from treatment. The findings from this study, are presented at the 2018 WCLC (4,5). In brief, we found that assessing change from baseline (20% decline) with the 3-IGI after only 2 cycles of systemic treatment identifies those patients who have poor response and survival outcomes if continued on the same therapy. Patients with this decline continued to receive more than two additional treatment cycles on average, even though PRO assessment showed meaningful declines at a much earlier point. The economic cost of this additional treatment was an average of almost $11,000 per patient. Additionally, nearly all patients who at 3 months after starting treatment regretted having received treatment were those who had this 20% decline of the 3-IGI at 6 weeks. This PRO assessment is rapid, easy, and inexpensive. Reports to physicians need to include analysis of the impact in that even when physicians were aware of the PRO worsening, they often did not act on the findings. The 3-IGI at baseline provided a better indication of the burden of the cancer experienced by the patient. This resulted in better prediction of survival, which could aid in better design of clinical trials.

      Quality of life, symptom assessment, and PRO evaluation has become practical for both research trials and clinical practice. Responding to PRO changes can result in better decisions concerning continuing treatment, changing treatment, lessening toxicity, and savings in cost of unhelpful treatment.

      References:

      1) Gralla RJ, et al. Journal of Thoracic Oncology. 2014. 9: 1243-8.

      2) Hollen PJ, et al. Supportive Care in Cancer. 2013. 21: 165 – 172.

      3) Hollen PJ, et al. Seminars in Oncology 1996. 23: 31-40.

      4) Hollen PJ, et al. Proceedings of WCLC 2018.

      5) Gralla RJ, et al. Proceedings of WCLC 2018.

      Supported by: NIH/NCI R01 CA157409

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      MS21.06 - Immunotherapy - Sequence or Combination? (Now Available) (ID 13379)

      16:05 - 16:15  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Abstract

      Despite advances in the treatment of cancer, with novel molecularly targeted therapies and drug combinations, lung cancer continues to be one of the leading causes of cancer death worldwide. For this reason, significant efforts have been made to examine the interaction between cancer and the immune system. This has led to the discovery of the programmed death 1 (PD1) and ligand (PDL1) pathway, which was found to play a key role in immune evasion by cancer cells and the formation of a tumor microenvironment. Blockade of this pathway enables the ability of the innate immune system to activate their anticancer responses and to reverse the tumor microenvironment. Newly approved drugs, such as nivolumab and pembrolizumab, have mechanisms of action that inhibit PD1, while others like atezolizumab, block PDL1. Although, responses with these drugs have shown significant activity in some patients, only 20-30% of patients respond overall. In this talk, mechanistic studies to identify predictive markers of response will be discussed along with markers of resistance (both primary and acquired). In addition, novel combinations of immunotherapy with chemotherapy, targeted therapy and even chemotherapy will be explored including their use in sequence or combination.

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      MS21.07 - The Growing Role of Biomarkers in Treatment Selection: “The Tissue is the Issue” (Now Available) (ID 13380)

      16:15 - 16:25  |  Presenting Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Abstract

      Much progress has occurred in the treatment of lung cancer over the last decades. A main reason for this progress is due to technology developments, which make it possible to identify new targets and develop new active drugs targeting the molecular abnormalities. However, developing predictive biomarkers for selection of the right group of patients to the right treatment has been crucial in this progress.

      The detection of EGFR mutations as predictive biomarkers for EGFR TKIs paved the way for biomarker development and was shortly followed by the detection of Anaplastic Lymphoma Kinase fusions and the development of ALK-inhibitors. Later, many other targets have been identified (i.e. ROS1, BRAF, RET, TRAKS) and specific targeted drugs developed with impressive clinical effect in biomarker defined subgroups, particularly of NSCLC (1).

      The International Association for the Study of Lung Cancer (IASLC) has together with the College of American Pathologists (CAP) and the Association for Molecular Pathology (AMP) developed guidelines for molecular testing of patients with advanced NSCLC, which second edition has recently been published (2). Those guidelines have been the role model for several other guidelines globally.

      Assay developments have been crucial in the biomarker development. While traditional immunohistochemistry (IHC) is still relevant for selection of patients to certain targeted therapies, e.g. ALK- inhibitors, more technological advanced assays based on DNA or RNA have become more” relevant” as multiplexed marker analysis seems in many cases “mandatory” as (sparse) “Tissue is the Issue” (3). The last revision of the CAP/IASLC/AMP guidelines recommend the use of Next Generation Sequencing (NGS) if possible, as this assay gives more information and detect mutations as well as fusions. Today only a limited number of targets are linked to FDA approved drugs for treatment of lung cancer and the use of NGS gives a broad molecular profiling of the patients’ tumor. This knowledge gives the patient opportunity to seek clinical trials, of which many are ongoing, including a broad range of molecular targets.

      Many molecular targets have seen several generations of specific targeted drugs, e.g. EGFR and ALK and more knowledge has emerged on resistance mechanisms, a knowledge, which in some cases, leads to targeted agents specifically targeting the resistance mechanisms. The third generation EGFR TKI represented by osimertinib targeting T790 M mutation is the best example. This development has paved the way for the need for biopsy at progression, which is a change in the current “culture”. However, acquiring tissue at this stage can often be challenging, and the development of liquid biopsy is rapidly emerging. The IASLC has just published a consensus report on the role of liquid biopsy in the management of patients with NSCLC (4). The liquid biopsy technology has the capability to be applied to NGS and several other DNA and RNA assays with high specificity (90-100%) and increasing high sensitivity (70-90%).

      The progress with immunotherapy has been remarkable for patients with lung cancer; however, the role of predictive biomarkers in immunotherapy has been challenging. PD-L1 has been pursued by the relevant pharmaceutical companies, but, unfortunately, with the development of their own proprietary assays that differ with regard to antibodies, processing platforms, and with different cut-off points for definition of “high’- versus “low” PD-L1 expression in the clinical trials. IASLC has compared the analytical performances of the different assays in order to see if harmonization is possible, and the results of the “Blueprint Project” indicate that three assays (Dako’s 28-8 and 22C3 and Ventana’s SP 263) perform very similar and seem to be interchangeable when the same clinical cut-offs for the different categories are used (5,6). Tumor mutation burden has also emerged as a predictive biomarker for immunotherapies (7); however, the tumor mutation burden assays need to be compared and standardized as well. Much research today is devoted to try to identify new and better predictive biomarker(s) for immunotherapy. While we have primarily focused on “single” biomarker assays for immunotherapy thus far, it might be time to look into the role of “combined” biomarkers or assays for the most optimal selection of patients, who benefit from immunotherapy.

      In conclusion, a tremendous development of biomarkers and assays have been seen over the last decade(s), which has made it possible to identify subgroups of patients with dramatic effect of new targeted therapies. Future drug development needs to ensure the biomarker development occurs simultaneously in the clinical development to ensure validation and proper selection of subgroups of patients, who will benefit from the new agents. Development of “masterprotocols” seems to be one mechanism for speeding up this development (8).

      REFERENCES:

      1.Hirsch FR, Scagliotti GV, Mulshine JL et al: Lung Cancer: Current Therapies and New Targeted Treatments. Lancet 389 (10016); 299-331, 2017.

      2.Lindeman NI, Cagle PT, Aisner DL et al: Updated Molecular Testing Guidelines for Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors. Guideline from the College of American Pathologists, The International Association for the Study of Lung Cancer and the Association for Molecular Pathology. J Thorac Oncol 142(3); 321-346, 2018.

      3.Hirsch FR, Wynes MW, Gandara DG, Bunn PA: “The Tissue is the Issue”. Clin Cancer Res 16 (20); 4909-4911. 2010

      4.Rolfo C, Mack PC, Scagliotti GV et al: IASLC Statement Paper: Liquid Biopsy for Advanced Non-Small Cell Lung Cancer. J Thorac Oncol , June 6th, 2018 (E-pub ahead of time).

      5.Hirsch FR, McElhinny A, Stanforth D et al; PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase1 of the Blueprint PD-L1 Comparison Project. J Thorac Oncol 12(2); 208-222, 2017.

      6.Tsao MS, Kerr KM, Kockx M et al: PD-L1 Immunohistochemistry Comparison Study in Real-Life Samples; Results from Blueprint Phase 2 Project. J Thorac Oncol , May 22, 2018 (Epub ahead of time).

      7.Hellman MD, Callahan MK, Awad MM: Tumor Mutation Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilumumab in Small Cell Lung Cancer. Cancer Cell 14(33): 853-861, 2018.

      8.Malik SM, Pazdur R, Abrams JS et al: Consensus Report from a Joint NCI Thoracic Malignancy Steering Committee- FDA workshop on strategies for integration of biomarkers into clinical development of new therapies for lung cancer leading to inception of “Masterprotocols” in lung cancer. J Thorac Oncol 9 (10); 1443-1448. 2014

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      MS21.08 - Where will we be in 10 years? (Now Available) (ID 13382)

      16:25 - 16:35  |  Presenting Author(s): Paul A. Bunn, Jr.

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the leading cause of cancer death in the world, accounting for as many as one fourth of all cancer deaths. Mortality rates for lung cancer in the US and the world have been declining, albeit in varying amounts around the world. The decline is due mostly to decreasing tobacco consumption and early detection through CT screening. Improvements in therapy have also contributed and therapeutic improvements have come mostly in recent years. In the US, annual lung cancer deaths in males have decreased from 90/100,000 to 45/100,000 in males and from 45 to 35/100,000 in females from 1960-2018. Over this period 5 year survival rates have increased from 5% to 18%. However, the annual number of US deaths has remained about 160,000 per year due to increasing population and aging of the population. Social pressures and new agents to assist in smoking cessation should continue to reduce the incidence of lung cancer although some of these gains may be offset by increased air pollution. We should see agents that can reduce lung cancer incidence through prevention in high risk populations including the potential of low dose aspirin, eicosanoid, and immunotherapeutics including IL1beta inhibitors and checkpoint inhibitors. New biomarkers of early progression including circulating tumor DNA may markedly improve early detection.

      For early stage therapy in resectable patients, adjuvant chemotherapy improved 5 year survival by about 5%. For locally unresectable stage III lung cancer, the addition of chemotherapy (CT) to radiation therapy (RT) improved 5 year survival by 5-10%. More recently, the addition of immunotherapy to CT/RT for unresectable stage III disease has further improved survival. The use of immunotherapy for resectable lung cancer has produced considerably higher response rates than chemotherapy but its effects on survival remain to be determined. For stage 4 disease, the 5-year survival rates have increased from 1% to as much as 15%. Molecularly targeted therapy for patients with a driver alteration have improved outcomes considerably with 4 year survivals of over 50%. At present, tyrosine kinase inhibitors (TKIs) are approved for EGFR and BRAF v600E mutations and for ALK and ROS1 rearrangements. It is likely that TKIs for MET and HER2 mutations and for RET and NTRK rearrangements will be approved in the near future. The most common molecular driver is KRAS mutation but at present no KRAS inhibitors have been approved, although it is likely that KRAS inhibitors will be approved in the next decade.

      Immunotherapies with anti-PD-1 antibodies have improved 5 year survival rates for advanced disease to about 15% and the combination of chemotherapy and immunotherapy seems to produce even higher long term survival rates. Approved immunotherapies include the anti-PD-1 antibodies pembrolizumab and nivolumab, and the anti-PD-L1 antibodies atezolizumab and durvalumab. Other checkpoint inhibitor antibodies are in late clinical development and will likely be approved in the future. Combinations of checkpoint inhibitor antibodies with anti-CTLA antibodies are in advanced clinical development and will likely be approved in the near future. Agonists and antagonists to multiple other immunotherapeutic targets have been developed and are in early phase clinical trials alone and in combination with checkpoint inhibitor antibodies.

      Therapies for other targets such DNA repair enzymes, stem cell pathways inhibitors, antibody drug conjugates are in development and should become available in the next decade.

      Over the next decade we can anticipate further lowering of death rates and improved survival rates which will be attributed to declining smoking rates, improved adherence to screening recommendations and to improved therapy. Wide-spread molecular testing and treatment and understanding the immune system with novel immune therapies should lead the improvements over this next decade.

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    MTE03 - Clinical Trial Design With Novel Lung Cancer Therapy (Ticketed Session) (ID 813)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Targeted Therapy
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 105
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      MTE03.01 - Inclusion/Exclusion Updates (CNS Mets, Multiple Prior Cancers, Organ Dysfunction) (Now Available) (ID 11550)

      07:00 - 07:30  |  Presenting Author(s): Peter Michael Ellis

      • Abstract
      • Presentation
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      Abstract

      Introduction

      Randomized clinical trials (RCTs) represent the gold standard trial design for the evaluation of treatment interventions. Advancing knowledge in oncology has relied heavily on data from high quality RCTs focusing on important outcomes such as overall survival (OS) and more recently progression free survival (PFS). Many examples exist, even in recent times, where the use of alternate study designs, such as cohort and case control series, have concluded benefit for a therapy that was subsequently disproven by RCTs. Nevertheless, an increasing number of therapies are being approved by licensing authorities such as the FDA, based on intermediate outcomes such as objective response rate (ORR) from phase II clinical trials.

      Pragmatic versus explanatory trials

      RCTs can be either explanatory or pragmatic. Explanatory trials evaluate a treatment intervention under ideal conditions. They tend to have more restrictive inclusion and exclusion criteria to minimize the potential for confounding due to coexistent health problems. Pragmatic trials, on the other hand, evaluate treatment interventions in real life practice conditions. Inclusion and exclusion criteria are generally less restrictive and the results are considered more generalizable to the broad population of people with the underlying condition.

      RCTs in oncology are often explanatory in design. Inclusion criteria generally limit eligibility to the highest functioning patients. They often specify the type of diagnostic material needed and require samples to be available for correlative studies. Trials are generally very restrictive in regard to prior therapy that patients may have received and most trials require normal, or near normal organ function for eligibility. Exclusion criteria contain lengthy lists of criteria that make patients ineligible. Many trials exclude patients with brain metastases unless they have been treated and stable for some time. There are often lengthy lists of coexistent health problems, such as cardiac disorders, that commonly coexist in patients with lung cancer, that make an individual ineligible. The end result is that the generalizability of many RCTs is limited and healthcare providers need to extrapolate trial findings to a large proportion of their patients who might not have met inclusion and exclusion criteria for the trial generating the evidence of efficacy.

      Why should we rethink our current approach

      Historically, most advances from RCTs in lung cancer have represented small incremental gains in OS or PFS. Under these conditions, dependence on explanatory trials with multiple inclusion and exclusion criteria may well have been appropriate to minimize the confounding effects from intercurrent problems. However, many changes have taken place in therapeutic options for lung cancer patients over the last decade. Our understanding of underlying molecular abnormalities important in lung cancer development and growth has increased greatly. Multiple agents targeting underlying molecular abnormalities have demonstrated ORR almost twice that of conventional chemotherapeutic agents, with similarly impressive improvements in PFS. Additionally, many newer agents have been developed that cross the blood brain barrier and have demonstrated significant anti-tumor activity in patients with CNS metastases as well. Given the improved tolerability of these agents and increased expectation of benefit from therapy, less stringent inclusion and exclusion criteria should be considered. Trials of targeted therapies should include a broader spectrum of patients including those with lower performance status and untreated CNS disease. Criteria focusing on organ function should be limited to known toxicity concerns for the therapy under evaluation.

      The emergence of treatments targeting activation of the immune system also represents a significant therapeutic advance. Some trials evaluating immune checkpoint inhibitors have been very restrictive for patients with CNS metastases. Nevertheless, responses are seen in patients with CNS metastases, questioning the need for such restrictive exclusion criteria. Patients with underlying autoimmune disorders are excluded from the majority of trials of immunotherapy agents. Some emerging data exists though suggesting that these agents may be safely given to patients with underlying autoimmune diseases. These findings highlight the need to modify inclusion and exclusion criteria for trials of immunotherapy agents to gain information of safety and efficacy in these populations of patients and to increase the generalizability of trial findings.

      Conclusions

      The advancement of knowledge in oncology remains dependent on well conducted RCTs. However, we need to question the rigidity of a number of common inclusion and exclusion criteria in an attempt to improve the pragmatic aspect of many trials and increase the generalizability of current RCTs.

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      MTE03.02 - Novel Trial Design for Precision Medicine (Now Available) (ID 11551)

      07:30 - 08:00  |  Presenting Author(s): Fiona Blackhall

      • Abstract
      • Presentation
      • Slides

      Abstract

      Trial design for precision medicines has shifted to increasing use of platform protocols, ‘liquid’ biopsy and the practice of co-clinical trials using patient or circulating tumour cell derived (PDX/CDX) models. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were the first class of precision medicine approved for advanced non-small cell lung cancer (NSCLC) but initially for unselected patients following the traditional convention of phase I evaluation in heavily pretreated populations, phase II evaluation also in pretreated, ‘all comers’, and then in large, randomised, phase III, double blind, placebo controlled studies versus best supportive care. The linkage between sensitising EGFR mutations and their prediction for efficacy came later. It now seems remarkable that these agents made it through to standard of care and is questionable whether they would have been approved for all comers in the current health economic climate. The ‘EGFR story’ catalysed the current goal to integrate drug-target linkage early in clinical development. This was achieved for the first in class ALK inhibitor, crizotinib, initially developed as a MET inhibitor but on discovery of ALK gene fusion and its potency for ALK a strategy to enrich for patients with tumours positive for ALK gene fusion by fluorescent in situ hybridisation (FISH) ensued. The phase I trial (PROFILE 1001) led to accelerated approval within 4 years on the basis of response rate, setting the paradigm of ‘enrichment’ studies for precision medicine development. (2) In parallel, platform studies using ‘umbrella’ or ‘basket’ protocol designs emerged to screen prospectively for multiple targets simultaneously and enrol the patient to a study arm designed for the target/biomarker(s) present. The first of these studies to be conducted in lung cancer was the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial (3) and subsequent examples ongoing are the Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400 (4) and the National Lung Matrix Trial in the UK (5). Obvious strengths for umbrella studies are a single protocol, screening for a panel of molecular alterations simultaneously and flexibility to add new study arms (and testing modalities) but criticisms include a high attrition rate both due to sample inadequacy for molecular testing and lack of a study arm for the biomarker(s) identified. Regardless of the study design, translational science to rigorously evaluate serial predictive biomarkers of response and resistance is crucial and in this regard new technologies for liquid biopsy are proving transformational, overcoming the reliance on tissue biopsy that can be a barrier to participation in trials (6), and in the resistance setting may not be representative due to evolution and heterogeneity. Of note the 3rd generation EGFR-TKI, osimertinib, designed to target the EGFR T790M resistance mutation, was developed in trials that included serial tissue and ‘liquid’ biopsy for analysis of plasma circulating tumor DNA (ctDNA). While the application of ‘liquid biopsy’ proved the clinical utility of this approach and is now a standard of care (7), the high response rate rendered the second biopsy on treatment uninformative in many patients (8). A further use of tissue and liquid biopsy in precision medicine trials that is likely to increase is the practice of so-called ‘co-clinical trials’. This involves obtaining a fresh tumour biopsy and/or a circulating tumour cell sample from blood to establish as a xenograft mouse model from a patient at study entry and again on progression. The resultant patient derived or CTC derived explant model (PDX or CDX) is used to identify molecular mechanisms and candidate predictive biomarkers for subsequent clinical validation and is particularly applicable to trials for patients with small cell lung cancer (SCLC) (9,10). Although traditional, all comer, early phase study designs may soon be obsolete new designs of precision medicine trials will only be as effective as the enrichment strategy, scientific rationale and pharmacology underpinning them. To this end ‘team science’ approaches with close collaboration between academia and pharma will be essential for the golden age of precision medicines to be fully realised for lung cancer.

      (1) Tan DSW et al. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016. JTO 2016 Vol 11, Issue 7, Pages 946–963

      (2) Blackhall F and Cappuzzo F. Crizotinib: from discovery to accelerated development to front-line treatment. Ann Oncol. 2016 Sep;27 Suppl 3:iii35-iii41.

      (3) Kim ES et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011 Jun;1(1):44-53.

      (4) Herbst RS et al. Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400. Clin Cancer Res. 2015 Apr 1;21(7):1514-24.

      (5) Middleton G et al. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol. 2015 Dec;26(12):2464-9.

      (6) Lim C et al. Patients with Advanced Non-Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials? J Thorac Oncol. 2016 Jan;11(1):79-84.

      (7) Oxnard GR et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer.

      J Clin Oncol. 2016 Oct 1;34(28):3375-82.

      (8) Thress KS et al. Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial. J Thorac Oncol. 2017 Oct;12(10):1588-1594.

      (9) Lallo A et al. Circulating tumor cells and CDX models as a tool for preclinical drug development. Transl Lung Cancer Res. 2017 Aug;6(4):397-408.

      (10) Drapkin BJ et al. Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts. Cancer Discov. 2018 May;8(5):600-615.

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