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    ES02 - Management of Oncogene Addicted Patients with Stage III NSCLC (ID 5)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 4
    • Now Available
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      ES02.01 - Biomarker Testing in LA Disease (Now Available) (ID 3155)

      10:30 - 12:00  |  Presenting Author(s): Helena A Yu

      • Abstract
      • Presentation
      • Slides

      Abstract
      Routine biomarker testing in metastatic lung cancer has led to enormous improvements in outcomes for our patients with metastatic lung cancers. Oncogene testing has allowed us to identify the 50% of patients with metastatic lung cancer that are eligible for targeted therapies1. Consistently, targeted therapy for EGFR, ALK, ROS1, RET, BRAF have demonstrated superior progression-free survival compared to standard cytotoxic chemotherapy2. Identification of these genomic biomarkers has provided additional treatment options for our patients that are more effective and less toxic than standard treatments. In addition, serial biomarker testing allows us to also identify mechanisms of resistance to targeted therapy which can then inform subsequent treatment decisions. PDL1 testing is also routinely performed in the metastatic setting and assists us in identifying patients that may benefit from immunotherapy alone instead of first-line combination immunotherapy and chemotherapy treatment3. PDL1 testing allows us to predict likelihood of response to immunotherapy and selects patients that we can de-escalate treatment; patients with high PDL1 expression derive benefit from treatment with immunotherapy alone. Routine utilization of biomarker testing in metastatic lung cancer is easily the most importance advancement in this field to date.

      Current recommendations
      Biomarker testing for patients with locally advanced lung cancers is currently not recommended in the NCCN guidelines or any expert guidelines. This is likely because the current management for locally advanced lung cancers do not incorporate the use of biomarkers. Patients currently receive adjuvant durvalumab after concurrent chemoradiation for stage 3 disease irrespective of PDL1 status. Currently, adjuvant targeted therapies after definitive resection or radiation are not recommended in the NCCN or other cancer care guidelines.

      Oncogene testing
      The risk of recurrence for early stage lung cancers remain high. After surgical resection, adjuvant chemotherapy for high risk stage 1B, stage 3 and stage 4 and post-operative radiation for patients with mediastinal lymph node involvement are both recommended are they improve survival. Despite this, there is a large subset of patients that will have recurrent disease. Because of their demonstrated superiority over chemotherapy in the metastatic setting, there is great interest in assessing whether adjuvant targeted therapies would improve outcomes in the locally advanced disease setting. EGFR mutant lung cancer is the largest oncogene subset in which the bulk of previous studies have been done. However, all studies to date have been subsets of larger unselected patients (RADIANT study) or single arm studies (SELECT study). These smaller studies have shown a disease-free survival benefit but have been underpowered to demonstrate a survival benefit. There are several well-designed large studies ongoing that will definitively demonstrate whether adjuvant EGFR inhibitors improve overall survival. The ALCHEMIST study is a phase 3 randomized cooperative group study assessing erlotinib versus observation for patients with stage IB-IIIA resected lung cancers; accrual is ongoing. The ADAURA study is a randomized phase 3 study where patients with stage IB-IIIA resected lung cancers are randomized to osimertinib versus placebo for 3 years with a primary objective of DFS and a secondary objective of overall survival. These studies will help answer the question as to whether adjuvant targeted therapy should be utilized.

      PDL1 testing
      In stage 3 lung cancers, more than 60 percent of patients will ultimately die of their lung cancer4. Adjuvant durvalumab has improved outcomes with a clear improvement in overall survival but many patients still recur and ultimately die of their disease. An unplanned subset analysis of the PACIFIC study suggests that patients with PDL1 0% expression may not derive benefit from durvalumab. Further assessment will be needed to ascertain whether PDL1 expression can be used to select patients who would derive benefit from adjuvant durvalumab. Due to their efficacy in the metastatic setting, there are a significant number of studies looking at immunotherapy as both neoadjuvant and adjuvant treatment for locally advanced disease. Just as we utilize PDL1 as a biomarker that helps select appropriate therapies in the metastatic setting, I see similar use of PDL1 in the future in the locally advanced setting.

      Future directions
      As personalized medicine infiltrates our care of patients with lung cancers, we will need biomarker results for patients with locally advanced lung cancer to better tailor and personalize their care. In particular, if the EGFR TKI studies demonstrate improved overall survival with adjuvant EGFR TKI, we will certainly need to incorporate biomarker testing as standard of care for locally advanced disease. In addition, because a significant portion of patients recur, already having molecular test results available which were done on their surgical sample, makes their care later more stream-lined. We also need to assess whether PDL1 is a useful biomarker to select patients for immunotherapy in the adjuvant setting. Results from ongoing clinical trials will provide definitive answers.

      Works cited:

      1. Jordan, E.J., et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer discovery 7, 596-609 (2017).
      2. Sequist, L.V., et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013).
      3. Reck, M., et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 375, 1823-1833 (2016).
      4. Pisters, K.M., et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. Journal of clinical oncology 25, 5506-5518 (2007).

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      ES02.02 - Management of EGFR LA Disease (Now Available) (ID 3156)

      10:30 - 12:00  |  Presenting Author(s): Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Abstract

      Management of EGFR mutation(+) Locally Advanced Non-Small Cell Lung Cancer

      Keunchil Park, MD, PhD

      Division of Hematology-Oncology, Samsung Medical Center,

      Sungkyunkwan University School of Medicine, Seoul, Korea

      The standard of care for the locally advanced non-small cell lung cancer(LA-NSCLC) is concurrent chemoradiotherapy(CCRT). Recently, the addition of consolidation immune checkpoint inhibitor following CCRT demonstrated improved outcome and is now recommended as the new standard of care for this heterogeneous group of LA-NSCLC patients. In advanced/metastatic setting EGFR mutation (+), NSCLC cancer patients define a unique subset with a dramatic response to the EGFR TKIs. Currently, molecular profiling of tumor tissue for EGFR mutations (as part of multiplex testing) is a routine procedure at the time of initial diagnosis of patients with recurrent or metastatic NSCLC. For advanced or metastatic EGFR mutant NSCLC patients EGFR TKI therapy is the treatment of choice and the median overall survival is > 30 months.

      Despite the great success of EGFR TKI in metastatic NSCLC, the role of EGFR TKIs in LA-NSCLC is less well defined and controversial. Early clinical trials in unselected NSCLC patients failed to demonstrate the benefits of EGFR-TKIs as an adjuvant treatment. The first prospective randomized phase III trial to investigate the role of EGFR TKI in earlier stage NSCLC includes the SWOG 0023 study (J Clin Oncol 2008;26:2450-6) which failed to support the role of maintenance gefitinib (versus placebo) following definitive chemoradiation in unresectable stage III NSCLC. The CALGB 30106 phase II study also failed to show the benefits of adding gefitinib to sequential or concurrent chemoradiotherapy in unresectable stage III NSCLC (J Thorac Oncol 2010;5:1382-90). And the randomized prospective placebo-controlled adjuvant gefitinib trial in unselected patients with stage IB–IIIA resected disease (BR.19) was prematurely closed (J Clin Oncol 2013;31:3320-6). Another randomized double-blind trial in adjuvant NSCLC with tarceva (RADIANT) in patients with completely resected state IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization did not show prolonged DFS (J Clin Oncol 2015;33:4007-14).

      The prognostic or predictive value of EGFR mutation in early stage NSCLC patients is not well defined. In a retrospective single institutional analysis (J Thorac Oncol. 2012;7: 1815–1822), patients with resected stage I–III lung cancers and EGFR mutation have a lower risk of death compared to patients without EGFR mutation. There was a trend toward improvement in DFS among individuals with resected stages I to III lung adenocarcinomas harboring mutations in EGFR exon 19 or 21 who received adjuvant EGFR TKI therapy (J Thorac Oncol 2011;6:569–575).

      There have been recently reported several prospective trials of adjuvant EGFR TKI in early stage NSCLC patients enriched with EGFR mutation.

      CTONG1104 study (ADJUVANT), a randomized, open-label, phase III trial of adjuvant gefitinib for 24 months versus intravenous vinorelbine plus cisplatin for 4 cycles in patients with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC, demonstrated that adjuvant gefitinib compared to cisplatin-based chemotherapy significantly increases disease-free survival, diminishes toxic effects, and improves HRQoL in patients with completely resected stage II–IIIA EGFR-mutant NSCLC (Lancet Oncol 2018; 19: 139–48).

      In the phase II SELECT trial, adjuvant erlotinib for 2 years in patients with resected stage IA to IIIA EGFR-mutant NSCLC after standard adjuvant chemotherapy with or without radiotherapy (J Clin Oncol 2019;37:97-104) showed an improved 2-year DFS. Patients rechallenged with erlotinib after recurrence experienced durable benefits.

      There are also some neoadjuvant trials of EGFR TKI for locally advanced NSCLC.

      RTOG 1306, a randomized phase II study of individualized combined modality therapy for stage III NSCLC (12-weeks of either erlotinib hydrochloride or crizotinib followed by chemoradiation therapy in stage III NSCLC with EGFR TK mutations or EML4- ALK fusion). The primary objective was to assess whether patients with unresectable LA-NSCLC treated with EGFR or ALK TK targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. The study was, however, unfortunately prematurely terminated due to poor accrual (NCT01822496).

      CTONG 1103 is an open-label, randomized trial that compared the efficacy and safety of erlotinib versus gemcitabine plus cisplatin neoadjuvant therapy in patients with exon 19 or 21 EGFR mutations and untreated resectable stage IIIA-N2 NSCLC. The study did not meet the primary end point of ORR with 42 days of neoadjuvant erlotinib, but the secondary end point PFS was significantly improved (J Clin Oncol 37. © 2019; published at jco.org on June 13, 2019: DOI https://doi.org/10.1200/JCO.19.00075)

      There are also several ongoing clinical trials of EGFR TKIs in resected stage IB - IIIA NSCLC with activating EGFR mutations.

      The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is a prospective randomized double-blind placebo-controlled trial to investigate the benefits of the addition of molecularly targeted agents after standard postoperative chemotherapy in patients with resected NSCLC (Clin Cancer Res:2015; 21(24); 5439–44). It is worth noting that the primary objective for the ALCHEMIST adjuvant trials is overall survival (OS).

      ADAURA, a randomized phase III trial (osimertinib vs. placebo in patients with stage IB-IIIA NSCLC, following complete tumor resection with or without adjuvant chemotherapy; NCT02511106) has been designed to assess the efficacy and safety of adjuvant osimertinib versus placebo in patients with resected stage IB-IIIA EGFR mutation-positive (Ex19Del or L858R) NSCLC. The primary efficacy objective is DFS.

      In brief, many neoadjuvant/adjuvant EGFR TKI trials in earlier stage of NSCLC have demonstrated its safety and feasibility with an improved DFS esp. in EGFR mutation(+) LA-NSCLC. However, the real question should be “Can we improve the ‘overall survival’ and thus ultimately the ‘cure rate’ of locally advanced NSCLC with EGFR mutation?” In order to address this issue, there remain several critical questions to be answered, e.g., who is most likely to benefit from adjuvant EGFR TKI, what is the optimal duration of adjuvant TKI, what is the best regimen, etc. Whether the earlier introduction of EGFR targeted therapy in less advanced NSCLC would lead to improved ‘Cure Rate’ remains to be seen in future prospective trials in a larger number of EGFR mutation(+) patients.

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      ES02.03 - Management of Other Non EGFR Oncogene Addicted Tumors (Now Available) (ID 3157)

      10:30 - 12:00  |  Presenting Author(s): Charu Aggarwal

      • Abstract
      • Presentation
      • Slides

      Abstract

      Stage III non-small cell lung cancer accounts for heterogeneous group of diseases, due to differences in tumor size, location number of nodes involved, and lymph node station involved. Stage III non-small cell lung cancer comprises 2 distinct stages, stage IIIA and IIIB disease that have different prognosis, and are usually treated differently. Approximately 15% of all patients with newly diagnosed non-small cell lung cancer present with stage III disease. Options for stage III non-small cell lung cancer include surgery, with lobectomy or pneumonectomy depending on the tumor stage, and lymph node involvement. Chemotherapy may be administered in the neoadjuvant, concurrent or adjuvant setting. Radiation therapy can be given in a concurrent, sequential approach, or may be administered in the postoperative fashion. Combination approaches are often used, and due to the significant need of multi-modality therapy, treatment decisions are usually made in a multidisciplinary setting. The optimal therapeutic approach for patients with stage IIIA non-small cell lung cancer remains controversial. For subset of patients with T3 to T4 N0-1 disease, and superior sulcus location, surgery remains a viable and preferred option. However, the optimal treatment for patients with stage III A, with bulky lymph node involvement, or multi station lymph node involvement including N2 disease, remains an area of ongoing controversy. Tri-modality approaches using preoperative chemotherapy, or upfront chemoradiation therapy followed by surgery have been evaluated (1). For patients with surgically unresectable, or medically inoperable disease, concurrent chemoradiation therapy has been established as the standard of care for patients spanning the spectrum of stage IIIA and IIIB disease.

      Recently, the PACIFIC trial demonstrated an improvement in progression free survival and overall survival with the administration of durvalumab as consolidation therapy (regardless of PDL-1 status) for patients who had not progressed after 2 or more cycles of definitive concurrent platinum-based chemoradiation therapy (2, 3). This approach represents a new paradigm in the management of unresectable NSCLC, and has now been adopted as standard of care.

      Management of Stage III patients with non EGFR oncogene addicted tumors is an area of active research. ALK or ROS directed oral tyrosine kinase inhibitors (TKIs) are not typically administered in the adjuvant setting outside of a clinical trial. There are several trials evaluating the use of targeted therapies. ALINA, is one such trial, that is a phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive ALK positive NSCLC (4). Another study is comparing adjuvant alectinib versus adjuvant platinum-based chemotherapy in patients with ALK positive NSCLC, here the alectinib is administered for 2 years (NCT 03456076). The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing (ALCHEMIST) trial is actively enrolling patients with operable NSCLC and will perform genetic screening of their tumors. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively (NCT02194738). We await the results of these trials prior to routine incorporation of molecularly directed therapy in the management of locally advanced disease.

      References:

      1. Albain KS, Swann RS, Rusch VW, Turrisi AT, 3rd, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374(9687):379-86. Epub 2009/07/28. doi: 10.1016/S0140-6736(09)60737-6. PubMed PMID: 19632716; PubMed Central PMCID: PMC4407808.

      2. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. The New England journal of medicine. 2017;377(20):1919-29.

      3. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. 2018; 379:2342-2350

      4. Solomon BJ, Ahn JS, Barlesi F et al. ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol 37, 2019 (suppl; abstr TPS8569)

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      ES02.04 - Concurrent, Sequential and Combination Immunotherapy Regimens in LA-NSCLC (Now Available) (ID 3158)

      10:30 - 12:00  |  Presenting Author(s): Mariano Provencio

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy in Oncogenic-Addicted Stage III Patients

      At diagnosis of non small cell lung cáncer (NSCLC), at least 40% of patients are diagnosed at an advanced stage and a third locally advanced disease (stage III). The results of stage IIIA with induction treatment of clinical practice outside the clinical trial show a median survival of 22 months and a 3-year survival rate of 34%. Concurrent definitive chemoradiation has been established as the standard of care for unresectable stage IIIB (N3 disease) NSCLC, with a median overall survival (OS) of approximately 17 months. Strategies that have been investigated include induction chemotherapy, immunotherapy (IO), concomitant chemoradiotherapy, intensified radiotherapy and adjuvant treatment.

      The role of IO in NSCLC with oncogenic-addicted tumors is so far unclear. In EGFR-mutation positive patients there seems to be a worse effect of IO compared to those patients without actionable mutations,; nevertheless, no safe conclusions can be drawn due to the lack of randomized trials addressing this clinical issue. The available information from second lines with IO in patients with actionable mutations, is currently found in 2 meta-analyses[1].

      These meta-analyses show OS benefit between EGFR wild-type vs mutated patients with a Hazard Ratio (HR) of 0.67, p< 0.001, consistent in all the trials. There was no OS advantage for those with EGFR mutant tumors, with a HR of 1.11, p=0.54.

      Of note, data from other studies were not included in these meta-analyses. Study CA209-012 showed patients with EGFR mutation, overall response rate (ORR) 14% mutated vs 30% in wild type and PFS at 24 weeks: 14% vs 51% respectively[2].

      In KEYNOTE-001, best ORR based on mutation status was 15.8% in patients with EFGR mutation vs 37.1% without mutation, and 60% were unknown. Overall PD-L1 subgroups, EGFR mutated patients had lower ORR than patients with EGFR-wild type tumors. ORR was 20 % in TPS > 50% and 0% in patients with TPS<1% vs 12.7% in EGFR wild type[3]. An update of this study, and median OS in patients with EGFR mutation was 6 months (mo) (95%CI, 4.4-8.8) and 12 mo (95%CI, 9.2-14.3) in patients wild-type[4].

      In the Immunotarget Cohort study, patients with EGFR-mutation had response rates of 12% and PFS of 2.1 mo and with a positive correlation in patients with high expression of PDL1 and response.

      The BIRCH[5] study, also not included in the meta-analyses, provides us with similar information, with higher response rates in patients with higher expression of PDL1 (31% vs 23%), even achieving similar PFS to wild type patients (7.6 vs 7.7 mo) or OS with 28.5 mo (20.1, NE) in mutant vs 20.1 mo (15.5, 31.1) in wild-type. The phase II ATLANTIC trial testing durvalumab as third-line treatment included the largest cohort of EGFR mutant patients treated with IO after progression of TKI and chemotherapy. According to PD-L1 expression (< 25% or ≥ 25%), durvalumab achieved a response rate (RR) of 3.6% and 14.1%, a similar median PFS 1.9 months and a median OS of 9.9 months and 13.3 months, respectively[6].

      Despite improvements in the treatment of stage IV NSCLC with the introduction and dissemination of checkpoint inhibitors, very little progress has been made in the treatment of stage III. The PACIFIC trial was the first study to show a clear benefit for the approach. Patients were enrolled regardless of PD-L1 expression, and those with EGFR mutations were also eligible. The subgroup of patients with EGFR mutations did not clearly benefit from durvalumab maintenance. These patients were equally represented in the durvalumab (6%) and placebo (5.9%) arms. The HR was 0.76 in this setting, and whether because of a small sample size or true lack of efficacy, the findings were not significant (95% CI, 0.35–1.64).

      In NADIM Study, a Phase II, with neoadjuvant chemotherapy and immunotherapy in stage III, unprecedented pCR rates observed (around 70%) and with down-staging around 90%. We did not include patients with actionable mutations, and we do not have information about other trials using chemo and IO. In KN 189 using combination of chemo and IO in stage IV, no sensitizing EGFR or ALK alteration were included. In the ImPOWER 150 study[7] comparing the use of bevacizumab plus atezolizumab plus carboplatin, plus paclitaxel versus carboplatin plus paclitaxel plus bevacizumab in first-line stage IV, provides interesting results in PFS, with a HR of 0.41 (95% CI: 0.22-0.78), in patients with common mutations (already treated with TKIs) in the arm with atezolizumab plus chemo better than the control arm.

      In the light of these results, we may conclude that other biomarkers such as a tumor mutational burden (TMB) could be used in the future, but low TMB is especially significant among the oncogenic alterations strongly related with never-smokers, such as EGFR mutation and ALK rearrangements. Therefore, these data suggest a role for actionable mutations testing in the stage III setting and for additional trials specifically targeting EGFR-mutant patients and stage III disease.

      [1] Lee CK, Man J, Lord S et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma.A systematic review and meta-analysis. JAMA Oncol 2017

      [2] Gettinger S, Chow LQ, Borghaei H et al. Nivolumab monotherapy for first-line treatment of advanced non-samll cell lung cancer. JCO, DOI: 10.1200/JCO.2016.66.9929.

      [3] Hellman M et al. Efficacy of pembrolizumab in key subgroups of patients with advanced NSCLC. 16th World Conference on Lung Cancer, 2015.

      [4] Leighl NB, Hellamn MD, Hui R, et al. KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab. ASCO 2017.

      [5] Carcereny E, Felip E, Reck M, et al. Updated efficacy results from the BIRCH study: First-line atezolizumab therapy in PD-L1 –selected patients with advanced NSCLC. World Conference on Lung Cancer 2017.

      [6] Garassino MC, Cho B-C, Kim J-H, Mazières J, Vansteenkiste J, Lena H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol 2018;19:521–36.

      [7] Socinski M, Jotte RM, Capuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. NEJM DOI: 10.1056/NEJMoa176948.

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    ES14 - What First Line in Oncogene Addicted NSCLC (ID 17)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Targeted Therapy
    • Presentations: 5
    • Now Available
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      ES14.01 - First Line in EGFR Mutated Patients (Now Available) (ID 3230)

      15:15 - 16:45  |  Presenting Author(s): Thanyanan Reungwetwattana

      • Abstract
      • Presentation
      • Slides

      Abstract

      Precision medicine is currently applied for almost all cancer types, especially, in NSCLC which is the prototype of successful targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the first effective targeted drug found in NSCLC for treatment in EGFR-mutation positive patients. EGFR (also termed human epidermal growth factor receptor 1 [HER1] or ErbB1) is a member of the ErbB family of cell surface receptor tyrosine kinase1. It is a 170‑kDa RTK with an extracellular ligand‑binding domain, a transmembrane region and an intracellular tyrosine kinase. The RTKs form homodimers and heterodimers after binding to specific ligands, leading to autophosphorylation of tyrosine residues on the intracellular TK domain. This interaction recruits a diverse set of signal transduction cascades including the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR), signal transduction and transcription (STAT) transcription and RAS/RAF/ mitogen‑activated protein kinase (MAPK) proliferation pathway1. In 2004, somatic mutations in the TK domain of EGFR, found most frequently in adenocarcinomas from patients in Asia who were never or former smokers, were strongly correlated with sensitivity to EGFR-TKIs1. The prevalence of EGFR mutation in NSCLC patients is higher in Asian population compared to the other population (50-55% vs. < 20%). These mutations are mostly distributed in four exons (exon18 to exon21)2. In‑frame deletions of exon19 (44%; E746A750deletion) and L858R substitutions in exon21 (41%) are the most prevalent mutations associated with sensitivity to EGFR-TKIs. The point mutations in exon18 (G719C, G719S and G719A) and exon20 (V765A and T783A) are less frequent; 5% and 1%, respectively1.

      Presence of the “classical” mutations in exon19 and 21 are the best predictive biomarker for the efficacy of EGFR-TKIs with superior response rate (RR) of 60-70%, progression‑free survival (PFS) of 9-18.9 months, and overall survival (OS) more than 2 years compared with conventional chemotherapy in patients with tumors harboring EGFR‑sensitive mutations making EGFR-TKI is the first-line treatment3. Currently, there are 3 generations of EGFR-TKIs approved in the market. The strategy of first-line treatment in EGFR-positive patients can be categorized into 2 strategies. The first one is treating by the single agent EGFR-TKIs. The first and second-generation EGFR-TKIs have the efficacy in term of PFS of 9-14.7 months in first-line treatment, but if starting with third generation EGFR-TKI, the PFS is longer (18.9 months)3-4. The ORR is similar either starting with 1st, 2nd, or 3rd generation EGFR-TKIs (60-70%). The acquired resistance could be occurred after 9-14 months of treatment by 1st and 2nd-generation EGFR-TKIs and the majority of resistance mechanism is T790M (50-60%) which is now we have the 3rd-generation EGFR-TKI for overcoming this resistance. Moreover, the other bypass tracts (MET amplification, BRAF, HER2 mutation etc.)5 could be the mechanism of resistance as well and we have the potential targeted drugs in the clinical studies which some of them will be approved in the near future. The mechanism of resistance if we start the 1st-line treatment with 3rd-generation EGFR-TKI is different from the previous one. Recently, exploratory data from FLAURA study was reported. They found no T790M detected in the patients whom had progressive disease after 1st-line treatment with 3rd-generation EGFR-TKI. The most common detected acquired resistance genes in the blood were C797S and MET amplification. The other mechanism included HER2 amplification, PIK3CA and RAS mutations. Furthermore, the 3rd-generation EGFR-TKI has the significant strong evidence of better in survival outcome and CNS response in patient whom had the CNS metastases disease6. The second strategy is starting 1st-line treatment with the combination therapy. The recent studies reported in ASCO2018 and ASCO2019 showed the longer PFS (16-19 months) in combination of 1st- generation EGFR-TKI and anti-angiogenesis agents and also longer PFS (16-20 months) in combination of 1st-generation EGFR-TKI with doublet platinum-based chemotherapy compared to single agent 1st-generation EGFR-TKI.7-9 Definitely, there were more adverse events for the combination treatment. The rate of occurring T790M as the acquired resistance and the CNS efficacy are the issues to concern for the combination treatment (Figure 1). The most proper sequence of the treatment in EGFR-positive NSCLC is needed to explore more in the clinical studies. It has pros and cons in each approach and it depends on several factors such as; the patients’ performance status, the location of tumor (CNS metastases?), types of EGFR mutations, acquired resistance, toxicities, treatment after progression, cost of treatment and the reimbursement issue in each country.

      In summary, EGFR mutation is the crucial oncogenic-driven mutation in NSCLC with effective EGFR-TKI treatment making the patient has good quality of life (QOL) even though they have the advanced-stage disease. The journey of treatment in this group of patients is still underway of development and it is the good prototype for the other targeted drugs development in the clinical studies. I believe that there will be the other effective novel targeted treatments for NSCLC approved in the near future which would improve the long-term survival and QOL for patients.

      References:

      1. Salomon DS, et al. Crit Rev Oncol Hematol 1995

      2. Lynch TJ, et al. N Engl J Med 2004

      3. Reungwetwattana T, et al. Journal of Carcinogenesis 2013

      4. Soria JC, et al. N Engl J Med 2018

      5. Papadimitrakopoulou V, et al. ESMO Congress 2018

      6. Reungwetwattana T, et al. J Clin Oncol. 2018

      7. Furuya N, et al. ASCO Congress 2018

      8. Nakamura A, et al. ASCO Congress 2018

      9. Nakagawa K, et al. ASCO Congress 2019

      Figure 1: The survival outcome of each approach for EGFR-positive NSCLC

      thayanan_abstractpicture.jpg

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      ES14.02 - First Line in ALK Translocated Patients (Now Available) (ID 3231)

      15:15 - 16:45  |  Presenting Author(s): Alice T. Shaw

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chromosomal rearrangement of ALK defines a distinct subset of non-small cell lung cancer (NSCLC) with marked sensitivity to small molecule ALK tyrosine kinase inhibitors (TKIs). Currently, five ALK TKIs are approved as standard therapies for advanced ALK-positive NSCLC, including the first generation ALK/ROS1/MET inhibitor crizotinib, the second generation ALK inhibitors ceritinib, alectinib and brigatinib, and most recently the third generation ALK/ROS1 inhibitor lorlatinib. In three randomized phase 3 studies (J-ALEX, global ALEX, and ALESIA), alectinib has demonstrated superior efficacy compared to crizotinib, and has replaced crizotinib as the standard first-line therapy for advanced ALK-positive NSCLC. Recently, in a planned interim analysis of the ALTA-1L phase 3 study, brigatinib has also shown superior efficacy to crizotinib as first ALK TKI in advanced ALK-positive NSCLC. In this talk, we will review all the available first-line data with ALK TKIs, with a focus on next-generation ALK inhibitors. In addition to discussing second-generation ALK TKIs, we will also highlight available data with lorlatinib in the first-line setting. The phase 3 study of lorlatinib vs crizotinib as first-line therapy (CROWN) has completed accrual, with results expected within the next year. Finally, we will discuss the potential role of investigational combinations as first-line therapy in advanced ALK-positive NSCLC. These investigational strategies hold the promise of further extending front-line progression-free survival as well as overall survival for this molecular subgroup of patients.

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      ES14.03 - First Line in ROS1 Translocated Patients (Now Available) (ID 3232)

      15:15 - 16:45  |  Presenting Author(s): Frances Shepherd

      • Abstract
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      Abstract not provided

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      ES14.04 - First Line for Rare Mutations (RET, BRAF, HER2) (Now Available) (ID 3233)

      15:15 - 16:45  |  Presenting Author(s): David Planchard

      • Abstract
      • Presentation
      • Slides

      Abstract

      Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. In the recent years a number of other oncogenic drivers beyond EGFR, ALK, and ROS1 inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes BRAF, HER2, as well as RET rearrangements. A great number of clinical trials are currently underway, evaluating agents specifically designed to target these alterations. Here, we discuss both established and emerging targeted therapy approaches, as well as ongoing challenges for the treatment of NSCLC patients harboring these oncogenic alterations.

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      ES14.05 - Patients Harbouring a Driven-Mutation: Pro and Patient's Perspective (Now Available) (ID 3234)

      15:15 - 16:45  |  Presenting Author(s): Karen L Reckamp

      • Abstract
      • Presentation
      • Slides

      Abstract

      Patients Harbouring a Mutation-Driven NSCLC—Pro and Patient Perspective

      Karen L. Reckamp, MD, MS

      City of Hope Comprehensive Cancer Center, Duarte, CA, USA

      Genomic alterations in non-small cell lung cancer (NSCLC) define distinct subtypes with specific mechanisms leading to constitutive activity of a gene pathway, and tumor growth and metastasis. Targeted therapy for NSCLC with oncogenic driver mutations or alterations, usually with small molecule tyrosine kinase inhibitors (TKIs), has changed the paradigm for treatment of patients. New genetic alterations continue to be described with potential therapeutic interventions, and over 60% of patients with the adenocarcinoma subtype of NSCLC have a defined molecular alteration1. The perspective of the clinician and patient merges on the ideal that treatment for NSCLC should provide a long duration of cancer control (ideally tumor shrinkage) with limited side effects, and improvement in quality of life. Some aspects of treatment with targeted therapy may be more important to the treating physician, while patients may have a differing viewpoint during care. This will be explored.

      From a clinician’s lens, the treatment for patients with NSCLC harbouring an alteration that can be treated with a targeted therapy involves an algorithm that includes the ideal sequencing of therapy. This requires determining the best front line therapy based on progression free survival (PFS) and overall survival while including the toxicity profile into the algorithm, and also assessing possible mechanism of resistance and options for subsequent therapy. A front line option should not be withheld based on second line options, but sequencing of therapy to increase survival and quality of life becomes an important part of the treatment decision (Table 1). This may be best exemplified in the case of EGFR mutant NSCLC, in which osimertinib demonstrated clear PFS benefit over erlotinib or gefitinib.2 In this case, mechanisms of resistance are still being elucidated and subsequent therapy becomes chemotherapy combinations. Recent studies have shown PFS benefit with first generation EGFR TKIs in combination with ramucirumab or chemotherapy, but were not directly compared to osimertinib. Furthermore, the toxicity with the combination therapy was also increased. Therefore, the choice of osimertinib as front line therapy is optimal for most patients. Another important aspect in the physician choice of front line therapy is brain penetration, which most TKI therapy is able to achieve, but some are better than others. Importantly, patients will not be treated with novel targeted therapies if they are not tested. Testing can include single gene testing by PCR and FISH, NGS testing and hotspot analysis either on blood or tissue. The utility of liquid biopsies to identify alterations in the metastatic front line setting has been shown,3 and detection has led to actionable therapy.4

      Patients expect their physicians to be advocates for their therapy and their lives, and want a reason to hope. Most would like to avoid chemotherapy if possible in the course of treatment. They want the most current, and extensive testing done to determine the right therapy, but also encounter the economic impact of diagnosis and treatment of oncogene-driven NSCLC. Untangling the clinical trial data to provide the therapy most likely to prolong quality of life and survival is essential. Inadequate testing up front can lead to inappropriate treatments, and increased anxiety associated with additional tests and time required to find the right treatment. A NSCLC patient who is also a physician provides valuable insight into the patient perspective, “Everyone with lung cancer needs to have their cancer tissue tested for genetic mutations… That biopsy may lead to identifying mutations that can be successfully targeted. All therapies, whether conventional or targeted, provide bridges to keep you alive for the next therapy, to get to the next bridge. My ultimate goal is not necessarily to cure the disease, but to successfully manage the disease. Very much like the way HIV/AIDS and diabetic patients manage their disease for many, many years….to convert a death sentence to a chronic illness.”5

      References

      1. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA : the journal of the American Medical Association 2014;311:1998-2006.

      2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.

      3. Leighl NB, Page RD, Raymond VM, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2019.

      4. Rothwell DG, Ayub M, Cook N, et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nature medicine 2019;25:738-43.

      5. June 7, 2019

      Table 1.

      Oncogene

      Mutation prevalence

      Approved drugs

      First-line drug of choice

      Driver-oncogenes with approved agents

      EGFR

      Asian 30-40%/ Caucasian 10-20%

      Erlotinib

      Gefitinib

      Afatinib

      Osimertinib

      Osimertinib

      ALK

      1-7%

      Crizotinib

      Ceritinib

      Alectinib

      Brigatinib

      Lorlatinib

      Alectinib

      ROS1

      1.7%

      Crizotinib

      Ceritinib

      Crizotinib

      BRAF

      2%

      Dabrafenib/trametinib

      Dabrafenib/trametinib

      NTRK

      <1%

      Larotrectinib

      Larotrectinib

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    IBS07 - Enhancing Recovery in the Treatment of Thoracic Malignancy (Ticketed Session) (ID 38)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Nursing and Allied Professionals
    • Presentations: 2
    • Now Available
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      IBS07.01 - Enhanced Recovery for Thoracic Surgery (Now Available) (ID 3335)

      07:00 - 08:00  |  Presenting Author(s): Amy Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background

      Enhanced Recovery After Surgery (ERAS) also known as “fast track surgery”, was pioneered back in the 1990s by Henrik Kehlet in colorectal surgery. It has developed as a multimodal evidenced based approach which has been designed and tested to enable patients to recover more quickly after major surgery thus reducing the length of hospital stay and the associated costs, Its aim is to minimise the physical and psychological stress response to surgery and has been proven effective in many different areas, by delivering multiple interventions throughout the entire patient journey from referral to discharge and beyond. Over the years the evidence modified this approach and now ERAS programmes are growing in popularity and are becoming more established across a range of surgical specialities, but there is still a little way to go in thoracic surgery to build evidence and recommendations on the elements of the ERAS programme.

      Methods

      The main principles for ERAS programmes are; to enable the patients to be as healthy as possible before surgical treatment, receive the best possible care during their operation and have the best possible care while recovering (picture 1). There are as many as 45 enhanced recovery items throughout the entire pathway. The ideal start to the ERAS pathway is to optimise the pre-operative health which should commence when the referral from primary care is made. Interventions for smoking cessation and managing pre-existing comorbidities such as diabetes and hypertension are key elements in getting the patients in the best possible condition for surgery. Other pre surgery interventions are prehabilitation, nutritional screening, and patient information to manage expectations and discharge planning. Key recommendations for the admission on the day of surgery are to give patients pre surgery carbohydrate loading drinks and minimise their fasting period. In terms of intraoperative items, minimally invasive surgery, less opioid use, avoidance of urine catheters and fluid management are recommended elements. In the post-operative and follow-up phase, early oral hydration and nutrition to enable the removal of intravenous therapy, early mobilisation within 24 hours, early chest drain removal to facilitate discharge with a recommendation for telephone follow-up if applicable; these recommendations are becoming more common in thoracic surgery.

      Results

      In specialties such as colorectal, gastric and liver surgery the ERAS pathways are well established with good supporting evidence demonstrating a reduction in hospital length of stay, postoperative complication rates and cost reductions. Recommendations and guidance in thoracic surgery ERAS programmes has been published by the Enhanced Recovery after Surgery Society and the European Society for Thoracic Surgery (1). Some recommendations are based on high quality evidence; however in some cases thoracic surgery specific evidence is simply not available to support the recommendations therefore evidence from other surgical specialities has been extrapolated to thoracic surgery. The key recommendations include: pre surgery smoking cessation - a known risk factor for developing post-operative pulmonary complications (however there is a strong debate around smoking cessation timing prior to surgery); malnutrition increases risk of complications therefore nutritional screening is highly recommended as well as minimising starvation; the use of carbohydrate loading the evidence is low but the recommendation is strong due to proven reduction in insulin resistance in the context of general surgery. Patient education has been shown to reduce anxiety and improve expectations for both patients and carers. It is not clear if patients with good lung function and exercise capacity benefit from Prehabilitation but the evidence for the high risk group is strong, thus is highly recommended. There also is a strong recommendation for avoiding sedatives and the use of regional/non-opiate analgesia for pain relief, adequate control of nausea and vomiting, video-assisted approach when possible with early removal of chest drains.

      The guidance recommendation is high for dedicated pre-op counselling, prehabilitation, carbohydrate loading, use of regional anaesthetic techniques and short acting anaesthetic agents, dexamethasone to prevent post of nausea and pain, use of digital drainage with no external suction and early mobilisation after surgery but the evidence level is low.

      The impact of ERAS on the long term outcomes is another aspect that is yet to be determined. As the recommendation grade for most of the elements is strong, the use of a systematic perioperative care pathway has the potential to improve outcomes after surgery.

      Conclusion

      These guidelines outline recommendations for the perioperative management of patients undergoing lung surgery based on the best available evidence. However there are barriers to implement many aspects of the ERAS programme due to lack of evidence, so there is still a need for large-scale, multicenter randomised trials to test aspects of the pathway.

      (1) Guidelines for enhanced recovery after lung surgery: recommendations of the Enhanced Recovery After Surgery (ERAS®) Society and the European Society of Thoracic Surgeons (ESTS)

      picture 1. eras pathway.png

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      IBS07.02 - The Role of Prehabilitation in the Optimisation of Patients with Thoracic Malignancy (Now Available) (ID 3336)

      07:00 - 08:00  |  Presenting Author(s): Faye Dickinson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Surgical resection remains the best treatment option for patients with early stage of non-small cell lung cancer. However, it may be responsible of postoperative complication and mortality, especially in patients with impaired pulmonary function. Enhanced recovery after surgery (ERAS) programs have been focused mainly in minimal invasive surgery approach during lung resection and respiratory rehabilitation after surgery. Preoperative exercise-based intervention (Prehabilitation) has demonstrated reduction of morbi-mortality in other surgeries but in thoracic surgery continues to be under discussion. Impaired lung function with low predicted postoperative forced expiratory volume in first second (ppoFEV1) or/and diffusing capacity for carbon monoxide (ppoDLCO) are considered risk factors for anatomic lung resection. Cardio-pulmonary exercise test (CPET) is the gold standard technique to predict postoperative morbi-mortality. It seems reasonable to think that if we are able to improve FEV1 or CPET we will reduce postoperative risks.The implementation of a preoperative respiratory rehabilitation could optimize patient’s physical capacity before surgery and improve outcomes and enhance recovery. The aim of this presentation is to identify the effectiveness and safety of prehabilitation programs in thoracic surgery and review its impact on patients having lung cancer surgery. Define the type of exercise and its duration, and the group of patients with best benefit. During the presentation we will be able to check that Prehabilitation is a safe intervention without side effects in patients. High-intensity interval training (HIT) with duration of 2 to 6 weeks seems to be the best exercise programme in a prehabilitation intervention but it exists heterogeneity in terms of intensity and duration. Prehabilitation increase exercise capacity and significantly enhances pulmonary function. But the reduction of postoperative complication and mortality has not been clearly demonstrated. Different criteria selection, type of intervention and small sample size, in addition to no randomization, could justify disparate results. It seems that not all patients can benefit from prehabilitation and it could be indicated only in patients with impaired lung function. Further randomized clinical trials with enough patients, correct duration of HIT (2 to 6 weeks) and focused in COPD patients are needed to clarify the suitability of prehabilitation. Meanwhile, safety of prehabilitation and good results of some studies support this intervention in high-risk patients. This conclusion is supported by the recent published ERAS society and Eurpoean Society of Thoracic Surgeons (ESTS) guidelines for enhanced recovery after lung surgery, which recommends prehabilitation should be considered for patients with borderline lung function or exercise capacity, despite the low scientific evidence.

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    IBS17 - Undertaking Nursing and Allied Health Research...How to Survive It and Get Published (Ticketed Session) (ID 48)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Nursing and Allied Professionals
    • Presentations: 2
    • Now Available
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      IBS17.01 - Undertaking Nursing and Allied Health Research - How to Survive It and Get Published (Now Available) (ID 3366)

      07:00 - 08:00  |  Presenting Author(s): Kahren White

      • Abstract
      • Presentation
      • Slides

      Abstract

      The nursing and allied health professions include a diverse range of disciplines, such as many different specialist nurses, physiotherapy, occupational therapy, speech and language pathology, dietetics, social work, and others. The foundation of modern health service interventions is that of evidence-based practice, to ensure that patients are receiving interventions that have been proven, through robust research, to provide benefit for the patient. Nursing interventions have a longer history of research underpinning them than allied health. In the allied health professions, there remains a dearth of robust research providing a clear evidence base for interventions routinely used. This presentation will focus on the challenges faced by both nurses and allied health professionals, particularly clinicians, in undertaking research and, once a research study is completed, how to get the research published. This is even more challenging in the general speciality of oncology and within the sub-specialty of lung cancer.

      The lack of research among nursing and the allied health professions is not a new phenomenon. My unpublished undergraduate thesis for the BAppSc(OT) in 1994 was titled ‘The replication of research in the health sciences’, investigating the level of replication of research in occupational therapy, physiotherapy, speech pathology and nursing. The aim of this research was to ensure the scientific knowledge base of the interventions being utilised were valid and reliable. The outcome of the research demonstrated a significant limitation in the replication of research, with many interventions being utilised by these professions not having a strong evidence base, or any evidence base at all. Twenty-five years later the scientific base for these professions, as well as dieticians and new and emerging allied health professions, has improved. In the field of occupational therapy most national professional bodies now have a focus on supporting research through funding and the dissemination of research findings.

      How does a novice clinical researcher go about funding, designing, implementing and publishing a research study? One of the keys for novice researchers is to find an academic or clinical research mentor, who is able to support you in navigating the muddy waters of clinical research. Clinical research is key to ensuring research projects are designed to meet the needs of our rapidly changing clinical environment, emerging clinical areas and interventions. There are many challenges in being a clinical researcher. These include a lack of research competency and training, the pressure of large clinical caseloads, a lack of support from within nursing and allied health departments, as well as at a hospital level, where the priority is primarily for patient intervention, not research.

      In this presentation I will outline how I navigated my initial clinical research in lung cancer and progressed over time to become an applied public health researcher in cancer control. Throughout this research progression I have had the support of mentors and supervisors while completing higher degrees, as well as clinical champions in my workplaces. I will outline the steps required to develop a research project, including protocol development, practical tips for managing Human Research Ethics and Governance Committee applications, data collection and management.

      Once your research study is complete what next? Publish or perish remains a key concept for nursing and allied health professionals. While in some health conditions, such as paediatrics, spinal cord injury, and acquired brain injury to name a few, there is a strong body of evidence for allied health interventions, in oncology, specifically lung cancer, a dearth of evidence from the allied health professions continues. There has been an improvement in research in some specific areas of lung cancer management which involves allied health professionals, such as in exercise, rehabilitation, and psychosocial support. However, significant gaps in the evidence base for allied health interventions for people living with lung cancer remain.There has been a growth in nursing research, particularly in lung cancer, but how robust is this research output? Is the nursing profession producing robust RCT studies that inform clinical practice?

      Internationally, both nursing and allied health professionals may be completing research or quality improvement activities that are building on their evidence base. However, they may not be publishing these important findings. It is critical that the work being done is published and further built on, with ongoing research and investigation, to ensure a robust and evolving evidence base for all nursing and allied health interventions being provided to patients.

      There continues to be a dearth of research studies by allied health professionals, particularly in the area of oncology and more specifically lung cancer. For our professions to continue to grow in this speciality area and demonstrate our benefit, we need to engage and support clinicians to bring research into their daily clinical practice, to ensure a robust evidence base in oncology, and more specifically lung cancer, is developed.

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      IBS17.02 - How to Get Your Research Published (Now Available) (ID 3367)

      07:00 - 08:00  |  Presenting Author(s): Tom John

      • Abstract
      • Presentation
      • Slides

      Abstract

      It is becoming increasingly important for researchers to not only ask and answer questions, but to disseminate the information gained to the wider community. One of the most important and indeed respected means of disseminating information is publish your results in a peer reviewed journal. While this may sound very straightforward, those who have tried to publish their data will be familiar with the frustration with peer reviewers, of rejection without peer review, rejection following extensive peer review or the need to submit a completely revised manuscript.

      Here I will discuss some of the key principles of getting your paper published, based on my experience as an author, reviewer and associate editor.

      I will go cover a range of areas from writing a good cover letter, what to include in the paper, to how to respond to reviewers.

      There are no guarantees to getting your paper published where you want the first time round, but these pointers will hopefully enable you to pick the right type of publication, the right journal and the best way to frame your paper.

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    IBS28 - Managing Side Effects for Better Quality of Life (Ticketed Session) (ID 59)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Advocacy
    • Presentations: 2
    • Now Available
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      IBS28.01 - The Use of Digital Medicine for Symptoms Management in Lung Cancer Patients (Now Available) (ID 3402)

      07:00 - 08:00  |  Presenting Author(s): Rossie Navon

      • Abstract
      • Presentation
      • Slides

      Abstract

      The use of digital medicine for symptom management in lung cancer patients

      Lung cancer is one of the most common cancers affecting both men and women. Lung cancer is associated with high symptom burden and psychological distress. As a result, lung cancer patients’ family caregivers also show high rates of distress. In addition, the common treatments, radiation and chemotherapy, may have severe side effects. Both treatments disrupt normal daily living activities and diminish well-being. Hence, symptom management in lung cancer patients may lead to improvements in various aspects, such as: quality of life, emotional stability and supportive environment. Additionally, the prolonged longevity of lung cancer patients nowadays significantly increased the burden of symptom management on the health system. Therefore, the need to optimize symptom management is of great significance.

      Contemporary technology enables the use of digital medicine, to provide information and interaction with patients in order to improve symptom management. It can help in overcoming several barriers and in reducing the health system's costs. For example, gathering information about the patients' needs may help health care providers to adjust and improve the services according to the principles of personalized medicine; frequent automated digital reminders may improve patients' collaboration during treatments. Patients' confusion and uncertainty that may lead patients to avoid consulting about symptoms, can be prevented by using on line follow-up regarding these symptoms. Enhancement of the care provided to people with cancer can be translated into reduction in symptom prevalence and/or burden and, possibly, reduction in unnecessary hospital admissions, hospitalization days, or clinic visits.

      A particular population which may benefit from the use of digital medicine is patients from rural areas. These patients lack accessibility medical services. Inaccessibility causes delays in diagnosis, treatment, and follows up, as well as unavailability of advanced care including multimodality treatment options and enrollment in clinical trials.

      Computer-based systems which employ interactive telecommunication technology have a great potential for a revolutionary impact on healthcare delivery by expanding accessibility and reducing costs. This is particularly true for those using computer-controlled telephony known as interactive voice response technology.

      This presentation will bring conclusions from several digital medicine symptom management programs, and emphasize lessons which can be learned from their results and possible directions for the future.

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      IBS28.02 - Palliative Care for Improved Quality of Life; It’s Not End of Life Care (Hospice) (Now Available) (ID 3403)

      07:00 - 08:00  |  Presenting Author(s): Nicoleta Mitrea

      • Abstract
      • Presentation
      • Slides

      Abstract

      Since 1967, when the first Hospice has been opened by Dame Cicely Sounders (founder of St. Christopher’s Hospice, London, England), and palliative care has been blended with hospice, several definitions have been given to palliative care and hospice terms. In 1997, the palliative care definition by Field and Cassel was short and simple: "palliative care is seeking to prevent, relieve, reduce or soothe the symptoms of disease or disorder without effecting a cure". The current most common references for palliative care definition is the World Health Organization's, 2002: "Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual." (Sepulveda et al., 2002). Variations in defining palliative care have recently caused controversies among professionals in the multidisciplinary teams, as it is now the case with the definition given by International Association for Hospice and palliative care: "Palliative care is the active holistic care of individuals across all ages with serious health-related suffering due to severe illness, and especially of those near the end of life. It aims to improve the quality of life of patients, their families and their caregivers." (IAHPC, 2018). Even more controversies are surrounding the term Hospice as confusion exists regarding the differences and overlaps between hospice and palliative care.

      In this presentation several definitions of terms will be discussed, including palliative care, quality of life, hospice and death. In order to better illustrate the case, the principles of palliative care will be remembered: holistic care, objective of care = improved quality of life, affirms life and regards death as a normal process, doesn’t hasten or postpone death, patient in the center of care and families as units of care, care provided by a multidisciplinary team, bereavement support for families. Some suggestions will be made for aligning to the reality of living a finite life and for the acceptance of the universal mystery of death.

      Palliative care and hospice need to be destigmatized and promoted among both, the general public and the healthcare professionals, in order to be early on integrated in the trajectory of a serious disease progression. For this reason, the bow tie model of 21st century for palliative care - the enhanced model, will be described.

      In conclusion, palliative and hospice are about: quality of life, being human, meaningful relationships, control of pain and other symptoms, respect for the dignity of the person, growing throughout the trajectory of the disease. The take home message is valuable for all of us: “You matter because you are you. You matter to the last moment of your life, and we will do all we can, not only to help you die peacefully, but to live until you die.” (Dame Cicely Saunders)

      References:

      Field, M.J., & Cassel, C.K., (1997). Approaching death: Improving care at the end of life (Report of the Institute of Medicine Task Force). Washington, D.C.: National Academy Press.

      IAHPC. Global Consensus based palliative care definition. (2018).Houston, TX: The International Association for Hospice and Palliative Care.
      Retrieved from https://hospicecare.com/what-we-do/projects/consensus-based-definition-of-palliative-care/definition/

      Sepulveda, C., Marlin, A., Yoshida, T. & Ulrich, A. (2002). Palliative Care: The World Health Organization's global perspective. Journal of PAin & Symptom Management, 24(2), 91-96.

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    IS04 - Symposium by Bristol-Myers Squibb: Point/Counterpoint: Maximizing the Impact of I-O Across NSCLC (Not IASLC CME Accredited) (ID 368)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 12
    • Now Available
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      MA07.01 - Circulating Immature Neutrophils, Tumor-Associated Neutrophils and dNLR for Identification of Fast Progressors to Immunotherapy in NSCLC (Now Available) (ID 1618)

      13:30 - 15:00  |  Presenting Author(s): Laura Mezquita  |  Author(s): Patricia Martin-Romano, Edouard Auclin, Boris Duchemann, Lydie Cassard, David Planchard, Marie Naigeon, Ithar Gataa, Melinda Charrier, Roberto Ferrara, Lisa Boselli, Jonathan Grivel, Maud Ngocamus, Julien Adam, Nathalie Chaput, Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Neutrophils are active regulators of the antitumor immune response, with pro- and antitumor- properties, but generally are associated with progression (PD) and poor outcomes. We reported that pretreatment dNLR ((neutrophils/[leucocytes-neutrophils]; high>3) correlated with immune checkpoint inhibitor (ICI) outcomes in advanced (a) NSCLC pts. Although neutrophil population is heterogeneous, the immature neutrophils (i.e. CD15+CD244-CD16low, among others) seem to be a key subpopulation linked to PD. Tumor-associated neutrophils (TAN) can be also modulator on the microenvironment. We aimed to assess the role of pretreatment circulating immature-neutrophils and tissue-TAN, combined with dNLR, on ICI outcomes in aNSCLC pts.

      Method

      aNSCLC pts treated with ICI at our institution between 11/2012 and 08/2018 were eligible. Pretreatment immunophenotyping of monocytes, monocytic MDSC (mMDSC) and granulocytes (CD15, CD11b, CD33, CD244, CD16, CD14, CD32, CD64, HLA-DR) was prospectively performed by flow cytometry in fresh whole blood in 58 pts; we defined immature-neutrophils as CD15+CD244-CD16low. TAN in the stroma were assessed using H&E staining from archival specimen, available from 80 pts. dNLR was retrospectively collected; available from 343 pts. Correlation between baseline circulating neutrophils phenotype, TAN and dNLR was evaluated as well as their impact on outcomes: progression-free survival (PFS), overall (OS), including death before 12 weeks (12wk-death) (fast-PD)

      Result

      366 pts included; 320 (90%) smokers, median age 63; 280 (77%) nonsquamous, 117 (64%) ≥1%PDL1 and 183 missing. Median PFS (mPFS) was 1.93 months (m) [95%CI, 1.8-2.3] and mOS 8.8m [6.5-11.6]. Overall, 12wk-death rate was 31% [25.9-35.6].

      Pretreatment high-dNLR (143/343; 42%) was correlated with poor PFS (P=0.002), OS P=0.0003) and a 12wk-death rate of 43% [34.5-50.9]. Pretreatment high immature-neutrophils (30/58; 53%), defined by logrank maximization method (>0.22%), were also associated with poor PFS (P=0.04), OS (P=0.0007) and a 12wk-death rate of 48.7% [26.7-64.1]. TAN (9/80; 11%) were not correlated with outcomes. There was not a correlation between immature-neutrophils, tissue-TAN and dNLR.

      When evaluating pretreatment immature-neutrophils and dNLR together, we identified a fast-PD phenotype (high immature-neutrophils/high-dNLR, 10/58; 17%), with a mOS of 1.3m [0.73- not reached (NR)] and 12wk-death rate of 60% [14.5-81.3] compared to a responder-phenotype (low immature-neutrophils/low-dNLR, 12/58; 21%), associated with good outcomes: mOS NR [18.23-NR] (P=0.002).

      Conclusion

      Pretreatment high circulating immature-neutrophils (CD15+CD244-CD16low) correlate with early failure to ICI and fast-PD phenotype. The combination of circulating immature-neutrophils and dNLR could improve the identification of this population. The impact of immature-neutrophils on ICI should be more deeply explored.

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      • Abstract
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      Background

      The [neutrophils/[leucocytes-neutrophils] ratio (dNLR) correlates with immune checkpoint inhibitors (ICI) outcomes in advanced non-small cell lung cancer (aNSCLC) patients. Significance of early dNLR change after the first course of ICI is unknown.

      Method

      Patients with NSCLC treated with ICI (PD(L)1+/-CTLA4) between Nov. 2012 and Jun. 2018 at 16 EU/US centers were included. A control group treated with chemotherapy (CT) only was also evaluated (NCT02105168). dNLR was collected at baseline (B) and at cycle 2 (C2). Patients were categorized as low vs high dNLR at each timepoint (defined as < vs > 3, as previously done), and the change between B and C2 (good = low at both timepoints, poor = high at both timepoints, mixed = different at each timepoint).

      Result

      1485 patients treated with ICI were analyzed. PDL1 was negative in 162 (11%), 1-49% in 178 (12%), ≥50% in 201 (14%), and missing in 944 (64%). dNLR at B and C2 did not associate with PD-L1 status.

      At baseline, dNLR was high in 509 (34%) patients and associated with worse PFS compared to those patients with low dNLR at baseline (HR 1.56, P<0.0001) and OS (HR 2.02, P<0.0001). At C2, dNLR was high in 484 (34%) and similarly associated with worse outcomes compared to patients with low dNLR at C2 (PFS HR 1.64, P<0.0001; OS HR 2.13, P<0.0001).

      Between B and C2, dNLR remained low in 804 (56%, « good ») or high in 327 (23%, « poor ») or changed in 310 pts (22%, « intermediate »). Those with a good dNLR demonstrated mPFS 5.3, mOS 18.6 mo), followed by those intermediate with mixed dNLR (mPFS 3, mOS 9.2 mo), and finally poor dNLR (mPFS 2, mOS 5mo). Outcomes were independant of PD-L1 expression (adjusted HR for PFS 1.94 for intermediate and 3.16 for poor groups, compared to good dNLR group, P<.001; adjusted HR for OS was 2.08 for intermediate and 3.67 for poor groups, P<0.001).A bootstrap tested the stability of OS/PFS prediction (P<0.001).

      In the chemo-cohort (n=173), high C1-dNLR (n=81, 47%) was not associated with OS (P=0.84).

      Conclusion

      dNLR at baseline, at cycle 2, and the change between these two timepoints associated with outcomes in patients treated with immunotherapy independent of PD-L1, but not in patients treated with chemotherapy alone. dNLR is specifically prognostic in the context of immunotherapy.

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      MA07.03 - A Circulating MicroRNAs-Based Test as Biomarker of Primary and Secondary Resistance in PD-L1 ≥50% NSCLC Treated with Immunotherapy (Now Available) (ID 2495)

      13:30 - 15:00  |  Presenting Author(s): Claudia Proto  |  Author(s): Arsela Prelaj, Carla Verri, Diego Signorelli, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Benedetta Trevisan, Mavis Mensah, Filippo Guglielmo Maria De Braud, Marina Chiara Garassino, Gabriella Sozzi, Mattia Boeri

      • Abstract
      • Presentation
      • Slides

      Background

      PD-L1 represents the only clinically approved biomarker to select patients for immunotherapy. However, about 20-25% of PD-L1≥50% NSCLC patients do not benefit of ICIs treatment. We showed that a plasma microRNA signature classifier (MSC), reflecting the switch towards an immunosuppressive profile of immune cells, identifies NSCLC patients with worse prognosis after ICIs, irrespective from PD-L1 expression. Aim of this trial is to prospectively define the MSC role as biomarker of primary or secondary resistance in PD-L1≥50% NSCLC treated with ICIs.

      Method

      Fifty consecutive advanced NSCLC patients with PD-L1≥50% treated with ICI as first (n=32) or further line were enrolled. Plasma samples, as well as demographics information, smoking history and ECOG PS were collected before starting ICI treatment. The MSC test identified patients at high (H) risk vs intermediate/low (I/L) risk levels. According to RECIST 1.1 criteria, patients were classified as responders (R), patients with stable disease (SD), and progressors (P). Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) in MSC risk level strata at the baseline were considered as endpoints. For 26 R or SD patients with extended follow-up, additive, not mandatory plasma samples were collected and analyzed at the time of revaluations. To determine changes in the risk level during follow-up, we evaluated changes in the probability of having progressive disease after two consecutive MSC tests, considering all possible combinations.

      Result

      Overall 17 (34%) R, 17 (34%) patients with SD, 11 (22%) P and 5 (10%) not evaluable patients were identified. Considering the baseline blood samples 11 (22%) NSCLC patients were MSC H. ORR was 0% in MSC H vs 45% for other patients (p=0.0090). Median PFS was 2.3 months for MSC H vs 10.9 months for other patients (HR=0.38; 95%CI=0.17-0.84; p=0.0174). Median OS was 2.9 months for MSC H vs 22.0 months for other patients (HR=0.18; 95%CI=0.07-0.47; p=0.0004). Data remained significant adjusting for age, sex, pack-years and ECOG performance status: PFS HR=0.31 (95%CI=0.13-0.73; p=0.0072) and OS HR=0.13 (95%CI=0.04-0.39; p=0.0003). Among the 26 patients with longitudinal evaluation of MSC risk level, all the 12 patients reaching progression during treatment showed an increase in the risk level (Sign-test p-value=0.0039). Conversely, when considering the 14 NSCLC patients still maintaining SD or responding to ICIs at the time of the analysis, the risk level decreased for 9 (64%) of them (Sign-test p-value=0.1655).

      Conclusion

      These preliminary results suggest that MSC risk level at the baseline and during treatment could help to identify primary or secondary resistance in PD-L1≥50% NSCLC patients treated with ICIs. Ongoing clinical trials are validating these results.

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      MA07.04 - Discussant - MA07.01, MA07.02, MA07.03 (Now Available) (ID 3739)

      13:30 - 15:00  |  Presenting Author(s): Sara Pilotto

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
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      Background

      Anti-PD1/PDL1 deeply changed the NSCLC therapeutic algorithm in the past few years. Unfortunately, a majority of patients experiences disease progression. ICPis re-challenge could be an attractive option but no data supporting this strategy are available. Here we report outcomes of a large cohort of NSCLC patients treated with anti-PD1/PDL1 re-challenge.

      Method

      We retrospectively collected data about 144 advanced NSCLC patients (diagnosis between 2010 and 2018) from 26 French centers. Patients were re-challenged with ICPis after at least 12 weeks of discontinuation for toxicity, disease progression or clinical decision. Progression Free Survival (PFS) and Overall Survival (OS) were calculated from the start of first or second ICPi to disease progression (PFS1;PFSR) and death or last follow-up (OS1;OS2) respectively.

      Result

      Median age was 63 year [39 –83], most of patients were male (67%), smokers (87%), adenocarcinomas (62%) and stage IV at diagnosis (66%). Most of patients received the first ICPi round in first or second line (66%) and the second ICPi round in third line or later (79%). In both settings patients received preferentially an anti-PD1 (87%) and no differences were detected regarding brain metastasis or ECOG PS (P = 1.10-1 and P = 1.10-1 respectively). The Best Response during the re-challenge was not associated to that one achieved to the first ICPi (P = 1.10-1). The median PFS1 and PFSR were 13 months [95% CI 10-16.5] and 4.4 months [95% CI 3-6.5] respectively. PFSR was longer in patients discontinued because of clinical decision (6.5 months [95% CI 2.5-11.9]) or toxicity (5.8 months [95%CI 3.5-18]) compared to disease progression (2.9 months [95% CI 2.0-4.4]) (P = 2.10-2) and in those not receiving chemotherapy between the two ICPis (5.8 months [95%CI 4.1-10.5]) compared to those who did (3.0 months [95% CI 2.0-4.4])(P = 2.10-3). Median OS1 was 3.3 years [95% CI 2.9-3.9] without differences according to the discontinuation reason (P =2.10-1). Median OS2 was 1.5 y [95%CI 1.0-2.1] and was longer in patients discontinuing the first ICPi due to toxicity (2.1y [95%CI 1.4-NR]) compared to disease progression (1.0y [95%CI 0.4-1.5]) or clinical decision (1.5y [95%CI 0.4-NR]) (P = 3.10-2). Neither OS1 nor OS2 were affected by treatments received between the two ICPis (P = 3.10-1 and P = 1.10-1 respectively).

      Conclusion

      ICPis re-challenge might be a useful option mainly in patients discontinuing the first ICPi because of toxicity or clinical decision and in those able to keep a treatment-free period between the two ICPis.

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      MA07.06 - Immunotherapy Re-Challenge After Nivolumab Treatment in Advanced Non-Small Cell Lung Cancer in French Real-World Setting (Now Available) (ID 1281)

      13:30 - 15:00  |  Presenting Author(s): Matteo Giaj Levra  |  Author(s): François-Emery Cotté, Romain Corre, Christophe Calvet, Baptiste Jouaneton, Ronan Jolivel, Anne-Françoise Gaudin, Valentine Grumberg, Jean-Baptiste Assié, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Real‐world evidence of nivolumab as treatment for advanced non-small cell lung cancer (aNSCLC) can complement evidence from clinical trials to optimize routine usage and personalization of care. Further, little is known about treatment options and outcomes after discontinuation of nivolumab.

      Method

      Based on the National hospitals database (PMSI), we built a retrospective cohort of all NSCLC patients (ICD code: C34*) starting nivolumab in 2015-2016 and followed them until Dec 2017. Information on patients’ baseline characteristics (demographics, comorbidities, treatment history) was retrieved. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Time to treatment discontinuation (TTD) and overall survival (OS) were estimated with Kaplan-Meier methodology. Re-challenged patients were analyzed according to their first nivolumab treatment duration i.e. <3; 3-6; ≥6 months.

      Result

      We identified 10,452 NSCLC patients initiating nivolumab during the inclusion period (male: 71%; mean age; 63.8±9.6 years; squamous histology: 44%; cerebral metastasis: 17.4%; median aNSCLC history: 12.5 months; previous curative surgery: 15.6%; median time since first chemotherapy: 10.5 months; mean dose of nivolumab: 213±54mg). Median TTD and OS were 2.8 months and 11.6 months. One-year and 2-year OS rates were 48.8% and 27.4%. Overall, 5118 (53.4%) patients received subsequent systemic therapy after nivolumab discontinuation. Among them, 1517 patients (29.6%) were re-treated with anti-PD1 agents (nivolumab: 98.8%) either after a therapeutic break (‘immunotherapy resumption group’: n=1127; mTTD: 4.1 months; mOS: 14.9 months from second initiation) or after chemotherapy (‘immunotherapy re-challenge group’: n=390; mTTD: 3.0 months; mOS: 18.2 months from second initiation). The Figure presents OS curves of the ‘re-challenge group’ according to first nivolumab treatment duration.

      graph os re-challenge according to ttd 1st nivo.jpg

      Conclusion

      After nivolumab discontinuation, around 30% of patients received immunotherapy again, either as a resumption or as a re-challenge following non-immunotherapy treatment. The influence of the first nivolumab treatment duration on re-challenged patients' OS should be further investigated.

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      MA07.07 - Discussant - MA07.05, MA07.06 (Now Available) (ID 3740)

      13:30 - 15:00  |  Presenting Author(s): Helena Linardou

      • Abstract
      • Presentation
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      Abstract not provided

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      MA07.08 - The Role of a Cachexia Grading System in Patients with NSCLC Treated with Immunotherapy: Implications for Response and Survival (Now Available) (ID 2046)

      13:30 - 15:00  |  Presenting Author(s): Jenny Georgina Turcott  |  Author(s): Andrés Felipe Cardona, Laura Alejandra Ramírez-Tirado, Zyanya Lucia Zatarain Barrón, Feliciano Barrón, Luis Corrales, Claudio Martin, Pablo Alan Barragán Castillo, Diana Flores-Estrada, Alejandro Ruiz-Patiño, Oscar Gerardo Arrieta

      • Abstract
      • Presentation
      • Slides

      Background

      The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes is well established. However, many of these studies were performed in the chemotherapy era. Meanwhile, current standard of care for NSCLC patients has shifted towards the more efficacious immunotherapy agents (IO). IO has improved survival outcomes, nonetheless clinicians face the challenge of identifying who will derive substantial clinical benefit from these more costly agents. Response to IO is influenced by several patient-related factors, including microbiome, medications, and nutritional status.

      Method

      In this study we sought to evaluate the effect of cachexia in survival of NSCLC patients undergoing treatment with IO. Included patients had advanced NSCLC (IIIB, IV), who received IO agents in any line of therapy, and had a good performance status. All the patients were evaluated by the nutritionist specialist and were graded according to a previously documented cachexia scale which takes into consideration body mass index (BMI) and weight loss in order to stratify patients into 5 risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS), secondary endpoints included objective response rate (ORR) and progression-free survival.

      Result

      A total of 181 patients met the inclusion criteria and were included in the analysis. Among these 82 (45%) were classified in the first category (risk grade 0-1 [low risk]), 83 (46%) were classified in the second category (risk grade 2-3[intermediate risk]) and 9% were in the third category (risk grade 4 [high risk]). Patients classified as low-risk had a significantly longer OS compared to those with intermediate or high risk (22.4 months [95%CI: 18.7-26.1] vs. 15.7 [95%CI: 10.8-20.7] vs. 3.9 [0.0-7.8]; p<0.001; Hazard ratio: 1.81 [1.29-2.53]; p<0.001). In the multivariate analysis ORR, hemoglobin and risk category were independent factors associated with OS. Grade of cachexia was also significantly associated with ORR, with low-risk patients having a significantly higher ORR compared to intermediate and high-risk patients (36.6% vs. 17.3% vs. 25%; p=0.021). PFS was also influenced by risk category, with low risk patients having a longer PFS compared with intermediate and high-risk patients. diapositiva1.jpg

      Conclusion

      Cachexia is independently associated with worse OS in NSCLC patients who receive IO, while better nutritional status is related to higher ORR, highlighting a potential role for nutritional assessment in the selection of patients who are candidates for IO. Early assessment of nutritional status in these patients is imperative in order to timely diagnose and treat anorexia-cachexia and improve outcomes.

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      MA07.09 - Impact of Body Mass Index on Clinical Outcomes of Immune Checkpoint Blockers in Advanced Non-Small Cell Lung Cancer (Now Available) (ID 653)

      13:30 - 15:00  |  Presenting Author(s): Amit Arun Kulkarni  |  Author(s): Shijia Zhang, Todd De For, Manish Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Studies have suggested that obesity may have a paradoxical effect on the efficacy of immune check-point blockers (ICB). Higher Body Mass Index (BMI) has been associated with favorable outcomes with ICB. There is limited data on the impact of BMI on ICB efficacy in real-world patients with advanced non-small-cell lung cancer (NSCLC). We evaluated whether BMI is associated with survival outcomes in metastatic NSCLC patients treated with ICB.

      Method

      We identified advanced NSCLC patients treated with anti-PD1/PD-L1 at our institution between 5/2015 to 1/2019. Data regarding BMI at the beginning of ICB treatment were collected. Patients with BMI > 25 (overweight and obese) were assigned to high-BMI group and patients with BMI < 25 were assigned to low-BMI group. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Cox proportional hazards model were used for statistical analysis.

      Result

      148 patients with NSCLC were eligible for inclusion. The median follow-up time was 12 months. Median age was 66 years. Majority of patients were female (52.1%), Caucasian (93%), had adenocarcinoma histology (66%), current or previous smokers (88%) and received Nivolumab (88%) in the 2nd or later line setting. The median number of treatment doses were 7. Median BMI of the patient population was 25.4 kg/m2. 64/148 (43%) of patients were in the low-BMI group (BMI < 25) and 84/148 (57%) patients were included in the high-BMI group (BMI > 25). Patients in high-BMI group had superior OS (HR=0.64, 95% CI 0.45-0.90; p=0.01) that was statistically significant. 1-year OS was 46.4% and 39.0% in the high-BMI and low-BMI group respectively. PFS was also greater in high-BMI group with a trend towards statistical significance (HR=0.73, 95% CI 0.51-1.03; p=0.07). 1-year PFS was 25.0% and 15.6% in the high-BMI and low-BMI group respectively. In multivariate analysis, OS benefit remained statistically significant after adjustment for clinical covariates (age, sex, performance status, number of previous lines of therapy, smoking status and brain metastasis).

      Conclusion

      Our study provides independent validation of previously published results demonstrating an association of BMI with survival outcomes in NSCLC patients treated with ICB. The OS benefit in the high-BMI group is independent of classical prognostic factors. While the reasons underlying this relationship remains unknown, prospective studies are needed to confirm this association. Future clinical trials with ICB should consider stratification of patients based on BMI.figure 1.png

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      MA07.10 - The Influence of Sex on Immunotherapy Efficacy in Non-Small Cell Lung Cancer (Now Available) (ID 712)

      13:30 - 15:00  |  Presenting Author(s): Stephanie Tuminello  |  Author(s): Rajwanth Veluswamy, Naomi Alpert, John Lazar, Raja Flores, Maaike Van Gerwen

      • Abstract
      • Presentation
      • Slides

      Background

      Patient’s sex impacts clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC). A recent meta-analysis demonstrated sex may also impact response to novel immunotherapeutic agents, where men appear to derive greater benefit than women. However, the role of important clinical confounders of immunotherapy response that differ according to sex was not accounted for. The aim of this project was to investigate the effect of sex on immunotherapy benefit for NSCLC patients using a large, nationally representative database while adjusting for important clinical confounders.

      Method

      Advanced metastatic NSCLC patients diagnosed between 2013-2015 were identified in the National Cancer Database (NCDB). A Cox Proportional Hazards model was used to assess the interaction between sex and immunotherapy treatment for overall survival. This model was also adjusted for histology, stage, age, race, tumor size, comorbidities and other treatment (i.e. chemotherapy, radiation).

      Result

      Of 103,525 advanced NSCLC patients, 69,120 (67%) had adequate follow-up information for survival analysis. Of these, 37,423 (54.1%) were males and 31,697 (45.9%) females; 4,012 patients received immunotherapy as first-course treatment. In the adjusted model, both males (Hazard Ratio [HR]adj: 0.77, 95% Confidence Interval [CI] 0.73-0.81) and females (HRadj: 0.80, 95% CI 0.76-0.85) receiving immunotherapy had improved survival compared to those not receiving immunotherapy. The interaction between sex and immunotherapy was not significant (p=0.2539) after adjusting for clinical variables. Among the covariates, younger age, adenocarcinoma histology, Black race, smaller tumor size, lower comorbidity score and additional cancer treatment (either chemotherapy or radiation) were independently associated with better survival (p<0.0001 for all comparisons).

      Conclusion

      Patient sex does not appear to affect the benefit of immunotherapy in advanced NSCLC patients after adjusting for potential clinical confounders. Other clinical factors may play a role in immunotherapy response and should be explored in future research.

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      MA07.11 - Survival Outcomes Based on Gender of Advanced Nonsmall Cell Lung Cancer Patients Treated with Pembrolizumab or Nivolumab in Everyday Clinical Practice (Now Available) (ID 841)

      13:30 - 15:00  |  Presenting Author(s): Doran Ksienski  |  Author(s): Elaine S Wai, Nicole Croteau, Ashley T. Freeman, Leathia Fiorino, Angela Chan, Dave Fenton, Georgia Geller, Edward Brooks, Zia Poonja, Sarah Irons, Mary Lesperance

      • Abstract
      • Presentation
      • Slides

      Background

      Women are underrepresented in clinical trials of PD1 Ab. We investigated the relationship between gender and overall survival (OS) in aNSCLC patients (pts) treated with PD1 Ab in a large Canadian provincial cohort.

      Method

      All aNSCLC pts treated with nivolumab (NIV) or pembrolizumab (PEM) between 06/2015 and 11/2018 at BC Cancer were identified. Demographic, tumor, treatment details, and survival status were collected from chart review. Kaplan-Meier (KM) curves of OS from initiation of PD1 Ab were generated and compared by the log-rank test.

      Result

      Of 527 pts analyzed (58.9% NIV, 36.1% PEM), 50.5% were female. Women were more likely to have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0/1 at PD1 Ab initiation (72.9% vs. 64.8%, p=0.05), lower median Charlson Comorbidity Index score (CCI, 2.0 vs. 3.0, p=0.006), and tumors with non-squamous histology (83.5% vs. 69.7%, p<0.001) or Epidermal Growth Factor Receptor (EGFR) mutation (9.8% vs. 3.4%, p=0.006). No significant gender variation in age at diagnosis, smoking status, and programmed death ligand 1 tumor proportion score (PD-L1 TPS) was observed. In addition, there were no differences in type of PD1 Ab, line of treatment, duration of treatment, or treatment discontinuation due to immune related adverse events. With a median follow-up of 16.3 months by reverse KM method, 65% of pts had died. In the entire cohort, women had a longer median OS than men (10.2 vs. 8.1 months, p=0.029). In the subgroup of ECOG PS 2/3 pts, men had worse OS (3.9 vs. 6.5 months, p=0.034). Women ≥60 years of age at initiation of PD1 Ab demonstrated superior median OS to men (12.2 vs. 6.1 months, p=0.006). On multivariable analysis of NIV pts, male gender (HR=1.3, 95% CI 1.0-1.7, p=0.02), baseline ECOG PS 2/3 (HR=2.5, 95% CI=1.9-3.2 p<0.001), CCI score≥3 (HR=1.6, 95% CI=1.3-2.1, p<0.001), and EGFR/ALK aberration (HR=2.3, 95% CI 1.4-3.9, p<0.001) predicted for worse survival; for PEM pts, only ECOG PS 2/3 (HR=2.5, 95% CI 1.6-3.9, p<0.001) was associated with OS.

      Conclusion

      In this large series with a significant proportion of women, females treated with PD1 Ab for aNSCLC lived longer than men (especially if ECOG PS 2/3 or age≥ 60 years.) Despite similarities in smoking status and PD-L1 TPS, gender divergence in outcome could be attributed to more favorable histology and baseline ECOG PS in females. Increased enrollment of women in PD1 Ab trials would facilitate evaluation of gender as a predictive variable.

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      MA07.12 - Discussant - MA07.08, MA07.09, MA07.10, MA07.11 (Now Available) (ID 3741)

      13:30 - 15:00  |  Presenting Author(s): Sonja Loges

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Now Available
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      MA13.01 - Associations Between Baseline Serum Biomarker Levels and Cachexia/Pre-Cachexia in Pretreated Non-Small Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 2991)

      14:00 - 15:30  |  Presenting Author(s): Jeffrey Allen Borgia  |  Author(s): Gabriela C Lobato, Mary Jo Fidler, Jared D Fialkoff, Maneet Multani, Conner Wakefield, Sanjib Basu, Marta Batus, Philip Bonomi

      • Abstract
      • Presentation
      • Slides

      Background

      We previously reported associations of pretreatment serum biomarkers with clinical outcomes in a cohort of advanced NSCLC patients that progressed on front-line therapy. This study aims to elucidate mechanisms underlying cancer cachexia/ pre-cachexia by evaluating relationships between baseline serum biomarker values and sequential changes in body weight, body mass index (BMI), and neutrophil/lymphocyte ratio (NLR) in NSCLC patients.

      Method

      We used Luminex immunobead assays to survey 101 protein biomarkers in sera from advanced NSCLC (n=138) collected prior to their salvage regimen. Serial parameters associated with cancer cachexia included body weight, BMI, and NLR. Outcome variables (progression-free survival (PFS) and overall survival (OS)) were extracted with full IRB-approval. Biomarkers were evaluated as continuous variables with the cachexia surrogates using Pearson correlations, whereas associations of PFS and OS were accomplished with the Cox PH test.

      Result

      High baseline values of BMI and low baseline NLR were associated with both OS and PFS (each p<0.05), though weight failed to reach significance. PFS and OS were similarly associated with percent changes (relative to baseline) in weight (p<0.01), BMI (p<0.01), and NLR (p<0.001). Thirteen biomarkers were found to be associated (p<0.05) with baseline BMI values, including positive correlations with leptin, sol.VEGFR2, and c-peptide and inverse correlations with adiponectin, ferritin, ghrelin, IGFBP-1 and IL-8; fifteen biomarkers were associated with baseline NLR (all p<0.05), including positive correlations with visfatin, insulin, and serum amyloid A and inverse correlations with IGF-II. Fifteen biomarkers were found to be associated (p<0.05) in common with percent weight and BMI changes, including positive correlations with IGFBP-3 and inverse correlations with insulin, FGF-2, TNF-alpha, and resistin. Only prolactin and placental growth factor were found to be associated (p<0.05) with percent change in NLR.

      Conclusion

      A series of circulating protein biomarkers primarily connected with metabolic regulation and systemic inflammation/ acute phase response were found to be associated with cachexia/ pre-cachexia in NSCLC patients. Additional cohorts are currently being tested to verify these findings.

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      MA13.02 - Incidence of Venous Thromboembolism at the Time of Lung Cancer Diagnosis: A Multicenter, Prospective Observational Trial (Rising-VTE/NEJ037) (Now Available) (ID 1195)

      14:00 - 15:30  |  Presenting Author(s): Kosuke Hamai  |  Author(s): Yukari Tsubata, Naoki Furuya, Tae Hata, Ryota Saito, Takeshi Masuda, Takamasa Hotta, Megumi Hamaguchi, Shoichi Kuyama, Ryoichi Honda, Kikuo Nakano, Masamoto Nakanishi, Kunihiko Funaishi, Masahiro Yamasaki, Nobuhisa Ishikawa, Kazunori Fujitaka, Tetsuya Kubota, Kunihiko Kobayashi, Takeshi Isobe

      • Abstract
      • Presentation
      • Slides

      Background

      Venous thromboembolism (VTE) is a most well-known kind of cancer associated thrombosis, and a common complication of malignancy. However, little is known about the incidence of VTE at the time of lung cancer diagnosis. This information is important for clinicians and patients to inform their decision-making about cancer treatment.

      Method

      The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study with 40 participating Japanese institutions. It included 1,021 patients diagnosed with lung cancer unsuitable for radical resection or radiation between June 2016 and August 2018. The incidence of VTE and characteristics of patients diagnosed with VTE based on contrast-enhanced computed tomography or ultrasonography of the leg are described. Diagnosis of VTE was confirmed via central review by two radiologists.

      Result

      Baseline data was available for 1,013 patients. The median age was 71 years (range 30-94). Eighty-six percent of patients had non-small cell lung cancer and 13.5% had small cell lung cancer. Histological types included adenocarcinoma (N=645, 63.7%), squamous cell carcinoma (N=180, 17.8%), small-cell lung cancer (N=137, 13.5%) and others (N=42, 4.1%). There were 59 patients (5.8%) diagnosed with VTE, of whom 53.9% had deep vein thrombosis (DVT), 28.7% had pulmonary embolism (PE) and 24.6% had both DVT and PE. Most patients with VTE had adenocarcinomas (89.1%).

      Conclusion

      The incidence of VTE in this study seems to be higher than in the clinical setting, suggesting that screening may be desirable. Adenocarcinoma of the lung seems to be a risk factor for VTE that we should consider more carefully. The primary endpoint of this trial is the rate of symptomatic or asymptomatic recurrence or newly diagnosed VTE during 2 years after registration. Follow-up is ongoing, with a report of final findings planned for 2021. Clinical trial information: UMIN000020194. Funding: Daiichi Sankyo Company.

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      MA13.03 - Retrospective Study of Intrathecal Therapy for Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Carcinomatosis (Now Available) (ID 2086)

      14:00 - 15:30  |  Presenting Author(s): Noelia Vilariño  |  Author(s): Juan Antonio Marín, Marta Simó, Roser Velasco, Montserrat Alemany, Maria Jove, Jose Carlos Ruffinelli, Isabel Brao, Monica Arellano, Ramon Palmero Sánchez, Jordi Bruna, Ernest Nadal

      • Abstract
      • Presentation
      • Slides

      Background

      Leptomeningeal carcinomatosis (LMC) is a devastating cancer-related neurological complication with poor prognosis. In EGFR-mutant (mut) NSCLC patients (pts), osimertinib achieves high penetration into cerebral-spinal fluid (CSF) and promising efficacy. However, for EGFR-mut T790M-negative pts treated with prior 1st- and 2nd-generation tyrosine kinase inhibitors (TKI) and for driver negative NSCLC pts, a combination of intrathecal therapy (IT) and systemic therapy (ST) seems to be an appropriate approach. Our purpose is to explore the clinical outcome of IT combined with ST among NSCLC with LMC depending on EGFR status.

      Method

      NSCLC pts with LMC treated with IT in our institution between 2010 and 2018 were retrospectively studied. After LMC diagnosis, intrathecal methotrexate (scheduled: 12mg twice weekly for 4 weeks, then 12mg weekly for 4 weeks) was given in combination with ST. A Kaplan-Meier survival analysis was performed for overall survival (OS) and progression free survival (PFS).

      Result

      A total of 39 pts were included. Patient’s clinical characteristics are summarized in table 1. EGFR status was 17 mut (del19: 11pts); 11 wild-type (wt) and 11 unknown (unk). LMC and NSCLC diagnosis were more likely to be synchronous in EGFR wt compared with EGFR mut. The median follow-up from LCM diagnosis was 10.2 months. At the time of this analysis, only 6 pts were alive. Thirty-two pts received ST in combination with IT, 18 (46%) pts chemotherapy (6wt/ 3mut/ 9unk), while 14 (36%) pts an EGFR TKI (1wt/ 13mut). Clinical response (improvement of neurological symptoms and/or KPS) was seen in 11 (65%) EGFR mut pts vs 2 (18%) wt pts (p=0.033). Median OS and PFS for the whole cohort were 23 weeks (95%CI, 8.1 to 37.9) and 10 weeks (95%CI, 7.1 to 12.8) respectively. Median OS was higher for EGFR mut pts compared to wt pts, 38 weeks (95%IC 13.6-62.4) and 19 weeks (95%IC, 4.06-33.9) respectively, however this difference was not statistically significant (p=0.36) probably due to lack of statistical power.

      table1_lmc.jpg

      Conclusion

      Methotrexate-based IT given concurrently with systemic TKI may confer a higher clinical benefit and a trend toward OS benefit in NSCLC patients with LCM and EGFR activating mutations.

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      MA13.04 - Discussant - MA13.01, MA13.02, MA13.03 (Now Available) (ID 3776)

      14:00 - 15:30  |  Presenting Author(s): Ramaswamy Govindan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA13.05 - Nab-Paclitaxel Maintenance in Squamous Non-Small Cell Lung Cancer (NSCLC): Updated Results of the Phase III ABOUND.sqm Study  (Now Available) (ID 294)

      14:00 - 15:30  |  Presenting Author(s): David R Spigel  |  Author(s): Robert M Jotte, Santiago Ponce Aix, Laurent Gressot, Daniel Morgensztern, Michael McCleod, Mark A Socinski, Davey Daniel, Oscar Juan, Kathryn F Mileham, HOWARD WEST, Ray Page, Niels Reinmuth, Jeanna Knoble, Olivia Yu Tian, Rafia Bhore, Marianne Wolfsteiner, Teng Jin Ong, Cesare Gridelli, Michael Thomas

      • Abstract
      • Presentation
      • Slides

      Background

      Background: nab-Paclitaxel maintenance therapy after nab-paclitaxel/carboplatin induction in patients with advanced squamous NSCLC was evaluated in the phase III, randomized, controlled, open-label, multicenter ABOUND.sqm trial. At the 12-month follow-up, there was no statistically significant difference in progression-free survival (PFS) between patients randomized to maintenance nab-paclitaxel + best supportive care (BSC) vs BSC alone. However, a trend of an overall survival (OS) advantage was observed with nab-paclitaxel + BSC vs BSC alone. Here we report the 18-month follow-up of OS.

      Method

      Methods: Patients (aged ≥ 18 years) with histologically or cytologically confirmed stage IIIB/IV squamous NSCLC and no prior chemotherapy were eligible. Patients received four 21-day cycles of nab-paclitaxel 100 mg/m2 (days 1, 8, and 15) plus carboplatin AUC 6 (day 1) as induction. Patients with radiologically assessed complete or partial response or stable disease without clinical progression after 4 cycles were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 of each 21-day cycle) plus BSC or BSC alone until disease progression. The primary efficacy analysis was performed on the ITT population. PFS from randomization into the maintenance part of the study was the primary endpoint. Secondary endpoints included safety, OS (from randomization), and response.

      Result

      Results: 420 patients received induction therapy; 202 were randomized to maintenance nab-paclitaxel + BSC (n = 136) or BSC alone (n = 66). The median PFS in patients in the nab-paclitaxel + BSC arm vs those in the BSC-alone arm was 3.1 vs 2.6 months (HR, 0.85; P = 0.349), respectively; the median OS was 17.8 vs 12.2 months (HR, 0.71; P = 0.058), respectively. The overall response rate was 69.1% vs 57.6% (RRR, 1.20; P = 0.087). Following the maintenance part, 73.5% (nab-paclitaxel + BSC) and 68.2% (BSC alone) of patients received subsequent anti-cancer treatment. Over the entire study, the most frequent grade 3/4 TEAEs were neutropenia (53.1% vs 50.0%) and anemia (33.1% vs 32.3%); only peripheral neuropathy occurred in ≥ 5% of patients during maintenance (13.1% in the nab-paclitaxel + BSC arm).

      Conclusion

      Conclusion: Although PFS and OS differences were not statistically significant in the ITT population, the 18-month follow-up of OS demonstrated the feasibility of nab-paclitaxel maintenance therapy for patients with anced squamous NSCLC.

      ClinicalTrials.gov identifier: NCT02027428

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      MA13.06 - Ph3 Study of Maintenance Therapy with S-1 vs BSC After Induction Therapy with Carboplatin + S-1 for Advanced Squamous Cell Lung Cancer (WJOG7512L) (Now Available) (ID 563)

      14:00 - 15:30  |  Presenting Author(s): Kaoru Tanaka  |  Author(s): Satoshi Morita, Masahiko Ando, Takuma Yokoyama, Atsushi Nakamura, Hiroshige Yoshioka, Takashi Ishiguro, Satoru Miura, Ryo Toyozawa, Tetsuya Oguri, Haruko Daga, Ryo Ko, Akihiro Bessho, Motoko Tachihara, Yasuo Iwamoto, Katsuya Hirano, Yoichi Nakanishi, Kazuhiko Nakagawa, Nobuyuki Yamamoto, Isamu Okamoto

      • Abstract
      • Presentation
      • Slides

      Background

      Our previous phase 3 study established carboplatin plus the oral fluorinated pyrimidine formulation S-1 as a standard option for first-line treatment of advanced non–small cell lung cancer (NSCLC) (J Clin Oncol 2010; 28:5240). The importance of maintenance therapy for patients with advanced squamous NSCLC has been unknown, however.

      Method

      WJOG7512L was designed as a randomized phase 3 study to evaluate whether maintenance therapy with S-1 improves clinical outcome after induction therapy with carboplatin plus S-1 in such patients. Before randomization, patients received carboplatin (AUC of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1 to 14 every 3 weeks) as induction therapy. Those who did not progress after four cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective was to confirm the superiority of S-1 plus BSC with regard to progression-free survival.

      Result

      Of the 365 patients enrolled, 347 participated in the induction phase and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). Baseline demographics and clinical characteristics of the subjects, including the response to induction therapy, were well balanced. Patients receiving S-1 plus BSC showed a significantly reduced risk of disease progression compared with those receiving BSC alone (hazard ratio [HR], 0.548; 95% confidence interval [CI], 0.374–0.802; P = 0.0019). Median overall survival from randomization did not differ significantly between the two arms: 17.8 months for BSC alone and 16.7 months for S-1 plus BSC (HR, 0.890; 95% CI, 0.583–1.357). Time to deterioration in quality of life also showed no significant difference (P = 0.8754 for FACT-TOI, P = 0.9016 for FACT-LCS). The incidence of adverse events during maintenance therapy was low, with neutropenia, anemia, and thrombocytopenia of grade 3 or 4 each occurring in ~1% to 4% of patients.

      Conclusion

      Maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC.

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      MA13.07 - Phase I/II Study of Carboplatin Plus Weekly Nab-Paclitaxel in Aged ≥75 Patients with Squamous-Cell Lung Cancer: TORG1322   (Now Available) (ID 1369)

      14:00 - 15:30  |  Presenting Author(s): Yoshitaka Zenke  |  Author(s): Seiji Niho, Shigeki Umemura, Masashi Ishihara, Ryosuke Ochiai, Naoyuki Nogami, Yukio Hosomi, Tsuneo Shimokawa, Takaaki Tokito, Yasushi Goto, Yosuke Miura, Haruhiro Saito, Naoya Hida, Satoshi Ikeda, Hiroshi Tanaka, Naoki Furuya, Toshihiro Misumi, Yuichiro Ohe, Hiroaki Okamoto

      • Abstract
      • Presentation
      • Slides

      Background

      Combination chemotherapy of carboplatin (CBDCA) plus weekly nab-paclitaxel (nab-PTX) showed a favorable efficacy for elderly (70 year or older) patients with squamous non-small cell lung cancer (Sq-NSCLC) in a subgroup analysis of the CA031 study. We conducted a phase I/II study of CBDCA plus nab-PTX in chemo-naïve elderly patients with advanced Sq-NSCLC.

      Method

      Patients aged ≥75 years with untreated, measurable lesion, advanced Sq-NSCLC, performance status (PS) 0-1, and adequate organ function were eligible. In a phase I study, doses of carboplatin at an area under the curve (AUC) of 5 or 6 mg/mL min on day 1 (levels 1 and 2, respectively) were administered along with weekly nab-PTX (100 mg/m2) on days 1, 8, and 15 every 4 weeks up to 6 cycles using a modified 3 + 3 design. The primary endpoint for the phase II study was the 6-month progression-free survival (6m PFS) rate and hypothesis required 36 patients to be enrolled with expecting and threshold values for the primary endpoints of 40% and 25% (one-sided alpha = 0.05; beta = 0.2).

      Result

      A total of 46 patients were enrolled in this study. The median age was 78 (range 75-85 years); male (n = 41); PS 0/1, (n = 15/31). Ten patients were enrolled in the phase I part. At dose level 1, 2/7 patients showed dose-limiting toxicities (DLTs) of grade 3 diarrhea and febrile neutropenia, and at dose level 2, 1/3 patient showed DLT of grade 3 anorexia. The recommended dose was determined to be level 2. Additional 36 patients were enrolled, and a total of 39 patients were evaluated in the phase II study. The median number of cycles was 4 (range 1-6), and the median follow-up time was 17.5 months (range 5.6-28.9). The 6m PFS rate was 59% (90% CI, 44.8-71.4), and the primary endpoint was met. The median overall survival time was 23.5 months (95% CI, 11.6-35.4), and the median PFS was 6.8 months (95% CI, 5.4-9.1). The response rate was 54% and disease control rate was 92%. Nineteen patients (49%) received post-study treatment and 14 out of 19 patients (74%) received immunotherapy. Common toxicities of grade 3 or 4 were neutropenia (61.5%), anemia (46.2%), thrombocytopenia (17.9%), and febrile neutropenia (15.4%). There was no treatment-related death.

      Conclusion

      Combination chemotherapy of CBDCA plus weekly nab-PTX had a promising efficacy and acceptable toxicities in elderly (aged ≥75) patients with advanced Sq-NSCLC. Clinical trial information: UMIN000011216.

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      MA13.08 - Discussant - MA13.05, MA13.06, MA13.07 (Now Available) (ID 3775)

      14:00 - 15:30  |  Presenting Author(s): Karen L Reckamp

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA13.09 - Cisplatin Sustains Lung Cancer Metastasis Through the Systemic Activation of SDF-1/CXCR4 Axis (Now Available) (ID 2821)

      14:00 - 15:30  |  Presenting Author(s): Giulia Bertolini  |  Author(s): Valeria Cancila, Claudio Tripodo, Gabriella Sozzi, Giuseppe Lo Russo, Orazio Fortunato, Massimo Milione, Giovanni Centonze, Monica Tortoreto, Stefania Scala, Luca Roz

      • Abstract
      • Presentation
      • Slides

      Background

      Standard chemotherapy regimens have limited long-term efficacy in lung cancer patients due to chemoresistance and inefficacy in controlling metastatic disease. In pre-clinical models we have shown that cisplatin treatment enriches for the chemoresistant fraction of CD133+CXCR4+ lung cancer metastasis initiating cells (MICs), increasing distant metastasis development that can be prevented by CXCR4 blockade. Therefore, we hypothesize that the SDF-1/CXCR4 axis, implied in MICs maintenance/migration and in immune and stromal cells trafficking, could play a critical role in cisplatin-induced pro-metastatic effects.

      Method

      To study the effects of cisplatin in promoting a pre-metastatic niche, naïve SCID mice were treated with cisplatin plus/minus peptide R (5mg/kg), a novel inhibitor of CXCR4 and after 72h injected intravenously with metastatic H460 cell line. To assess the effect of the combination treatment in pre-clinical model, H460 subcutaneous xenografts were treated with cisplatin alone or with peptide R for three weeks. Content of MICs in xenografts, number and phenotype of lung metastasis and immune cells modulationt were evaluated by FACS and IHC

      Result

      We showed that cisplatin treatment of naïf SCID mice resulted in a rapid BM expansion of the subset of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM), concomitantly with their recruitment to murine lungs guided by increased level of SFD-1 released by PDGFRβ+ stromal cells in response to cisplatin. Peptide R partially prevented these effects.

      Tail-vein injection of H460 human lung cancer cells 72h after cisplatin administration resulted in augmented number of lung metastases (p=0.003), that showed a 3.5-fold enrichment in CD133+CXCR4+ MICs (p=0.005) and increase of IM and derived macrophages. Pre-treatment with peptide R abolished these effects. We verified that the abundance of CXCR4+CCR2+IM together with increased endothelial permeability caused by cisplatin may favor tumor cells extravasations and expansion of MICs through SDF-1/CXCR4 axis activation which determined metastasis overgrowth.

      SDF-1 was also increased in cisplatin-treated subcutaneous H460 xenografts that expanded the subset of chemoresistant CD133+CXCR4+ MICs and recruited CXCR4+tumor associated macrophages which may allow MICs to escape primary tumor. At the metastatic site cisplatin treatment of H460 xenografts caused an increase in stromal SDF-1 and recruitment of both CXCR4+ inflammatory monocytes/macrophages (1.6-fold change p=0.01) and MICs subset (1.8-fold change p=0,04), overall resulting in a boost in micrometastases. CXCR4 inhibition prevented the co-recruitment and cross-talk of MICs and IM at distant site, counteracting the pro-metastatic effects of cisplatin.

      Matched case series of stage III chemo-naive NSCLC patients and cisplatin-based neo-adjuvant treated patients demonstrated a significant increased in SDF-1 after chemotherapy (p=0,0001). An high expression of tumoral SDF-1 ( Score: staining intensity x % positive tumor cells >6) induced by cisplatin neo-adjuvant treatment was associated with a shorter DFS (p=0,0056) and poor OS (p=0,029).

      Conclusion

      Conclusions: Our data reveal a paradoxical pro-metastatic effect of cisplatin that fosters MIC-IM recruitment and cross-talk via SDF-1/CXCR4 axis activation. A new combination strategy based on CXCR4 inhibition may disrupt these interactions, providing more effective and long-lasting results for lung cancer treatment

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      MA13.10 - A Phase II Study of Carboplatin and Nab-Paclitaxel for Advanced Non-Small Cell Lung Cancer with Interstitial Lung Disease (HOT1302) (Now Available) (ID 990)

      14:00 - 15:30  |  Presenting Author(s): Hiroshi Yokouchi  |  Author(s): Hajime Asahina, Satoshi Oizumi, Kei Takamura, Toshiyuki Harada, Masao Harada, Kenya Kanazawa, Yuka Fujita, Tetsuya Kojima, Fumiko Sugaya, Hisashi Tanaka, Ryoichi Honda, Takahiro Ogi, Eiki Kikuchi, Tomoo Ikari, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura

      • Abstract
      • Presentation
      • Slides

      Background

      Because of the high risk of exacerbation of pre-existing interstitial lung disease (ILD), patients with concomitant advanced non-small cell lung cancer (NSCLC) and ILD have been excluded from most clinical trials of chemotherapy, despite the high prevalence (around 10%) of all NSCLC cases. This study prospectively evaluated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in advanced NSCLC patients with pre-existing ILD.

      Method

      Enrolled patients had treatment-naïve, advanced NSCLC with pre-existing ILD. Patients received 100 mg/m2nab-paclitaxel weekly and carboplatin at area under the concentration-time curve (AUC) 6 once every 3 weeks for 4-6 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS) and overall survival (OS). The interactions between histology [Squamous (Sq) vs. Non-Squamous (Non-Sq)] and treatment outcomes were also investegated.

      Result

      Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had an adenocarcinoma, followed by 15 (41.7%) squamous cell carcinoma, and 5 (13.9%) non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR, the primary endpoint, was 55.6% (95% confidence interval [CI]: 39.6-70.5%). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2 months) and 15.4 months (95% CI: 9.4-18.7 months), respectively. There was no significant difference between two groups, however, numerically better treatment outcomes were observed in the Sq group: the ORR was 66.7% (95% CI: 41.7–84.8%) in the Sq group compared with 47.6 % (95% CI: 28.3–67.6%) in the Non-Sq group (P =0.254); median PFS was 8.2 months (95% CI: 4.0–10.2 months) in the Sq group vs. 4.1 months (95% CI: 3.3-5.4 months) in the Non-Sq group (HR, 0.60 [95% CI, 0.30–1.20]; p=0.15); median OS was 16.8 months (95% CI: 9.8 months–not reached) in the Sq group vs. 11.9 months (95% CI: 7.3-17.4 months) in the Non-Sq group (HR, 0.56 [95% CI, 0.24–1.28]; p=0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and one patient (2.8%) died.

      Conclusion

      This is the first prospective phase 2 study of weekly nab-paclitaxel in combination with carboplatin in advanced NSCLC patients with pre-existing ILD. This treatment showed favorable efficacy and was well tolerated.

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      MA13.11 - A Randomized Phase III Study of Cisplatin-Polymeric Micelle Paclitaxel vs Cisplatin-Solvent-Based Paclitaxel in 1st Line Advanced NSCLC (Now Available) (ID 696)

      14:00 - 15:30  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Baohui Han, Meiqi Shi, Haiyan Tu, Aiqin Gu, Cheng Huang, Huijuan Wang, Zhuang Yu, Xiuwen Wang, Lejie Cao, Yongqian Shu, Huaqing Wang, Runxiang Yang, Xingya Li, Jianhua Chang, Yanping Hu, Peng Shen, Yi Hu, Zhongliang Guo, Min Tao, Yiping Zhang, Xunyan Liu, Qian Sun, Xin Zhang, Zuguang Jiang, Junhui Zhao, Feng Chen, Jing Sun, Duan Li, Jinsong Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Cisplatin-sb-Pac is the one of current standard of chemotherapy in aNSCLC, It produced 15% to 32% objective response rate (ORR) and 7.9 to 10.6 months of median overall survival (OS). Alternative nab-paclitaxel to sb-Pac only increased ORR but not improved progression-free survival (PFS) and OS. Thus the unmet medical need for new chemo regimen remains.

      Method

      From May 2015 to Jan 2018 448 untreated patients (pts) with stage IIIB to IV NSCLC from 24 sites were randomly assigned 2:1 to receive 230 mg/m2 pm-Pac and cisplatin 70 mg/m2 on day 1 of a 3-week cycle, and then dose escalation of pm-Pac to 300 mg/m2 from the second cycle if no prespecified toxic effects observed or 175 mg/m2 sb-Pac plus cisplatin 70 mg/m2 once every 3 weeks. Pts were stratified by stage and histology. The primary end point was ORR by Independent review committee (IRC) and Investigator (INV) in the intent-to-treat population. The second endpoints included PFS, OS and safety. Data cutoff was Jan 26, 2019.

      Result

      300 pts were assigned to pm-Pac and 148 to sb-Pac. Baseline characteristic were balance in both arms. Nonsquamous carcinoma (non-squ) and stage IV were 57.3% and 81.0% in pm-Pac and 58.1% and 81.8% in sb-Pac respectively. 73.2% pts in pm-Pac arm escalated their dose to 300mg/m2, 0.7% down to 184mg/m2. ORR and PFS in pm-Pac were significant better than that in sb-Pac (table 1). OS was immature. For histology subgroup the ORR was 58.6% v 37.1% (P=0.0054) in squamous carcinoma (Squ) and 44.2% v 18.6% (P<0.0001) in non-squ. Grade ≥3 AEs was 80.0% for pm-Pac and 79.7% for sb-Pac. No new safety issues were identified.

      Conclusion

      The phase 3 trial met its primary endpoint. pm-Pac significantly improved ORR and PFS than sb-Pac, and pm-Pac regimen should be a new standard chemo for aNSCLC. (NCT 02667743).

      Tab. Efficacies comparison between pm-Pac and sb-Pac

      pm-Pac

      sb-Pac

      P value

      ORR % (95% CI)

      IRC

      INV

      50.3 (44.5-56.1)

      52.0 (46.2-57.8)

      26.4 (19.5-34.2)

      28.4 (21.3-36.4)

      <0.0001

      <0.0001

      PFS (months)

      6.4 (6.2-6.9)

      5.3 (4.6-6.0)

      HR 0.66 (0.52-0.84), P=0.0006

      OS at 12 months

      67.3%

      61.8%

      -

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      MA13.12 - Discussant - MA13.09, MA13.10, MA13.11 (Now Available) (ID 3774)

      14:00 - 15:30  |  Presenting Author(s): Lyudmila Bazhenova

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS05 - Novel Biological Pathways and Druggable Targets (ID 68)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Biology
    • Presentations: 5
    • Now Available
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      MS05.01 - Epigenetic Therapeutics in Lung Cancer (Now Available) (ID 3461)

      11:00 - 12:30  |  Presenting Author(s): Kwok-kin Wong

      • Abstract
      • Presentation
      • Slides

      Abstract

      Epigenetic Targets and Drugs to enhance immune response in Lung Cancer

      Kwok-Kin Wong

      Effective therapies for non–small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with ability to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. We have previously demonstrated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we have shown that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells. The pan-bromodomain inhibitor JQ1 attenuated CD4+FOXP3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Finally, we have recently performed in vivo CRISPR screens to identify additional novel epigenetic targets that would synergize with PD1 blockade in KRAS driven NSCLC.

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      MS05.02 - Genetics Abnormalities in Chromatin Modifiers: Connection with MYC Pathway and Exploration for Therapeutics (Now Available) (ID 3462)

      11:00 - 12:30  |  Presenting Author(s): Montse Sanchez-Cespedes

      • Abstract
      • Presentation
      • Slides

      Abstract

      The understanding about the complexity of the molecular networks that regulate the epigenetic control of gene expression is boosting. Moreover, it is accepted that an abnormal function of these networks, due to genetic alterations of its components, play an essential role during tumorigenesis. Among the networks involved in this epigenetic control, there is the SWI/SNF-chromatin remodeling complex, a regulator of the accessibility of the chromatin to DNA-binding proteins (1-2). Inactivating mutations at different members of the complex have been found to be inherent to most human cancers. Our team had pioneered these investigations, being the first to report inactivating mutations at BRG1 (also SMARCA4) which codes for the ATPase of the SWI/SNF complex (3-4). In lung cancer (LC), alterations at any member of this complex affect about half of the tumors and occur in a background of wild type MYC (either C, L or N) (3). In the lasts years, inactivating mutations at other members of the complex (e.g. SNF5, PRBM, ARID1A, ARID2) have been shown to evolve in most human cancers (2,5). More recently, our laboratory also pioneered the identification of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in small cell lung cancers, where it is present in tumors that are wild type for MYC and BRG1 (6). Altogether, the genetic observations indicate the existence of an important network, involving SWI/SNF and MAX/MYC, which is critical to LC development. Using LC as a model, we have scrutinized genomic data, whole exome sequencing (WES) and RNA-sequencing, collected from patient-derived xenografts (PDXs), from patient-derived cells (PDCs) and from public databases (Sanger-COSMIC and CCLE), to delineate the gene alteration profile at epigenetic controllers (including already known drivers and novel candidates) in LC. Combined, all the alterations at epigenetic controllers include different members of the SWI/SNF complex (SMARCA4/BRG1, ARID1A, PBRM1) as well as interesting candidates such as the MAX-binding protein, MGA, or the histone-modifying enzymes (KMT2D/MLL2, KMT2G/SETD1B), among others. Some of these alterations appeared in a mutually exclusive pattern, suggesting a functional connection

      We have also integrated this information to search for cancer vulnerabilities.Components of the SWI/SNF complex are known to bind to various nuclear receptors, such as those of estrogens, progesterone, androgens, glucocorticoids (GCs) and retinoic acid (RA), thereby adapting the gene expression programs to the demands of the cell environmental requirements (7-9). We found that the restitution of BRG1 in LC cells restores the gene expression signature of normal lung and that cells lacking BRG1 did not respond to RA or GCs, while restoration of BRG1 restored sensitivity (10). The co-administration of the epigenetic compounds azacitidine (demethylating agent) and SAHA (inhibitor of histone deacetylases) enhanced all these effects, both in cell cultures and in vivo, accompanied by sustained reductions in genome-wide DNA methylation. Together, these data support the notion that an inactive BRG1 confers resistance to RA and GCs, which prevents cancer cell differentiation. In contrast, the observations also indicate that RA/GC-based treatments could be designed to treat LC patients with MYC-amplified tumours. On the other hand, recent investigations have searched for vulnerabilities of BRG1-mutant cells that may be therapeutically approachable and have found that the inhibition of cyclin-dependent kinase 4/6 (CDK4/6) appear to be synthetic lethal in BRG1-deficient tumours (10). In my presentation I will be showing our last and novel observations of epigenetic-related compounds that promote cell growth inhibition specifically in BRG1-mutant lung cancers.

      In parallel, gene alterations at other epigenetic-related components have also been reported in cancer. Some of these include the methyltransferase EZH2, a transcriptional repressor, the transcriptional co-activator protein p300, a histone acetyltransferase that regulates transcription via chromatin remodelling or the histone acetyltransferase CREBBP, which also acts as a scaffold to stabilize additional protein interactions with the transcription complex. In LC these alterations are more common in small cell lung cancer (SCLC). In SCLC, there is also recurrent inactivation of MAX and of MGA, proteins directly linked to the MYC trans-activation activities. Here, we found that the gene expression profile of MAX-mutant SCLC cells cluster to that of the ASCL1-transcription factor dependent group of SCLCs, which also includes NMYC- and LMYC-activated but not with MYC or BRG1-mutant SCLC cells. MGA, is an extraordinary large protein that is also recurrently inactivated in NSCLC. The MYC-MAX and MADs/MGA-MAX complexes have opposed functions in transcription, being MAX a central player in this network. MAX and MGA have shown to also act as part of the Polycomb Repression Complex 1 (PRC1), specifically the non-canonical PRC1 complex designated as ncPRC1. I will also present our data on the functional characterization of the role of MYC and of MGA in the MAX-deficient SCLC cells.

      References:

      1.Peterson CL et al. Five SWI/SNF gene products are components of a large multisubunit complex required for transcriptional enhancement. Proc Natl Acad Sci USA. 1994; 91: 2905-8.

      2.Wilson GB, Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11: 481-92.

      3.Medina PP et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mut. 2008; 29: 617-22a.

      4.Rodriguez-Nieto S et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mut. 2011; 32: E1999-2017.

      5.Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. Oncogene 2014; 33: 2681-9.

      6. Romero OA et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov. 2014; 4: 292-303.

      7. Chiba H, et al. Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucleic Acids Res. 1994; 22: 1815-182015.

      8.Romero OA et al. The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med. 2012; 4: 603-16.

      9. Romero OA et al. Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming. Oncogene 2017;36:1287-96.

      10. Xue Y, et al.SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat Commun. 2019;10:557.

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      MS05.03 - Notch Signalling (Now Available) (ID 3463)

      11:00 - 12:30  |  Presenting Author(s): Shirish Gadgeel

      • Abstract
      • Presentation
      • Slides

      Abstract

      Notch Signaling

      The Notch signaling pathway is a highly conserved pathway that has a vital role in embryonic development and post-embryonic functions such as hematopoiesis, neural cell development and angiogenesis (1). The signaling pathway is activated by the interaction of 4 Notch receptors and their interactions with 5 different ligands. Signaling is characterized by juxtacrine interaction between ligands and receptors on neighboring cells or within the same cell. Alterations in this pathway have been detected in several tumors both as tumor promoter and tumor suppressor.

      Notch signaling does appear to have relevance in non-small cell lung cancers (NSCLC) (2). In approximately 30% of NSCLCs loss of Numb, a negative regulator of Notch1, leads to increased Notch activity and about 10% of NSCLCs have gain of function mutations in Notch1. A meta-analysis demonstrated that higher expression of Notch1 was correlated with more advanced tumors (3). In addition, higher expressions of both Notch1 and Notch3 were associated with poor prognosis (4,5). In pre-clinical studies inhibition of Notch3 signaling has reduced growth of lung cancers. In addition, it has been demonstrated that there is cross talk between Notch3 and EGFR pathways and inhibition of both pathways can induce expression of anti-apoptotic protein BIM. Finally, Notch signaling may have a role in induction of the epithelial to mesenchymal phenotype (EMT) in cancers (6). EMT is known to be associated with resistance to both cytotoxic agents and targeted agents and inhibition of Notch signaling can not only reverse EMT but also can enhance the anti-tumor activity of cytotoxic agents such as cisplatin and targeted agents such as erlotinib. The EMT phenotype is frequently observed in a sub-population of cancer cells with self-renewal capacity or cancer stem cells. Notch signaling may be crucial to survival of cancer stem cells and persistence of this population may contribute to resistance to therapeutic agents.

      In squamous cell lung cancers Notch signaling may have tumor suppressive properties (7). Loss of function mutations in Notch family of genes, predominantly in Notch receptors, are frequently identified in several squamous cell cancers including squamous cell cancer of the lung. Similarly, loss of function mutations in Notch genes, particularly Notch1 have been identified in small cell lung cancer (SCLC). Expression of Notch receptor in a mouse model of SCLC reduced tumor burden, suggesting its tumor suppressive properties. The expression of DLL3, one of the Notch ligands is induced in SCLC by a key transcription factor ASCL1.DLL3 is shown to downregulate Notch signaling in SCLCs and enhance the carcinogenic phenotype.

      All the above data suggest that Notch signaling is highly contextual. In some tumors this pathway may have tumor suppressive properties but in others tumor promoting properties. Defining the role of this pathway in tumor types may guide development of therapeutic strategies targeting the Notch signaling pathway.

      References

      Bigas A, Espinosa L. The multiple usages of Notch signaling in development, cell differentiation and cancer. Curr Opin Cell Biol 2018;55:1-7.

      Westhoff B, Colaluca IN, D’Ario G, et al. Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci 2009;106:22293-8.

      Yuan X, Wu H, Xu H, et al. Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis. Sci Rep 2015;5:10338.

      Donnem T, Andersen S, Al-shibili K, et al. Prognostic impact of Notch ligands and receptors in nonsmall cell lung cancer: coexpression of Notch-1 and vascular endothelial growth factor-A predicts poor survival. Cancer 2010:116:5674-85.

      Hassan WA, Yoshida R, Kudoh S, et al. Evaluation of role of Notch3 signaling pathway in human lung cancer cells. J Cancer Res Clin Oncol 2016;142:981-93.

      Yuan X, Wu H, Han N, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol 2014;7:87.

      Nowell CS, Radtke F. Notch as a tumor suppressor. Nat Rev Cancer 2017;17:145-159.

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      MS05.04 - Innate Immune Mediators in Lung Cancer (Now Available) (ID 3464)

      11:00 - 12:30  |  Presenting Author(s): Antonio Calles Blanco

      • Abstract
      • Presentation
      • Slides

      Abstract

      Non-small-cell lung cancer (NSCLC) accounts for about 85% of total lung cancer cases. The major types of NSCLC—squamous cell carcinoma and adenocarcinoma—harbor distinct histopathologies, biomarker expression, genomic alterations, and response to therapy [1,2]. Recent studies have shown that there are also differences in their tumor immune microenvironments [3–6]. Specifically, adenocarcinomas have increased infiltration of tumor-associated macrophages, while squamous lung tumors exhibit an enrichment in tumor-associated neutrophils (TANs) in both mouse and human lung tumors. The two major subtypes of NSCLC are also associated with distinct lineage-specific master regulators: SOX2 is commonly amplified and up-regulated in the vast majority of squamous tumors anddrives the squamous fate, whereas NKX2-1 is highly expressed in adenocarcinoma and governs adenocarcinoma fate [2]. We developed novel genetically engineered mouse models (GEMMs) of squamous lung cancer on the basis of overexpression of the transcription factor Sox2 and loss of the tumor suppressor Lkb1 (SL mice) (Mukhopadhyay et al, Cell Rep, 2014 [7]). SL tumors recapitulated gene expression and immune infiltrate features of human squamous NSCLC, including an enrichment of TANs and a decrease in expression of NKX2-1. Deletion of Nkx2-1in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. We further employed multiple GEMMs to elucidate the role of SOX2 and NKX2-1 in tumor cell fate and TAN recruitment. In Kras-driven adenocarcinomas,mis-expression of Sox2 or loss of Nkx2-1 led to TANrecruitment. SOX2 recruits, whereas NKX2-1 suppresses, TANs at least partly through inverse regulation of the chemokineCxcl5. Tumor-derived CXCL5 is sufficient to recruit TANs. Single cell RNA sequencing (scRNA-seq) revealed that TANs exhibit tumor-promoting features, including production of reactive oxygen species (ROS), and distinct gene expression profiles compared to blood neutrophils (Mollaoglu et al, Immunity, 2018 [8]). Depletion of TANs through LY6G blocking antibodies or CXCR2 inhibitors in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Furthermore, TAN depletion coupled with scRNA-seq suggests that TANs regulate distinct aspects of tumor cell fate. Together, these data suggest that lineage-defining transcription factors determine the tumor immune microenvironment, which in turn can impact the nature of the tumor.

      References

      1 Langer, C.J. et al. (2016) Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment. J. Thorac. Oncol.11, 2066–2081.

      2 Campbell, J.D.et al. (2016) Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet.48, 607–616.

      3 Kargl, J. et al. (2017) Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat. Commun.8, 14381

      4 Nagaraj, A.S. et al. (2017) Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1. Cell Reports 18, 673–684.

      5 Xu, C. et al. (2014) Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression. Cancer Cell 25, 590–604.

      6 Ferone G., et al. SOX2 Is the Determining Oncogenic Switch in Promoting Lung Squamous Cell Carcinoma from Different Cells of Origin. Cancer Cell. 2016;30(4):519-532. doi:10.1016/J.CCELL.2016.09.001.

      7 Mukhopadhyay, A. et al. (2014) Sox2 Cooperates with Lkb1 Loss in a Mouse Model of Squamous Cell Lung Cancer. Cell Reports 8, 40–49.

      8 Mollaoglu, G. et al. (2018) The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment. Immunity 49, 764-779.e9.

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      MS05.05 - Harnessing Oncogene Dependencies in Lung Cancer (Now Available) (ID 3465)

      11:00 - 12:30  |  Presenting Author(s): Martin L Sos

      • Abstract
      • Presentation
      • Slides

      Abstract

      The introduction of precision medicine had a dramatic impact on the overall survival of genomically selected lung cancer patients. This is primarily true for lung adenocarcinomas in which druggable targets like mutant EGFR or rearranged ALK are frequently oncogenically activated. The major challenge in these patients is the inevitable emergence of drug resistant clones that abrogate the effects of selected tyrosine kinase inhibitors. Through a detailed characterization of patients that relapse under osimertinib treatment we identified novel routes to overcome individual resistance mutations in EGFR. At the same time, the majority of lung lacks directly druggbale targets and thus remains largely unaffected by this therapeutic revolution. The induction of programmed cell death by perturbing the pro- and anti-apoptotic members of the BCL-2 family may represent an attractive strategy to circumvent this medical need. We sought to explore dependencies on individual BCL-2 family members with different therapeutic strategies to identify therapeutically relevant pathways in lung cancer models.

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    MS11 - Addressing Challenges with Surgical Resection of Lung Cancer (ID 74)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 6
    • Now Available
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      MS11.01 - Neoadjuvant Chemotherapy or Neoadjuvant Chemoradiation for Potentially Resectable Nsclc - a Surgeon's Perspective (Now Available) (ID 3500)

      15:45 - 17:30  |  Presenting Author(s): Ricardo Mingarini Terra

      • Abstract
      • Presentation
      • Slides

      Abstract

      Early studies of neoadjuvant therapy compared chemotherapy alone to surgery alone. Later, the Intergroup 0139 study utilized concurrent chemotherapy and radiation as its induction strategy, and this was the basis for adding radiation in the neoadjuvant strategy. Both strategies, neoadjuvant chemotherapy and neoadjuvant chemoradiation are considered alternatives for patients with stage IIIA non-small cell lung cancer deemed operable.

      However, the toxicity of combined chemotherapy and radiation is significant. Radiotherapy has an inflammatory effect that leads to a more difficult surgical procedure and increases the number of postoperative complications. Moreover, studies comparing both strategies failed to demonstrate superiority of any of the two strategies in terms of overall survival.

      On top of that, due to the limited number of radiotherapy clinics in emerging countries, radiotherapy schedules might delay the beginning of the patient’s treatment. This is also an issue to be considered when offering neoadjuvant chemoradiation.

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      MS11.02 - Role of Surgery in Oligometastatic NSCLC (Now Available) (ID 3501)

      15:45 - 17:30  |  Presenting Author(s): C S Pramesh

      • Abstract
      • Presentation
      • Slides

      Abstract

      Role of Surgery in Oligometastatic NSCLC

      The management of oligometastatic non-small cell lung cancer (NSCLC) is controversial. Sixty percent of patients with NSCLC present with metastatic disease; 45% of those with initially localized disease eventually develop metastatic disease. With 15% of these being oligometastatic disease, this is a significant problem. Over the last two decades, several advances have occurred which frame this question better. First, advances in imaging techniques including improved PET-CT and MRI have helped identify what is likely to be truly oligometastatic disease. Second, there have been advances in local therapy including minimally invasive and robotic approaches and perioperative management, as well as advanced radiation techniques including stereotactic ablative radiotherapy (SABR) which have made it safer. Finally, systemic therapy has undergone major changes with targeted therapy and immunotherapy making considerable progress. Most patients with metastatic NSCLC would be treated with systemic therapy with local treatment being offered only for symptomatic palliation. However, recognition of a “oligometastatic” state (where metastases are limited in number and location) has led to series of patients being treated with potentially curative intent using local treatment options, predominantly surgical.

      Randomized trials to evaluate the role of surgery in oligometastatic NSCLC have not been performed, compelling a reliance on several published case series and meta analysis of these studies. These series have included highly selected patients with oligometastases, typically 1-3 metastases, most commonly located in the brain, and long term outcomes have been highly variable. Overall median five year survival of a meta analysis of studies was 23.3 percent. Five year survivals in patients treated with surgery both for the primary and the metastases range from as low as <10% to as high as 80% - this wide range is more likely a reflection of selection criteria for patients undergoing surgery rather than true variations in care. Moreover, with the lack of a true comparator arm, these results should be interpreted with caution. Important favourable prognostic factors include definitive treatment of the primary tumour, negative mediastinal nodal status and a longer disease-free interval.

      Lack of well conducted prospective studies make conclusive recommendations on surgery for treatment of oligometastatic disease difficult. This is especially true now when better radiation techniques like SABR and improved outcomes with systemic treatment in selected patients with targeted and immunotherapy are available. Given the available evidence, it appears reasonable to consider surgical treatment in patients with oligometastatic disease fulfilling the following criteria: good performance status, accurately staged, with PET-CT and MRI brain showing no other sites of metastases, metachronous disease with relatively long disease free interval, negative mediastinal nodes on invasive staging, and controlled primary disease. With randomized trials being unlikely in this setting, further studies are required which prospectively collect real-world data systematically, enabling better selection criteria for patients for surgery in oligometastatic NSCLC.

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      MS11.03 - Minimizing Peri-Operative Morbidity with Pneumonectomy (Now Available) (ID 3502)

      15:45 - 17:30  |  Presenting Author(s): Shun-ichi Watanabe

      • Abstract
      • Presentation
      • Slides

      Abstract

      1. Introduction

      The incidence of surgical morbidity after standard pneumonectomy is reportedly 30 to 60%. Many previous studies have addressed several risk factors for surgical morbidity after pneumonectomy, including age, cardiovascular disease, recent body weight loss, high smoking index, low FEV1.0 value, chronic obstructive pulmonary disease (COPD), right pneumonectomy, massive blood loss during surgery, long operation time, neoadjuvant therapy and so on. Although surgical morbidity after pneumonectomy easily lead to patients’ mortality. When pneumonectomy seems to be inevitable to remove the tumor, surgeons sometimes intraoperatively weigh the oncological benefit of pneumonectomy against the postoperative poor QOL and high morbidity rate.

      In this paper, the cause and proper management of postpneumonectomy complications are discussed to minimize peri-operative morbidity with pneumonectomy as for especially following two life-threatening categories, cardiovascular and respiratory complications.

      2. Type of Complications

      2.1 Cardiovascular Complications

      2.1.1 Supraventricular Arrhythmias

      Most of supraventricular arrhythmias present 1 to 4 days after standard pneumonectomy, but it sometimes present even a week after surgery. The incidence of supraventricular arrhythmia after pneumonectomy is reportedly 4 to 25%. Risk factors for supraventricular arrhythmias include old age, right pneumonectomy, intrapericardial pneumonectomy, major co-morbidities, and so on. For patients who are considered to be high risk for postoperative atrial fibrillation, following prevention strategies are indicated. According to the 2014 AATS guidelines, continuing β blockers in patients taking β-blockers before surgery, using intravenous magnesium supplementation if serum magnesium levels are low, using diltiazem in those patients with preserved cardiac function who were not taking β-blockers preoperatively, or using amiodarone in patients at an intermediate to high risk of developing postoperative atrial fibrillation. For hemodynamically stable patients with new onset atrial fibrillation, intravenous β-blockers or calcium channel blockers are used to reduce a heart rate down to 100 beats per minute. When patients are hemodynamically unstable, direct current cardioversion should be used. And for patients with refractory atrial fibrillation, systemic anticoagulation therapy should be used carefully weighing benefits against the risk of bleeding, especially after EPP.

      2.1.2 Ischemic Heart Disease

      Ischemic heart disease is known to be an independent risk factor for severe complications after pneumonectomy. The risk of a myocardial infarction after pneumonectomy is reportedly approximately 0.2 to 2.1%. Patients who are candidates for pneumonectomy should undergo careful preoperative assessment to screen for untreated coronary ischemic disease.

      2.1.3 Cardiac Herniation

      Cardiac herniation is a rare complication after intrapericardial pneumonectomy. Patients develop cardiac herniation when the intrathoracic pressure changes rapidly by severe cough or vomit with decubitus position. Rapid and severe hemodynamic collapse following a change in patient positioning should heighten the clinical suspicion. Chest X-ray and electric cardiogram clearly show the abnormal position of the heart (Figure 1 and 2). Correction of the cardiac herniation should be conducted immediately by re-thoracotomy after successful resuscitation. Sewing the patch to the weak tissues around the pericardium rather than the pericardium itself after intrapericardial pneumonectomy could increase the risk of cardiac herniation.

      2.2 Respiratory Complications

      2.2.1 Pneumonia

      The incidence of pneumonia after pneumonectomy is reportedly 2 to 10%. Since pneumonia after pneumonectomy could be a life-threatening complication, care must be taken to lessen the risk of pneumonectomy. Preoperative smoking cessation, chest physiotherapy by nurses or respiratory therapists, use of enough amount of post-thoracotomy painkillers, and bronchial toilet by bronchoscope are important practical factors for minimizing the risk of pneumonia.

      2.2.2 Acute Respiratory Distress Syndrome (ARDS)

      According to the previous literatures, ARDS occurs in 2.7 to 3.1% of patients after standard pneumonectomy with very high mortality of 50 to 70%. Treatment of ARDS is supportive. Mechanical ventilation with small tidal volumes of less than 6 mg/kg body weight should be used to minimize the barotrauma, and the FiO2 level should be decreased to the lowest level to minimize the oxidative trauma. There has been no evidence that steroids improve the prognosis of patients developing ARDS.

      2.2.3 Bronchopleural Fistula (BPF)

      The incidence of BPF, which is a life-threatening complication, is reportedly 2 to 11%. The mortality of BPF after pneumonectomy is very high rate of around 40%. Risk factors for BPF includes diabetes mellitus, malnutrition, long stump (especially for left side), right pneumonectomy, preoperative chemoradiation therapy, and so on. When a patient develop the BPF, open window technique should be applied to control thoracic cavity infection which can lead the patient to death.

      3. Conclusion

      The mortality and morbidity rates after pneumonectomy are very high compared with those after lobectomy, simply because the patients have less cardio-pulmonary reservations. Therefore, when complications occur, surgeons must aggressively treat them not to lose the patient with taking abovementioned knowledge into consideration.

      Figure 1

      fig.1.jpgfig. 2.jpg

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      MS11.04 - Surgical Resection of SCLC - Not so Obsolete Any Longer (Now Available) (ID 3503)

      15:45 - 17:30  |  Presenting Author(s): Gustavo Lyons

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      • Presentation
      • Slides

      Abstract

      More than 2 million new lung cancer cases were detected worldwide in 2018, and small cell lung cancer (SCLC) represents about 13-15 % of all lung cancers.

      Although surgery was initially regarded as the treatment of choice for all types of lung cancer, it was abandoned for SCLC almost 30 years ago after the results of the Medical Research Council (MRC) randomized trial conducted by Fox et al. in 1973, which showed poor mean survival for the surgical group when compared to the RT group (6.5 months vs. 10 months, P = 0.04). (1) These results led to the abandonment of surgery as a standard treatment in favor of chemotherapy. Two subsequent meta-analyses revealed that the addition of thoracic radiation to systemic chemotherapy improved survival, and that has become the standard of care. (2)

      After the introduction of TNM classification, investigators proposed that surgery was postulated to be indicated in limited-SCLC, particularly stage T1, N0, with 5-year survival rates of as high as 52.6% for stage 1 disease. (3) Further, surgical resection after induction chemoradiotherapy demonstrated a control of local relapse in almost 100% of the patients and 5- and 10-year survival rates for patients with stage IIB to IIA were 39% and 35%, respectively, for all patients (resected or not) and 44% and 41% for patients treated with a trimodality approach including adjuvant surgery. (4) Another argument for surgical resection is that the final histology of SCLC might reveal a component of NSCLC in 11-25% cases. (5)

      In a recent series of Wakeam et al. including 2,089 patients with SCLC undergoing surgery who were matched 1:1 to those undergoing NST, surgery was associated with longer survival for stage I (median overall survival [OS] 38.6 months vs. 22.9 months), for stage II (median OS 23.4 months vs. 20.7 months), and stage IIIA (median OS 21.7 vs. 16.0 months. In analyses by T and N stage, longer OS was observed in resected patients with stage T3/T4 N0 (median OS 33.0 vs. 16.8 months, p=0.008) and node positivity (N1+ 24.4 vs. 18.3 months p=0.03; N2+ 20.1 vs. 14.6 months p=0.007). (6)

      A recent meta-analysis that included a total of 41,483 patients concluded that surgical resection was associated with superior OS in stage I (HR = 0.56, 95% CI: 0.49–0.64, p< 0.001), stage II (HR = 0.75, 95% CI: 0.57–0.99, P = 0.04), and stage III diseases (HR = 0.70, 95% CI: 0.56–0.88, P = 0.002). (11) Unlike stage I disease, there is no consensus for surgery in stage II and stage IIIA SCLC.

      Surgical resection is concordant with NCCN and ASCO guidelines; however, evidence shows that in the vast majority of T1 and T2 N0M0 patients, surgery is not offered in the absence of any documented contraindication. Rostadt et al., in a series of 2,442 patients with SCLC, found out that 26% were stages IA and IB and thus candidates for surgical resection, while only 38 patients (1.5%) underwent surgical therapy. (8)

      CT screening identifies SCLC at an earlier stage – with better survival – than usual care and offers the hope that more SCLC patients may become long-term survivors. Austin et al. carried out a multinational study of baseline and annual repeat CT screenings of 48,037 volunteers at risk for lung cancer. (9) They found 48 SCLC cases, 92% of which were asymptomatic at diagnosis. Clinical stage was IA in 16 patients (33%), II in 5 (11%), III in 20 (42%), and IV in 7 (15%). Estimated cure rates were 36% overall and 54% for the clinical stage I cases.

      Conclusions

      Surgical resection is indicated in SCLC in stages I and IIA after precise staging including mediastinoscopy. Patients should receive systemic therapy after resection and mediastinal radiation therapy in cases with nodal metastases. Surgical resection in stages I and IIA SCLC is concordant with NCCN and ASCO guidelines; however, surgery is offered only in one-third of the patients in the absence of any documented contraindication. CT screening identifies SCLC at an earlier stage and offers the hope that more SCLC patients may be candidates for surgical resection and become long-term survivors. Selected cases in stages IIB and IIIA may be candidates for surgery as part of the multidisciplinary treatment.

      References

      1) Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet. 1973; 2: 63–5.)

      2) Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1999;341:476-484. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol. 1992;10:890-895.)

      3) Schreiber D, Rineer J, Weedon J, Vongtama D, Wortham A, Kim A, et al. Survival outcomes with theuse of surgery in limited-stage small cell lung cancer: should its role be re-evaluated? Cancer. 2010;116: 1350–57.

      4) Eberhardt W, Korfee S. New approaches for small-cell lung cancer: Local treatments. Cancer Control 2003;10:289-96.

      5) Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, et al. Neuroendocrine neoplasms of the lung: A prognostic spectrum. J Clin Oncol 2006;24:70-6.)

      6) Wakeam E, Acuna SA, Leighl NB, Giuliani ME, Finlayson SRG, Varghese TK, et al. Surgery Versus Chemotherapy and Radiotherapy For Early and Locally Advanced Small Cell Lung Cancer: A Propensity-Matched Analysis of Survival. Lung Cancer. 2017; 109: 78–88.

      7) Liu T, Chen Z, Dang J, Li G (2018) The role of surgery in stage I to III small cell lung cancer: A systematic review and meta-analysis. PLoS ONE 13(12): e0210001.

      8) Hans Rostadt, Anne Naalsundb, Randi Jacobsena, Trond Eirik Stranda, Helge Scottc, Erik Heyerdahl Strømc, Jarle Norsteina. Should more patients have been offered surgical therapy? European Journal of Cardio-thoracic Surgery 26 (2004) 782–786)

      9) Austin JH, Yip R, D'Souza BM, Yankelevitz DF, Henschke CI, International Early Lung Cancer Action Program Investigators. Small-cell carcinoma of the lung detected by CT screening: stage distribution and curability. Lung Cancer. 2012 76(3): 339-43.)

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      MS11.05 - Pathological Reporting of Resected Lung Cancer - the Importance of Using Additional TNM Descriptors (Now Available) (ID 3504)

      15:45 - 17:30  |  Presenting Author(s): Ellen Caroline Toledo Nascimento

      • Abstract
      • Presentation
      • Slides

      Abstract

      Context. The anatomopathological examination aims to establish a specific diagnosis of the tumor and to provide essential information related to cancer staging, patient management and prognosis. Such information, as histologic type, lymphovascular invasion, spread through air spaces, margins, treatment effect, and TNM descriptors should be disclosed concisely, following previously defined protocols, and correlate satisfactorily with radiological exams and clinical aspects in order to allow the best management for the patient.

      Histopathological (macroscopic and microscopic evaluation) combined with complementary immunohistochemical and molecular studies, provides prognostic and predictive information on tumor biology and clinical behavior. The TNM staging classifies the tumors according to the anatomic extent with an important prognostic impact. In addition, it allows the establishment of criteria for inclusion and exclusion of patients in protocol studies and subgroups of treatment, cancer registry, epidemiology and multidisciplinary management.

      The T component analysis is complex because it has many elements: presence or absence of invasion, tumor size, endobronchial location, atelectasis / pneumonitis and invasion of the various anatomical structures around the lung. The determination of the largest tumor diameter requires accurate measurements since in the eighth edition TNM stage classification for lung cancer each centimeter separates tumors with different prognoses from 1 to 5 centimeters (cm). Appropriate size measurement is especially important when it comes to subsolid tumors since the correlation with the computed tomographic imaging in this context is of great value. Tumors measuring larger than 5 cm up to 7 cm (T3 in the eighth edition) had a worse prognosis than found in the seventh edition of the TNM classification. Tumors larger than 7 cm (T4 in the eighth edition) have similar prognosis to other descriptors in the T4 category. Atelectasis or pneumonitis involving the whole lung (T3 in the seventh edition) has the same prognosis for partial atelectasis / pneumonitis (T2 descriptor in the seventh edition). Endobronchial tumor location less than 2 cm from carina (a T3 descriptor in the seventh edition), but without carina involvement, had the same prognosis as the endobronchial location further than 2 cm from carina (a T2 descriptor in the seventh edition). In the eighth edition, tumors involving the main bronchus and associated with atelectasis / pneumonitis are classified as T2. On the other hand, diaphragm invasion (a T3 descriptor in the seventh edition was upstaged to T4 in the eighth edition) since it has similar prognosis of T4 tumors.

      No changes to the N descriptors were proposed in the 8th TNM as the four N categories (N0, N1, N2, N3). The reassessment of the M component validated the proposed M1a category descriptors in the seventh edition and separated the distant metastases into two categories with different prognoses, M1b (single metastatic tumor in one organ), and M1c (multiple metastases in either single organ or multiple organs).

      Objective. To review and discuss the 8th edition of the TNM classification of lung cancer with an emphasis on prognostic relevance and implications for the pathologist's report.

      Data Sources. The review is based on the available literature.

      Conclusion. The TNM (tumor-node-metastasis) classification system for lung cancer is the strongest prognostic indicator and fundamental for decisions on therapy. The eighth edition of the TNM classification of lung cancer enhances the prognostic discrimination of the different T categories and differentiates unique extrathoracic metastasis (better prognosis) from multiple metastases in one or several organs providing better definition of oligometastatic disease. Thus, the eighth edition of TNM improves the understanding of tumor anatomic extent and stratification of tumors for clinical trials.

      References:

      1) Rami-Porta R, Call S, Dooms C, Obiols C, Sanchez M, Travis WD et al. Lung cancer staging: a concise update. Eur Respir J. 2018;51(5).

      2) Rami-Porta R, Bolejack V, Crowley J, Ball D, Kim J, Lyons G et al. The IALSC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10(7):990-1003.

      3) Detterbeck FC. The eighth edition TNM stage classification for lung cancer: what does it mean on main street? J Thorac Cardiovasc Surg. 2018;155(1):356-359.

      4) Eberhardt WE, Mitchell A, Crowley J, Kondo H, Kim YT, Turrisi A 3rd et al. The IALSC lung cancer staging project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2015;10(11):1515-1522.

      5) Kay FU, Kandathil A, Batra K, Saboo SS, Abbara S, Rajiah P. Revisions to the tumor, node, metastasis staging of lung cancer (8th edition): rationale, radiologic findings and clinical implications. World J Radiol. 2017;9(6):269-279.

      6) Rami-Porta R, Asamura H, Travis WD, Rusch VW. Lung cancer – major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):138-155.

      7) Nicholson AG, Tsao MS, Travis WD, Patil DT, Galateau-Salle F, Marino M et al. Eight edition staging of thoracic malignancies: implications of the reporting pathologist. Arch Pathol Lab Med. 2018;142(5):645-661.

      8) Aokage K, Miyoshi T, Ishii G, Kusumoto M, Nomura S, Katsumata S et al. Clinical and pathological staging validation in the eighth edition of the TNM classification for lung cancer: correlation between solid size on thin-section computed tomography and invasive size in pathological findings in the new T classification. J Thorac Oncol. 2017;12(9):1403-1412.

      9) Butnor KJ, Beasley MB, Dacic S, Berman M, Flieder D, Jones K et al. Protocol for the examination of specimens from patients with primary non-small cell carcinoma, small cell carcinoma or carcinoid tumor of the lung. Version: Lung 4.0.0.3. 2017. https://documents.cap.org/protocols/cp-thorax-lung-2017-protocol-4003.pdf

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      MS11.06 - The Impact of Prehabilitation on Patients Having Lung Cancer Surgery (Now Available) (ID 4060)

      15:45 - 17:30  |  Presenting Author(s): David Sanchez-Lorente

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      Abstract not provided

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