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
    • Now Available
    • 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 (Now Available) (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.

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      ES04.02 - Mechanisms of Resistance to Targeted Therapy (Now Available) (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 (Now Available) (ID 11369)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      The use of oral drugs for the treatment of cancer is rising. Over the last two decades, oral antineoplastic agents have increasingly become a primary form of treatment for many cancers. Advances in oral therapies have not only improved outcomes and survival but also have reduced the burden of care by allowing for convenient dosing outside the hospital.1,2,3

      To estimate treatment compliance, it is possible to use some methods, such as: patient self-report, review of patient medical records, family report, residual pill counting, electronic dispensing, prescription refill rates, serum drug, assays to quantify medications or their metabolites and therapeutic outcomes.2

      Despite the notable advantages of using oral medications, there are an array of challenges are created related to patient safety, monitoring of adverse effects, and medication compliance.1,2

      Nonadherence is a problem that has many determinants and the responsibility for compliance has to be shared by health professionals, the health care system and patients. The main factors affecting adherence include, at least, five dimensions: socioeconomic-related factors, health care team/health system-related factors, clinical condition-related factors, treatment-related factors and patient-related factors, as shown in Table 1.²

      Specifically in non-small cell lung cancer (NSCLC), there is a significant fraction of activating-mutations in targetable oncogenes. These include mutations in EGFR (10-40%, depeding on the population)5, BRAF (∼7%)6, and activating gene rearrangements involving ALK7 and ROS1 (1–2%)7, all of which encode protein kinases, and result in hyperactivation of downstream signaling pathways that drive cell growth, proliferation and survival. The identification of these driver kinases has led to the clinical use of oral kinase inhibitors that suppress these oncoproteins such as erlotinib, gefinitib, afatinib and osimertinib which target mutant EGFR; vemurafenib and dabrafenib for mutant BRAF; and crizotinib, ceritinib, alectinib for ALK and/or ROS1 gene rearrangements.

      Although targeted therapy agents of NSCLC are directed against tumor cells, they are still associated with toxicities affecting multiple organs. Overall, the side effects described include skin rash, diarrhea, constipation, eyesight alterations, nausea, edema, fatigue, hypophosphatemia, hypokalemia, bradycardia, neutropenia, increased serum ALT and AST, prolonged Q-T interval on EKG, among others. Some studies show that these factors are the main reason for non-adherence. It has become evident that when those side effects are managed appropriately, patients are more likely to want or be able to adhere to established treatment plans.8.9

      The effects of missed doses significantly increase the probability of developing resistance, such as the T790M mutation, which provides tumor resistance against EGFR targeted drugs, and witch is the most frequent mechanism found in NSCLC5. Therefore, treatment interruptions and non-compliance may lead to undesirable clinical outcomes: increased morbidity, mortality and also increased health care costs. Short interruptions or dose reductions, when medically necessary, may not have a negative impact on disease control.10

      In order to improve compliance, which leads to overcoming resistance and reducing health-related costs, a set of strategies is needed: (1) simplifying the dosage regimen and putting in motion several complex strategies, including: combinations of thorough patient instructions and counseling, reminders, close follow-up, electronic monitoring, supervised self-monitoring, rewards for success, family therapy, couple-focused therapy, psychological therapy, crisis intervention, and manual telephone follow-up; (2) a qualified team acting in the prevention, early identification and management of adverse events; (3) patient awareness and education regarding their treatment; and (4) a health system that facilitate access to oral medications.2,4

      Table 1 - Factors affecting compliance and interventions for improviment.

      Factors

      Interventions to improve adherence

      Socioeconomic

      Optimizing the cooperation between services; assessment of social needs;

      Health care, team/health

      system

      Training of health professionals regarding adherence; support to caregivers; multidisciplinary care; supervision in home setting;

      Poor understanding

      of the disease

      Eduacation regarding adequate use of medications

      Therapy

      Simplification of regimens; education on use of medications; giving clear instructions; patient-tailored prescriptions; side effects management

      Patient

      Education on use of medications; behavioral and motivational intervention; good patient–provider relationship; self-management

      of disease and treatment; selfmanagement of side-effects

      In summary, the number of patients receiving oral chemotherapy is increasing. However, studies have proved that non-adherence to treatment was associated with poor responses in some diseases, and there is an urgent need to develop safe and effective systems to administer and manage these agents. The relationship between noncompliance and outcome in NCLC needs to be better studied.

      REFERENCES:

      1- Greer, J.A., Amoyal, N., Nisotel, L. et al, A Systematic Review of Adherence to Oral Antineoplastic Therapies. The Oncologist, 2016; 21: 354–376.

      2- Adherence to long-term therapies: evidence for action. Geneva, World Health Organization 2003.

      3- Hess L.M., Louder A., Winfree K. et al. Factors Associated with Adherence to and Treatment Duration of Erlotinib Among Patients with Non-Small Cell Lung Cancer. Journal of Managed Care & Specialty Pharmacy, 2017; 23(6): 643-652.

      4- Haynes R.B., Ackloo E., Sahota N. et al. Interventions for enhancing medication adherence. Cochrane Database of Systematic Reviews, 2008.

      5- Cadranel J, Ruppert A, Beau-Faller M, et al.: Therapeutic strategy for advanced EGFR mutant non-small-cell lung carcinoma. Crit Rev Oncol Hematol. 2013; 88(3): 477–93.

      6 - Davies H, Bignell GR, Cox C, et al.: Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892): 949–54.

      7 - Koivunen JP, Mermel C, Zejnullahu K, et al.: EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Rev. 2008; 14(13): 4275–83

      8- Rothenstei, J.M., Letarte, N.. Managing treatment–related

      adverse events associated with Alk inhibitors. Current Oncology. 2014; 21(1): 19-26.

      9 - Hirsh V. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Current Oncology. 2011; 18(3): 126-138.

      10 - Foo J., Chmielecki J., Pao, W. et al. Effects of Pharmacokinetic Processes and Varied Dosing Schedules on the Dynamics of Acquired Resistance to Erlotinib in EGFR-Mutant Lung Cancer. J Thorac Oncol.; 7(10): 1583–1593.

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

      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.

      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).

      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 (Now Available) (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.

      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).

      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

      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 (Now Available) (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.

      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.

      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).

      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 (Now Available) (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 (Now Available) (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.

      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.

      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
      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. (Now Available) (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.

      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.

      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%).

      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.

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      MA08.08 - Discussant - MA 08.05, MA 08.07 (Now Available) (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 (Now Available) (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..

      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.

      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

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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
    • Now Available
    • 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 (Now Available) (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.

      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.

      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

      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 (Now Available) (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.

      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.

      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.

      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) (Now Available) (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.

      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).

      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

      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 (Now Available) (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 (Now Available) (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.

      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.

      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)].

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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.

      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).

      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 (Now Available) (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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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.

      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).

      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 (Now Available) (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
    • Now Available
    • 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 (Now Available) (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.

      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.

      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

      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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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. (Now Available) (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.

      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.

      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).

      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) (Now Available) (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.

      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.

      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.

      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) (Now Available) (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.

      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).

      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.

      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 (Now Available) (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 (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.

      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).

      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.

      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 (Now Available) (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.

      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.

      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

      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 (Now Available) (ID 14647)

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

      • Abstract
      • Presentation
      • Slides

      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
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 203 BD
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      MA25.01 - EORTC Lung Cancer Group Survey to Define Synchronous Oligometastatic Disease in NSCLC (Now Available) (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.

      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.

      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).

      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 (Now Available) (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).

      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.

      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 / -

      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.

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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.

      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).

      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.

      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 (Now Available) (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 (Now Available) (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.

      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.

      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

      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 (Now Available) (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.

      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.

      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).

      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

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

      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.

      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.

      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 (Now Available) (ID 14602)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (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).

      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.

      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).

      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   (Now Available) (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).

      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.

      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).

      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.

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

      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.

      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.

      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.

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

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

      • Abstract
      • Presentation
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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
    • Now Available
    • 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? (Now Available) (ID 11410)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Radiotherapy is a treatment modality commonly used in efforts to manage oligometastatic disease. It is now recognised that radiotherapy does not only directly kill tumour cells, but it also changes the tumour microenvironment, enhancing tumour cell recognition by the immune system, therefore acting as an in situ vaccine. Radiotherapy increases expression of tumour-associated antigens, causes the release of cytokines, stimulates recruitment of dendritic cells and most importantly stimulates the proliferation and priming of cytotoxic CD8+ T-cells in the tumour microenvironment. This immunologic cascade specifically generates activated T-cells able to induce immunogenic cell death directed against cancer cells bearing those antigens. The cellular changes induced by radiotherapy are becoming increasingly important as it is recognised that the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors. The benefit of those agents is limited to patients who have pre-existing active immune microenvironment that can be re-activated by immunotherapeutic agents. By its ability to overcome some tumour immune escape mechanisms, radiation provides a non-pharmacological and cost-effective approach to potentially improve the systemic response to immune checkpoints inhibitors. In the context of oligometastatic disease, it is unclear what the ideal integration of immunotherapy and radiotherapy should be. Most studies are currently investigating ‘abscopal’ effects with combination radio/immunotherapy strategies in patients with widespread metastases. In the oligometastatic state, does this make sense? Given the local efficacy of radiotherapy, treatment of all macroscopic sites of disease if safe would appear to be a prudent strategy in combination with immunotherapy. Additionally, what is the optimal duration of immunotherapy in this context? What is the ideal timing of radiotherapy, and should it be given upfront or as consolidation? These are some of the issues that will be explored in this short lecture.

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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
    • Now Available
    • 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 (Now Available) (ID 11548)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      The most significant changes in the 2015 WHO classification of the lung tumors include classification criteria for small biopsy and cytology specimens, use of immunohistochemistry, integration of molecular testing, adoption of the IASLC/ATS/ERS adenocarcinoma classification and a strict definition of large cell carcinoma limited to surgical resection specimens only. 1,2 Tumors that show unequivocal morphology of adenocarcinoma or squamous cell carcinoma on a small specimen should be diagnosed without immunohistochemistry. Immunohistochemical work up of poorly differentiated tumors should be limited to TTF-1and p40/p63, while neuroendocrine markers should be used only if morphologically indicated. This approach should reduce the diagnosis of NSCC, NOS to less than 5 % and preserve tissue for molecular testing. 1,2

      Major changes in the adenocarcinoma classification for resected specimens include addition of adenocarcinoma in situ (AIS) to preinvasive group that already includes atypical adenomatous hyperplasia. Minimally invasive adenocarcinoma (MIA) defined as a solitary, lepidic predominant adenocarcinoma presenting measuring in gross size 3 cm or less and with invasion of ≤
5 mm was added as a new category. These tumors are also recognized by the 8th edition of the AJCC staging of lung cancer and include Tis(adenocarcinoma) and T1a-mi. T stage of non-mucinous lepidic predominant adenocarcinomas is based on the microscopic size of invasion, but gross size should be recorded in the pathology reports. Multifocal ground glass opacities/lung nodules most frequently present as MIAs and should be classified by the T category of the lesion with the highest T along with the number of lesions (#) or simply (m) for multiple indicated in parentheses, and with a single N and M category that applies to all of the multiple tumor foci. This approach should be applied to grossly or microscopically identified lesions occurring in the same or in different ipsilateral or contralateral lobes.3 For non-lepidic adenocarcinoma T stage is determined by gross size in 1.0 cm increments as each size subgroup carries prognostic significance.

      Former mucinous BAC are reclassified as invasive mucinous adenocarcinoma, excluding tumors that meet criteria for AIS or MIA. Signet ring and clear cell carcinomas are considered to represent cytologic variants rather than specific subtypes.

      Invasive adenocarcinomas should be subtyped by semi-quantitatively estimating the percentage of the various subtypes in 5% increments. 1,2 Reproducibility for lung adenocarcinoma predominant subtypes among pulmonary pathologists was good to moderate (κ-values 0.44 to 0.72).4 For untrained pathologists, κ-values were lower ranging from 0.38 to 0.47, but these improved after a training session and particularly for individual reviewer. 5

      The 2015 WHO classification defines large cell carcinomas based on morphology, as carcinomas without morphologic evidence of glandular, squamous or neuroendocrine differentiation, and also based on null immunophenotype and genotype. 1This change in definition reflect what was already happening in the pathology practice. According to National Cancer Institute (NCI) Surveillance Epidemiology and End Results registry the diagnosis of large cell carcinoma started to decline about the time that TTF-1 was introduced into clinical diagnosis. 6

      References:

      Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer, 2015.

      
Travis WD. Et al. The 2015 World Health Organization Classification of Lung Tumors Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015; 10 (9); 1243-1260

      Frank C. Detterbeck, MD et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification . J Thorac Oncol 2016;11(5): 639-650

      Thunnissen E, Beasley MB, Borczuk AC, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod Pathol 2012;25:1574–1583. 


      Warth A, Cortis J, Fink L, et al.; Pulmonary Pathology Working Group of the German Society of Pathology. Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ ATS/ERS classification. Virchows Arch 2012;461:185–193. 


      Lewis DR, Check DP, Caporaso NE, Travis WD, Devesa SS. US lung cancer trends by histologic type. Cancer 2014;120:2883–2892. 


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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Squamous cell carcinoma comprises approximately 20% of lung cancer cases and is classified into keratinizing, non-keratinizing and basaloid types (1,2,3). The p40 (or p63) immunohistochemical stain is helpful in diagnosing squamous cell carcinoma, if keratinization of the tumor cells is not appreciable.

      Neuroendocrine tumors comprises of four categories: small cell carcinoma, large cell carcinoma, typical carcinoid and atypical carcinoid (1), with variable degrees of malignant potential. Small cell carcinoma comprises approximately 14% of lung cancer cases and is further categorized into small cell carcinoma and combined small cell carcinoma (1,4,5). The tumor is composed of densely packed small-size tumor cells with scant cytoplasm, finely granular chromatin, and absence of distinct nucleoli. Mitotic figures and apoptotic bodies are frequently seen. Nuclear molding and smearing may be observed. Rosette formation and peripheral palisading, characteristics of neuroendocrine tumors, are consistently found. Large cell neuroendocrine carcinoma has the cytological morphology of large cell carcinoma and the growth pattern of neuroendocrine tumor. Both small cell carcinoma and large cell neuroendocrine carcinoma are high grade tumors. Carcinoid tumors are usually centrally located with endobronchial growth and are further divided into two categories: typical carcinoid (intermediate grade) and atypical carcinoid (low grade).

      Adenosquamous carcinoma is rare and comprises 0.4-4% of lung cancer cases (1,6,7). Presence of both adenocarcinoma and squamous cell carcinoma components and each component comprising more than 10% is required.

      Sarcomatoid carcinoma comprises less than 1% of lung cancer cases and is further subcategorized into pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma (1,8). Given the marked histological heterogeneity, sarcomatoid carcinoma need to be thoroughly sampled before the final diagnoses are made.

      Salivary gland-type carcinomas include mucoepidermoid carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma, arising from the salivary-type glands of the bronchial mucosa (1).

      In summary, the major types of lung carcinomas are outlined in Figure 1.

      180629 histology lung cancer classification.jpg

      References:

      1. William D. Travis EB, Allen P. Burke, Alexander Marx, Andrew G. Nicholson (Eds.). WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (4th Edition). 4 ed: IARC: Lyon; 2015.

      2. Tomashefski JF, Jr., Connors AF, Jr., Rosenthal ES, Hsiue IL. Peripheral vs central squamous cell carcinoma of the lung. A comparison of clinical features, histopathology, and survival. Archives of pathology & laboratory medicine. 1990;114(5):468-74.

      3. Funai K, Yokose T, Ishii G, Araki K, Yoshida J, Nishimura M, et al. Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung. The American journal of surgical pathology. 2003;27(7):978-84.

      4. Fraire AE, Johnson EH, Yesner R, Zhang XB, Spjut HJ, Greenberg SD. Prognostic significance of histopathologic subtype and stage in small cell lung cancer. Hum Pathol. 1992;23(5):520-8.

      5. Mangum MD, Greco FA, Hainsworth JD, Hande KR, Johnson DH. Combined small-cell and non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1989;7(5):607-12.

      6. Fitzgibbons PL, Kern WH. Adenosquamous carcinoma of the lung: a clinical and pathologic study of seven cases. Hum Pathol. 1985;16(5):463-6.

      7. Ishida T, Kaneko S, Yokoyama H, Inoue T, Sugio K, Sugimachi K. Adenosquamous carcinoma of the lung. Clinicopathologic and immunohistochemical features. Am J Clin Pathol. 1992;97(5):678-85.

      8. Travis WD. Sarcomatoid neoplasms of the lung and pleura. Archives of pathology & laboratory medicine. 2010;134(11):1645-58

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 203 BD
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      MTE11.01 - Novel Therapeutic Targets in SCLC (Now Available) (ID 11564)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Small cell lung cancer (SCLC) remains the most lethal form of lung cancer, in part because of its rapid growth and dissemination, and also because of its ability to evade therapy. In the last few years, however, a number of studies have taken advantage of improved pre-clinical mouse models of SCLC as well as increased access to primary human samples to identify novel candidate therapeutic targets against SCLC. Some of these new therapeutic targets include activation of the immune system (T cells, NK cells, or macrophages), as well as cell-intrinsic signaling pathways that often act in autocrine or paracrine manners (e.g. Hedgehog or Notch signaling). This presentation will put these different approaches in context and discuss signaling pathways that may not be mutated in SCLC but can still significantly contribute to the proliferation and the survival of SCLC cells during SCLC progression and metastasis.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Small cell lung cancer (SCLC) is an exceptionally lethal cancer for which new therapeutic approaches are needed. Over the past few years several research teams have applied global profiling approaches to characterize the SCLC genome, epigenome, transcriptome, and proteome. Despite the seemingly homogeneous microscopic appearance of SCLC, these studies have consistently suggested the presence of biologically distinct subsets of disease. Parallel studies across libraries of patient-derived xenografts and in a diversity of genetically engineered mouse models of SCLC have validated these subset distinctions. Some models suggest that these subsets reflect parallel programs of oncogenesis, perhaps emerging from distinct cells of origin. Conversely, other data imply a temporal hierarchy among disease subsets, or at least that transition from one phenotypic subset to another is possible. Most exciting from a treatment perspective, several research groups have reported unique therapeutic vulnerabilities among these subsets. Several of these therapeutic strategies are being actively tested in SCLC patients, and emerging correlative data further confirm the predicted differential sensitivities among SCLC subsets. Together, these studies advocate for a very different approach to clinical translation in SCLC than that taken to date. Rather than treating all SCLC the same, a more successful approach may be to consider focused trials among biomarker-selected subsets of disease, exploiting the distinct dependencies and vulnerabilities of biologically relevant subsets. This presentation will highlight some of the recent preclinical studies that have defined determinants of these subsets, together with recent clinical work emphasizing their importance to the field, and to our patients.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 07:00 - 08:00, Room 203 BD
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      MTE24.01 - Surgery vs SABR for Early NSCLC (Now Available) (ID 11589)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Surgery vs SABR/SBRT for Early Stage NSCLC

      Initially, SBRT was used primarily to treat NSCLC patients deemed inoperable secondary to other medical conditions or poor pulmonary function. SBRT is now also being actively investigated to determine its role in the management of patients who can tolerate surgery, though three separate randomized clinical trials have been terminated early secondary to poor accrual. Retrospective single and multi-institutional studies have shown both comparable and improved results with SBRT when compared to surgery. However, two recent large cohort studies reported decreased survival with SBRT compared to surgical resection, though these studies were not focused to wedge resection and considered larger T2 tumors.

      Three recent studies highlight important advantages of surgery.

      Wedge resection vs SBRT

      Limiting the comparison of SBRT and surgical resection to only surgical wedge resection may be more appropriate than considering all types of surgical resections, considering that both SBRT and wedge resection essentially limit treatment to only the immediate lung parenchyma in the area of a lung cancer. A study was undertaken to test this hypothesis using the National Cancer Date Base to assemble a large cohort of stage IA NSCLC patients who were treated with either wedge resection or SBRT. Of the 6295 patients included, 1778 (28.2%) underwent SBRT, and 4517 (71.8%) underwent wedge resection. SBRT was associated with significantly reduced 5-year survival compared with wedge resection in both unmatched analysis (30.9% vs 55.2%,

      P<.001) and after adjustment for covariates (31.0%vs 49.9%, P<.001). SBRT also was associated with worse overall survival than wedge resection after 2 subgroup analyses of propensity-matched patients (P<.05 for both). Centers that used stereotactic body radiotherapy more often

      as opposed to surgery for patients with cT1N0 patients with tumors <2 cm were more likely to have an observed/expected mortality ratio>1 for 3-year mortality (P= .034).

      Another analysis by Puri and colleagues, also using the NCDB, reported outcomes of 117,618 patients undergoing either surgical resection or SBRT, showing a survival advantage for surgical resection. They also performed a subgroup analysis of patients who underwent sublobar resection compared to SBRT which also showed a survival advantage for resection.

      Role of LN staging

      Clinical lymph node staging for stage I NSCLC remains inaccurate, presenting potential treatment dilemmas for patients treated with SBRT, particularly among patients otherwise fit for surgery. We sought to characterize the rate of nodal upstaging among patients with stage I disease, and the downstream implications of these inaccuracies for patients treated with SBRT.

      Patients diagnosed from 2006-2015 with clinical stage I NSCLC were identified in the

      National Cancer Database. A total of 62,451 patients were identified who underwent lobectomy for clinical stage I NSCLC. A median 9 (IQR: 5, 14) lymph nodes were examined. Nodal upstaging occurred in 11.3% of cases (pN1: 7.2%, pN2: 4.1%). Rates of pathologic nodal upstaging by AJCC T-stage subgroup were as follows: T1a: 179/3949 (4.5%), T1b: 2083/24443 (8.5%), T1c: 2823/21776 (13.0%), and T2a: 1995/12283 (16.2%), p<.001. An additional 773 patients were identified who met inclusion criteria and for whom surgical resection was recommended, but who refused surgery and instead opted for SBRT. Propensity-adjusted survival for these patients compared with a matched cohort treated with lobectomy, demonstrated significantly superior survival for patients treated with surgery (5-year survival 63% [95% CI: 59.9-66.3%) vs. 41.9% (95% CI: 36.7- 47.8%), p<.001).

      Recent Systematic Review and Meta-analysis

      A systematic review of relevant studies was performed through online databases and the most updated studies were selected for meta-analysis according to unmatched and matched patient cohorts. Thirty-two studies were identified in the systematic review, and 23 were selected for quantitative analysis. Surgery was associated with superior overall survival in both unmatched (OR, 2.49; 95% CI, 2.10-2.94; p<0.00001) and matched (OR, 1.71; 95% CI, 1.52-1.93; p<0.00001) cohorts. Subgroup analysis demonstrated superior overall survival for lobectomy and sublobar resection, compared with SBRT. In unmatched and matched cohorts, cancer-specific survival, disease-free survival, and freedom from locoregional recurrence were superior after surgery.

      Summary

      These issues related to observational research highlight the need for a prospective randomized clinical trial, but unfortunately this has not been achievable. The three initial randomized clinical trials comparing SBRT to surgery (STARS, ROSEL, and ACOSOG Z4099/RTOG 1021) have all been terminated secondary to poor patient accrual likely related to the patient difficulty of randomizing between dramatically different treatment modalities. However Chang et al. published the combined results of 58 patients with Stage I NSCLC in the STARS and ROSEL trials reporting a survival advantage with SBRT compared with lobectomy. Even these results though are difficult to interpret though given the different inclusion criteria of both trials. Additionally, the overall survival was significantly different in the STARS trial alone (p=0.0067) but not in the ROSEL trial (p = 0.78). New randomized trials including the STABLEMATES (NCT01622621, formerly ACOSOG Z4099), SABRTooth (ISRCTN13029788), and VALOR (CSP 2005) are now ongoing, but their ability to accrue patients remain to be determined and it is likely to be several years before results are reported.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      The development of SABR has revolutionised the non-surgical treatment of small, node negative lung tumors, both primary and metastatic. SABR is a convenient, painless, inexpensive outpatient procedure and there is now randomized evidence that it not only results in better local control than conventionally fractionated radiotherapy in patients with inoperable peripheral stage I non-small cell lung cancer, but increases survival as well. The impressive local control rates of over 80% have tempted some investigators to expand the indications for high dose hypofractionated SABR beyond small peripheral tumors.

      Perhaps the most controversial extended indication is the use of SABR for “central” lung tumours. There is no agreed definition of what constitutes a central tumor, although in the absence of consensus, the “no-fly zone” described by Timmerman is widely used even though it was based on a very small number of events.1 Phase II trials have been interpreted as indicating that SABR of central tumors has acceptable toxicity (RTOG 0813), even though there was a 3% mortality likely resulting from treatment; or conversely as unsafe, with the Nordic HILUS trial reporting around 10% mortality after SABR of tumours close to the main or a lobar bronchus. The European Lung Tech trial should throw more light on the safety of treating central tumors with a “risk-adapted” approach using a more fractionated schedule of 60 Gy in 8 fractions.2

      Many patients referred for SABR have poor respiratory or cardiac function making them unsuitable for surgical resection. Does this make them unsuitable for high dose SABR as well? The available evidence suggests not,3 but extreme caution should be taken in patients who have underlying interstitial lung disease.4 The relationship between SABR and cardiac injury, especially in the era of combined immunotherapy and SABR, remains under investigation. This high risk group of patients are currently eligible for the Stablemates trial, which is comparing sublobar resection with SABR. Eligibility includes FEV1 or DLCO < 50% predicted.

      A patient’s suitability for SABR will also depend on the dose constraints on nearby organs at risk. The chest wall is less concerning than previously, but is it the dose to the neurovascular bundle, rib or the whole musculoskeletal structure that most accurately predicts risk of chest wall pain? The brachial plexus tolerates hypofractionation poorly, and as with other scenarios where there is doubt about the safety of SABR, it is well to recognise that less effective but safer fully fractionated schedules are available.

      Other considerations, not in terms of risk, but of practical delivery of the treatment include synchronous multiple tumors, large tumors (>5 cm), and visibility for image guidance: Well defined? Too small? Image degraded by implanted fiducials?

      1. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive Toxicity When Treating Central Tumors in a Phase II Study of Stereotactic Body Radiation Therapy for Medically Inoperable Early-Stage Lung Cancer. J Clin Oncol 2006;24:4833-9.

      2. Adebahr S, Collette S, Shash E, et al. LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective. Br J Radiol 2015;88:20150036.

      3. Guckenberger M, Kestin LL, Hope AJ, et al. Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol 2012;7:542-51.

      4. Bahig H, Filion E, Vu T, et al. Severe radiation pneumonitis after lung stereotactic ablative radiation therapy in patients with interstitial lung disease. Pract Radiat Oncol 2016;6:367-74.

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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
    • Now Available
    • 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  (Now Available) (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.

      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.

      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.

      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 (Now Available) (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.
      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 (Now Available) (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).

      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.

      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

      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 (Now Available) (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 (Now Available) (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.

      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.

      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).

      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 (Now Available) (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.

      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.

      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).

      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. (Now Available) (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.

      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.

      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

      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 (Now Available) (ID 14571)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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