Virtual Library

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    ES04 - Liquid Biopsies in Lung Cancer (ID 772)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Targeted Therapy
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 203 BD
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      ES04.00 - Introduction with Poll Questions (ID 14931)

      15:15 - 15:20  |  Presenting Author(s): Sai-Hong Ignatius Ou, Ignacio I. Wistuba

      • Abstract
      • Slides

      Abstract not provided

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      ES04.01 - Liquid Biopsies in Lung Cancer (ID 11366)

      15:20 - 15:40  |  Presenting Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract

      A liquid biopsy in cancer patients generally refers to the sampling and analysis of circulating tumor cells (CTC) or circulating tumor-derived (ct) DNA for the diagnosis and management of patients (1). This contrasts with the traditional tissue biopsy, which still represents the gold-standard to assess the accuracy of liquid biopsies. Liquid biopsy has significant advantage over tissue biopsy as it is more convenient to perform with minimal risk to the patients, thus potentially allows more frequent sampling to monitor disease progression or treatment efficacy (2,3). More recently, liquid biopsy also has been proposed as primary tool for early detection and diagnosis of cancer, or in cancer genotyping to make therapeutic decisions (4). While rapid advances in microfluidic and/or high throughput sequencing technologies have demonstrated the feasibility of quantitative analysis of CTC and ctDNA in advanced stage lung cancer patients, the adoption of these technologies as clinical diagnostics should conform with the accepted principles of laboratory medicine in analytical validity, interpretation, reporting, clinical validity and utility (5).

      Although circulating tumor cells has been validated and approved by the FDA as a useful prognostic method for many cancer types (6), CTC in lung cancer has not become a clinically useful clinical assay in non-small cell lung cancer (NSCLC), primarily due to the small number of CTC detectable in these patients. In small cell lung cancer patients, CTC has greater number (7), yet its clinical utility still needs to be established.

      In contrast to CTC, the clinical adoption of ctDNA in lung cancer has occurred rapidly, especially in the detection of T790M resistant mutation during first and second-generation EGFR TKI therapies (8). Since ctDNA represents only a small fraction (<1%) of cell-free (cf) DNA in the blood, most of which are derived from leukocytes, highly sensitive methods are required to detect ctDNA. In general, two methodological approaches are used to “detect” the presence of ctDNA: PCR amplification or hybrid capture of tumor-derived target DNA fragments +/- next generation sequencing. With these techniques, the detection of mutant ctDNA sequences in advanced lung cancer patients with EGFR mutated adenocarcinoma has achieved 60-85% sensitivity and >95% specificity, using tissue-based diagnosis as the reference. Many pre-analytical conditions may influence the reliability of results of ctDNA analyses. Additional biological factors (e.g. tumor stage/burden, type, heterogeneity) could also influence the sensitivity of detection of specific tumor genomic aberrations. Since lysis of white blood cells will dilute the ctDNA with leukocyte-derived DNA, it is imperative to collect blood in tubes containing EDTA or leukocyte stabilizing agents (e.g. Streck tube). For the former, blood needs to be processed within 2-4 hours or sooner after collection, while with the latter, they can be kept for up to 48 hours or longer. Plasma is also preferred over serum as clotting increases the amount of non-tumor cf DNA resulting from leukocyte lysis.

      With the current achievable sensitivity, ctDNA should not be used in treatment naïve patients as the primary method to determine the mutation status of EGFR or other actionable driver oncogenes, except when biopsy tissue is insufficient and re-biopsy is not feasible for timely molecular testing. However, despite its suboptimal sensitivity, extensive studies have established the clinical utility of ctDNA for testing T790M in patients with EGFR mutant lung adenocarcinoma, who have progressed on first/second generation EGFR TKI therapy (9). The ctDNA assay may include DNA derived from all tumors in the body, thus has the potential of better representation of total body mutation status than tissue biopsy, which usually targets only one of many tumor nodules in metastatic setting. However, the suboptimal specificity mandates that a negative result triggers a tumor tissue re-biopsy to exclude false negative result or to identify other resistant mechanisms, including small cell carcinoma transformation. Other candidate ctDNA assays being studied for their clinical utility in lung cancer include resistant mutations to ALK inhibitors, and tumor mutation burden as predictive biomarker for immune checkpoint inhibitor therapies.

      Liquid biopsy has generated great excitement among oncologists as it potentially may overcome many of the “tissue is the issue” limitations in current biomarker testing paradigm. However, it is crucial that we apply the same stringency of evidence on liquid biopsy as that has been applied to tissue-based biomarker testing, including the demonstration of clinical validity and utility in clinical trial patient samples. While promising data are rapidly being generated on the roles of ctDNA assay for monitoring and adjusting treatment, or in early detection of lung cancer or residual disease, significant research is still required before they become standards in routine clinical practice.

      References:

      1. Crowley E, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 2013;10: 472–484

      2. Sacher AG, et al. Application of Plasma Genotyping Technologies in Non-Small Cell Lung Cancer: A Practical Review. J Thorac Oncol. 2017;12:1344-1356

      3. Diaz LA, Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014;32: 579–86.

      4. Santarpia M, et al. Liquid biopsy for lung cancer early detection. J Thorac Dis. 2018;10(Suppl 7): S882-S897.

      5. Merker JD, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol 2018;36: 1631-41.

      6. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014 Sep;14(9):623-31.

      7. Hou JM, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30: 525-32.

      8. Rolfo C, et al. IASLC Statement Paper: Liquid biopsy for advanced non-small cell lung cancer (NSCLC). J Thorac Oncol 2018 Jun 6. [Epub ahead of print]

      9. Lindeman NI, et al. Updated molecular testing guideline for the 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. 2018;13: 323-358.

      e353dbe42c8654f33588d4da0b517469

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      ES04.02 - Mechanisms of Resistance to Targeted Therapy (ID 11367)

      15:40 - 16:00  |  Presenting Author(s): Christine Lovly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES04.03 - Overcoming Resistance by Improving Treatment Compliance (ID 11369)

      16:00 - 16:20  |  Presenting Author(s): Felipe Gomes

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES04.04 - Guiding Second Line Treatment in ALK + Patients (Sequence of Drugs, Rebiopsy?) (ID 11368)

      16:20 - 16:40  |  Presenting Author(s): Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA08 - Clinical Trials in Brain Metastases (ID 906)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 11
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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      MA08.01 - Phase 3 Trial of Whole Brain Radiotherapy with Concurrent Erlotinib Versus WBRT Alone for NSCLC with Brain Metastases (ENTER) (ID 12987)

      15:15 - 15:20  |  Presenting Author(s): ZhenZhou Yang  |  Author(s): Yan Zhang, RongQing Li, Abulimiti Yisikandaer, BiYong Ren, JianGuo Sun, JianJun Li, Long Chen, Ren Zhao, JuYing Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      Brain metastasis (BM) is a leading cause of death for non-small cell lung cancer (NSCLC). Whole Brain Radiotherapy (WBRT) is a standard-of-care treatment for NSCLC patients with multiple brain metastases. Elevated EGFR expression and activity are important causes of tumor resistance to radiotherapy. This phase 3 trial sought to determine if concurrent erlotinib with WBRT will benefit patients with multiple BM compared with WBRT alone.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In this open-label, randomised, multicenter phase 3 study in China (NCT01887795), we enrolled NSCLC patients with at least two metastatic brain lesions who were naive to brain radiation and free from any EGFR-TKI for at least 4 weeks. Participants were randomly assigned (1:1) to receive either WBRT (2.0 Gy per day, 5 days per week, to 40 Gy) or WBRT plus concurrent oral erlotinib 150 mg daily (Erlotinib was given for 6 days then concurrently with WBRT). Subsequent treatments were maintenance therapy of erlotinib for EGFR-positive patients or standard chemotherapy for EGFR-negative patients until unacceptable adverse events or disease progression. The primary endpoint was intracranial progression-free survival (iPFS), defined as time from randomisation to either intracranial disease progression or death for any cause.

      4c3880bb027f159e801041b1021e88e8 Result

      Between August 7, 2013 and November 25, 2016, in total 222 patients from 11 centers across China were randomized to treatments: 115 with WBRT alone and 107 with WBRT and concurrent erlotinib. Median follow-up was 11.2 months (IQR 4.6-18.2). Median iPFS was 11.2 months (95% CI: 7.2-13.7) with WBRT and concurrent erlotinib versus 9.2 months (95% CI: 6.7-10.9) with WBRT alone (HR 0.926; 95% CI: 0.695-1.234; P=0.601). In the subgroup of 109 patients who were positive for the EGFR mutation, iPFS was not significantly longer among those who received WBRT with concurrent erlotinib than WBRT with sequential erlotinib (14.6 [95% CI 11.8-17.7] vs 12.8 [7.9-14.9] months; HR 0.743; 95% CI: 0.489-1.129; P=0.164). Median PFS of concurrent erlotinib arm was 5.3 months versus 4.0 of WBRT alone (HR 0.969; 95% CI: 0.735-1.277; P=0.825) and median overall survival (OS) was 12.9 versus 10.0 months (HR 0.913; 95% CI: 0.680-1.226; P=0.545).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This multi-institutional study demonstrated WBRT with concurrent erlotinib improved neither iPFS significantly than WBRT alone in the intention-to-treat population and the EGFR-positive subgroup, nor improved PFS or OS in intention-to-treat population, indicating that erlotinib played limited role when concurrently used with WBRT and for EGFR-positive NSCLC patients, WBRT with concurrent erlotinib was not significantly superior to WBRT with sequential erlotinib.

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      MA08.02 - Prophylactic Cranial Irradiation Reduces the Risk of Brain Metastases in High-Risk Lung Cancer Patients: EGFR and ALK Mutations (ID 13496)

      15:20 - 15:25  |  Presenting Author(s): Oscar Arrieta  |  Author(s): Federico Maldonado, Laura-Alejandra Ramírez-Tirado, Feliciano Barron, Yelitza Esmeralda Campos-Salgado, Monica Blake, Andrés F. Cardona, Jaime G De La Garza

      • Abstract
      • Presentation
      • Slides

      Background

      Prophylactic Cranial Irradiation (PCI) is considered standard-of-care for small-cell lung cancer, due to consistent findings of a reduced risk of developing brain metastases (BM) and a survival benefit. The role of PCI for patients with Non-small cell lung cancer (NSCLC) is less well established, since a clear survival benefit has not been identified, although high-risk subgroups have been identified, including patients with driver mutations and with elevated carcinoembryonic antigen (CEA) levels.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We assessed the use of PCI compared to observation in patients with stage IV NSCLC (NCT01603849). PCI dose was set 25 Gy/10 f. An amendment to the original record was requested so that patients who received PCI after January 2016 had hippocampal sparing. Primary end point was Intracranial Progression-Free survival (IPFS), secondary was overall survival (OS).

      4c3880bb027f159e801041b1021e88e8 Result

      84 patients were included, 43 were randomized to observation and 41 to PCI. 83.3% had a driver mutation (DM). Baseline characteristics were well balanced among groups. Median IPFS was 21.0 months (95%CI 16.2-25.9). Factors which were independently, positively associated with IPFS included ECOG (p=0.012) and therapeutic arm (p=0.006). PCI was associated with lower odds of progression to CNS (OR:0.16 (0.04–0.53), p=0.006).Cumulative incidence of BM at 1-yr was higher among patients without PCI (22% vs. 3%, p<0.001). Relative risk for IPFS in patients with DM was 0.29 (0.10-0.82, p=0.01), HR for OS was 0.48 (0.20-1.16, p=0.098). Median OS was higher in the PCI group compared to control [42.8 (95%CI: 28.1–57.6) vs. 25.9 (95%CI: 17.7 – 34.2)] months. Last, PCI was associated with lower hazards of death, 0.47 (0.24–0.95), p=0.035.rt-prof figure.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      PCI significantly increases IPFS and decreases risk of death in patients with advanced NSCLC, without neurocognitive impairment or decreased QoL. This intervention appears to be particularly useful for patients with good performance status and driver mutations. PCI increased IPFS without neurocognitive impairment or decreased QoL.

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      MA08.03 - EGFR-TKI Plus Brain Radiotherapy Versus EGFR-TKI Alone in the Management of EGFR Mutated NSCLC Patients with Brain Metastases: A Meta-Analysis (ID 12990)

      15:25 - 15:30  |  Presenting Author(s): Wenhua Liang  |  Author(s): Xiaojun Xia, Minzhang Guo, Jianxing He

      • Abstract
      • Presentation
      • Slides

      Background

      It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) presented better efficacy than brain radiotherapy (brain RT) in the treatment of brain metastasis (BM) in EGFR mutated NSCLC patients. However, whether the combination of EGFR-TKI and brain RT is better than EGFR-TKI alone remains unclear. We aim to compare the benefit of adding brain RT to EGFR-TKI by a meta-analysis of currently available data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A systematic search for relevant articles was conducted in six databases (PubMed, EMBASE, Cochrane database, Medline, Web of Science, Google scholar). The primary outcome was overall survival (OS) between groups, and the secondary outcome was intra-cranial progression-free survival (icPFS), both being measured as hazard ratios (HRs). The data was synthesized by random-effects model using STATA 13.0.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of four retrospective studies involving 507 EGFR mutated patients with BM at the first diagnosis were included, 209 patients received brain RT (predominantly whole brain RT). Combined therapy of EGFR-TKI and brain RT reduced 19% risk of deaths (OS HR=0.81, 95% CI 0.53-1.26; P=0.36) and 16% risk of intracranial progression (icPFS HR=0.84, 95% CI 0.55-1.27; P=0.40) compared with EGFR-TKI alone, however, no statistically significance was observed. Further subgroup analyses suggested that patients with 21 exon L858R mutation were more inclined to have greater icPFS benefit under combination therapy (HR 0.67, 95% CI 0.19-2.40) in contrast to 19 exon deletion patients (HR 1.35, 95% CI 0.88-2.09). In addition, patients older than 65 (HR 0.74, 95% CI 0.37-1.48) might benefit more from combination than those younger than 65 (HR 4.47, 95%CI 0.29-70.13).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This meta-analysis suggested that the combination of EGFR-TKIs and brain radiotherapy showed similar but potentially better OS and intracrnial control in EGFR-mutated NSCLC patients when compared to EGFR-TKI alone, especially for those with L858R mutations or older than 65. The current results underscore the importance of future randomized control trials and provide information for study design.

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      MA08.04 - Discussant - MA 08.01, MA 08.02, MA 08.03 (ID 14599)

      15:30 - 15:45  |  Presenting Author(s): Nasser Hanna

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA08.05 - Brain Penetration of Lorlatinib and Cumulative Incidence Rates for CNS and Non CNS Progression from a Phase 1/2 Study (ID 12760)

      15:45 - 15:50  |  Presenting Author(s): Todd M. Bauer  |  Author(s): Alice T. Shaw, Melissa L. Johnson, Alejandro Navarro, Justin F Gainor, Holger Thurm, Yazdi K. Pithavala, Antonello Abbattista, Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Background

      The potent, selective, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) lorlatinib was designed to penetrate the blood-brain barrier (BBB). In a phase 1/2 study, lorlatinib showed robust clinical activity in patients with ALK-positive non-small cell lung cancer (NSCLC), most of whom had CNS metastases and failed ≥1 ALK TKI. In preclinical studies, lorlatinib demonstrated high BBB permeability with rapid brain uptake in vivo and significant activity against ALK-positive intracranial tumor models.1,2 To assess brain penetration of lorlatinib in a clinical setting, we report exploratory analyses from a phase 1/2 study (NCT01970865), evaluating CSF-to-plasma concentration ratios from a small sample of patients and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and deaths for pretreated patients with ALK-positive NSCLC ± baseline CNS metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Across the ongoing phase 1/2 study, 5 patients at lorlatinib 100 mg QD starting dose underwent CSF sampling. Patients with ALK-positive NSCLC with ≥1 prior ALK TKI were analysed for progressive disease, categorized as either CNS or non-CNS progression, based on independent central review. CIRs for patients in expansion cohorts EXP2–5 from the phase 2 portion of the phase 1/2 study (N=198) were calculated using competing risks methodology.

      4c3880bb027f159e801041b1021e88e8 Result

      In patients (n=5), mean CSF-to-plasma concentration ratio was 0.73 (SD 0.14). The table shows CIRs at 6 and 12 months.

      Months Cumulative Incidence Probability
      Patients with ≥1 prior ALK TKIa CNS Progression

      Non-CNS

      Progression

      Death
      All patients (n=198)

      6 mos

      12 mos

      0.13

      0.18

      0.25

      0.37

      0.05

      NE
      Patients with baseline CNS metastases (n=131)

      6 mos

      12 mos

      0.14

      0.22

      0.21

      0.31

      NE

      NE
      Patients with no baseline CNS metastases (n=67)

      6 mos

      12 mos

      NE

      NE

      0.32

      0.49

      0.05

      NE

      aPatients in expansion cohorts EXP2–5 from the phase 2 study

      NE, not evaluable
      8eea62084ca7e541d918e823422bd82e Conclusion

      Lorlatinib showed high BBB permeability as evidenced by a high mean CSF-to-plasma concentration ratio, in line with preclinical rat studies showing CNS penetration. This translated into high activity against CNS metastases as suggested by the numerically higher probability of the first progression event being extracranial rather than intracranial, including in patients with a history of CNS metastases.

      References

      1. Collier, et al. Mol Imaging 2017;16:1–3.

      2. Zou, et al. Cancer Cell 2015;28:70–81.

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      MA08.07 - Real World Data of Osimertinib in Patients with Central Nervous System (CNS) Metastasis in ASTRIS Korean Subset. (ID 13581)

      15:50 - 15:55  |  Presenting Author(s): Jin-Hyoung Kang  |  Author(s): Byoung Chul Cho, Dong-Wan Kim, Keunchil Park, Jong-Seok Lee, Seung soo Yoo, Sung Yong Lee, Cheol Hyeon Kim, Seung Hun Jang, Young-Chul Kim, Hyoung-Kyu Yoon, Sang-We Kim

      • Abstract
      • Presentation
      • Slides

      Background

      More than 40% of non-small cell lung cancer (NSCLC) patients develop CNS metastasis in their lifetime. Osimertinib is a third-generation EGFR-TKI which selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations. Clinical studies have shown superior efficacy of osimertinib in CNS compared to platinum chemotherapy. Treatment efficacy in patients with or without CNS metastasis were observed within the second interim analysis of ASTRIS (NCT02474355). Data cut-off (DCO) was 20 October 2017.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In ASTRIS, advanced NSCLC patients with a locally confirmed T790M mutation, WHO performance status 0-2, prior EGFR-TKI therapy were enrolled. Patients with stable CNS metastases were allowed. The primary endpoint was overall survival (OS); other endpoints included investigator-assessed response rate (RR), progression-free survival (PFS), time to treatment discontinuation (TTD) and safety. These endpoints were also analyzed according to presence of CNS metastasis.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 466 patients received at least one dose of osimertinib 80mg from 31 Korean sites. CNS metastasis was evaluated in 310 patients and was present in 211 (68.1%) patients (CNS-met); 181 brain only, 1 leptomeningeal only, 29 both. 99 (31.9%) patients did not have CNS metastasis (CNS-no), and 155 patients were not evaluated (CNS-ne). At DCO, 236 patients (50.6%) were ongoing and median duration of exposure was 11.2 (0–19) months. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, RR was 71.0% (320/451; 95% CI, 66.5–75.1): Patients with (N=211), without (N=99), and not-evaluated CNS metastasis (N=155) had RR of 68% (134/197; 95% CI, 61.0-74.5), 79.6% (78/98; 95% CI, 70.3-87.1), and 69.7% (108/155; 95% CI, 61.8-76.8), respectively. Median PFS was 12.4 months (95% CI, 11.1-13.6 months); 10.8 months (95% CI, 9.5-11.5) in CNS-met,11.0 months (95% CI, 9.2-14.5) in CNS-no, and 15.1 months (95% CI, 13.6-18.2) in CNS-ne. Median TTD was 16.5 months (95% CI, 14.1-NC); 11.2 months (95% CI, 9.4-14.8) in CNS-met, 14.7 months (95% CI, 12.2-NC) in CNS-no, and NC (95% CI, 15.5-NC) in CNS-ne. OS was not reached (data maturity: 19.7%). Serious adverse event (AE) regardless of causality were reported in 116 patients (24.9%) and AEs leading to death in 13 patients (2.8%). ILD/pneumonitis-like events were reported in 8 patients (1.7%), and QTc prolongation in 7 patients (1.5%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In ASTRIS Korean subset, patients with or without CNS metastasis had comparable efficacy outcome. This data continues to support osimertinib’s clinical benefit on EGFRm T790M NSCLC patients with CNS metastasis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA08.08 - Discussant - MA 08.05, MA 08.07 (ID 14601)

      15:55 - 16:10  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA08.09 - Impact of Brain Metastases in Immune Checkpoint Inhibitors (ICI) Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 12575)

      16:10 - 16:15  |  Presenting Author(s): Lizza Hendriks  |  Author(s): Clémence Henon, Eduard Auclin, Laura Mezquita, Roberto Ferrara, Clarisse Audigier-Valette, Julien Mazieres, Corentin Lefebvre, Sylvestre le Moulec, Sophie Cousin, Boris Duchemann, Cecile Le Pechoux, Angela Botticella, Samy Ammari, Anas Gazzah, Caroline Caramella, Julien Adam, David Planchard, Dirk De Ruysscher, Anne-Marie C. Dingemans, Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Brain metastases (BM) are frequent in NSCLC. Unfortunately, patients with (untreated) BM are often excluded from ICI trials so that their outcome on ICI is largely unknown..

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective data collection of all consecutive advanced ICI treated NSCLC patients in 6 centers (5 French, 1 Dutch) (nov 2012 – march 2018). Active BM was defined as non-irradiated new and/or growing lesions on brain imaging < 6 weeks before ICI start. Progression free survival (PFS), overall survival (OS) and site of progression on ICI was collected.

      4c3880bb027f159e801041b1021e88e8 Result

      945 patients included: 63% male, 83% WHO PS 0-1, median age 64 years, 73% non-squamous, 4% targetable driver mutations, 33% known PD-L1 (65% ≥1% expression). ICI treatment was median 2nd line (range 1-12), 94% had monotherapy PD-(L)1 inhibition. 241 patients (26%) had BM, 68% had previous cranial irradiation, 40% had active BM. BM patients were significantly younger than others (61 vs 66 years), had more adenocarcinoma (78 vs 62%), more organs involved (median 3 vs 2), a poorer PS (0-1: 76 vs 85%) and more steroids at baseline (26 vs 9%). Median follow-up: 15 months. Median (95% CI) PFS and OS without and with BM were 2 (2-3) vs 2 (1-2) months and 13 (9-16) vs 9 (7-13) months, respectively. In multivariate analysis, > 2 metastatic sites, PS ≥2 and steroids use were associated with worse PFS and OS, BM were not (table 1). In univariate analysis of BM patients, active BM were not associated with worse outcome compared to stable BM (HR PFS 0.98 (p=0.66), HR OS 0.93 (p=0.92)). Progressing BM patients had more often brain PD and a dissociated response (not specifically brain dissociated) on ICI (40 vs 12% and 13 vs 7%, respectively).

      Factor PFS HR (95% CI) p-value OS HR (95% CI) p-value
      Age > 65 vs ≤ 65 1.02 (0.87-1.20) 0.79 1.11 (0.92-1.34) 0.29
      Smoking yes vs no 0.53 (0.41-0.69) <0.001 0.81 (0.59-1.12) 0.20
      Histology squamous vs adeno 1.07 (0.89-1.28) 0.78 1.24 (0.99-1.55) 0.12
      Nr of organs with metastases > 2 vs ≤ 2 1.28 (1.09-1.50) 0.003 1.48 (1.22-1.80) <0.001
      Immuno line > 2 vs ≤ 2 1.11 (0.94-1.30) 0.22 1.10 (0.91-1.33) 0.34
      WHO PS 0-1 vs ≥2 2.14 (1.75-2.62) <0.001 3.48 (2.78-4.36) <0.001
      Use of corticosteroids yes vs no 1.36 (1.10-1.69) 0.005 1.31 (1.03-1.68) 0.03
      BM yes vs no 1.05 (0.88-1.26) 0.58 0.96 (0.77-1.19) 0.70

      8eea62084ca7e541d918e823422bd82e Conclusion

      BM, treated or active, do not negatively impact outcome on ICI although BM failure is more common in these patients.

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      MA08.10 - Real-Life Intracerebral Efficacy of Nivolumab in Non-Small Cell Lung Cancer Patients with Brain Metastases (ID 14201)

      16:15 - 16:20  |  Presenting Author(s): Margaux Geier  |  Author(s): Renaud Descourt, Romain Corre, Guillaume Léveiller, Regine Lamy, Eric Goarant, Jean-Louis Bizec, Cyril Bernier, Gilles Quéré, Francis Couturaud, Gilles Robinet

      • Abstract
      • Presentation
      • Slides

      Background

      Data regarding intracerebral efficacy of nivolumab in advanced non-small cell lung cancer (NSCLC) are lacking because of routinely exclusion of patients with active brain metastases (BMs) from clinical trials. We aimed at assessing intracranial activity of nivolumab in patients with BMs in a real-life setting and determining the potential role of prior radiotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Between 01/09/2015 and 30/09/2016, all consecutive advanced NSCLC patients treated with nivolumab after failure of at least one line of chemotherapy were included. Nivolumab was administered at a dose of 3 mg/kg q2w until progression or unacceptable toxicity. Primary endpoint was intracerebral objective response rate (IORR) assessed by brain magnetic resonance imaging or brain computed-tomography scans. Secondary endpoints were overall response rate (ORR) and median duration of intracerebral response.

      4c3880bb027f159e801041b1021e88e8 Result

      259 patients were treated with nivolumab in 9 centers. Among them, 77 patients who presented BMs before nivolumab initiation were enrolled: 53 (20.5%) at diagnosis and 24 (9.3%) during the course of treatments. Median age at diagnosis was 57 years [29-78]. Most patients were males (72.7%) with smoking history (90.9%) and had adenocarcinoma (72.7%). 23 patients harbored a KRAS mutation. PD-L1 status was unknown. The median of prior lines was 1 [1-6]. BMs were pretreated in 48 (62.3%) patients: 16 received prior SBRT, 32 WBRT. Median time between prior radiotherapy and nivolumab initiation was 4 months [1-;27]. IORR and ORR were 10.4% and 20.8%, respectively. Among the 8 patients with intracerebral response, 5 (6.5%) had pretreated BMs, 3 (3.9%) had radiotherapy-naïve BMs. Median duration of intracerebral response was 11.5 months. No neurological adverse events occurred during nivolumab treatment. Among 259 patients, 36 (13.8%) developed BMs during nivolumab treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab intracerebral response achieved 10.4% in real-life with a satisfactory neurological safety profile. If prior radiotherapy improves IORR must be determined by further investigations.

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      MA08.11 - Early Safety Data of a Phase I/II Combining Nivolumab and Stereotactic Brain Radiosurgery for Treatment of Brain Metastases in Patients with NSCLC (ID 14064)

      16:20 - 16:25  |  Presenting Author(s): Raafat Alameddine  |  Author(s): Philip Wong, Laura Masucci, David Roberge, Cynthia Menard, Bertrand Routy, Mustapha Tehfe, Normand Blais, Marie Florescu

      • Abstract
      • Presentation
      • Slides

      Background

      Radiotherapy can stimulate the immune system through various means. Highly cytotoxic stereotactic radiosurgery (SRS) doses (>10Gy per fraction) may synergize with anti-PD1 to reduce intracranial disease progression or recurrence.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Within a phase I/II trial evaluating the combination of nivolumab with SRS in the treatment of brain metastases from NSCLC and RCC (NCT02978404), 8 patients were enrolled (1 RCC and 7 NSCLC) in the first trial cohort. Herein, only the NSCLC cases are reviewed. Patients were eligible if their KPS ≥70, were minimally symptomatic (RTOG neurological function <2), and had ≤10cc of untreated brain metastases. Prophylactic corticosteroids were not given. Nivolumab (240mg IV q2 weeks) was started 2 weeks prior to SRS, and administered until RECIST progression. SRS (15-20Gy in 1 fraction) was given to each brain metastasis. The aim of the first patient cohort is to estimate the tolerability of the combined treatment strategy.

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up of the three male and four female patients was 2 months. Median age was 63 years (55-84 years). Five NSCLC patients completed ≥1 cycle of nivolumab and SRS, and were evaluated for tolerability of the combination. One patient elected to withdraw before the first nivolumab dose and 1 patient died prior to SRS. Median baseline brain edema and total brain metastases volumes were 0.5cc (0-46.97cc) and 1.25 cc (0.1-3.46cc), respectively. To date, the median number of nivolumab cycles administered is 4.5 (1-15). Intracranial adverse effects were limited to apraxia and paresthesias in the patient who had the largest volume of peri-tumoral brain edema at baseline (46.97cc). Nivolumab was held and dexamethasone was given for 74 days at doses >1mg/day until neurological symptoms resolved. Systemic adverse events included one patient with grade 2 arthritis necessitating a 6-week treatment delay and 51 days of prednisone ≥10mg. At last follow-up, three patients had died of extracranial disease progression, including the two patients who did not receive protocol SRS. Among the three patients evaluable for intracranial response, there was one partial response and two stable diseases. All three patients had stable extracranial disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combining SRS and immunotherapy is safe in regards to acute toxicity with a manageable side effect profile. Close monitoring may be required for patients with significant baseline brain edema. Evaluation for efficacy awaits further follow-up and completion of recruitment in the phase 2 component of the trial.

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      MA08.12 - Discussant - MA 08.09, MA 08.10, MA 08.11 (ID 14604)

      16:25 - 16:40  |  Presenting Author(s): Arjun Sahgal

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA11 - Biomarkers of IO Response (ID 912)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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      MA11.01 - Comparative Efficacy of T-Cell Intrinsic Versus Extrinsic PD-1 Blockade to Overcome PD-L1+ Tumor-Mediated Exhaustion (ID 14194)

      10:30 - 10:35  |  Presenting Author(s): Jordan Dozier  |  Author(s): Nan Chen, Jasmeen Saini, Navin Chintala, Prasad S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD-1 agents are effective in overcoming PD-L1+ mediated T-cell exhaustion. Effective therapeutic regimens include multiple, long-term administration. We hypothesized that a single dose of T-cell intrinsic PD-1 blockade by expression of a dominant negative receptor (PD1-DNR) can be equally effective as multiple doses of anti-PD-1 agent administration in the treatment of PD-L1 overexpressing thoracic cancers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Human T cells engineered to target the cancer-antigen mesothelin (MSLN) by expression of a chimeric antigen receptor (CAR) with or without co-transduction with a PD1-DNR underwent repeated antigen stress with cancer cells with constitutive overexpression of PD-L1. For comparative efficacy evaluation, anti-PD-1 antibody was co-administered with CAR T cells (CARs). In vitro efficacy was evaluated by cytotoxicity (chromium-51 release assay). In vivo, mice with established pleural tumor were treated with either a single dose of MSLN CARs (with and without anti-PD-1 agent) or MSLN PD1-DNR CARs. Tumor burden regression by bioluminescence imaging and median survival were evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      In vitro, constitutive PD-L1 overexpression (Fig. A) inhibits MSLN CAR effector function as evidenced by a decrease in cytotoxicity following repeated stimulation with MSLN+PD-L1hi tumor cells (Fig B). MSLN PD1-DNR CARs had increased cytotoxicity when compared to MSLN CARs with or without high frequency anti-PD-1 antibody supplementation. In vivo, mice treated with MSLN CAR (with or without anti-PD-1 antibody) or MSLN PD1-DNR CARs demonstrated enhanced tumor regression (Fig C) and prolonged median survival (Fig D) compared to MSLN CARs alone. Furthermore, a single low dose of MSLN PD1-DNR CARs shows equal anti-tumor efficacy compared to MSLN CARs with multiple doses of anti-PD-1 antibody.

      dozier_figure 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results demonstrate that CAR T cells engineered to express a cell-intrinsic PD-1 dominant negative receptor overcome PD-L1 mediated T-cell inhibition equally compared to multiple doses of anti-PD-1 antibody administration. A clinical trial with MSLN CAR PD1-DNR CAR T cells is being initiated.

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      MA11.02 - Increased CD3+ TIL Infiltration and Low FOXP3+/CD8+ TIL Ratio Can Predict Anti-PD-1 Therapeutic Response in Non-Small Cell Lung Cancer Patients (ID 12553)

      10:35 - 10:40  |  Presenting Author(s): Hyojin Kim  |  Author(s): Hyun Jung Kwon, Yeon Bi Han, Soo Young Park, Eun Sun Kim, Jin-Haeng Chung

      • Abstract
      • Presentation
      • Slides

      Background

      To determine whether distinct tumor microenvironments differentially affect the clinical response to anti-PD-1 therapy in non-small cell lung cancer (NSCLC), we investigated the expression level of PD-L1 and tumor infiltrating lymphocytes (TILs) and elucidate their predictive role.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Forty pretreated specimens (including 21 resected and 19 biopsied tissues) from 36 advanced, treatment-refractory NSCLC patients who underwent PD-1 blockade therapy were analyzed. PD-L1 expression by tumor cells and the distribution of CD3, CD8, CD4, FOXP3 and PD-1 positive TILs were immunohistochemically assessed. The mean number of cells positive for each marker in covered total fields was expressed in density per mm2 using digital image analyzer. In addition, CD8+/CD3+, CD8+/CD4+, FOXP3+/CD8+, and PD-1+/CD8+ ratios were calculated for each specimen using the mean number of total fields.

      4c3880bb027f159e801041b1021e88e8 Result

      CD3+ and CD8+ TILs were distributed more in PD-L1 positive group compared to PD-L1 negative group. Inversely, EGFR mutant group showed fewer CD3+ TILs than EGFR-naïve group. The patients in the clinical benefit group with PD-1 blockade showed a higher number of CD3+, CD8+ TILs and a higher CD8+/CD3+ TIL ratio (p=0.003, p=0.001, and p =0.042) and a lower FOXP3+/CD8+ TIL ratio compared to non-responders (p=0.001). We analyzed the effects of TIL, PD-L1 and clinicopathologic factors in PD-1 blockade therapeutic response using logistic regression. In multivariate analysis, increased CD3+ TIL infiltration and low FOXP3+/CD8+ TIL ratio were found to be independent predictors of clinical benefit with PD-1 blockade. (p=0.014 and p=0.03, respectively). Using receiver operating characteristic curves, levels of CD3+ TIL and FOXP3+/CD8+ TIL ratio that provide the best distinguishing point between responder versus non-responder to PD-1 blockade were 617.5/mm2 and 25%, respectively (p=0.007 and p=0.003). Considering that 1 mm2 is about 5 high power fields (HPF), a good response to the PD-1 blockade can be expected when CD3 + TIL is observed in 120 per 1 HPF and CD8 + TIL : FOXP3 + TIL are greater than 4 : 1. In addition, there were no difference between sample acquisition method (resection vs. biopsy) and duration (3, 6, and 12 months before PD-1 blockade treatment), and TIL expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Based on our results, TIL is an independent predictive factor of response to PD-1 blockade and we suggested a cutoff value of TIL to predict responder group. In addition, properly sampled small biopsy tissue and well preserved archival specimens are feasible to evaluate TIL status.

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      MA11.03 - Interaction of Tumor Infiltrating Lymphocytes and Cancer Nuclei Predicts Response to Nivolumab in Non-Small Cell Lung Cancer (NSCLC) (ID 14143)

      10:40 - 10:45  |  Presenting Author(s): Xiangxue Wang  |  Author(s): Cristian Barrera, Cheng Lu, Vamsidhar Velcheti, Anant Madabhushi

      • Abstract
      • Presentation
      • Slides

      Background

      Immune checkpoint inhibitors, particularly drugs targeting the Programmed death-1 (PD-1) pathway, are promising agents in NSCLC. These drugs however are effective in only a small subset of patients. Programmed death Ligand-1 (PDL1) expression in the tumor predicts response to these agents but is not an optimal biomarker because of spatial and temporal heterogeneity associated with PDL1. PD-L1 is upregulated in response to inflammation in the tumor and strongly correlates with Tumor-infiltrating lymphocytes (TILs). In this work, we evaluated whether quantitative measurements relating to the spatial interplay and arrangement of TILs and cancer nuclei from diagnostic biopsy tissue slide images (H&E) was predictive of response to Nivolumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tumor biopsies of total 82 NSCLC patients previously treated with Nivolumab from two different institutions were employed in this study. The RECIST criteria was used to define response. [vv1] The 492 features characterizing the global interaction of TILs and cancer cells through graph interplay metrics are extracted from tumor regions delineated by two expert pathologists to interrogate the difference of phenotypes. Top 5 features were learnt on learning set by random forest classifier from one institution (n=32) and independently validated on patients from a second site (n=50).

      4c3880bb027f159e801041b1021e88e8 Result

      The most predictive features comprised of difference of characteristic path length between lymphocyte graph and cancer nuclei graph and cosine similarity between lymphocyte node and cancer nuclei node based on their node centrality index. The random forest classifier yielded an area under the receiver operating characteristic curve (AUC) of 0.76 on the training cohort and 0.68 on the validation set (Figure 1).til40.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results showed that quantitative measurements relating to the spatial interplay and arrangement of lymphocyte and cancer nuclei from H&E slide images were predictive of response to Nivolumab in NSCLC. Additional independent multi-site validation of these features is needed.

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      MA11.04 - Discussant - MA 11.01, MA 11.02, MA 11.03 (ID 14619)

      10:45 - 11:00  |  Presenting Author(s): Donald Morris

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA11.05 - Indoleamine 2,3-Dioxygenase Expression in Non-Small-Cell Lung Cancer: Analyses of Prevalence, Clinical Correlations and Prognostic Impact (ID 13309)

      11:00 - 11:05  |  Presenting Author(s): Francesco Agustoni  |  Author(s): Hui Yu, Kim Ellison, Derek Smith, Paul Mitchell, Gareth Rivalland, Rafal Dziadziuszko, Dexiang Gao, Kenichi Suda, Shengxiang Ren, Christopher J. Rivard, Charles Caldwell Jr, Leslie Rozeboom, Kristine Brovsky, Diego Cortinovis, Paolo Bidoli, Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background

      Indoleamine 2,3-dioxygenase-1 (IDO-1) is a cytosolic enzyme involved in the catabolism of tryptophan; IDO-1-related immune suppression is due to decreased tryptophan availability and to the generation of tryptophan metabolites, culminating in substantial suppression of T-lymphocytes. Here we investigate IDO-1 expression in a cohort of non-small-cell lung cancer (NSCLC) specimens, both in tumor cells and in immune infiltrate, with correlation of IDO-1 to PD-L1 expression, clinical patient demographics and outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A cohort of 1.200 NSCLC samples were obtained from 437 patients who underwent surgical lung resections at Austin Health, Melbourne, Australia. IDO-1 expression was evaluated by immunohistochemistry. Correlations were assessed using Spearman and Kendall tests. A Cox proportional hazards (PH) model was used to assess if overall survival (OS) was associated with IDO-1 positivity in univariate and multivariable settings.

      4c3880bb027f159e801041b1021e88e8 Result

      Samples from 437 patients were analyzed for IDO-1 expression, with 111 (25.4%) determined as positive (H-Score 1) and 326 patients (74.6%) as negative (H-Score: 0). IDO-1 expression was determined to be greater in tumor immune infiltrate, with 406 patients (93.8%) determined as positive, while just 27 (6.2%) were IDO-1 negative. There was a significant positive correlation between IDO-1 positive tumor cells and immune cells (0.2167, p < 0.001). Both continuous and binary versions of tumor H-Score showed a significant positive correlation with the amount of tumor immune infiltrate (0.1806 and 0.1698, p < 0.0001, respectively). None of the analyzed variables (age, sex, histology, stage, EGFR, KRAS and PD-L1 status) were found to display a significant correlation with IDO-1 positivity in tumor and immune cells. IDO-1 positivity in tumor cells was found to be significantly associated with OS in the univariate setting and in the multivariable model where variables age, sex, histology, stage, EGFR, KRAS and PD-L1 status were included [P-value = 0.009 and 0.021, respectively; HR: 0.72 (95% CI: 0.55-0.95)]. IDO-1 positivity in immune cells was found to be significantly associated with OS in the univariate setting and was borderline significant in the multivariable model [P-value = 0.006 and 0.053, respectively; HR: 0.798 (95% CI: 0.635-1.003)].

      8eea62084ca7e541d918e823422bd82e Conclusion

      To our knowledge, this is the most extensive analysis of IDO-1 expression in NSCLC patients reported in the literature. Our results suggest the possible prognostic role of IDO-1 expression in tumor and immune cells, highlighting the relevance of IDO-1 detection in tumor tissue. Since new compounds targeting IDO-1 are actually under investigation, the identification of potential prognostic and predictive biomarkers will be needed.

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      MA11.06 - Prognostic Value of Complement System in NSCLC and its Association with PD-1 and PD-L1 Expression (ID 12372)

      11:05 - 11:10  |  Presenting Author(s): Luis M Montuenga  |  Author(s): Daniel Ajona, María José Pajares, Javier Freire, Javier Gomez-Roman, Elena Martinez-Terroba, Sergio Ortiz-Espinosa, Ana Lledo, Elisabeth Arenas-Lazaro, Jackeline Agorreta, Fernando Lecanda, Ruben Pio

      • Abstract
      • Presentation
      • Slides

      Background

      Recent research has unveiled novel molecular mechanisms linking imbalanced complement activation and cancer progression. In this context, complement inhibition has emerged as a treatment option for maximizing the clinical efficacy of current immunotherapies that target the PD-1/PD-L1 immune checkpoint.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lung cancer tissues were obtained from 140 patients treated by surgery at the Clinica Universidad de Navarra. Inclusion criteria were: NSCLC histology, complete resection of the primary tumor, absence of cancer within the five years previous to the lung cancer surgery, and no treatment with chemo- or radiotherapy prior to surgery. Resected primary lung tumors were fixed in formalin and embedded in paraffin. After antigen retrieval samples were incubated with anti-human C4d, C5aR1, C1q, PD-1 and anti-PD-L1 followed by detection with the Envision system (Dako). Peroxidase activity was visualized with 3,3’-diaminobenzidine. Sections were slightly counterstained with hematoxylin. Two independent and blinded observers calculated an H -score based on intensity and extension of the staining. Survival curves were generated using the Kaplan–Meier method, and statistically significant differences were analyzed with the log rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Immunohistochemistry of complement proteins in NSCLC was performed for C1q, the target recognition of the complement pathway in NSCLC, C4d, a split product of complement activation, and C5aR1, the complement C5a anaphylatoxin receptor. Immunohistochemical analysis showed positive staining for all these proteins, indicating complement activation in primary lung tumor cells. Importantly, high levels of C1q, C4d, and C5aR1 predict poor disease-free survival (P=0.004; P=0.044; and P=0.02; respectively) and poor overall survival (P=0.031; P=0.022; and P=0.048; respectively) in NSCLC patients. A significant association between PD-1 expression levels in immune cells and disease-free survival was found (P=0.002) but this association was not significant for overall survival. PD-L1 expression levels in both immune cells and tumor cells were not associated with prognosis in NSCLC patients. Interestingly, those patients with high levels of C4d presented a significant decrease of PD-L1 expression in tumor cells (P<0.001) suggesting a link between complement activation and the immune homeostasis of the tumor microenvironment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Complement activity in primary NSCLC tumors predicts poor prognosis. C4d, a marker of complement activation, is associated with low levels of PD-L1 expression in tumor cells. Harnessing complement system as therapeutic target may enhance PD-1/PD-L1 immune checkpoint-based immunotherapies.

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      MA11.07 - Expression of LAG-3 and NY-ESO-1 In Tumor Cells is Promising Biomarker Predicting Durable Clinical Benefit of PD-1 Blockade in Advanced NSCLC (ID 12403)

      11:10 - 11:15  |  Presenting Author(s): Hee Ryeong Jang  |  Author(s): Se Hyun Kim, Kyoung Jin Suh, Yu Jung Kim, Mi So Kim, Bhumsuk Keam, Tae Min Kim, Jin-Haeng Chung, Dong-Wan Kim, Dae Seog Heo, Jong-Seok Lee

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD-1 antibodies are currently used in treating advanced non-small cell lung cancer (NSCLC). PD-L1 expression in tumor cell or immune cell is the only available predictive biomarker in the clinic. Lymphocyte activation gene-3 (LAG-3) is an inhibitory checkpoint in immune cells and NY-ESO-1 is an antigen expressed in tumor cells. We investigated LAG-3 and NY-ESO-1 protein expression and its relationship to response to anti-PD-1 therapy in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the medical records of 38 patients with advanced NSCLC who were enrolled in prospective clinical trials of nivolumab or pembrolizumab monotherapy (NCT01295827, NCT01905657, and NCT02175017) between October 2013 and April 2016 at Seoul National University Hospital and Seoul National University Bundang Hospital. Immunohistochemial staining (IHC) of NY-ESO-1(E978, Invitrogen), and PD-L1 (22C3, Dako) in tumor cell and LAG-3(EPR4392, Abcam) in immune cell was performed to determine protein expression.

      4c3880bb027f159e801041b1021e88e8 Result

      LAG-3 and NY-ESO-1 protein expression were assessed in 38 patients. LAG-3, NY-ESO-1 and PD-L1 were expressed in 76.3% (29/38), 50% (19/38) and 18.5% (7/36, 50% cut-off value), respectively. Sixteen patients with durable clinical benefit (DCB, anti-PD-1 therapy more than 6-month) were grouped as responder. NY-ESO-1 expression (DCB 11/19 vs 5/19, p= .05) and LAG-3 expression (DCB 16/29 vs 0/9, p= .003) were significantly correlated with the DCB to Anti-PD-1 therapy, while PD-L1 expression was identified in 5 patients with DCB (5/7 vs 11/29, p= .12). Patients with both NY-ESO-1 and LAG-3 expression had high rate of DCB (73.3%, 11/15 pts). With the results of the interaction with DCB, the calculation of positive predictive value and negative predictive value about durable clinical benefit is assessed and the significance of each measurement was proven by Fisher’s exact test. As a result, NPV of LAG-3 expression in tumor cell was 100% and PPV of each protein expression was LAG-3 (55.17%), NY-ESO-1(57.89%) and PD-L1 (71.43%) respectively. In survival analysis, LAG-3 expression was a significant predictor for PFS (HR 0.170; CI 0.066-0.437; p< .0001) and OS (HR 0.250; CI 0.140-0.599; p= .002).

      8eea62084ca7e541d918e823422bd82e Conclusion

      NY-ESO-1 expression on tumor tissue and LAG-3 expression on tumor microenvironment may be useful for identifying advanced NSCLC patients for the treatment of anti-PD-1 therapy. These protein markers seem quite promising and warrant further investigation in large sample size.

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      MA11.08 - Discussant - MA 11.05, MA 11.06, MA 11.07 (ID 14620)

      11:15 - 11:30  |  Presenting Author(s): Erin Schenk

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA11.09 - Single-Cell Characterization of the Immunologic Microenvironment in Advanced-Stage, Oncogene-Driven NSCLC (ID 12122)

      11:30 - 11:35  |  Presenting Author(s): Julia Rotow  |  Author(s): Caroline McCoach, Ashley Maynard, David Naeger, Yaron Gesthalter, K Pallav Kolli, Spyros Darmanis, Trever G Bivona, Collin Blakely, Jonathan Weissman

      • Abstract
      • Presentation
      • Slides

      Background

      The immunologic microenvironment in oncogene-driven non-small cell lung cancer (NSCLC) is poorly understood. Despite high initial response rates to tyrosine kinase inhibitors (TKIs) in patients with oncogene-driven NSCLC, responses are incomplete and transient. Furthermore, response rates to subsequent checkpoint inhibitor immunotherapies are very low. Understanding the immunologic microenvironment may facilitate understanding treatment resistance in this population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From October 2016 to March 2018 we performed single-cell sequencing on 35 tissue samples from 28 patients with NSCLC. Fresh tissue samples were obtained at time of standard of care biopsies and as research sample collections. Single-cell level whole transcriptome RNA sequencing was performed using SmartSeq2. Cells were clustered into distinct cell states on a multi-dimensional gene expression space and visualized using t-distributed stochastic neighbor embedding (t-SNE) for further dimensionality reduction. Cellular identities for each cluster were established by examining the enrichment of known cell-type specific genes across all distinct clusters.

      4c3880bb027f159e801041b1021e88e8 Result

      Tumor samples were obtained from predominantly stage IV lung adenocarcinoma (90.6%) harboring an oncogenic driver (EGFR-mutant 50%, ALK-rearranged 21.9%, BRAF V600E 9.4%, ROS1-rearranged 9.4%, MET exon 14 skipping 6.3%, and KRAS-mutant 3.1%). Samples were collected prior to treatment (21.9%), during treatment (46.9%), and at disease progression on therapy (31.3%). All patients with a targetable oncogenic driver received a standard of care TKI and the KRAS-mutant patient received pembrolizumab monotherapy. A total of 6048 cells were isolated, including 3457 immune cells, with an average of one million reads and 2500 genes per cell. The immunologic microenvironment (average 108 immune cells/sample) included macrophages/monocytes (33% of cells), T cells (31.9%), and B cells (11.6%), as well as a smaller fraction (<10%) of dendritic cells, Langerhans cells, mast cells, neutrophils, and NK cells. Unbiased gene expression-based subclustering of T cells identified 7 distinct T cell populations, including naïve (22.6%), cytotoxic and/or memory T cells (44.1%), and T regulatory cells (5.6%), as well as 6 tumor-associated macrophage populations with distinct gene expression patterns.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Single-cell RNA sequencing to identify immune cell populations is feasible in advanced-stage NSCLC biopsy specimens across multiple time points during treatment. Here, we describe the heterogeneity of infiltrating immune cell phenotypes including T cell and macrophage subtypes. An improved understanding of the immunologic microenvironment in oncogene-driven NSCLC may facilitate patient selection for immunotherapy treatment and aid in the rational design of alternative or combination immunotherapy strategies for a patient population rarely responsive to current immunotherapeutic agents.

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      MA11.10 - Identification of Mismatch Repair Deficient Lung Adenocarcinomas Using Targeted Next-Generation Sequencing (ID 12439)

      11:35 - 11:40  |  Presenting Author(s): Navin Rajput Mahadevan  |  Author(s): Priyanka Shivadasani, Jonathan Nowak, Mark M. Awad, Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Background

      Mismatch repair (MMR) deficiency/microsatellite instability (MSI) results from the inactivation of DNA mismatch repair proteins. Due to the defect in DNA repair, MMR-deficient (D) tumors display an elevated tumor mutation burden (TMB) and a characteristic increase in small insertions/deletions within homopolymer tracts (“homopolymer indels”), a signature that can be detected using next generation sequencing methods. MMR-D/MSI predicts response to immune oncology (IO) agents (Le et al., 2017) and is an approved biomarker for pembrolizumab therapy in the relapse setting irrespective of histologic diagnosis. In this study, we retrospectively analyzed a large cohort of non-small cell lung carcinomas using targeted next generation sequencing to examine the prevalence and clinicopathologic associations of MMR-D in this tumor type.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      TMB and MSI status was derived from a 309-447 gene targeted next generation sequencing panel (OncoPanel) using an internally validated method (Nowak et al., 2017), that relies on an empirically defined homopolymer indel cutoff of >=1.52/Mb to identify candidate MMR-D tumors. MMR/MSI status was confirmed using MSI PCR (5 marker panel) and/or immunohistochemistry (IHC) for MLH1, PMS2, MSH2, and MSH6. When indicated, MLH1 promoter methylation status was evaluated by methylation-specific PCR.

      4c3880bb027f159e801041b1021e88e8 Result

      2242 lung tumors, including 1835 non-squamous non-small cell lung carcinomas (NSCLC), were interrogated. A total of three lung tumors (all adenocarcinoma) with confirmed MSI/MMR-D by orthogonal methods were identified, for a prevalence of 0.1% of all lung tumors and 0.2% of non-squamous NSCLC. The TMB of these tumors averaged 42.5 mutations/Mb with 7-10 homopolymer indels /Mb. All three tumors showed loss of MLH1 and PMS2 staining by IHC; two cases had somatic loss-of-function MLH1 variants and one showed MLH1 promoter methylation. All were from female patients whose mean age was 68 years (range: 53-83). All showed a poorly-differentiated histology with moderate to brisk lymphoid infiltrates. One patient was a never-smoker; her tumor had a concomitant EML4-ALK rearrangement. The other two patients had moderate/heavy smoking histories (12.5-80 pack-years) both showed RASA1 and NF1 inactivating mutations. One tumor evolved in the context of usual interstitial pneumonia.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MMR-D is very rare in lung tumors, where it appears to arise as somatic event and is enriched in adenocarcinoma. MMR-D may coexist with other relatively uncommon driver alterations, including those not traditionally associated with IO response. Additional investigation is needed to determine if MMR-D confers sensitivity to IO in lung carcinomas.

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      MA11.11 - Discrepancy of Tumor Neoantigen Burden Between Primary Lesions and Matched Metastases in Lung Cancer (ID 12289)

      11:40 - 11:45  |  Presenting Author(s): Tao Jiang  |  Author(s): Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Personalized vaccine based on tumor neoantigens showed the striking antitumor effect on several solid tumors, suggesting its significant and potential role in curing cancer. However, whether tumor neoantigens identified from primary lesions were similar to their matched metastases remain unknown. Here, we aimed to compare the tumor neoantigen burden (TNB) between primary lesions and matched metastases in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Primary lung cancers, matched metastatic sites and peripheral blood (10 mL, EDTA) were collected before any systemic therapy as part of the standard clinical care. Genomic DNA was extracted from all included samples. The matched peripheral blood leukocytes were used as the source for germline DNA control. DNA libraries were subjected to whole-exome capture and then sequenced on an Illumina HiSeq X-TEN platform. The criteria for tumor neoantigen identification were tumor specific mutations (missense, frameshift, inframe insertion or deletions), fold change > 10, high predicted affinity (IC50 < 500 nM) and predicted peptide of 9-10 amino acids in length.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally, 14 cases with matched lung primary lesions and metastases were enrolled, including 10 patients with liver metastases and 4 with brain metastases. A wide range of TNB were identified in both primary lesions (median 157, range 21-1156) and metastases (median 135, range 35-1902). We observed a large discrepancy of TNB between primary lesions and matched metastases, with a median unique percentage of 82.20% (74.03%-95.24%) in primary lesions and 84.50% (77.45%-97.14%) in metastases. In patients with brain metastases, primary lesions had a percentage of 90.98% (79.57%-95.24%) unique tumor neoantigens, while metastases had 86.03% (77.45%-97.14%). For those with liver metastases, the median unique percentage of tumor neoantigens was 80.58% (74.03%-88.66%) in primary lesions and 83.35% (78.49%-91.14%) in metastases. Smoking history and histological types had no impact on the discrepancy of TNB (P > 0.05, P > 0.05; respectively). TNB of primary lesions was similar to matched metastases (P = 0.733). However, primary lesions of brain metastases had a significantly higher percentage of unique tumor neoantigen than that of liver metastases (P = 0.025).

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is a large percentage of different tumor neoantigens between primary lesions and matched metastases in lung cancer. Whether this discrepancy could affect the efficacy of following personalized vaccine on primary lesions or matched metastases need further investigation.

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      MA11.12 - Discussant - MA 11.09, MA 11.10, MA 11.11 (ID 14621)

      11:45 - 12:00  |  Presenting Author(s): Ignacio Gil-Bazo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 11
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.01 - Frequency and Genomic Context of Emerging Markers for Molecular Testing in Lung Adenocarcinoma in Cell-Free DNA NGS Analysis (ID 13465)

      13:30 - 13:35  |  Presenting Author(s): Vincent K Lam  |  Author(s): Lesli Ann Kiedrowski, Zofia Piotrowska, Anne S. Tsao, Ashley M. Wells, Richard B Lanman, Vassiliki A Papadimitrakopoulou, Rebecca J Nagy

      • Abstract
      • Presentation
      • Slides

      Background

      The recently updated CAP/IASLC/AMP lung cancer molecular testing guideline (Lindeman et al 2018) recommends several genes be analyzed by next-generation sequencing (NGS) in lung adenocarcinoma (LUAD), including EGFR, ALK, BRAF, KRAS, and others. It also includes a list of 20 emerging markers (EMs) for molecular testing and suggests practitioners remain aware of these and other genes between guideline updates. We investigated the frequency of genomic alterations (GAs) in several of these EMs in a cohort of patients with advanced lung adenocarcinoma who underwent clinical cell-free DNA (cfDNA) NGS analysis and assessed co-occurrence with canonical driver GAs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Genomic data was reviewed from 6530 patients with at least one GA detected on clinical Guardant360 cfDNA NGS testing (Guardant Health, Inc) with an indicated diagnosis of lung adenocarcinoma from 11/25/16-3/1/18. Synonymous alterations were excluded from further analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      2600 patients (40%) had at least one nonsynonymous alteration in the EM genes assessed; excluding GAs classified as variants of unknown significance (VUS), 1350 patients (21%) had at least one characterized alteration. Table 1 shows number and frequency of GAs observed per patient by gene and alteration type. Of EMs assessed, GAs were observed most commonly in NF1, PIK3CA, PDGFRA, KIT, and FGFR1-2. GAs in multiple EMs, including RIT1, NRAS, FGFR2-3, NTRK1, KIT, and AKT1, were observed co-occurring with established driver alterations, often in a genomic context consistent with resistance to targeted therapy at allelic fractions suggestive of subclonality.

      table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Effective therapies are continually emerging for a growing number of molecular biomarkers in lung cancer. Comprehensive genomic profiling with cfDNA NGS can identify GAs in both recommended and EM genes to guide therapeutic decision-making and catalyze clinical trial enrollment. Further investigation of mutual exclusivity and co-occurrence of established drivers and EMs may reveal novel resistance mechanisms and facilitate identification of rational combination therapeutic strategies.

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      MA16.02 - Prospective Clinical Validation of the InVisionFirst™ ctDNA Assay for Molecular Profiling of Patients with Advanced NSCLC (ID 13885)

      13:35 - 13:40  |  Presenting Author(s): Ramaswamy Govindan  |  Author(s): Michael A. Pritchett, Ross Camidge, Manu Patel, Jamil Khatri, Steven Boniol, Elke K. Friedman, Abderrahim Khomani, Samir Dalia, Katherine Baker-Neblett, Vincent Plagnol, Karen Howarth, Nitzan Rosenfeld, Clive Morris

      • Abstract
      • Presentation
      • Slides

      Background

      Clinical practice guidelines advocate molecular profiling as a part of the evaluation of advanced NSCLC, with ctDNA based profiling being an option for those with insufficient tissue. Thorough prospective clinical validation studies of NGS based ctDNA assays are lacking. Here we report the multi-centered prospective clinical validation of a ctDNA NGS panel for stratification of patients with advanced untreated NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      InVisionFirst™ (Inivata) is a ctDNA NGS assay for detection of genomic alterations in 36 genes commonly mutated in NSCLC and other cancers. 264 patients with untreated advanced NSCLC were prospectively recruited by 41 US centers. 178 patients had tumour tissue available for molecular profiling (predominantly by NGS) and the remaining 86 patients without tissue were included to compare ctDNA profiles obtained from patients with and without tissue for profiling.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 204 patients (77.3%) had detectable ctDNA alterations. Using tissue results as the reference, overall concordance for the full 36 genes in the InVisionFirst™ panel with matched tissue profiling was 97.8% with 82.9% PPV, 98.5% NPV, 70.6% sensitivity and 99.2% specificity. Considering a subgroup of 8 genes that can influence routine clinical patient management (EGFR, ALK, ROS1, ERBB2, MET, BRAF, KRAS, STK11) the PPV was 93.7%, 96.8% NPV, 72.4% sensitivity and 99.4% specificity. Excluding patients with undetectable ctDNA, these figures become 93.7% PPV, 98.4% NPV, 87.3% sensitivity and 99.3% specificity. The observed pattern of genomic changes seen in ctDNA was consistent across patients with and without tissue for profiling. Across the whole study, 44 patients with actionable alterations were identified by ctDNA testing compared to only 36 by tissue testing. 47% of patients tested by ctDNA had an actionable alteration or an alteration that is generally mutually exclusive for such actionable changes such as KRAS or STK11.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The InVisionFirst™ assay demonstrates excellent concordance with tissue profiling in this multi-centered prospective clinical validation study. The performance of this assay in terms of overall sensitivity and specificity appears comparable if not higher than other established commercial ctDNA assays. Utilization of InVisionFirst™ ctDNA testing led to the detection of 22% more actionable alterations than standard of care tissue testing in this study supporting its use for the molecular stratification of patients with advanced NSCLC. Further analyses on the features associated with detectable ctDNA signatures are ongoing.

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      MA16.03 - Discussant - MA 16.01, MA 16.02 (ID 14645)

      13:40 - 13:55  |  Presenting Author(s): Geoffrey R. Oxnard

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA16.04 - Clinical and Molecular Characteristics of EGFR Mutant Lung Cancers with Concurrent TP53 and RB1 Mutations. (ID 12513)

      13:55 - 14:00  |  Presenting Author(s): Michael Offin  |  Author(s): Megan Tenet, Ronglai Shen, Natasha Rekhtman, Hira Rizvi, Matthew D. Hellmann, Maria E Arcila, Marc Ladanyi, Charles M. Rudin, Mark G Kris, Helena Yu

      • Abstract
      • Presentation
      • Slides

      Background

      20% of patients with metastatic lung adenocarcinoma have activating EGFR-mutations. EGFR-mutant lung cancers can undergo histologic transformation to small cell lung cancer (SCLC) as a response to the selective pressure of EGFR-TKIs in <5% of patients after earlier-generation EGFR-TKIs and have been reported after osimertinib. SCLC nearly universally harbor TP53/RB1-alterations which are rarely seen in EGFR-mutant lung adenocarcinomas. We sought to identify this subset of patients, describe their clinical course and likelihood of SCLC transformation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective review of targeted next generation sequencing (NGS, MSK-IMACT) at Memorial Sloan Kettering (MSK) was performed to identify patients with concurrent EGFR-activating mutations and TP53/RB1-mutations within the same tumor sample from NGS between April 2014 to February 2018 with a data cutoff of March 2018. For comparison, consecutive patients with lung cancers harboring EGFR-mutations who were EGFR-TKI naïve and TP53/RB1-wildtype were also collected during that time-period.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 21% of lung cancer patients with activating EGFR-mutations (759/3662), 5% (40/759) had concurrent TP53/RB1-mutations. 43% (17/40) were female, 58% former-smokers (23/40, median pack-years: 8), and median age of 68 (range 25-86 years). 88% (35/40) were adenocarcinoma at diagnosis, of which 11% (4/35) transformed to SCLC during treatment; 10% (4/40) were de-novo SCLC at diagnosis, and 1 was large cell neuroendocrine. The transformation rate was significantly higher compared to previous work from MSK evaluating EGFR-mutant patients showing 4% (4/155) transformation (p=0.04). Concurrent PIK3CA mutations were more frequently seen in the EGFR/TP53/RB1 mutant group compared to the TP53/RB1-wildtype group (17% (n=6/35) vs 7% (n=4/60), p=0.11). 20 patients were EGFR TKI-naïve at the time of NGS; the median time on EGFR-TKI (ToT) was 7.6 months versus 14.2 months in the TP53/RB1-wildtype group (HR 4.48, p=0.0003). The overall survival (OS) of this cohort versus TP53/RB1-wildtype was not different (4.3 vs 4.1 years, HR 1.35, p=0.51). In the 4 patients with SCLC transformation, the median time to transformation was 2.4 years after a median of 1.5 EGFR-TKI therapies (range 1-5 lines). Median OS from time of transformation was 7 months. 63% (25/40) of the EGFR/TP53/RB1-mutant cohort had brain metastases during their disease course as compared to 50% (n=30) in the TP53/RB1-wildtype group (p=0.30).

      8eea62084ca7e541d918e823422bd82e Conclusion

      SCLC transformation is enriched in EGFR/TP53/RB1-mutant lung cancers, occurring in 11% of patients. Once SCLC transformation occurs, overall survival is short. Patients with EGFR/TP53/RB1 have a shorter time on EGFR-TKI. Further investigation into optimal treatment for this subset of EGFR/TP53/RB1 mutant lung cancers is critical.

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      MA16.05 - MET Kinase Domain Rearrangements (KDRE) in Non-Small Cell Lung Cancer (NSCLC) Identified Through Comprehensive Genomic Profiling (CGP) (ID 13401)

      14:00 - 14:05  |  Presenting Author(s): Sai-Hong Ignatius Ou  |  Author(s): Alexa B Schrock, Dean Pavlick, Mark Rosenzweig, Rachel L Erlich, Lee A Albacker, Garrett M Frampton, Jeffrey S. Ross, Vincent A Miller, Siraj M Ali

      • Abstract
      • Presentation
      • Slides

      Background

      MET is a known oncogenic driver in NSCLC, and activation via various means including gene amplification, exon 14 skipping, and fusion has been reported to be targetable in the clinical setting. However, the prevalence and characteristics of NSCLCs harboring MET kinase fusions as well as diverse KDRE have not been comprehensively assessed.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Hybrid-capture based CGP was performed on 32,643 FFPE or 3,076 blood-based ctDNA NSCLC specimens during the course of clinical care. Tumor mutational burden (TMB) was determined on 0.83-1.1 megabases (Mb) of sequenced DNA and is reported as mutations/Mb.

      4c3880bb027f159e801041b1021e88e8 Result

      In 35,719 unique NSCLC patient cases assayed, RE retaining the MET kinase domain were detected in 63 (0.2%) cases. These included MET fusions with an identified 5’ fusion partner (n=8, 12.7%), probable MET fusions with an unidentified fusion partner (n=32, 50.8%), MET kinase domain duplications (KDD, n=7, 11.1%), MET exon 14 skipping rearrangements (n=6, 9.5%), and MET rearrangements of the 5’ terminus (n=10, 15.9%). Fusion partners identified include CAPZA2 (2 cases), CAV2, CD47, INPPL1, LHFPL3, PRKAR2B and SPECC1. MET kinase-inactivating rearrangements were also detected in the larger cohort (n=10, 0.03%). MET KDRE cases harbored at least one targetable NSCLC NCCN guidelines driver alteration in 27.0% (n=17) of cases including EGFR activating subs (L858R, L861Q) or exon 19 deletions (n=8), MET exon 14 skipping short variants (n=6), ALK fusions (n=2), and a BRAF V600E mutation. KRAS short variants were detected in 6 additional cases. MET amplification also co-occurred in 36.5% of cases with MET KDRE (n=23, median copy number 16). The median TMB in cases with MET KDRE was 6.1 mut/Mb, as compared to a median of 7.0 mut/Mb for NSCLC samples overall. Clinical treatment information for a subset of cases will be presented, including paired cases in which the MET KDRE may represent an acquired mechanism of resistance to EGFR- or ALK-targeted therapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Potentially targetable MET rearrangements retaining the kinase domain were observed in 0.2% of NSCLCs, which may be an underestimate considering that these assays sequence all MET exons, but do not specifically bait MET intronic breakpoints. These data suggest that MET KDRE, including, but not limited to fusions and KDD, may represent a distinct subset of driver alterations and potential resistance mechanisms. The value of testing for and potentially targeting these alterations as part of routine clinical care in NSCLC warrants further investigation.

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      MA16.06 - EGFR Clonality and Tumor Mutation Burden (TMB) by Circulating Tumor DNA (ctDNA) Sequencing in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13146)

      14:05 - 14:10  |  Presenting Author(s): Xinghao Ai  |  Author(s): Yingcheng Lin, Jiexia Zhang, Congying Xie, Anwen Liu, Xiaohua Hu, Qiong Zhao, Yuansheng Zang, Chuangzhou Rao, Xiaohua Hu, Lianpeng Chang, Qin Li, Yanfang Guan, Rongrong Chen, Xin Yi, Shun Lu

      • Abstract
      • Presentation
      • Slides

      Background

      TKI has significantly improved survival time of NSCLC pts with sensitive mutation. However, pts present different outcome while receiving TKI treatment. We conduct a prospective multicenter clinical trial to determine whether clonality of sensitive mutation is related to the efficacy of TKI. We also evaluate the consistency of TMB between tissue and blood in this cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve pts with advanced NSCLC. DNA was sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR mutation was defined if EGFR mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR mutation. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3 % and ≥0.5 %, respectively. TMB-high pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).

      4c3880bb027f159e801041b1021e88e8 Result

      During February 2017 to April 2018, 127 advanced NSCLC pts were enrolled from 9 centers. A total of 653 somatic variations were detected in tissues. Mutations occurred most frequently in EGFR (57 %), TP53 (54 %), KRAS (9 %), ALK (8 %). In matched plasma, 405 (62 %) tumor-derived mutations were detected by pan-caner panel sequencing. A total of 90 EGFR mutations were detected in 73 pts, most of which occurred in tyrosine kinase domain (L858R, 41%; Ex19del, 33%). Most EGFR mutation were clonal in tissue and plasma, with a consistence of 83 % in paired samples. In addition, bTMB was significantly correlated to tTMB (Pearson r= 0.85, p-value= 1.8e-30), with a consistence of 89 %. Interestingly, high TMB was observed in a small fraction of patients (8 %) with driver mutations, such as mutations in EGFR, ALK fusion, ERBB2 and PIK3CA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Deep sequencing with the pan-cancer panel can effectively detect mutations and evaluate TMB in both tissue and blood with high consistence. EGFR mutations can be clonal or subclonal in both tissue and blood. Prospective multicenter study is ongoing to determine the EGFR clonality as a predictive factor for the TKI efficacy in NSCLC (TRACELib-NSCLC, NCT03059641).

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      MA16.07 - Discussant - MA 16.04, MA 16.05, MA 16.06 (ID 14646)

      14:10 - 14:25  |  Presenting Author(s): Ben J Solomon

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA16.08 - Clinical Utility of Detecting ROS1 Genetic Alterations in Plasma (ID 13522)

      14:25 - 14:30  |  Presenting Author(s): Ibiayi Dagogo-Jack  |  Author(s): Rebecca J Nagy, Lorin A Ferris, Jessica Jiyeong Lin, Justin F Gainor, Richard B Lanman, Alice T. Shaw

      • Abstract
      • Presentation
      • Slides

      Background

      ROS1-rearranged lung cancer harbors an oncogenic fusion protein created by the juxtaposition of the ROS1 gene to various fusion partners. Due to the lack of a conserved breakpoint and inclusion of intronic segments, ROS1 rearrangements can be challenging to identify with DNA-based sequencing approaches. The feasibility and clinical utility of detecting ROS1 fusions in circulating tumor DNA is not well established.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The Guardant360 de-identified database was queried to identify lung cancer cases with plasma ROS1 fusions and describe the molecular features of the ROS1-rearranged cohort. In addition, we performed longitudinal analysis of plasma specimens from four patients at our institution who were treated with next-generation ROS1 inhibitors after progressing on crizotinib.

      4c3880bb027f159e801041b1021e88e8 Result

      From review of 24,009 plasma specimens from lung cancer patients, we identified 56 patients with ROS1 fusions. CD74 was the most common of 7 identified fusion partners [n=35 (62%) CD74, n=7 (12.5%) SDC4, n=7 (12.5%) EZR, n=3 (5%) TPM3, n=2 (4%) TFG, and n=1 (2%) each of CCDC6 and SLC34A2]. ROS1 fusions commonly co-occurred with TP53 mutations (n=36, 64%) and genes involved in cell-cycle regulation (n=11, 20%) or the WNT/ß-catenin pathway (n=16, 29%). In 4 (80%) of 5 cases where plasma genotyping occurred at crizotinib progression, we identified a putative resistance mechanism, including a ROS1 resistance mutation in 3 patients (n=2 G2032R & n=1 L2026M) and a BRAF V600E mutation in 1 patient. We analyzed longitudinal plasma specimens from 4 patients with crizotinib-resistant lung cancer who were subsequently treated with a next-generation ROS1 inhibitor (n=3 lorlatinib, n=1 entrectinib). One patient treated with lorlatinib had a pretreatment ROS1 G2032R mutation (in plasma and tissue); plasma analysis revealed stability of the G2032R allelic fraction in the setting of primary progression of pleural disease. Of the 2 patients without pretreatment ROS1 mutations who received lorlatinib, one developed a ROS1 G2032R mutation after initial response to treatment. The second patient experienced primary progression and plasma genotyping revealed low level FGFR1 copy number gain (3.3 copies); pre-crizotinib plasma was not available for comparison. One patient had a plasma PIK3CA E545K mutation at the time of crizotinib progression, and did not respond to next-line entrectinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Next-generation sequencing can be used to detect ROS1 fusions and resistance mutations in plasma. Longitudinal plasma analysis may provide insight into the activity of investigational drugs against ROS1 mutations that mediate resistance to crizotinib.

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      MA16.09 - Feasibility, Clinical Relevance of ALK/ROS1 Fusion Variant Detection by Liquid Biopsy in Advanced Non-Small Cell Lung Cancer (ID 13492)

      14:30 - 14:35  |  Presenting Author(s): Aurélie Swalduz  |  Author(s): Laura Mezquita, Sandra Ortiz-Cuaran, Cecile Jovelet, Virginie Avrillon, David Planchard, Solène Marteau, Gonzalo Recondo, Séverine Martinez, Karen Howarth, Vincent Plagnol, Clive Morris, Emma Green, Luc Odier, Ludovic Lacroix, Stéphane Hominal, Etienne Rouleau, Claire Tissot, Caroline Caramella, Pierre Fournel, Luc Friboulet, Maurice Pérol, Benjamin Besse, Pierre Saintigny

      • Abstract
      • Presentation
      • Slides

      Background

      Liquid biopsy offers an alternative non-invasive approach to reflect the tumor genomic landscape of NSCLC patients; however, the potential of liquid biopsies for ALK/ROS1 fusion detection is poorly described. Herein, we evaluated an amplicon-based NGS assay for ctDNA detection of ALK and ROS1 fusions in a large cohort of ALK and ROS1 NSCLC patients and correlation of variants with clinical data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      ALK- and ROS1-translocated advanced NSCLC patients, were prospectively enrolled from October 2015 to April 2018 in 9 French institutions. ALK or ROS1 positivity was as confirmed by immunochemistry and FISH or RNAseq. ALK (EML4 variants v1, v2, v3), ROS1 (CD74, SLC34A2, SDC4 and EZR) fusions, and mutations in a panel of 36 NSCLC-associated genes were investigated in ctDNA using InVisionFirst™ (Plagnol V PLoS ONE, 2018).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 120 patients were included: 96 ALK and 24 ROS1. 30 samples were collected from patients who were TKI-treatment-naive, 257 during follow-up and 73 at progressive disease (PD) under TKI. The median age was 55 years-old (range 23-75); most patients were female (57%) and had a non-smoking history (59%). At diagnosis, 20% of patients presented with brain metastasis. All patients received at least 1 ALK-TKI (median: 1.6; range:1-6).

      Preliminary results are available for the first 54 patients: 21 at diagnosis and 33 at PD under TKI. ALK/ROS1 fusions were detected in 13/21 patients (62%) at diagnosis: 12/20 ALK-fusions (7 v1, 2 v2 and 3 v3) and in 1/1 ROS1-fusion (CD74-ROS1). No fusion was detected in 8 patients, which may be due to partner genes or variants not covered by this panel. However, 5 of these 8 patients had exclusive thoracic or brain PD.

      Liquid biopsies collected at the radiographic evaluation under therapy revealed complete ctDNA clearance of the fusion when patients experienced PR (n=4). In samples at PD, fusion was detected in 44% of patients (24/55) with evidence of acquired resistance in patients both positive and negative for fusion.

      Results for the remaining samples, correlation between fusion variant and survival, fusion variant and mechanism of resistance will be presented at the Congress.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results suggest that ctDNA profiling is a promising non-invasive tool for identification of ALK/ROS1 fusions and monitoring of response in advanced NSCLC patients. Systematic identification of the fusion partner may help to better understand the heterogeneity and evolution (sensitivity profile to targeted inhibitors and associated-mechanisms of resistance) of NSCLC driven by ALK and ROS1 rearrangement.

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      MA16.10 - Clinical Utility of Cerebrospinal Fluid Cell-Free DNA for Clarifying Genetic Features of Leptomeningeal Metastases in ALK Rearrangement NSCLC (ID 12142)

      14:35 - 14:40  |  Presenting Author(s): Meimei Zheng  |  Author(s): Yangsi Li, Ben-Yuan Jiang, Hai-Yan Tu, Xu-Chao Zhang, Jun-Yi Ye, Wen-Fang Tang, Shannon Chuai, Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Leptomeningeal metastases (LM) were associated with a poor prognosis in non small cell lung cancer (NSCLC). LM were much more frequent in EGFR mutant patients, and cerebrospinal fluid (CSF) cell-free DNA (cfDNA) has shown unique genetic profiles of LM in patients harboring EGFR mutations in our previous studies. However, studies in ALK positive NSCLC patients with LM are scarce.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Lung cancer patients with ALK rearrangement were screened from Sept 2011 to Feb 2018 at our institute. Leptomeningeal metastases were diagnosed by MRI or CSF cytology or next-generation sequencing (NGS) of CSF cfDNAs. Paired plasma were also tested by NGS.

      4c3880bb027f159e801041b1021e88e8 Result

      LM were diagnosed in 22 (7.6%) of 288 ALK rearrangement patients with lung cancer. A total of 11 ALK positive patients with LM were enrolled with CSF cfDNA tested by NGS (one case used CSF precipitates instead of CSF cfDNA). Paired plasma were available in 11 patients. Driver genes were detected in 75.0% CSF samples and 45.5% plasma respectively (P=0.214). Max allele fractions were higher in CSF cfDNA than in plasma (40.8% versus 0%, P=0.021). ALK variant 1 (E13:A20) was detected in 3 cases of CSF and paired plasma, respectively. ALK variant 2 (E20:A20) was identified in 5 cases of CSF and 1 paired plasma. Multiple copy number variants (CNV) were mainly found in CSF cfDNA, including EGFR copy number gains. Resistance mutations including gatekeeper gene ALK G1202R was identified in CSF cfDNA with ALK variant 1 and ALK G1269A was detected in plasma. The detection rate of TP53 was 45.4% versus 27.3% in CSF cfDNA and plasma.

      figures.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      CSF cfDNA was more sensitive than plasma to reveal genetic features of ALK-fusion LM, confirming its role as a liquid biopsy medium for LM in driver gene positive NSCLC.

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      MA16.11 - Discussant - MA 16.08, MA 16.09, MA 16.10 (ID 14647)

      14:40 - 14:55  |  Presenting Author(s): Robert C. Doebele

      • Abstract
      • Presentation
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      Abstract not provided

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    MA25 - Oligometastasis: Defining, Treating, and Evaluating (ID 929)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Oligometastatic NSCLC
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 203 BD
    • +

      MA25.01 - EORTC Lung Cancer Group Survey to Define Synchronous Oligometastatic Disease in NSCLC (ID 13770)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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      MA25.03 - Defining Oligometastatic Non-Small Cell Lung Cancer (NSCLC): An Evolving Multidisciplinary Expert Opinion (ID 12573)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      table 1
      Case TNM8

      oligometastatic

      yes answer %

      2012 / 2017

      Number of tx

      proposals

      2012 / 2017

      Radical tx

      answers %

      2012/2017

      Real life radical

      tx intent

      real life survival

      (months) /

      5Y survival

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

      Summary of consensus statement

      Defining sOMD-NSCLC

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

      All sites must be technically and safely treatable.

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

      Diffuse serosal metastases and bone marrow involvement are excluded.

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

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

      Staging of sOMD-NSCLC

      PET-CT and brain imaging are considered mandatory.

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

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

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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      MA25.04 - Discussant - MA 25.01, MA 25.02, MA 25.03 (ID 14600)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA25.05 - Characteristics &amp; Survival of Resected Stage IV Non-Small Cell Lung Cancer (NSCLC) in the Mid-South Quality of Surgical Resection Cohort (ID 13381)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

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

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

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

      image001.png

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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      MA25.06 - RPA Analysis for Oligometastatic Non-Small Cell Lung Cancer: Smoking Combine T3/4 Patients May Not Be Benefit from Local Consolidative Treatment (ID 11994)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      fig.png

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.07 - Effectiveness of Systemic Therapy Combined with Thoracic Radiotherapy for Patients with Oligometastatic NSCLC: A Pooled Analysis (ID 12572)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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      MA25.08 - Discussant - MA 25.05, MA 25.06, MA 25.07 (ID 14602)

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

      • Abstract
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      Abstract not provided

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      MA25.09 - M1b Disease in the 8th Edition of IASLC Staging of Lung Cancer: Pattern of Single Extrathoracic Metastasis and Clinical Outcom (ID 11942)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

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      MA25.10 - Complete Response by PET-CT After Radical Treatment in Oligometastatic Non-Small Cell Lung Cancer Predicts Longer Survival   (ID 14232)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.11 - Clinical and Molecular Predictors of Outcome in Patients with EGFR mutant NSCLC Brain Metastases treated with RT (ID 14529)

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      a9ded1e5ce5d75814730bb4caaf49419 Method

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

      4c3880bb027f159e801041b1021e88e8 Result

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

      8eea62084ca7e541d918e823422bd82e Conclusion

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA25.12 - Discussant - MA 25.09, MA 25.10, MA 25.11 (ID 14603)

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

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      Abstract not provided

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    MS03 - New Frontiers in Oligometastases (ID 782)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Oligometastatic NSCLC
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 203 BD
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      MS03.01 - The Biology of Oligometastases: What Have We learned? (ID 11410)

      10:30 - 10:45  |  Presenting Author(s): David Palma

      • Abstract
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      Abstract not provided

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      MS03.02 - Biomarkers in Oligometastatic Patients i. Monitoring Diseases Response - Imaging vs Serum (ID 11411)

      10:45 - 11:00  |  Presenting Author(s): Max Diehn

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      Abstract not provided

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      MS03.03 - Investigations into Alternative Clinical Endpoints for OM Beyond Survival (ID 11412)

      11:00 - 11:15  |  Presenting Author(s): Alexander Louie

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      Abstract not provided

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      MS03.04 - Treatment of Oligoprogression: Real Progress or False Hope? (ID 11413)

      11:15 - 11:30  |  Presenting Author(s): Fiona McDonald

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      Abstract not provided

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      MS03.05 - Integration of Immunotherapy in the Oligometastatic Paradigm (ID 11414)

      11:30 - 11:45  |  Presenting Author(s): Shankar Siva

      • Abstract
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      Abstract not provided

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    MTE02 - Update on WHO Classification and Staging of Lung Cancer (Ticketed Session) (ID 812)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Pathology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 203 BD
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      MTE02.01 - Update on WHO Classification and Staging of Lung Cancer (ID 11548)

      07:00 - 07:30  |  Presenting Author(s): Sanja Dacic

      • Abstract
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      Abstract not provided

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      MTE02.02 - Update on WHO Classification and Staging of Lung Cancer (ID 11549)

      07:30 - 08:00  |  Presenting Author(s): Teh-Ying Chou

      • Abstract
      • Presentation
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      Abstract not provided

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    MTE11 - Biology of Small Cell Lung Cancer (Ticketed Session) (ID 821)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Biology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 203 BD
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      MTE11.01 - Novel Therapeutic Targets in SCLC (ID 11564)

      07:00 - 07:30  |  Presenting Author(s): Julien Sage

      • Abstract
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      Abstract not provided

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      MTE11.02 - Biological Subsets of SCLC (ID 11565)

      07:30 - 08:00  |  Presenting Author(s): Charles M. Rudin

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      Abstract not provided

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    MTE24 - Multiple Lung Nodules; Resect, Radiate or Watch? (Ticketed Session) (ID 834)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/26/2018, 07:00 - 08:00, Room 203 BD
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      MTE24.01 - Surgery vs SABR for Early NSCLC (ID 11589)

      07:00 - 07:30  |  Presenting Author(s): Thomas A. D'Amico

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      Abstract not provided

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      MTE24.02 - Small Lung Tumours: High Risk Lesions and Contraindications to Stereotactic Ablative Body Radiotherapy (SABR) (ID 11590)

      07:30 - 08:00  |  Presenting Author(s): David L Ball

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      Abstract not provided

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    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 8
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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      OA13.01 - The Impact of [<sup>18</sup>F]fludeoxyglucose PET/CT in Small-Cell Lung Cancer: Analysis of the Phase 3 CONVERT Trial  (ID 13319)

      10:30 - 10:40  |  Presenting Author(s): Corinne Faivre-Finn  |  Author(s): Prakash Manoharan, Ahmed Salem, Hitesh Mistry, Michael Gornall, Susan V Harden, Peter Julyan, Imogen Locke, Jonathan McAleese, Rhona McMenemin, Nazia Mohammed, Michael Snee, Thomas Westwood, Sarah Woods

      • Abstract
      • Presentation
      • Slides

      Background

      The role of 18fludeoxyglucose (18F-FDG) PET/CT in the management of limited stage small-cell lung cancer (LS-SCLC) is uncertain. Previous studies have shown that 18F-FDG PET/CT upstages up to 30% of LS-SCLC patients. Data from the CONVERT trial was analysed to investigate the impact of 18F-FDG PET/CT in the management of LS-SCLC. The prognostic significance of pre-treatment 18F-FDG PET parameters was also investigated in an exploratory analysis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CONVERT is an international multi-centre phase III trial that randomly assigned fit patients to receive either twice-daily (45Gy in 30 fractions) or once-daily (66Gy in 33 fractions) radiotherapy starting on day 22 of chemotherapy cycle 1 (NCT00433563). Chemotherapy consisted of 4-6 cycles of cisplatin and etoposide. Prophylactic cranial irradiation was offered, if indicated. Contrast-enhanced thorax and abdomen CT and brain imaging (with/without bone scintigraphy according to clinical indication) were mandated for all CONVERT participants (conventional imaging). Staging with 18F-FDG PET/CT was allowed but not mandated. The primary endpoint was overall survival. Pre-treatment 18F-FDG PET metabolic parameters were investigated in a subset of patients (n=96) including standardised uptake values (max, mean and peak), volumetric and heterogeneity parameters.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 547 patients recruited to CONVERT, 540 patients with data on staging investigations and outcome were included in this analysis. The use of staging 18F-FDG PET/CT was variable in the 8 countries recruiting to CONVERT (range, 41-100%). Compared to patients who underwent conventional imaging (n=231), patients who were also staged with 18F-FDG PET/CT (n=309) had smaller gross tumour volume (p=0·003), were less likely to have elevated pre-treatment serum lactate dehydrogenase (p=0·035), and received more chemotherapy cycles (p=0·026). There were no other significant differences in baseline and treatment characteristics between the two groups. There were no significant differences in overall (hazard ratio 0·87 [95% CI 0·70-1·08]; p=0·192) and progression-free survival (hazard ratio 0·87 [95% CI 0·71-1·07]; p=0·198) between patients staged with 18F-FDG PET/CT in addition to conventional imaging or with conventional imaging alone. These results were observed irrespective of treatment group (once-daily and twice-daily radiotherapy). Pre-treatment 18F-FDG PET parameters were also not prognostic.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In CONVERT, survival outcomes were not different in LS-SCLC patients staged with or without 18F-FDG PET/CT. This was despite those patients staged with 18F-PET/CT having more favourable baseline and treatment characteristics. Our findings suggest that conventional imaging is sufficient to select LS-SCLC patients for concurrent chemoradiotherapy.

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      OA13.02 - Two Novel Immunotherapy Agents Targeting DLL3 in SCLC: Trials in Progress of AMG 757 and AMG 119 (ID 14538)

      10:40 - 10:50  |  Presenting Author(s): Taofeek Owonikoko  |  Author(s): Marie-Anne Damiette Smit, Hossein Borghaei, Ravi Salgia, Michael Boyer, Erik R. Rasmussen, Lauren Byers

      • Abstract
      • Presentation
      • Slides

      Background
      Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by initial response to chemotherapy and radiotherapy followed by relapse or progression with chemoresistant disease. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is specifically upregulated in SCLC. IHC profiling of tumor samples showed DLL3 expression in 86% of SCLC tumors and minimal expression in normal tissue.
      We are conducting clinical trials of two novel immunotherapy agents that target DLL3. AMG 757 is a half-life extended bispecific T cell engager (BiTE®) antibody construct that is designed to transiently crosslink DLL3-positive SCLC cells to CD3-positive T cells and induce T cell–mediated tumor cell lysis and concomitant T cell proliferation. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane chimeric antigen receptor that targets DLL3 on the surface of SCLC cells. Both AMG 119 and AMG 757 showed potent killing of SCLC cell lines with a broad range of DLL3 expression in vitro and inhibition of tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose GLP toxicology study, with no evidence of tissue damage at weekly doses as high as 4.5 mg/kg.
      a9ded1e5ce5d75814730bb4caaf49419 Method
      NCT03319940 is an open label, phase 1 study evaluating the safety, tolerability and pharmacokinetics of AMG 757 that will initially enroll adult patients with SCLC who have progressed or recurred following platinum-based chemotherapy. Key inclusion criteria: ECOG PS 0–2, life expectancy ≥12 weeks, at least 2 measurable lesions per modified RECIST 1.1 criteria, and adequate organ function. The study will later enroll patients with extended disease SCLC with ongoing clinical benefit following no more than 6 cycles of first-line platinum-based chemotherapy. AMG 757 will be administered as an intravenous infusion once every 2 weeks.
      NCT03392064 is an open-label, phase 1 study evaluating the safety, tolerability and efficacy of AMG 119 in adult patients with SCLC whose disease has progressed or recurred after at least one platinum-based regimen. Key inclusion criteria: ECOG PS 0–1, at least 2 measurable lesions per modified RECIST 1.1 criteria, no evidence of CNS metastasis, and adequate organ function. AMG 119 will be administered as a one-time intravenous infusion.
      Both of these studies are currently enrolling patients. For more information, please contact Amgen Medical Information: medinfo@amgen.com.
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      OA13.03 - Anlotinib as Third-Line or Further-Line Treatment in Relapsed SCLC: A Multicentre, Randomized, Double-Blind Phase 2 Trial (ID 12102)

      10:50 - 11:00  |  Presenting Author(s): Ying Cheng  |  Author(s): Qiming Wang, Kai Li, Jianhua Shi, Lin Wu, Baohui Han, Gongyan Chen, Jianxing He, Jie Wang, Haifeng Qin, Xiaoling Li

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment for patients with relapsed small cell lung cancer (SCLC) who failed ≥ 2 lines of chemotherapy have high unmet needs. Anlotinib is a novel TKI with highly selective inhibition effects on multi-targets, especially on VEGFR, c-Kit, PDGFR, FGFR. Here we report results of a phase 2 study of anlotinib for the third-line and further-line treatment of SCLC. (ALTER1202, NCT03059797).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible either limited- or extensive-stage SCLC patients with disease progression after ≥ 2 lines of chemotherapy were randomized 2:1 to anlotinib or placebo (12 mg PO QD from day 1 to 14, every 3 weeks). The primary endpoint was PFS and secondary endpoints was OS, ORR, DCR, quality of life and safety.

      4c3880bb027f159e801041b1021e88e8 Result

      Between March 2017 and May 2018, 120 patients from 11 centers were randomized to either anlotinib arm (n=82) or placebo arm (n=38). Until the data cutoff date (30 Jun 2018), median PFS was 4.1 months (95%CI, 2.8 to 4.2 months) in anlotinib arm and 0.7 months (95% CI, 0.7 to 0.8 months) in placebo arm (HR, 0.19; 95% CI, 0.12 to 0.32, p<0.0001). OS data were not sufficiently mature for analysis. Although ORR was similar, considerable improvement in DCR was observed in anlotinib arm (71.6% vs 13.2%, p<0.0001). Treatment-related adverse events (TRAEs) occurred more frequently in anlotinib arm than that in placebo (87.7% and 74.4%). The most common TRAEs were hypertension, anorexia, fatigue, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 29 (35.8%) of patients in anlotinib arm and 6 (15.4%) in placebo arm, respectively.

      figure 1 kaplan-meier estimates of progression-free survival.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      ALTER 1202 study demonstrates anlotinib should be considered a treatment option for patients with relapsed SCLC who have experienced treatment failure with two lines of chemotherapy. The safety profile was consistent with the previous report and no newly adverse events were identified.

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      OA13.04 - Discussant - OA 13.01, OA 13.02, OA 13.03 (ID 14570)

      11:00 - 11:15  |  Presenting Author(s): Normand Blais

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA13.05 - Prophylactic Cranial Irradiation (PCI) for Limited-Stage Small-Cell Lung Cancer: Results from the Phase 3 CONVERT Trial (ID 13762)

      11:15 - 11:25  |  Presenting Author(s): Cecile Le Pechoux  |  Author(s): Antonin Levy, Hitesh Mistry, Isabelle Martel-Lafay, Andrea Bezjak, Delphine Lerouge, Laetitia Padovani, Paul Taylor, Corinne Faivre-Finn

      • Abstract
      • Presentation
      • Slides

      Background

      PCI is considered standard of care in limited-stage small-cell lung cancer (LS-SCLC) patients. However the impact of the dose and fractionation of thoracic radiotherapy (RT) on the risk of developing brain metastasis (BM) has not been evaluated prospectively.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      CONVERT is an international, phase 3 trial that randomly assigned patients to receive twice-daily (BD 45Gy in 30 fractions) or once-daily (OD 66Gy in 33 fractions) RT starting on day 22 of chemotherapy (CT) cycle 1 (NCT00433563). PCI was offered, if indicated. Data on thoracic and brain RT delivery and timing, rate of BM and overall survival (OS) in patients treated with PCI was analysed. The association of the risk of developing BM/OS and predictor variables, using a competing risk regression model developed by Fine and Gray for BM or the standard Cox proportional hazards model for OS, was investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 547 patients recruited to the study, 449 (82%) received PCI after completion of CTRT. PCI was delivered to 220/273 participants (81%) in the BD group and 229/270 in the OD group (85%; p=0.49). Pre-CTRT brain imaging consisted of CT-scan in 356/449 patients (79%) and MRI in 83/449 (18%) patients. Total median PCI dose was 25 Gy in both BD and OD groups (p=0.74). PCI was delivered later after CT in the OD group compared to the BD group (median days post CT 37 vs. 35 days, respectively; p=0.04). In patients who received PCI, 75 (17%) developed BM (35 [8%] in OD and 40 [9%] in BD) and 173 (39%) other extracranial progression. In the univariate analysis, GTV was associated with an increased risk of BM (HR: 1.37 [95%CI 1.09-1.73]; p=0.007) or other radiological progression events (HR: 1.43 [95%CI 1.11-1.85]; p=0.006), whereas in a multivariate analysis both GTV and PS were associated with either progression type. The median OS of patients treated with PCI was 29 months (95%CI 25.8-35.7). Median OS was 28 months in BD (95%CI 22-35) and 31 months in OD (95%CI 27-52; p=0.1). In the univariate analysis of OS, PCI timing from end of CT, weight loss >10%, and thoracic GTV were prognostic factors associated with OS. In the multivariate analysis, only thoracic GTV was associated with OS. Delay between end of CT and PCI was not associated with OS (p=0.2).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Patients receiving OD or BD thoracic RT have the same risk of developing BM. Larger tumours are associated with a higher risk of BM.

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      OA13.06 - Final Report of a Prospective Randomized Study on Thoracic Radiotherapy Target Volumes in Limited-stage Small Cell Lung Cancer with Radiation Dosimetric and Pathologic Analyses (ID 11970)

      11:25 - 11:35  |  Presenting Author(s): Xiao Hu  |  Author(s): Yong Bao, Yu Jin Xu, Hui Neng Zhu, Jin Shi Liu, Li Zhang, Xinmin Yu, Yun Fan, Yi Ping Zhang, Wen Yong Sun, Weimin Mao, Ming Chen

      • Abstract
      • Presentation
      • Slides

      Background

      The interim analysis of our prospective trial, which compared irradiation to pre-chemotherapy or post-chemotherapy tumour extent while application of involved field radiotherapy (IFRT) for limited-stage small cell lung cancer (SCLC), showed that reduced field did not result in increased local/regional out-field recurrence. This report presents the final results of the clinical study with radiation dosimetric and pathologic analysis as interpretations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Chemotherapy consisted of 4 to 6 cycles of etoposide and cisplatin (EP). After 2 cycles of EP, patients were randomly assigned to receive thoracic radiotherapy (TRT) to either the post- or pre-chemotherapy tumour extent as study arm or control. TRT was administered concurrently with cycle 3 chemotherapy. IFRT was applied for both arms. The lymph node regions (groups 1 to 10) were contoured in treatment planning system. The intentional or incidental radiation doses to each lymph node regions were recorded. Patients with stage T1-2N0-1M0 SCLC received radical lobectomy. The minimal distances between microscopic nidus and the edge of gross tumor were measured. The clinical target volume of the primary tumor (CTV-T) was defined as the margins covering 95% of microscopic disease extension.

      4c3880bb027f159e801041b1021e88e8 Result

      Between June, 2002 and January, 2017, 159 and 150 patients were randomly assigned to study arm or control. The 1-, 3-, and 5-year local/regional progression free probability were 79.4%, 60.1% and 60.1% respectively in the study arm versus 79.8%, 64.5%, and 57.3% in the control (p=0.73). The median overall survival (OS) time was 22.1 months in the study arm (95% CI, 18.2-26.0) and 26.9 months (95% CI, 23.5-30.3) in the control, the 1-, 3-, 5-, and 7-year OS rates were 81.1%, 31.6%, 23.9% and 22.2% respectively in the study arm versus 85.3%, 36.6%, 26.1% and 20.0% in the control arm (p=0.51). A total of 1680 lymph node regions in 105 patients were contoured. The lymph node regions that received incidental radiation doses over 30Gy were: 7, 3P, 4L, 6, 4R, 5 and 2L. Eight patients were enrolled in the pathologic evaluation of CTV-T. The median range of CTV-T in patients received or did not receive neoadjuvant chemotherapy were 0.4mm and 1.7mm respectively, a margin of 1.4mm and 10.2mm could cover 95% of microscopic nidus extension respectively (p=0.00).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Irradiating post-chemotherapy tumour extent and applicant of IFRT didn't increase local/regional failure, and the OS difference wasn't statistically significant between the two arms. TRT could be limited to post-chemotherapy tumour extent, while IFRT could be routinely applied for limited-stage SCLC patients.

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      OA13.07 - Survival Outcomes After Whole Brain Radiotherapy for Brain Metastases in Elderly Patients with Newly Diagnosed Metastatic Small Cell Carcinoma. (ID 13900)

      11:35 - 11:45  |  Presenting Author(s): Paul Renz  |  Author(s): Shaakir Hasan, Andrew Turrisi Iii, Athanasios Colonias, Rodney Wegner

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive malignancy with a tendency to affect the elderly and to metastasize to the brain. However, elderly patients tolerate whole brain radiotherapy (WBRT) poorly with potentially detrimental effects on quality of life. Accordingly, the survival benefit of WBRT in this population is unclear. We utilized the national cancer database (NCDB) to evaluate the survival outcomes following WBRT in elderly patients with SCLC and brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We analyzed 1615 patients >75 years old diagnosed with SCLC and brain metastases at diagnosis. Patients were categorized by type of therapy: chemotherapy + WBRT (n=576), chemotherapy alone (n=238), WBRT alone (n=360) and no chemotherapy or WBRT (n=441). Clinical and demographic characteristics were reported for each treatment cohort with a subsequent multivariable regression analysis for survival. Propensity score-matching analysis was used for balance between comparison groups.

      4c3880bb027f159e801041b1021e88e8 Result

      Median patient age was 79 years. 51% had brain-only metastatic disease. Whole brain radiation median dose delivered was 30 Gy (1.8-40 Gy). Median follow up was 2.8 months (0.03-68.01) for all patients. Of the patients included in this study, 1530 had died at time of analysis yielding a median OS of 2.9 months with 6 month and 1 year survivals of 31% and 12%, respectively.

      For patients without chemotherapy, median OS with WBRT was 1.9 months compared to 1.2 months without WBRT (p<0.0001). For patients receiving chemotherapy with, and without WBRT, median OS was 5.6 months and 6.4 months, respectively (p=0.43). Multivariable cox regression revealed age >80, extracranial disease, male sex, and rural location as predictors of increased risk of death.

      figure 1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      In elderly patients 75 years old or greater with SCLC brain metastasis, WBRT was associated with a modest increase in survival in patients not fit for chemotherapy, and there was no association with increased survival over chemotherapy alone.

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      OA13.08 - Discussant - OA 13.05, OA 13.06, OA 13.07 (ID 14571)

      11:45 - 12:00  |  Presenting Author(s): Inga Grills

      • Abstract
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      Abstract not provided

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