Virtual Library

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    MA02 - Improving Outcomes for Patients with Lung Cancer (ID 895)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 BD
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      MA02.01 - ROS1 Gene Rearrangements Are Associated with an Exaggerated Risk of Peri-Diagnosis Thromboembolic Events (Now Available) (ID 12442)

      10:30 - 10:35  |  Presenting Author(s): Terry L. Ng  |  Author(s): Derek E Smith, Rao Mushtaq, Tejas Patil, Anastasios Dimou, Shuo Yang, Qian Liu, Xuefei Li, Caicun Zhou, Flora Yan, I. Alex Bowman, Stephen V Liu, Robert C. Doebele, Dara L. Aisner, Shengxiang Ren, Ross Camidge

      • Abstract
      • Presentation
      • Slides

      Background

      Based on clinical observation, we hypothesized that ROS1 gene-rearranged non-small cell lung cancer (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. A multicenter, retrospective cohort study of TEE in advanced ROS1+, KRAS+, ALK+ and EGFR+ NSCLC was conducted.

      Method

      Venous (DVT / PE) and arterial (MI/TIA/CVA) TEE within +/- 365 days of diagnosis of ROS1+, KRAS+, ALK+ or EGFR+ advanced NSCLC at 4 academic centers in USA and China from October 2002 to January 2018 were captured. The primary endpoint was the incidence of TEE in ROS1+ compared to KRAS+ NSCLC as a control group within +/- 90 days of diagnosis. Secondary endpoints compared TEE incidence between ROS1+ and ALK+, and ROS1+ and EGFR+. Fine-Gray Model was used to detect differences in TEE incidence while accounting for death as a competing risk.

      Result

      105 ROS1+, 101 ALK+, 112 EGFR+, and 114 KRAS+ NSCLC patients were enrolled. Incidence rate of TEE within +/- 90 days of diagnosis was 30.5% (32/105), 12.9% (13/101), 7.1% (8/112), and 12.3% (14/114) in the respective molecular cohorts. Compared to the ROS1+ cohort, the risk of TEE was significantly lower in the three other cohorts (KRAS+ HR 0.334, 95% CI: 0.18-0.62, p=0.001; ALK+ HR 0.357, 95% CI: 0.188-0.68, p=0.002; EGFR+ HR 0.193, 95% CI: 0.089-0.421, p<0.001) (Figure 1). First event TEEs were venous as opposed to arterial in 59.5% (22/37) ROS1+, 87.1% (27/31) ALK+, 80.6% (25/31) EGFR+, and 80% (16/20) KRAS+ cases. The median time (Interquartile Range) to TEE from the time of diagnosis for ROS1+/ALK+/EGFR+/ KRAS+ was 0 days (-6.75 to 7.0), 0 days (-20.0 to 35.0), 0.50 days (-43.7 to 21.3), and 13 days (0.49 to 32.0), respectively.

      Conclusion

      Among common molecular subtypes of NSCLC, ROS1+ oncogene is associated with a significantly higher risk of developing TEE within +/- 90 days of advanced NSCLC diagnosis.

      figure 1 ros1 90 day.tif

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      MA02.02 - Multistate Healthcare Network Underutilizes Valuable End-of-Life Resources in Stage IV Non-Small Cell Lung Cancer (Now Available) (ID 13935)

      10:35 - 10:40  |  Presenting Author(s): Candice Leigh Wilshire  |  Author(s): Joshua Robert Rayburn, Christopher R Gilbert, Roshanthi K Weerasinghe, Brian E Louie, Ralph W Aye, Alexander S Farivar, Eric Vallieres, Jed A Gorden

      • Abstract
      • Presentation
      • Slides

      Background

      Early implementation of outpatient palliative care (OPC) in stage IV non-small cell lung cancer (NSCLC) patients has been associated with increased survival, improved quality of life and reduction in unnecessary health care. However, medical systems have struggled with the adoption of end-of-life resources. We aimed to determine the utilization of OPC services in stage IV NSCLC patients within our multistate, community-based healthcare network.

      Method

      We reviewed 4,298 stage cIV NSCLC patients diagnosed between 1/2013-12/2017, in a community-based healthcare network encompassing 34 centers in Alaska, California, Montana, Oregon and Washington. We excluded 899 patients managed at 9 sites without OPC services, and 92 patients who received inpatient palliative care only. Eligible patients were stratified by whether or not they received OPC; then further by early OPC, which was defined as within 11 weeks of diagnosis. Survival was compared using Kaplan-Meier with log rank tests.

      Result

      Of the 3,307 patients reviewed, only 8% (252/3,307) received OPC and 6% (182/3,307) early OPC. Median time from diagnosis to death was significantly longer for OPC patients (347 days, 95% CI 273-421) versus no PC (151 days, 95% CI 138-164), p<0.001; and similarly for early OPC (216 days, 95% CI 167-265) versus no PC, p=0.008. Documentation of advance directive/living will/power of attorney was low in all categories, with rates of documentation at 32%, 31% and 27% for patients receiving OPC, early OPC and no OPC, respectively.

      figure iaslc days dx to death.png

      Conclusion

      We identified that OPC services are broadly underutilized in stage cIV NSCLC patients across our multistate, community-based healthcare network. In addition, end-of-life documents were rarely completed in all clinical settings regardless of OPC. We confirmed prolonged survival associated with OPC in the community setting, but greater utilization is required to increase this benefit. These findings, as well as the additional benefits/value of OPC, require further study.

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      MA02.03 - ASTRIS: A Real World Treatment Study of Osimertinib in Patients with EGFR T790M-Positive NSCLC (Now Available) (ID 12972)

      10:40 - 10:45  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Byoung Chul Cho, Qing Zhou, Gee-Chen Chang, Liyan Jiang, Giulio Metro, Claudio Martin, Gilberto De Castro, Johan F. Vansteenkiste, David Vicente, Alvin Milner, James R. Rigas, Yuh-Min Chen, Mariano Provencio

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations. We report results from a second planned protocol, optimal interim analysis of the ongoing ASTRIS study (NCT02474355).

      Method

      Eligible patients receive osimertinib 80 mg once daily. Inclusion criteria: stage IIIB/IV T790M-positive non-small cell lung cancer (NSCLC); T790M status confirmed locally by validated test, not restricted by sample type; prior EGFR-TKI therapy received; WHO performance status (PS) 0−2; acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Asymptomatic, stable CNS metastases are permitted. The primary efficacy outcome is overall survival (OS).

      Result

      From Sept 18, 2015, first patient in, to Oct 20 2017 data cut-off (DCO), 3014 patients were enrolled across 16 countries and received ≥1 dose of osimertinib (full analysis set [FAS]): median follow-up 7.9 months (range <1−24), median age 62 yrs (27–92), 64% female, 69% Asian, 30% White, 11% WHO PS 2, 45% prior chemotherapy, 34% prior radiotherapy. All patients had T790M-positive status, identified from tissue in 1610 patients (53%), plasma ctDNA in 1241 patients (41%) and from other sources in 162 patients (5%). At DCO, 1276 patients (42%) had discontinued treatment (1738 [58%] ongoing); median duration of exposure 7.4 months (<1–25); 1289 patients (43%) had a progression-free survival (PFS) event, 1276 (42%) had a time to treatment discontinuation (TTD) event, and 593 (20%) had died. In patients evaluable for response, the investigator-assessed clinical response rate was 56.6% (1625/2872; 95% confidence interval [CI] 54.7, 58.4). In the FAS, estimated median PFS was 11.0 months (95% CI 10.6, 11.1), median TTD was 12.6 months (95% CI 12.2, 13.7), and median OS was not reached (OS at 12 months was 75.8% (95% CI 73.7, 77.8). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 321 patients (11%) and 147 patients (5%), respectively. Serious AEs were reported in 505 patients (17%). ILD/pneumonitis-like events were reported in 41 patients (1%), and QTc prolongation in 48 patients (2%).

      Conclusion

      ASTRIS, the largest reported study of osimertinib in T790M-positive NSCLC, demonstrates clinical activity similar to that observed in the osimertinib clinical trial program with no new safety signals.

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      MA02.04 - Discussant - MA 02.01, MA 02.02, MA 02.03 (Now Available) (ID 14575)

      10:45 - 11:00  |  Presenting Author(s): Alona Zer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA02.05 - A Double-Blind, Randomized, Placebo-Controlled Phase 3 Noninferiority Study of Darbepoetin Alfa for Anemia in Advanced NSCLC (Now Available) (ID 13816)

      11:00 - 11:05  |  Presenting Author(s): Rajnish Nagarkar  |  Author(s): Pere Gascón, Martin Šmakal, Kostas Syrigos, Carlos Barrios, Jesús Cárdenas Sánchez, Li Zhang, Dianne Tomita, Joseph Park, Cisio De Oliveira Brandao

      • Abstract
      • Presentation
      • Slides

      Background

      The effect of erythropoiesis-stimulating agents on overall survival (OS) in patients with chemotherapy-induced anemia has long been debated. This study (NCT00858364) evaluated noninferiority of darbepoetin alfa (DAR) versus placebo for OS and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin ceiling.

      Method

      Adults with stage IV NSCLC expected to receive ≥2 cycles of myelosuppressive chemotherapy, life expectancy >6 months, ECOG 0–1, and hemoglobin ≤11.0 g/dL were randomized 2:1 to DAR (500 µg SC) or placebo Q3W. Patients were stratified by region, histology, and hemoglobin. Primary endpoint was OS; a Cox proportional hazards model, stratified by randomization factors, was used to evaluate noninferiority (margin based on upper confidence limit [CL] for hazard ratio [HR] ˂1.15). Secondary endpoints were PFS (noninferiority) and incidence of transfusions or hemoglobin ≤8.0 g/dL from week 5 to end of efficacy treatment period (EOETP).

      Result

      4161 patients were screened, 2549 enrolled, and 2516 included in the primary analysis set: 1680 randomized to DAR and 836 to placebo. The study was stopped early per independent DMC recommendation. Patients were well matched between arms for age (mean 61.8 years), sex (66.0% male), and race (47.5% white). DAR was noninferior to placebo for OS (HRadj 0.92; 95%CL 0.83–1.01) and PFS (HRadj 0.95; 95%CL 0.87–1.04). DAR was superior to placebo for transfusion or hemoglobin ≤8.0 g/dL from week 5 to EOETP (OR 0.70; 95%CL 0.57–0.86; P<0.001). Objective tumor response was similar between arms (DAR 36.2%; placebo 32.6%). Incidence of serious adverse events was the same in both arms (31.1%). No unexpected adverse events or cases of antibody-mediated PRCA were observed (Table).

      DAR (n=1685)

      %

      Placebo (n=833)

      %
      All treatment-emergent adverse events 84.5 86.3
      Serious adverse events 31.1 31.1
      Fatal adverse events 12.2 13.6
      Adverse events leading to discontinuation of blinded drug 2.8 4.2
      Adverse events of interest (standardized MedDRA query)
      CNS vascular disorders 1.5 1.0
      Hypersensitivity 10.6 9.0
      Severe cutaneous adverse reactions 2.1 1.3
      Embolic and thrombotic events 5.3 4.1

      Conclusion

      DAR dosed to a 12.0-g/dL hemoglobin ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or hemoglobin ≤8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

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      MA02.06 - A Randomized, Double-Blind, Placebo-Controlled Trial of Chemotherapy Combined with Yangzheng Xiaoji in Advanced NSCLC (Now Available) (ID 13562)

      11:05 - 11:10  |  Presenting Author(s): Ligang Xing  |  Author(s): Junsheng Wang, Luming Li, Zhiyong Ma, Changlu Hu, Haibo Zhang, Li Shan, Zhendong Chen, Jiandong Zhang, Qin Zhou, Shegan Gao, Xuezhen Ma, Ping Sun, Qinyou Ren, Meina Wu, Jin Wu, Jingao Li, Juntao Yao, Hongbing Ma, Wei Wang, Wenxiu Yao, Delin Wang, Jingbo Kang, Guixin Li, Xiuwen Wang, Wanqi Zhu, Jie Wang, Jinming Yu

      • Abstract
      • Presentation
      • Slides

      Background

      Yangzheng Xiaoji (YZXJ) is a Chinese medicine formulation made of 16 herbs and used in patients with solid cancers. The aim of this randomized, double-blind and placebo-controlled multi-center trial (YANG-1,ClinicalTrials.gov registration No. NCT02195453) is to evaluate the impact of Yangzheng Xiaoji capsule on the quality of life (QoL) and treatment-related side effects in patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy.

      Method

      Patients with advanced NSCLC and with Eastern Cooperative Oncology Group performance status 0 to 1, who receive first-line chemotherapy (gemcitabine or pemetrexed and cisplatin), were randomized (1:1) to Yangzheng Xiaoji (YZXJ) or placebo combined with chemotherapy. The primary endpoint was QoL (Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)) after two or four cycles of chemotherapy. The second endpoints included overall response rate, progression free survival and toxicity.

      Result

      Between 10/2014 and 4/2017, the trial enrolled and randomized 504 patients from 25 centers in China. 397 patients received at least two cycles of chemotherapy and were included for final analysis. Baseline characteristics, including FACT-L and LCSS scores, were well balanced between two groups. The mean FACT-L scores were significantly changed in both groups from the baseline to that after chemotherapy (97.58 increase to 100.89 in YZXJ/chemotherapy arm, P<0.001; 93.83 decrease to 97.93 in placebo arm, P<0.001). The mean score of LCSS from baseline was significantly changed in YZXJ/chemotherapy groups(25.84 decrease to 22.31, P<0.001), but there was no statistical difference in the placebo group(25.59 vs. 26.45, P=0.136). The YZXJ/chemotherapy arm had a better QoL than the placebo/chemotherapy arm (FACT-L, 3.30 vs. -4.09; P<0.001) as well as improved lung cancer symptoms compared with placebo (LCSS, -3.53 vs. -0.86; P<0.001). There was no statistical difference in chemotherapy completion rate, ORR and PFS between two groups. The most common adverse events were bone marrow toxicity (70.92% vs. 67.59%) and gastrointestinal reaction (34.66% vs. 63.24%) (YZXJ vs. Placebo, P=0.441 and P<0.001, respectively). The rate of fatigue was significantly lower in YZXJ group than placebo group (4.38% vs. 30.04%, P<0.001).

      Conclusion

      For patients with advanced NSCLC who received platinum-based chemotherapy, Yangzheng Xiaoji Capsule significantly improved the quality of life and symptoms, especially fatigue and gastrointestinal reaction.

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      MA02.07 - Aprepitant for Cough Suppression in Advanced Lung Cancer: A Randomized Trial (Now Available) (ID 14540)

      11:10 - 11:15  |  Presenting Author(s): Kumar Prabhash  |  Author(s): Vanita Noronha, A Bhattacharjee, Vijay Patil, Amit Joshi, Srushti Shah, S Kannan, Sandeep Ishi

      • Abstract
      • Presentation
      • Slides

      Background
      Cough is a distressing symptom in patients with lung cancer. Effective management of cough leads to improvement in quality of life (QoL) and optimal palliative care. Aprepitant, a centrally acting neurokinin-1 inhibitor, has been shown in a pilot study to significantly decrease the cough frequency. Method
      A randomized open-label study in patients with advanced lung cancer with cough for over 2 weeks despite therapy with a cough suppressant, with an ECOG performance status 0 to 2. Patients were randomized 1: 1 to Arm A: aprepitant 125 mg orally on day 1, followed by 80 mg orally on days 2 to 7 along with physician’s choice of antitussive therapy. Patients on Arm B received physician’s choice of antitussive therapy. Patients were evaluated at baseline and then on days 3, 7, 9 and 12. Primary efficacy endpoint was subjective improvement in cough, measured with the Visual Analog Scale (VAS) and the Manchester Cough in Lung Cancer Scale (MCLCS). Secondary endpoints included toxicity and QoL, measured by the EORTC QLQ-C30 and LC13. The trial was approved by the` institutional IEC and registered with (CTRI/2017/05/008691). Result
      Between June 2017 and June 2018, 128 patients were randomized: 64 to each arm. The median age was 53 yrs, 65% male, 64% never-smokers, 82% had adenocarcinoma. 88% had Stage IV disease; 80% had PS 1 and 20% PS 2. The median duration of cough was 90 days. VAS scores at baseline and day 9 was 67.93, 38.50 in Arm A and 63.15, 48.57 Arm B , with p<0.001 and the MCLCS scores at baseline and day 9 was 30.03, 22.32 in Arm A and 27.53, 23.80 Arm B , with p<0.001. Overall, there was no significant difference in the QoL scores in patients in the two arms, however there was a significant improvement in the cough-specific QoL domain in the patients on the aprepitant arm, p=0.017. There was no increase in the grade 3 and higher adverse events in the patients on the aprepitant arm. Conclusion
      Aprepitant led to a significant improvement in cough in patients with advanced lung cancer, with no increase in severe side-effects. Aprepitant should be considered as one of the treatment options for cough in lung cancer patients.

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      MA02.08 - The Effect of Nabilone on Appetite, Nutritional Status, and Quality of Life in Lung Cancer Patients: A Randomized, Double-Blind Clinical Trial (Now Available) (ID 13428)

      11:15 - 11:20  |  Presenting Author(s): Jenny G. Turcott  |  Author(s): María del Rocío Guillen- Núñez, Diana Flores, Luis F Oñate, Zyanya Lucia Zatarain-Barrón, Feliciano Barrón, Oscar Arrieta

      • Abstract
      • Presentation
      • Slides

      Background

      Over one half of the patients diagnosed with advanced lung cancer experience anorexia. In addition to its high incidence, cancer-induced anorexia promotes the development of the anorexia-cachexia syndrome, which is related to poor clinical outcomes. Recently, drugs derived from cannabinoids, such as Nabilone, have been recognized for their appetite improvement properties; however, clinical trials to support their use in cancer patients are necessary.

      Method

      This is a randomized, double-blind, placebo-controlled clinical trial to assess the effect of Nabilone vs. placebo on the appetite, nutritional status, and quality of life in patients diagnosed with advanced Non-small cell lung cancer (NSCLC) (NCT02802540).

      Result

      A total of 65 patients from the outpatient clinic at the National Institute of Cancer (INCan) were assessed for eligibility and 47 were randomized to receive Nabilone (0.5 mg/2 weeks followed by 1.0 mg/6 weeks) or placebo. After 8 weeks of treatment, patients who received Nabilone increased their energy intake (342-kcal) and had a significantly improvements in Quality of life parameters.

      diapositiva1.jpgdiapositiva1.jpg

      Conclusion

      Nabilone is an adequate and safe therapeutic option to aid in the treatment of patients diagnosed with anorexia. Larger trials are necessary in order to draw robust conclusions in regard to its efficacy in lung cancer patients.

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      MA02.09 - Discussant - MA 02.05, MA 02.06, MA 02.07, MA 02.08 (Now Available) (ID 14576)

      11:20 - 11:35  |  Presenting Author(s): Paul Wheatley-Price

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA02.10 - The First Year of Implementing a Lung Cancer Screening Program in an Urban Safety-Net Health System (Now Available) (ID 13436)

      11:35 - 11:40  |  Presenting Author(s): Heidi Hamann  |  Author(s): Simon Lee, Travis Browning, Claudia Chavez, Joanne Sanders, Suhny Abbara, David Balis, Hsienchang Chiu, Brett Moran, Noel Santini, David E Gerber

      • Abstract
      • Presentation
      • Slides

      Background

      Little is known about implementing low-dose computed tomography (LDCT) -based screening for lung cancer in settings that care for minority and underinsured populations. These patients may benefit most from guideline-based screening but may also be least likely to complete this multi-step process.

      Method

      Parkland Health & Hospital system provides care through a combination of federal, state, and county-supported funding for more than one million, racial/ethnically diverse residents of Dallas County, Texas.

      A systematic protocol for LDCT screening was implemented in February 2017. We report initial screens and follow-up procedures for this first year through June 2018.

      Result

      844 LDCTs were ordered; 528 (63%) were completed, 68 (8%) had been scheduled. We detail demographics of completers and non-completers (Table 1) and proportion of LungRADS scores (Figure 1). For every year older, patients are 3% more likely to complete their scan. Of 249 completers requiring some form of follow-up (47%), only 3 required CT biopsy.

      table1_-1.jpgfigure1 (1).jpg

      Conclusion

      While a systematic screening program in an urban safety-net setting generates high volume, a significant percentage of patients do not complete their initial screen. Of those who complete, many require follow-up procedures. More long-term data are needed to understand non-completion trends and subsequent annual screening.

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      MA02.11 - Achieving Value in Cancer Diagnostics: Blood Versus Tissue Molecular Profiling - A Prospective Canadian Study (VALUE) (Now Available) (ID 13611)

      11:40 - 11:45  |  Presenting Author(s): Doreen Anuli Ezeife  |  Author(s): Jason S Agulnik, Rosalyn Juergens, Janessa Laskin, Scott A. Laurie, Lisa Le, Desiree Hao, Gwyn Bebb, Jennifer H Law, Stan Skrzypczak, Daniela Juri, Richard B Lanman, Natasha B Leighl

      • Abstract
      • Presentation
      • Slides

      Background

      Cell-free DNA (cfDNA) next-generation sequencing (NGS) has emerged as an effective molecular profiling technique that is potentially faster and cost-saving in comparison to standard-of-care (SOC) tumour biopsy and tissue-based profiling. In a public payer system, the added value of cfDNA blood-based profiling compared to SOC remains unknown. This study will determine the incremental clinical utility and cost of cfDNA NGS versus SOC genotyping in patients with advanced non-squamous non-small cell lung cancer (NSCLC).

      Method

      This multicentre, non-randomized, longitudinal study will be conducted at 6 sites across Canada (BC, Alberta, Ontario, Quebec). The Guardant360® assay will be used to perform plasma-based cfDNA testing, and includes mutations, rearrangements and copy number variations in 73 known cancer associated genes. Two patient cohorts will be recruited: (1) treatment naïve patients with ≤10 pack year smoking history; and (2) patients with known abnormalities of EGFR, ALK, ROS-1 or BRAF after disease progression on all standard targeted therapies. SOC tissue profiling will be performed for all patients per institutional standards. The study will begin recruiting in May 2018, with estimated completion in 12 months. The primary endpoints are comparison of response rate (RR), progression-free survival (PFS) and time-to-treatment failure (TTF) using cfDNA versus tissue genomic testing. Secondary endpoints include time to treatment initiation, number of actionable genomic abnormalities identified, result turnaround time, potentially avoidable repeat tissue biopsies, costs, patient-reported quality of life (EQ-5D) and willingness-to-pay. Exploratory analyses of treatment outcomes in selected molecular subgroups will also be undertaken, including response to immunotherapy in those with KRAS/STK11 co-mutations. A decision-analytic model will be developed to perform cost-consequence analyses using a cfDNA versus tissue-based approach.

      Result

      A total of 210 patients will be recruited across Canada, (Cohort 1 N=150, Cohort 2 N=60). Based on testing with either blood-based GUARDANT360TM or tissue-based profiling, the costs and benefits of blood-based profiling either at initial diagnosis or upon TKI progression will be determined versus initial or repeat tumour biopsy and tissue-based profiling. Data from patients accrued until 08/2018 will be presented at the meeting.

      Conclusion

      This study will determine the added value of cfDNA blood-based genotyping compared to SOC from the perspective of a public payer system (Canada).

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      MA02.12 - Discussant - MA 02.10, MA 02.11 (Now Available) (ID 14577)

      11:45 - 12:00  |  Presenting Author(s): William Kenneth Evans

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA19 - Genomic Markers of IO Response (ID 922)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 10
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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      MA19.01 - Efficacy and Genomic Correlates of Response to Anti-PD1/PD-L1 Blockade in Non-Small Cell Lung Cancers Harboring Targetable Oncogenes (Now Available) (ID 12921)

      15:15 - 15:20  |  Presenting Author(s): Natalie Vokes  |  Author(s): Elizabeth Jimenez Alguilar, Anika Adeni, Renato Umeton, Lynette M Sholl, Hira Rizvi, Matthew D. Hellmann, Mark M. Awad, Eliezer M. Van Allen

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint inhibitors (ICIs) are associated with improved outcomes in a subset of patients with advanced non-small cell lung cancer (NSCLC). NSCLCs with targetable oncogenes are thought to be less responsive to ICI therapy, possibly due to association with never smoking status and reduced tumor mutational burden (TMB), but this has not been comprehensively characterized. We evaluated the responsiveness of NSCLCs with targetable oncogenes to ICIs, and if mutation type or TMB influence response.

      Method

      Clinicopathologic, radiographic response, and sequencing data for patients with advanced NSCLC treated with ICI therapy was acquired from two separate cohorts (DFCI Oncopanel, n=296; MSKCC MSK-IMPACT, n=202). Durable clinical benefit (DCB) was defined as responsive/stable disease > 6 months. Samples with activating mutations in EGFR, ALK, ROS, BRAF, MET, and RET were identified. TMB was calculated as the sum of nonsynonymous mutations divided by the coding region captured in each panel. Objective response rates (ORR), DCB, and TMB were compared in targetable oncogene positive (TOP) vs oncogene negative (TON) patients. TMB was considered within each cohort to avoid confounding for differences in NGS panel technique.

      Result

      Targetable oncogenes were identified in 16% (82/498) of patients; 44(9%) EGFR, 15(3%) MET exon 14 splice site mutated, 8(2%) BRAF V600E, 6(1%) ROS1 rearranged, 5(1%) ALK rearranged, and 4(1%) RET re-arranged. Response to ICIs was similar in TOP vs TON patients, with ORR of 18% and 20%, and median PFS of 2.7 vs 2.8 months in TOP vs TON patients respectively. Among TOP patients, response rates differed by mutation type; ORR rate was 11%(5/44) in EGFR mutated, 40%(6/15) in MET mutated, 25%(2/8) in BRAF mutated, 33%(2/6) in ROS1 rearranged, and 0% in RET and ALK rearranged cancers (0/4, 0/5 respectively). Compared to WT, TMB was lower in TOP tumors (OncoPanel median 9vs11, p=0.0064; IMPACT median 4vs8, p=2.25e-06). TMB did not correlate with objective response or DCB in TOP tumors when considered collectively or by mutation type (OncoPanel median TMB 10vs8 in DCB vs NDB, p=0.52; IMPACT median TMB 3vs5 in DCB vs NDB, p=0.31)(Mann-Whitney U for all).

      Conclusion

      Despite lower TMB in oncogene positive NSCLC, these patients still derive clinical benefit from ICIs. ICI responsiveness is likely mutation specific, and is most pronounced in MET and BRAF mutated cancers. Among targetable oncogene positive NSCLC, TMB did not distinguish benefit. Taken together, low TMB in the presence of oncogenic driver mutations should not preclude ICI therapy.

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      MA19.03 - Discussant - MA 19.01 (Now Available) (ID 14639)

      15:20 - 15:35  |  Presenting Author(s): Jonathan W. Goldman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA19.04 - The Clinical Implication of Frameshift Indel Mutation Burden in Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 12592)

      15:35 - 15:40  |  Presenting Author(s): Young Kwang Chae  |  Author(s): Wungki Park, Diana Saravia, Vaia Florou, Sangmin Chang, Si Wang, Lauren Chiec, Ashkon Alexander Rahbari, Nisha Mohindra, Victoria Villaflor, Lee Chun Park, Gilberto de Lima Lopes

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor mutational burden (TMB) has been proposed as a potential predictive marker for immune checkpoint inhibitor (ICI) response in many cancers, including NSCLC. Recently, research has revealed frameshift indel (fsindel) of all mutations to be significantly associated with ICI response in melanoma patients. However, little is currently known regarding its clinical implication in NSCLC patients treated with PD1/PD-L1 inhibitors (ICIs).

      Method

      Next generation sequencing of 324 genes (FoundationOneTM) was used to derive fsindel burden and TMB. A total of 128 patient data with NSCLC treated with ICIs were analyzed from Northwestern University (N=68) and the University of Miami (N=60). A total of 128 patients were divided into two groups with 0 fsindel (FS-) and more than 1 fsindel (FS+). Progression free survival (PFS) and overall survival (OS) were compared between FS+ and FS- groups. PFS and OS outcomes of TMB high group (H-TMB, upper¼) and TMB low group (L-TMB, lower¼) were also compared.

      Result

      figure 1.jpg

      Among 128 patients, 51.6% belonged to FS+ group (N=66). Between FS-/FS+ groups, there were no significant differences in mean age (66.2/66.0) and performance status (0.9/0.9). Lines of ICIs used in the FS-/FS+ groups were 1st (19/19%), 2nd (47/56%), 3rd (24/11%), and 4th line or more (10/14%). FS+ group had significantly longer PFS compared with FS- group (median 6.2/2.7 months, P=0.02, Figure 1). No significant difference in OS was seen between the two groups (median 16.8/11.2 months, P=0.70). In contrast, however, H-TMB did not show any significant difference in PFS (median 5.6/4.0 months, P=0.14) and OS (median 15.8/15.1 months, P=0.69) compared to L-TMB.

      Conclusion

      This is the first report to illustrate an association between fsindel and outcome in patients with NSLC treated with ICIs. Our findings suggest its potential role as a predictive marker for immunotherapy.

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      MA19.05 - Difference of Tumor Mutational Burden Is Associated with Distinct Immune Microenviroment in the T Cell-Inflamed Lung Adenocarcinoma (Now Available) (ID 13495)

      15:40 - 15:45  |  Presenting Author(s): Takahiro Karasaki  |  Author(s): Kentaro Kitano, Kazuhiro Nagayama, Jun-ichi Nitadori, Masaaki Sato, Masaki Anraku, Kazuhiro Kakimi, Jun Nakajima

      • Abstract
      • Presentation
      • Slides

      Background

      PD-L1 expression on tumor cells, tumor infiltrating lymphocytes (TILs), and tumor mutational burden (TMB) have been reported as predictive biomarkers for checkpoint inhibitor immunotherapies. However, little is known about the relationship between each biomarkers. The aim of this study was to assess the relationship between these biomarkers, especially TIL and TMB.

      Method

      RNA-seq data of 533 primary lung adenocarcinoma were downloaded from The Cancer Genome Atlas (TCGA). Gene expression and gene set enrichment were analyzed. Clinical information and somatic missense mutation data were also integrated.

      Result

      Weak correlation between PD-L1 and CD8A expression (Spearman’s R=0.32, P<0.001), and PD-L1 expression and TMB (R=0.10, P=0.019) were seen, but not between CD8A expression and TMB (R=0.03, P=0.45). Next, we performed gene signature analysis related to cancer-immunity cycle (ref. Karasaki et al. J Thorac Oncol 2017). Hierarchical clustering resulted in 3 clusters: T cell non-inflamed phenotype with high antigenicity (Cluster 1), inflamed phenotype with low antigenicity (Cluster 2), and inflamed phenotype with high antigenicity (Cluster 3).(Fig.1) Compared with Cluster 3, Cluster 2 was featured by lower gene expression signature of cytolytic activity (P<0.0001, U-test), as well as lower expression of PD-L1 (P<0.0001, U-test).

      To further investigate the relationship between TMB and TILs, T-cell inflamed phenotype tumors were divided into four groups according to the quartiles of TMB. We estimated immune cell phenotypes of TMB-high (upper quartile) and TMB-low (lower quartile) groups using ssGSEA and CIBERSORT. Either analysis showed significant enrichment of activated CD4 T cells in TMB-high group (P<0.0001, T-test).

      Conclusion

      Existence of Cluster 1 and 2 suggested that tumor antigenicity (TMB) does not necessarily correlate with TIL enrichment. TMB-low tumors may form T cell-inflamed tumors (Cluster 2), although the immune status may differ from TMB-high inflamed tumors (Cluster 3). Integrating multiple biomarkers for the assessment of tumor immune microenvironment is important for optimal immunotherapy.

      図color.jpg

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      MA19.06 - Blood Based Biomarkers: RNA, KRAS and PD-L1 Strongly Matching with Tissue and Showing Correlation with Clinical Responses In NSCLC Patient’s (Now Available) (ID 12358)

      15:45 - 15:50  |  Presenting Author(s): Luis E Raez  |  Author(s): Joshua Usher, Cheryl Habaue, Kathleen Danenberg, Brian Hunis, Yolanda Jaimes, Shahrooz Rabizadeh, Aurelio Castrellon, Peter Danenberg

      • Abstract
      • Presentation
      • Slides

      Background

      Circulating cell-free tumor RNA (cfRNA) can be now safety isolated as cfDNA and used to measure changes in the tumor burden in the blood and changes in gene expression in non-small cell lung cancer (NSCLC) patients (pts). We are correlating these changes in cfRNA and PD-L1 with clinical response to therapy (chemotherapy, immunotherapy (IMMUNO) or targeted therapy) in stage IV NSCLC pts. Our group has been the first one to use cfRNA to detect PD-L1.

      Method

      Blood was drawn from 31 pts under various treatments (tx) every 6-8 weeks, at the same time that CT scans were done. CfRNA was extracted from the resulting plasma and reverse transcribed with random hexamers to cDNA. Levels of cfRNA were quantitated by RT-qPCR and correlated with pts clinical response (CR/PR/SD/PD), as determined by CT scans.

      Result

      A total of 31 lung cancer pts were enrolled in a 2-year clinical study. 25 of 31 pts completed already the first two cycles of tx and had CT scans done. Of these, 6/8 pts with progressive disease (PD) showed increased (INC) levels of cfRNA, 9/13 pts with stable disease (SD) showed either no change (NC) or decreased (DEC) cfRNA, and 4/4 pts with partial response (PR) had NC or DEC cfRNA, corresponding to 76% concordance between cfRNA and clinical responses. PD-L1 expression measured in plasma cfRNA matched the tissue expression in 7/10 pts. In the one pt where PD-L1 was (-) in blood and (+) in tissue there was PD on IMMUNO. Among 8 pts treated with IMMUNO: 3/3 pts with PD showed INC PD-L1 cfRNA expression, 3/3 pts with SD had NC in negative PD-L1 status, and 2 pts with PR showed DEC PD-L1 cfRNA, corresponding to 100% correlation between PD-L1 expression levels and pt response. Of the 31 pts, 32% (10/31) harbored KRAS mutations in cfDNA. Of those with KRAS+ status by tissue-based testing, 83% matched with cfDNA results. Among KRAS+ pts, 80% (8/10) showed PD-L1 cfRNA expression in same blood draws with KRAS+ cfDNA, suggesting correlation between these cfDNA and cfRNA analyses.

      Conclusion

      Significant association was observed between clinical response and changes in plasma cfRNA levels in NSCLC pts (76%). There was concordance between tissue- and blood-based testing in both DNA (KRAS mutations, 83%) and RNA (PD-L1 expression, 70%). While on IMMUNO levels of PD-L1 expression could be used to monitor response to immunotherapy.

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      MA19.07 - Discussant - MA 19.04, MA 19.05, MA 19.06 (Now Available) (ID 14640)

      15:50 - 16:05  |  Presenting Author(s): Claudia Poleri

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA19.08 - Detection of Primary Immunotherapy Resistance to PD-1 Checkpoint Inhibitors (PD1CI) in 2nd Line NSCLC (Now Available) (ID 13916)

      16:05 - 16:10  |  Presenting Author(s): Joachim G.J.V. Aerts  |  Author(s): Egbert F Smit, Mirte Muller, Anna-Larissa Nadia Niemeijer, Carlos Oliveira, Heinrich Roder, Joanna Roder

      • Abstract
      • Presentation
      • Slides

      Background

      PD1CI are capable of restoring immunity, but some patients do not benefit. While molecular tests like PD-L1 expression and TMB help in enriching response in respective subsets, a test identifying patients showing primary resistance to PD1CI which does not require tissue samples could help in optimizing treatment regimens.

      Method

      Sophisticated mass spectrometry profiling data from a development set (S) of pre-treatment serum from 116 2nd line NSCLC patients treated with nivolumab were correlated with outcome data (PFS/OS)using multivariate machine learning techniques related to deep learning. The resulting test stratified patients into three groups: group A having very poor outcomes, group B having intermediate outcomes, and group C having very good outcomes. Development results were obtained using out-of-bag estimators. Two additional patient cohorts treated with nivolumab, V1(N=58) and V2(N=75), were used for validation.

      Result

      The proportions of patients in A, B, and C were 41:43:32 in S, 23:18:17 in V1, and 32:19:24 in V2. Median PFS/OS in the poor prognosis group A was 43/132 days in S, 105/189 days in V1, 90/278 days in V2, and in the good prognosis group C 276/528 days in S, 192/459 days in V1, and 155/not reached days in V2. In a comparison with historical controls treated with single agent chemotherapy and analyzed with the same technique, nivolumab appeared substantially superior in the good prognosis group C, while there was no evidence of superiority in the poor prognosis group A. In multivariate analysis including performance status, smoking history, and histology, the test remained an independent predictor of outcome. The patterns of protein expression related to poor prognosis in group A patients were associated with elevated complement, wound healing, and acute phase reactants.

      Conclusion

      We developed and validated a test stratifying patients into three groups with significantly different outcomes on nivolumab. The poor prognosis group showed little benefit from nivolumab, and other treatments may be needed, while in the good prognosis group outcomes were very good for a 2nd line population. Our results emphasize the important role of the host immune response in the prediction of PD1CI efficacy. Data on PD-L1 IHC from these cohorts will be included in the multivariate analysis and presented at the meeting.

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      MA19.09 - Concurrent Mutations in STK11 and KEAP1 is Associated with Resistance to PD-(L)1 Blockade in Patients with NSCLC Despite High TMB (Now Available) (ID 11983)

      16:10 - 16:15  |  Presenting Author(s): Kathryn C Arbour  |  Author(s): Ronglai Shen, Andrew Plodkowski, Hira Rizvi, Ai Ni, Niamh Long, Darragh Halpenny, Francisco Sanchez-Vega, Charles M. Rudin, Gregory J Riely, Matthew D. Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      Targeted next generation sequencing (NGS) testing for lung cancer patients identifies recurrent patterns of co-mutations. STK11 is known to be associated with poor outcomes with immunotherapy. We have identified that STK11 is commonly co-mutated with KEAP1, but the impact of this pattern of co-mutation on response to immunotherapy is not known.

      Method

      We identified 308 patients with advanced lung cancer treated at Memorial Sloan Kettering Cancer Center who underwent NGS testing with MSK-IMPACT and received at least one dose of PD-(L)1 inhibitor. Progression free survival (PFS) and overall survival (OS) from treatment initiation of PD-(L)1 blockade were calculated using Kaplan-Meier methodology and compared using logrank method and t-test for continuous variables.

      Result

      In a cohort of 308 patients with NSCLC treated with PD-(L)1 blockade, STK11 or KEAP1 mutations occurred frequently (23% and 22% respectively) and concurrent STK11 and KEAP1 mutations (STK11mut/KEAP1mut) were common (56% of all STK11 mutant patients and 13% of all lung cancers, Fisher’s test of association p<0.0001). Other common co-mutations with STK11 included KRAS (50%) and TP53 (48%). STK11mut/KEAP1mut patients had higher TMB than STK11wt/KEAP1wt patients (median 9.4 vs 6.1, Mann-Whitney p= 0.0002).

      STK11mut/KEAP1mut (n=39) patients had diminished PFS and OS compared to patients with STK11wt/KEAP1wt (n=210) (PFS HR 1.5, p=0.02; OS HR 2.3, p=0.001). As context, outcomes in STK11mut/KEAP1mut patients were similarly poor to EGFR mutant patients (n=28) treated with PD-(L)1 blockade (PFS p=0.7) despite substantially different tumor mutation burden (9.4 vs 4.9 mut/Mb, p<0.0001). Among STK11mut/KEAP1mut patients, poor outcomes were unchanged irrespective of KRAS status (PFS p=0.8, OS p=0.5). Patients with mutations in STK11 alone (n=31) or KEAP1 alone (n=28) had outcomes that more closely mirrored STK11wt/KEAP1wt patients (PFS p=0.9 and 0.1 respectively, OS p=0.1 and 0.2 respectively).

      Conclusion

      KEAP1 plus STK11 co-mutation is a common event in NSCLC that is distinctly associated with poor outcomes with PD-(L)1 blockade despite otherwise favor molecular features.

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      MA19.10 - Impact of STK11/LKB1 Genomic Alterations on Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 14295)

      16:15 - 16:20  |  Presenting Author(s): Ferdinandos Skoulidis  |  Author(s): Yasir Y Elamin, Vincent K Lam, Jianjun Zhang, Jeff Lewis, Waree Rinsurongkawong, Jack Lee, Jack A Roth, Stephen Swisher, Vassiliki A Papadimitrakopoulou, John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab represents a standard of care for the first-line treatment of patients with metastatic non-squamous NSCLC, irrespective of tumor cell PD-L1 expression. Genomic determinants of response to chemo-immunotherapy in NSCLC have not been reported thus far. We previously identified STK11/LKB1 alterations as a major genomic driver of de novo resistance to PD-1/PD-L1 inhibitor monotherapy in NSCLC (Skoulidis et al., Cancer Discovery, 2018). Here, we examine the impact of STK11/LKB1 mutations on clinical outcomes with chemo-immunotherapy with pemetrexed/carboplatin/pembrolizumab.

      Method

      Patients with metastatic non-squamous NSCLC that received at least 1 cycle of pemetrexed/carboplatin/pembrolizumab at MD Anderson Cancer Center, were alive for ≥14 days thereafter and had available next generation sequencing- based comprehensive tumor genomic profiling were eligible. Response assessment was based on RECIST1.1. PD-L1 expression on tumor cells was evaluated using the FDA-approved 22C3 pharmDx assay. All patients consented to collection of clinical and molecular data as part of the GEMINI protocol.

      Result

      Among 49 eligible patients (median age 61 years, 51% female, 96% adenocarcinoma histology, 34.7% KRAS-mutant) the objective response rate to pemetrexed/carboplatin/pembrolizumab was 51% (25/49) for the overall population. The disease control rate (PR+SD≥ 6 months) differed significantly between STK11/LKB1-mutant and STK11/LKB1-wild-type tumors (31.3% vs 72.7%, P=0.011, two-tailed Fisher’s exact test). The objective response rate was 31.3% for STK11/LKB1-mutant and 60.6% for STK11/LKB1 wild-type tumors (P=0.07, two-tailed Fisher’s exact test). 37.5% (6/16) of STK11/LKB1-mutant tumors exhibited progressive disease as best overall response to chemo-immunotherapy compared with 6.1% (2/33) STK11/LKB1-wild-type tumors (P=0.01, two-tailed Fisher’s exact test). Patients bearing STK11/LKB1-mutant tumors exhibited shorter progression-free survival with chemo-immunotherapy (median PFS 4.4 months vs 11.0 months, P=0.039, log-rank test). STK11/LKB1-mutant tumors were less likely to be positive for PD-L1 expression (PD-L1 TPS ≥ 1%), although the difference did not reach statistical significance (43.8% vs 72%, P=0.1, two-tailed Fisher’s exact test).

      Conclusion

      STK11/LKB1 genomic alterations are associated with inferior clinical outcomes with chemo-immunotherapy in non-squamous NSCLC, with response rates comparable to those previously reported for platinum doublet chemotherapy alone. Assessment of STK11/LKB1 status may help refine treatment approaches in non-squamous NSCLC.

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      MA19.11 - Discussant - MA 19.08, MA 19.09, MA 19.10 (Now Available) (ID 14642)

      16:20 - 16:35  |  Presenting Author(s): Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.01 - Accumulation of Concomitant Mutations Involved in Drug Resistance in the Sequential ALK TKI Treatments of ALK-Positive NSCLC (Now Available) (ID 12550)

      13:30 - 13:35  |  Presenting Author(s): Shun Lu  |  Author(s): Yongfeng Yu, Yan Ding, Xue Wu, Hairong Bao, Yang W. Shao

      • Abstract
      • Presentation
      • Slides

      Background

      ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next-generation TKIs, have shown promising clinical outcomes for ALK-positive lung cancer patients. However, distinct resistant-mechanisms have been suggested for different ALK fusion variants in response to various TKIs. The genomic alterations associated with these heterogeneous resistant-mechanisms have not been adequately investigated, especially for patients received sequential ALK TKI treatments.

      Method

      The distribution of ALK fusion variants in 475 ALK-positive lung cancer patients (cohort I) out of 11842 lung cancer patients (4%) tested by next-generation sequencing were analyzed. In addition, mutation profiles of 416 cancer-relevant genes in the post-ALK TKI treatment tumor samples from 52 non-small cell lung cancer (NSCLC) patients (cohort II) who represent the similar distribution of ALK fusion variants as in cohort I were analyzed. Thirty-five patients received crizotinib treatment only (crizotinib group), whereas the other 17 patients were treated with multiple lines of ALK TKIs (multi-TKI group), including lorlatinib, alectinib, ceritinib and brigatinib.

      Result

      EML4-ALK v3 and v1 are the two most common ALK fusion variants in both cohorts. In cohort II, 18 different ALK activating mutations were found in 17 patients (49%) of the crizotinib group and 10 patients (59%) of the multi-TKI group, although with different mutation patterns. In the multi-TKI group, G1202R was the most frequent ALK activating mutation found in 35% of the patients, while L1196M (14%) and G1269A (11%) were more common in the crizotinib cohort. Of note, there was a significant enrichment of concomitant ALK activating mutations in the multi-TKI group (p=0.031), as well as a trend of increased number of patients carrying activation of ALK by-pass/downstream pathways (p=0.056) in this group compared with the crizotinib group, resulting in a significantly higher recurrence of dual activation of ALK and ALK by-pass/downstream pathways in the multi-TKI group (29%) than that in the crizotinib group (6%) (p=0.031). Patients with concomitant TP53 mutation had significantly shorter progression free survival (PFS) compared with TP53 wildtype patients upon crizotinib treatment (median PFS: 8 vs 13 months, HR 1.494, p=0.019) regardless of fusion variant types.

      Conclusion

      Significantly higher frequency of concomitant mutations, including concomitant ALK activating mutations, and dual activation of ALK and ALK by-pass/downstream pathways, was observed after multiple lines of ALK TKI treatments, indicating the diversity and complexity of resistance-mechanisms in response to next-generation ALK TKIs. Concomitant TP53 mutation might serve as a prognosis biomarker for worse clinical outcomes treated with crizotinib.

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      MA26.02 - Upfront or Sequential Strategy for New Generation Anaplastic Lymphoma Kinase (ALK) Inhibitors: An Italian Retrospective Study.  (Now Available) (ID 12790)

      13:35 - 13:40  |  Presenting Author(s): Elisa Gobbini  |  Author(s): Pamela Pizzutilo, Rita Chiari, Sara Pilotto, Claudio Dazzi, Giorgia Osman, Paola Bordi, Laura Ghilardi, Fabiana Letizia Cecere, Paolo Graziano, Evaristo Maiello, Gloria Borra, Olga Martelli, Vanesa Gregorc, Vieri Scotti, Clelia Casartelli, Ferdinando Riccardi, Piero Rizzo, Alessandro Del Conte, Angelo Delmonte, Claudia Bareggi, Diego Cortinovis, Concetta Sergi, Antonio Rossi, Giulio Rossi, Emilio Bria, Massimo Di Maio, Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background

      Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown.

      Method

      We retrospectively collected 242 ALK-positive advanced NSCLC diagnosed between 2010 and 2018 in 23 Italian institutions (expanded data collection from Gobbini et al. Lung Cancer 2017). 138 patients received exclusively crizotinib as ALKi (not considered for this analysis). 78 patients received crizotinib and a new (second or third) generation ALKis as further treatments (group A). 26 patients performed a new generation ALKi as upfront agent (group B). These groups are larger than those considered in a previous analysis (15 and 8 patients, respectively).

      Result

      Study population clinical features and treatments received are summarized in Table 1.

      Group A

      Crizotinib followed by new generation ALKis

      N= 78

      Group B

      Upfront new generation ALKis

      N=26

      Treatments per line n(%)

      Crizotinib

      28(36)

      50(64)

      -

      -

      -

      -

      2(8)

      -

      Alectinib

      -

      11(14)

      18(23)

      5(17)

      7(27)

      -

      -

      -

      Ceritinib

      -

      9(12)

      23(30)

      3(4)

      8(31)

      8(31)

      1(4)

      -

      Brigatinib

      -

      6(8)

      6(8)

      2(3)

      -

      2(8)

      -

      2(8)

      Lorlatinib

      -

      -

      4(5)

      5(6)

      -

      -

      1(4)

      -

      Chemotherapy

      50(64)

      2(3)

      10(13)

      na

      11(42)

      6(23)

      1(4)

      Na

      Clinical features n(%)

      Age (range)

      58 (27-83)

      55 (24-82)

      Male

      37(47)

      10(38)

      p= 0.42

      Female

      41(53)

      16(62)

      Current smoker

      8(10)

      5(19)

      p= 0.23

      Never/former smoker

      70(90)

      21(81)

      ALKi beyond PD

      27(34)

      4(15)

      p= 0.06

      With a median follow-up of 22.6 months (CI 95% 20.09-25.10), 33 patients had died (32%). In group B, the median progression free survival (PFS) for new generation ALKis administered as first (14.0 months, CI 95% 9.52-18.471), second (12.7 months, CI95% 7.22-18.17) or third-line (12.8 months, CI95% 6.24-19.35) was not statistically different (p= 0.522). The median time from the start of crizotinib to the disease progression after the new generation ALKi sequentially performed (group A) was longer than that one detected in group B for the upfront new generation ALKis (29 vs 14 months, HR 2.47 [CI95% 1.35-4.50], p=0.003). This result was confirmed even considering the time lost between the two treatments in group A. The median overall survival (OS) was not reached. The 12-months OS rate was 97% in group A and 84% in group B.

      Conclusion

      New generation ALKis maintain their efficacy regardless of the treatment setting considered. The sequential strategy seems to provide a substantial benefit, but a longer follow-up and larger samples are needed to clarify the survival impact.

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      MA26.03 - Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement (Now Available) (ID 14731)

      13:40 - 13:45  |  Presenting Author(s): Zofia Piotrowska  |  Author(s): H Isozaki, JK Lennerz, Subba Digumarthy, Justin F Gainor, Nicolas Marcoux, M Banwait, D Dias-Santagata, A. John Iafrate, Mari Mino-Kenudson, Rebecca J Nagy, Richard B Lanman, E Evans, C Clifford, B Wolf, AN Hata, Lecia Sequist

      • Abstract
      • Presentation
      • Slides

      Background
      The spectrum of acquired resistance (AR) to osimertinib is not yet fully characterized. We present a single-center cohort of osimertinib AR biopsies and results of a patient with RET-mediated AR treated with the investigational RET-specific TKI BLU-667 and osimertinib.
      Method
      We assayed tissue via SNaPshot or Foundation One next-generation sequencing (NGS) and plasma via Guardant360 NGS under an IRB-approved protocol. In vitro studies assessed implications of RET fusions in EGFR-mutant cancers. We treated one patient with osimertinib/BLU-667 using an IRB and FDA-approved compassionate use protocol.
      Result
      41 EGFR-mutant patients with AR to osimertinib were assessed histologically and queried by tissue NGS (n=22), plasma NGS (n=9) or both (n=10). Key AR findings: SCLC transformation (2/32 tissue); EGFR C797S (5/32 tissue, 5/19 plasma, all cis with T790M); MET amplification (7/32 tissue, 3/19 plasma); BRAF rearrangement (2/32 tissue) and CCDC6-RET rearrangement (1/32 tissue, 1/19 plasma [distinct case]).
      CCDC6-RET was expressed in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells, which maintained MAPK signaling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitized cells expressing CCDC6-RET to EGFR inhibition.
      A 60-year-old woman with EGFR del19 progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib AR showed acquired CCDC6-RET (T790-wt). She began osimertinib 80mg/BLU-667 200mg daily x2 weeks, then BLU-667 was increased to 300mg daily. Her dyspnea improved within days of initiation. Scans after 8 weeks revealed a marked response with RECIST tumor shrinkage of 78% (Figure). She experienced only grade 1 toxicities of fatigue, leukopenia, hypertension, dry mouth, and elevated transaminases.
      Conclusion
      RET rearrangements are rare but recurrent in EGFR-mutant patients with AR to osimertinib. In vivo models suggest they mediate AR and this patient provides proof-of-concept that combination EGFR+RET inhibition with osimertinib/BLU-667 is a well-tolerated and effective regimen for RET-mediated AR. Further study is ongoing.

      14731.jpg

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      MA26.04 - Discussant - MA 26.01, MA 26.02, MA 26.03 (Now Available) (ID 14584)

      13:45 - 14:00  |  Presenting Author(s): Caroline McCoach

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA26.05 - Comprehensive Analysis of Treatment Response and Progression Pattern in Chinese Patients with Different ALK Fusion-Variants (Now Available) (ID 13883)

      14:00 - 14:05  |  Presenting Author(s): Meng Qiao  |  Author(s): Chao Zhao, Xuefei Li, Tao Jiang, Fengying Wu, Xiaoxia Chen, Chunxia Su, Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      ALK inhibitors and chemotherapy are two major strategies in the treatment of patients with ALK-rearrangements in China. However, the respective treatment response varies and heterogeneous. This study aimed to comprehensively analyze the impact of ALK variants on different treatment response and explore progression pattern respectively.

      Method

      We retrospectively analyzed a cohort of 135 patients with determined ALK variants and medical record from January 2013 to July 2017 in Shanghai Pulmonary Hospital.

      Result

      figure 1.jpgThe most frequent ALK variant was variant 1 in 62 patients (46%), followed by variant 3a/b in 52 patients (38%) and variant 2 (12%). 69 (51.1%) of patients received chemotherapy, whereas 64 (47.4%) were treated with crizotinib and 2 (1.5%) with alectinib.The similar PFS was observed in patients ALK variant 1 and non-variant 1 regardless of first-line treatment strategy (crizotinib: 15.7 vs. 12.8 months, p=0.53; chemotherapy: 5.7 vs. 8.1 months, p=0.098). However, in the subgroup analysis, patients with ALK variant 1 and baseline brain metastasis had significantly shorter PFS in the first-line setting versus non-variant 1 (4.9 vs. 11.3 months, HR=2.96, p<0.01). Additionally, ORR was 21.6% and 50% in variant 1 and non-variant 1 patients with brain metastases, respectively. Moreover, in the analysis of progression pattern, 55 patients with ALK variant 1 and 57 patients with ALK non-variant 1 exhibited PD. As to ALK variant 1, the incidence of CNS relapse in patients treated with crizotinib was significantly higher than patients treated with chemotherapy (39.3% vs. 7.4%, p=0.005). In terms of ALK non-variant 1,the patients treated with chemotherapy had higher incidence of bone progression than patients treated with crizotinib (25% vs. 0%, p=0.021).

      Conclusion

      Our results firstly indicate the treatment-naïve patients with ALK variant 1 and baseline brain metastasis have inferior response to initial cancer treatment. Different ALK variants have distinct landscape of progression pattern when treated with crizotinib or chemotherapy.

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      • Abstract
      • Presentation
      • Slides

      Background

      Metastasized NSCLC with an ALK fusion are sensitive to a range of tyrosine kinase inhibitors. ALK-positive NSCLC has been identified in the pivotal phase III trial with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC+ FISH-. The aim of this study was to collect ALK IHC+ cases and compare within this group response to crizotinib treatment of ALK FISH+ cases with ALK FISH- cases.

      Method

      A prospective multicenter investigator initiated research study was started in Europe. Stage IV ALK IHC+ NSCLC cases treated with crizotinib were collected centrally. Slides were validated centrally for ALK IHC (with 5A4 ETOP and D5F3 Ventana protocol) and ALK FISH (Vysis probes).

      Result

      The study started April 1, 2014 and closed in November 2017. Fifteen centers participated. Registration of 3523 ALK IHC tests revealed prevalence of 2.6% ALK IHC+ cases. Local ALK FISH analysis resulted in 46 concordant (ALK IHC+/FISH+) and 18 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 6 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The time to treatment failure did not differ for concordant nor discordant cases, and neither for local nor validated ALK testing (HR=0.78; 95% CI= 0.27-2.3; p=0.64) and (HR=2.2; 95% CI= 0.72-6.5; p=0.16), respectively). However, overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010), but not according to local testing (HR=1.7; 95% CI= 0.45-6.2; p=0.44).

      Conclusion

      ALK IHC+ FISH- NSCLC cases are an infrequent finding. We recommend such cases to be validated carefully because our data indicate that ALK IHC+ FISH- cases have a worse survival when treated by crizotinib compared to ALK IHC+ FISH+ cases.

      This study was funded by an independent research grant by Pfizer

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      • Abstract
      • Presentation
      • Slides

      Background

      ROS1 positive non-small cell lung cancer (NSCLC) patients can be treated with specific tyrosine kinase inhibitors including crizotinib. ROS1 positivity is often clinically detected by fluorescence in situ hybridization (FISH), however ROS1 IHC can be used to screen samples prior to FISH confirmation of ROS1 status. The ROS1 (SP384) antibody detects ROS1 with high sensitivity, specificity, and consistency. Consistent interpretation of a ROS1 IHC assay between pathologists is important patient evaluation. Here we present inter-reader precision of 12 pathologists across 60 FFPE cases stained with ROS1 (SP384).

      Method

      A retrospective cohort of 60 FFPE NSCLC cases stained with H&E, Rabbit Monoclonal Negative Control Ig, and ROS1 (SP384) were selected to represent positive, negative, and borderline ROS1 IHC status. Twelve practicing lung pathologists independently scored the cases as positive or negative around a cutoff of cytoplasm staining in > 30% tumor cells at a ≥2+ intensity level using Pathotrainer software (Pathomation bvba). Scoring was blinded to other readers and ROS1 status of the cases. Overall percent agreement (OPA), negative percent agreement (NPA), and positive percent agreement (PPA) were calculated in comparison to the group mode. Average overall percent agreement (AOPA), average positive agreement (APA), and average negative agreement (ANA) were calculated pairwise for each reader pair. Following independent assessment, participating pathologists conducted a discordant case review establishing consensus reads for all 60 cases and compared 44 cases to available FISH results.

      Result

      OPA of each of the 12 readers to the mode was 96.4% (95% CI 93.9-98.6) with PPA of 96.3% (95% CI 92.7-99.4) and NPA of 96.5% (95% CI 92.8-99.5). Pairwise AOPA between each of the 12 readers was 94.5% (95%CI 91.2-97.7) with APA 94.0% (95% CI 89.5-97.6) and ANA 95.0% (95%CI 91.2-97.9).

      Consensus IHC scores were concordant with FISH 90.0% (40/44 cases).

      Conclusion

      Inter-reader precision around a cutoff of >30% tumor cells with cytoplasmic staining at a ≥2+ intensity level was high in interpreting ROS1 (SP384) in NSCLC samples. Case review highlighted confirmation with FISH in questionable cases and staining patterns to be considered when interpreting ROS1 (SP384) IHC.

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      MA26.08 - Discussant - MA 26.05, MA 26.06, MA 26.07 (Now Available) (ID 14586)

      14:15 - 14:30  |  Presenting Author(s): Dong-Wan Kim

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA26.09 - Lazertinib, a Third Generation EGFR-TKI, in Patients with EGFR-TKI-Resistant NSCLC: Updated Results of a Phase I/II Study (Now Available) (ID 12817)

      14:30 - 14:35  |  Presenting Author(s): Byoung Chul Cho  |  Author(s): Ji-Youn Han, Sang-We Kim, Ki-Hyeong Lee, Dong-Wan Kim, Yun-Gyoo Lee, Gyeong-Won Lee, Jong-Seok Lee, Eun Kyung Cho, Joo-Hang Kim, Sung Sook Lee, Young Joo Min, Jin-Soo Kim, Sang Won Shin, Hye Ryun Kim, Min Hee Hong, Jin Seok Ahn, Seonmi Kang, Sohee Kim, Seong Bok Jang, Soongyu Choi, Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Background

      Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that can penetrate the blood-brain barrier, and targets the activating EGFR mutations Del19 and L858R, as well as the T790M mutation, while sparing wild type. We report the updated results from a Phase I/II study of lazertinib (NCT03046992)

      Method

      Patients with advanced and metastatic NSCLC who had progressed after treatment with EGFR-TKIs with/without asymptomatic brain metastases (BM) were enrolled in an open-label, multicenter, phase I/II study with dose-escalation and expansion cohorts. Lazertinib was administered once daily at doses between 20 to 320 mg in a 21-day cycle. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy. T790M status was confirmed in the dose-expansion cohorts.

      Result

      A total of 115 patients (median age 62 years, female 62%) were enrolled. The dose-escalation cohort included 38 patients administered with 20 to 320 mg across 7 dose levels, and 77 patients in the dose-expansion cohort were administered with 40 to 240 mg across 5 dose levels. No dose-limiting toxicities were observed in the dose-escalation cohort. Systemic exposure increased dose-dependently. Of the evaluable patients (n=110) at data cut-off, the objective response rate (ORR) was 65% (95% confidence interval [CI], 54.9 to 73.4). The ORR for 93 of the T790M+ patients was 69% (95% CI, 58.4 to 78.0). In patients with BM (n=12), the intracranial ORR was 50% (95% CI, 21.1 to 78.9). The most common treatment-emergent adverse events (TEAEs) were pruritus (19%), decreased appetite (17%), rash (14%), and constipation (12%). The most frequently reported TEAEs of grade ≥ 3 were hyponatraemia (2%), nausea (2%) and pneumonia (2%).

      ORR in T790M+ patients
      Dose QD 20 mg 40 mg 80 mg 120 mg 160 mg 240 mg
      Evaluable patients*, n 2 25 18 22 18 8
      ORR, n (%) 2 (100) 17 (68) 11 (61) 17 (77) 11 (61) 6 (75)
      * Patients were deemed evaluable for response if they underwent a post-baseline radiological assessment (RECIST 1.1) or were discontinued prior to the post-baseline assessment.

      Conclusion

      Lazertinib was safe, well-tolerated and exhibited promising systemic and intracranial antitumor activity in EGFR T790M+ NSCLC patients. The dose-expansion cohort as the first and second-line setting has been initiated from April 2018.

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      MA26.10 - CNS Activity of Ramucirumab in Combination with Osimertinib in Patients with Advanced T790M-Positive EGFR-Mutant NSCLC (Now Available) (ID 12295)

      14:35 - 14:40  |  Presenting Author(s): Luis Paz-Ares  |  Author(s): David Planchard, James Chih-Hsin Yang, Ki Hyeong Lee, Pilar Garrido, Keunchil Park, Joo-Hang Kim, Dae Ho Lee, Huzhang Mao, Bo H Chao, Helena Yu

      • Abstract
      • Presentation
      • Slides

      Background

      Many patients with NSCLC develop central nervous system (CNS) metastasis. Osimertinib, a novel third-generation EGFR tyrosine kinase inhibitor (TKI), has previously demonstrated CNS and systemic efficacy in patients with EGFR-mutant NSCLC. Combination of an EGFR TKI with a VEGF/VEGFR2-directed monoclonal antibodies (mAb) have shown promising results in EGFR-mutant NSCLC. Ramucirumab, human IgG1 VEGFR2 mAb, was used in combination with osimertinib. Planned exploratory and CNS response analyses aim to examine the safety/efficacy of ramucirumab+osimertinib in patients with CNS metastasis.

      Method

      In this ongoing, open-label, multicenter Phase 1 study (NCT02789345), patients with T790M-positive EGFR-mutant (Ex19del or L858R) NSCLC who had relapsed after first-line EGFR TKI therapy were enrolled. Patients with asymptomatic and stable CNS metastasis (with/without prior radiotherapy) were eligible. Primary objective of the study was to assess safety and tolerability of ramucirumab+osimertinib. Secondary endpoints include objective response rate (ORR) and disease control rate (DCR). Exploratory endpoints relevant to CNS include CNS ORR and CNS DCR.

      Result

      Patients (N=25) were 45-80 years (median 64) with ECOG-PS 0 (n=3) or 1 (n=22) and 10 patients had CNS metastasis at enrollment while 15 never had CNS metastasis. Patients with CNS metastasis could have had prior radiotherapy (n=7) or no radiotherapy (n=3) to the CNS. Median follow-up time was 7.23 months. Fifteen patients remained on study treatment (five with CNS metastasis, ten without). TEAEs of interest (CNS metastasis, no CNS metastasis), such as headache (4/10, 5/15), vomiting (3/10, 4/15), and nausea (2/10, 4/15), were observed with comparable rates in patients with or without CNS metastasis. One patient developed TEAE of cerebral hemorrhage (Grade 1), related to CNS metastasis, but unrelated to study treatment, according to the investigator. Another patient with CNS metastasis developed Grade 5 TRAE of subdural hemorrhage, unrelated to CNS metastasis, ~7 weeks after the last dose of ramucirumab. Only one patient with CNS metastasis had measurable CNS lesions (tumor shrinkage of 24% [SD] as best response). The other nine patients with CNS metastasis had non-measurable CNS lesions, one of whom had a CNS complete response; his systemic best response was SD. The rest of patients had CNS non-CR/non-PD. To date, one patient (1/25) developed CNS progression (due to new CNS lesion); her CNS best response was SD.

      Conclusion

      Ramucirumab+osimertinib showed potential antitumor activity in the CNS. Patients with CNS metastasis, with/without prior radiotherapy, appeared to tolerate this combination similarly to patients without CNS metastasis.

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      MA26.11 - Effects of Dose Modifications on the Safety and Efficacy of Dacomitinib for EGFR Mutation-Positive NSCLC (Now Available) (ID 13318)

      14:40 - 14:45  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Tony S. Mok, Kazuhiko Nakagawa, Rafael Rosell, Ki Hyeong Lee, Jesus Corral, Maria Rita Migliorino, Adam Pluzanski, Rolf Linke, Geeta Devgan, Eric I. Sbar, Susan Quinn, Tao Wang

      • Abstract
      • Presentation
      • Slides

      Background

      In patients with EGFR mutation-positive advanced stage NSCLC, first-line dacomitinib significantly improved PFS, OS, DoR and time to treatment failure vs gefitinib (ARCHER 1050; NCT01774721).1,2 Dacomitinib starting dose was 45 mg QD for all patients, with reductions to 30 or 15 mg QD permitted. We explored effects of dacomitinib dose reduction on safety and efficacy in this ongoing study.

      Method

      Patients with newly diagnosed stage IIIB/IV or recurrent NSCLC harboring an EGFR mutation (exon 19 del or exon 21 L858R) randomized to dacomitinib received 45 mg PO QD. Study endpoints and protocol-defined dose reduction parameters were previously described.1 We evaluated reasons for dose reductions, and their effects on incidence and severity of common adverse events (AEs) and key efficacy endpoints (PFS, OS, ORR). Data cutoff dates: 17-Feb-2017 (OS), 29-Jul-2016 (other endpoints).

      Result

      Overall, 150 (66.1%) patients dose reduced for AEs (87 and 63 reduced to 30 and 15 mg QD as lowest dose, respectively); most commonly for skin toxicities (62.6%) and diarrhea (14.0%). Median time to each successive dose reduction was ~12 weeks. Incidence and severity of AEs declined following dose reduction, including grade ≥3 diarrhea (11.3% before vs 4.0% after), dermatitis acneiform (15.3% vs 6.7%), stomatitis (3.3% vs 2.7%) and paronychia (7.3% vs 4.7%).

      PFS was similar in dose-reduced and all dacomitinib-treated patients (Figure).

      pfzusdt200581 dacomitinib dose reduction figure 02.jpg

      Median OS results were also similar (dose-reduced patients: 36.7 mo [95% CI: 32.6, NR]; all dacomitinib-treated patients: 34.1 mo [95% CI: 29.5, 37.7] as were ORRs (dose-reduced patients: 79.3% [95% CI: 72.0, 85.5]; all dacomitinib-treated patients: 74.9% [95% CI: 68.7, 80.4]).

      Conclusion

      Efficacy was similar in the dose-reduced patients and the overall study population. Incidence/severity of dacomitinib-related AEs decreased with dose reduction, thereby allowing patients to continue treatment.

      References:

      Wu, et al. Lancet Oncol. 2017.

      Mok, et al. J Clin Oncol. 2018.

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      MA26.12 - Discussant - MA 26.09, MA 26.10, MA 26.11 (Now Available) (ID 14587)

      14:45 - 15:00  |  Presenting Author(s): Liza Villaruz

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS05 - Diagnostic Dilemma in Lung Cancer (ID 784)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Pathology
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 201 BD
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      MS05.01 - Staging and Pathology of Multiple Lung Nodules (Now Available) (ID 11419)

      13:30 - 13:50  |  Presenting Author(s): Alain C. Borczuk

      • Abstract
      • Presentation
      • Slides

      Abstract

      The evaluation of patients with multiple lung nodules, which include situations of synchronous as well as metachronous presentations, has become an area of focused interest. This is in part due to valuable outcome datasets that have evolved in conjunction with staging during the adoption of the AJCC 7th and now 8th edition for lung tumor staging. It has become evident that the evaluation requires an integration of clinical, radiologic, pathologic and molecular data to produce the most precise stage to guide patient management.

      In earlier staging editions, multiple nodules were largely assumed to represent advanced disease; however, the survival data pointed to a more heterogeneous patient group. Differences in histology were cited as reasons for a conclusion of synchronous primary tumors, but these differences needed to be relatively stark – for example adenocarcinoma versus squamous carcinoma. Three major shifts in knowledge impacted this field - 1) in pathology, movement away from the “lumping” of adenocarcinoma into mixed subtype with recognition of categories of early non-mucinous lepidic tumors 2) imaging advances, including the advent of successful lung cancer screening and imaging correlates of early lepidic pattern tumors and 3) the explosion of molecular pathology in lung cancer, particularly in adenocarcinoma.

      The result of these advances is a sophisticated approach that integrates these data into a stage as well as a conceptual conclusion regarding tumor biology and pathogenesis. Once lung malignancy is confirmed pathologically in a patient, the radiologist can use imaging features, especially ground glass nodules and the configuration of part solid nodules, to lead to clinically relevant conclusions about the likelihood of synchronous primaries when multiple nodules are encountered. In fact, other parameters, such as persistence, size, growth, imaging characteristics and evolution of a solid component in a part solid lesion may lead to relevant predictions in the absence of histologic confirmation. For the pathologist, non-mucinous lepidic tumors (adenocarcinoma-in-situ, minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma) and the recognition of unusual patterns of invasive carcinoma, function well in the decision making process, as non-mucinous AIS, MIA and LPA are considered primary tumors and unusual patterns of invasive carcinoma (e.g. micropapillary or invasive mucinous) within the multifocal lesions are an important feature in recognizing intra-pulmonary metastasis. This area still requires refinement, especially among the LPA tumors and tumor in which common patterns such as acinar patterns predominate.

      Several molecular features can also be introduced into the discussion. Certain molecular events, such as particular patterns of copy number alterations, may occur in an individual patient’s tumor but would otherwise be uncommon in that tumor type overall. Such a feature or set of features can assemble to form a molecular fingerprint of that primary tumor that is likely to be preserved in metastatic foci but unlikely to occur by chance in a new primary. In a similar fashion early molecular drivers of adenocarcinoma such as EGFR mutation and KRAS mutation, most often persist in metastatic foci. Discordance in such drivers can be valuable evidence to support synchronous primary carcinoma when used in conjunction with other information. Use of a wider set of mutational alterations may lead to more accurate information with regard to the likelihood of tumor evolution from one primary (i.e. intrapulmonary metastasis).

      After integration of these data, the authors of the AJCC staging 8th edition recognize 4 disease patterns with associated imaging, pathology, TNM classification and conceptual viewpoint. Second primary lung cancer (unrelated tumors), multifocal ground glass or lepidic nodules (separate tumors, despite common non-mucinous lepidic morphology), pneumonic-type adenocarcinoma (often mucinous, single tumor with diffuse pulmonary involvement), and separate tumor nodule (single tumor with intrapulmonary metastasis). While data already exist suggesting the staging, often downstaging, of multiple pulmonary carcinomas, widespread use of the AJCC 8th edition and accrual of cases, with survival information, that fit the above conceptual approach are needed to support its biological significance.

      References:

      Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016 11(5):651-65.

      Detterbeck FC et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016;11(5):666-80.

      Nicholson AG et al. Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung. J Thorac Oncol. 2018;13(2):205-217.

      Girard N et al. Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res. 2009;15(16):5184-90.

      Asmar et al, Use of Oncogenic Driver Mutations in Staging of Multiple Primary Lung Carcinomas: A Single-Center Experience. J Thorac Oncol. 2017;12(10):1524-1535.

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      MS05.02 - Defining Invasion in Minimally Invasive Adenocarcinoma (Now Available) (ID 11420)

      13:50 - 14:10  |  Presenting Author(s): Masayuki Noguchi

      • Abstract
      • Presentation
      • Slides

      Abstract

      For pathological diagnosis of early invasive forms of adenocarcinoma, such as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and early-stage lepidic adenocarcinoma, morphological criteria for “invasion” were defined by the recent WHO classification in 2015. However, the inter-observer agreement rate has not been examined in detail. The IASLC pathology committee has initiated a trial of the diagnostic reproducibility of morphological criteria for invasive lung adenocarcinoma, especially the minimally invasive form. Although the study is still ongoing, several interesting results have emerged. First, although total tumor size showed a good k-ratio, the extents of tumor invasion calculated by the participants revealed a very low k-ratio. Secondly, although the areas determined by the participants were similar, the criteria upon which their judgements were based varied, and the same morphological features were not always employed. These results suggest that the morphological criteria used for defining tumor invasion are very difficult to generalize.

      On the other hand, driver oncogene mutations such as EGFR, BRAF, and RAS, and activated fusion proteins such as ALK, ROS, and RET have been detected in invasive adenocarcinoma. Except for EGFR mutation, however, other genetic alterations have not been detected in AIS. My group has been investigating the expression and genetic profiles of AIS and early but invasive lung adenocarcinoma using a molecular biological approach, and characterized several genomic and epigenetic abnormalities in these tumors.

      Among them, stratifin (SFN) appears to be a promising biomarker of tumor malignancy at the early stage, its overexpression being very specific to the stage when AIS progresses to early invasive adenocarcinoma (Fig. 1). SFN, a member of the 14-3-3 protein family (14-3-3 sigma), is completely suppressed epigenetically in normal lung tissue. However, during the course of malignant progression, its promoter region becomes di-methylated and expression of SFN increases. SFN binds specifically to SKP1 and inhibits the function of E3 ubiquitin ligase, thus preserving the functions of specific proliferation-associated proteins such as p-cyclin E1 and p-c-Jun. Abnormally high expression of SFN is thought to be a biological marker of lung adenocarcinoma invasion. Interestingly, several inhibitors of SFN-SKP1 binding are very effective for suppressing tumor growth in nude mice.

      Another interesting biomarker of early adenocarcinoma is epithelial cell transforming sequence 2 (ECT2), a guanine nucleotide exchange factor physiologically localized in the nucleus and functioning to regulate cytokinesis. ECT2 is also localized in the cytoplasm of cancer cells. Aberrant cytoplasmic expression of ECT2 is thought to drive tumor growth and invasion. Cytoplasmic expression of ECT2 in 167 lung adenocarcinomas was evaluated by immunohistochemistry and its clinical significance was examined (Fig. 2). Cytoplasmic expression of ECT2 was found to increase during cancer progression. Cytoplasmic positivity for ECT2 was associated with a poor outcome in terms of both disease-free and overall survival (both P<0.001), and was an independent prognostic factor related to overall survival (P= 0.025).

      Reference

      Kosibaty Z, Dai T, Murata Y, Minami Y, Kano J, Nakagawa T, Sakashita S, Noguchi M. Cytoplasmic expression of epithelial cell transforming sequence 2 (ECT2) in lung adenocarcinoma and its implication for malignant progression. Lab Invest, 2018 (in press)

      Kim Y, Shiba-Ishii A, Nakagawa T, Iemura SI, Natsume T, Nakano N, Matsuoka R, Sakashita S, Lee S, Kawaguchi A, Sato Y, Noguchi M. Stratifin regulates stabilization of receptor tyrosine kinases via interaction with ubiquitin-specific protease 8 in lung adenocarcinoma. Oncogene, 2018. [Epub ahead of print]

      Shiba-Ishii A , YunJung Kim, Toshihiro Shiozawa, Shinji Iyama, Kaishi Satomi, Junko Kano, Shingo Sakashita, Yukio Morishita,Masayuki NoguchiStratifin accelerates progression of lung adenocarcinoma at an early stage.Molecular Cancer, 2015,14:142.

      Murata Y, Minami Y, Iwakawa R, Yokota J, Usui S, Tsuta K, Shiraishi K, Sakashita S, Satomi K, Iijima T, Noguchi M.ECT2 amplification and overexpression as a new prognostic biomarker for early-stage lung adenocarcinoma. Cancer Sci, 2014,105(4):490-7.

      Figure 1

      fig 1 mnoguchi.jpg

      Figure 2

      fig 2 mnoguchi.jpg

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      MS05.03 - Tumor Heterogeneity in Lung Cancer (Now Available) (ID 11421)

      14:10 - 14:30  |  Presenting Author(s): Elisabeth Brambilla

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer are composed of populations of cells with distinct molecular genetics , epigenetics and phenotypic features : this phenomenon called intra-tumor heterogeneity (ITH) adds complexity to the already well known inter-tumor heterogeneity which is responsible for the huge number of types and subtypes in each main histological category type as defined in the 2015 WHO classification. Intra-tumor heterogeneity impacts on tumor biopsy strategy, characterization of actionable targets , treatment planning and drug resistance.

      Tumor types which display the highest histological heterogeneity are adenocarcinoma (ADC) , adenosquamous carcinoma, pleomorphic carcinoma and the high grade neuroendocrine tumor small cell lung carcinoma (SCLC) and large cell neuroendocrine(LCNEC) when combined . However intra-tumor heterogeneity is not restricted to histology since molecular heterogeneity at the levels of genetics (mutations , copy number alterations), DNA methylation , mRNA expression profiling and immune context /PDL1 expression show high intra-tumor variability in most conventional lung tumor histologies. Capturing the full molecular landscape of each tumor and choosing the right target is indeed a crucial clinical dilemma facing intra-tumor heterogeneity . Although histological main type correlates with characteristic genomics (1) , histological heterogeneity relies more on transcriptomic expressions profiles and functional pathways ( embryonal, stemcellness, EMT ..) than on driver mutations , challenging the mechanisms of tumor plasticity and resistance.(2)

      A -Histological Heterogeneity

      1-Adenocarcinoma (60% of lung cancer) present with up to 5 histological patterns declined as predominant or not , lepidic, papillary, acinar/cribriform, micropapillary and solid (WHO 2015) requiring resection samples to allow an accurate diagnosis of combinations. Advantages derive from this complexity: some patterns have high prognostic value : high grade patterns solid , micropapillary and cribriform (even not predominant >= 5%) are independent determinants of short survival, whereas the pure lepidic pattern (AIS) or minimally invasise MIA predict 100% 5 years survival and predominant lepidic invasive ADC have statistically better prognosis than all other ADC .Spatial heterogeneity is well conserved temporally allowing discrimination of multiple primaries versus lung metastases when different or same combinations are compared . Disadvantage resides in interpretation of small samples showing only a part of the patterns . At molecular levels (genomics, expression profiling, immune context) adenocarcinoma show extended intra-tumor heterogeneity. Unfortunately each pattern does no predict specific driver mutations (EGFR,KRAS, BRAF, gene amplification) .

      2- Adenosquamous carcinoma (2% of lung cancer) is typically composed of both squamous cell carcinoma (SQCC) and adenocarcinoma (ADC) components (at least 10%). Both components might be morphologically obvious (ADC pattern, keratinizing SQCC ) or one is obvious and IHC is necessary to identify the other as SQCC (P40+) or ADC (TTF1) .Diagnostic challenges include size of the sample, one component missing on small sample with its associated mutations ,and variable components in primary and metastases. Molecular features are characteristic of one or both components: 56% tyrosine kinase mutations (32% EGFR; 11% KRAS;1-4% others) in ADC or in both ,FGFR1 amplification in SQCC. Dual histospecific mutations indicate common cell of origin with early clonal trunk mutation maintained at progression (2)

      3-Pleiomorphic carcinoma : ( 0.5% of lung cancer) is the most heterogeneous entity , composed of one or several components of NSCLC ( ADC, SQCC, large cell ) with at least 10% of spindle or giant cell carcinoma a clear feature of EMT (epithelial mesenchymal transition). Diagnosis requires resection sample. In undifferentiated areas IHC (TTF1/P40) will identify the NSCLC component and predict mutations. Mutations regionality is predicted and parallels histological components, if ADC (Kras, EGFR,BRAF Met ,ALK rearrangement ) if SQCC FGFR1 amplification. The most frequent MET exon 14 skipping mutation (20%) is heterogeneously distributed. Tumors with SMARC4 mutations described also in adenocarcinoma with obvious EMT transformation and BRG1 negative IH are now considered as pleomorphic carcinoma.

      4.Combined high grade tumors : Combined SCLC small cell Lung Carcinoma (SCLC) and combined Large cell neuroendocrine carcinoma LCNEC account for 20% of each in resected samples ,less readily detectable on small samples ,10% SCLC or LCNEC are sufficient. The genetic alterations are not therapeutically actionable yet, excepted in trials (DLL3) .Occurrence of mutations in the non- neuroendocrine component deserve recognition since it can induce drug resistance and transdifferentiation. Transformation of SCLC to NSCLC has been reported after cytotoxic SCLC chemotherapy (E. Brambilla JCO 1991 ) suggesting intra-tumor heterogeneity or cell plasticity under therapeutic pressure, and a common initiating stem cell between SCLC and NSCLC . Inter-tumor heterogeneity at molecular level is better documented than is intra-tumor heterogeneity, in absence of multi-region sequencing. NOTCH and DDL3 therapeutic targets shows both inter and intra-tumor heterogeneity(7)

      B-Temporal intra-tumor heterogeneity

      Genetic dynamics characterizes tumor progression , well studied during ADC progression from AAH to invasive ADC. The conservation of driver clonal but not subclonal mutations occur in metastases vs primary. Transdifferentiation is a typical exemple of temporal heterogeneity where a tumor treated ,more rarely spontaneously, transforms in another tumor type , SCLC to NSCLC , EGFR mutant adenocarcinoma to SQC or SCLC or pleiomorphic carcinoma with EMT, showing that tumor plasticity conferred by EMT results in temporal intra-tumor heterogeneity with transdifferentition (2)

      C-Spatial intra tumor heterogeneity across histology

      All studies (2-3) establish the concept of trunk and branches in the phylogenetic tree , the clonal trunk mutations are present in all regions (EGFR MET BRAF TP53 ALK … )in 75% of tumors and additional variant subclonal mutations in some but not all regions.

      Lessons :

      -One biopsy may not capture the extent of landscape ITH but trunk mutation are homogeneously distributed whereas branched mutations are heterogeneouly distributed . Cell free DNA overtime better capture genetic landscape.

      References:

      1-A genomic-based classification of human lung tumors, Sci Transl. Med 2013 5;209,153

      2-Xue et al. Evolution from genetics to phenotypes : reinterpretationof NSCLC plasticity,heterogeneity,and drug resistance Protein Cell 2017;8 :178-190

      3-Zhang J et al. Intra-tumor heterogeneity in localized lung adenocarcinoma delineated by multiregion sequencing, Science 2014; 10 ;346 :256-9 . DeBruin E et al . Spatial and temporal diversity in genomic instability processes defines lung cancer evolution Science 2014 346:251 . Jamal Hanjani M et al. Tracking the evolution of NSCLC, NEJM 2017 ;376:2109

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      MS05.04 - Diagnosis and Classification in Biopsies (Now Available) (ID 11422)

      14:30 - 14:50  |  Presenting Author(s): Andre Moreira

      • Abstract
      • Presentation
      • Slides

      Abstract

      In the last decade, significant progress has been made in the field of thoracic oncology, mostly in the management of patients with non-small cell carcinoma (NSCLC). The determination of subtypes of NSCLC is now directly linked with options of chemotherapy regimens, and further screening for targetable molecular alterations. In the 2015 W.H.O Classification of Lung cancer, the importance of small biopsies has been highlight as well as the use of immunohistochemical stains as an ancillary test to separate adenocarcinoma from squamous cell carcinomas.

      Despite the use of IHC, the classification of NSCLC remain based on histologic features and IHC is recommended in cases with no clear evidence of differentiation between adenocarcinoma and squamous cell carcinoma. It is important to notice that the diagnosis of Large Cell Carcinoma is not recommended in small biopsy specimens. For the histological diagnosis of adenocarcinoma, the following features need to be presence in the biopsy: acinar, papillary, micropapillary and lepidic patterns, and for the histological diagnosis of squamous cell carcinoma, the presence of keratinization and intracellular bridges must be presence. Therefore, in a biopsy with solid growth pattern and no evidence of keratinization, the use of IHC is recommended. The use of IHC improved diagnostic accuracy in the lung carcinoma classification, but the interpretation can be challenging and the pathologists must be aware of many interpretation pitfalls that can involve antibody clones, interpretation of the staining pattern and when to add more stains to the panels.

      When confronted with a tumor of likely lung origin for which the main question is subtyping of adenocarcinoma versus squamous carcinoma, the recommendation is to use a limited panel that includes TTF1 and p40. The use of this panel can classify most tumors and saves tissue for biomarker testing. Napsin-A can be added to the panel in challenging cases but there is no clear evidence that the latter marker is superior to TTF-1. Differences in sensitivity and specificity for napsin-A depends on whether a monoclonal or polyclonal antibody is used. Keratin 7 is not useful to separate adenocarcinoma from Squamous cell carcinoma.

      According to the classification, a NSCLC with immunohistochemical evidence of adenocarcinoma differentiation (any nuclear TTF-1 positivity) should be diagnosed as NSCLC-favor adenocarcinoma, whereas a tumor with evidence of squamous differentiation (strong and diffuse p40 positivity) should be classified as NSCLC, favor squamous cell carcinoma. In tumors with inconclusive immunoprofile, the best diagnostic term is NSCLC-NOS. For tumors with double positivity (TTF1/p40), it is important to remember that double positivity in the same cells does not define an adenosquamous carcinoma. For the diagnosis of adenosquamous carcinoma each marker should be seen in different components/areas of the tumor. Double staining is seen in adenocarcinomas or in NSCLC-Nos that carries mutations similar to adenocarcinoma.

      For double negative tumors (TTF-1 neg/p40 neg) in patients with no other history of malignancy, the diagnosis of NSCLC-NOS can be accepted because approximately 20-30% of adenocarcinoma of the lung are negative for these markers. If clinical history is not known, however, other stains should be added to the panel to rule out metastatic disease. One important marker is keratin, because metastatic melanomas or other non-epithelial tumors may mimic carcinoma, especially in small biopsy samples. For patients with known history of other malignancies, histological comparison with prior tumors should be pursued, targeted IHC with organ specific markers (PAX-8, GATA-3, NKX3.1, etc.) provides strong support to this interpretation, particularly when previous materials are unavailable for review.

      The current WHO classification recommends that neuroendocrine (NE) markers should be performed only when NE morphologic features are present. IHC positivity for NE markers alone is not diagnostic of a NE tumor because positivity for NE markers may be encountered in approximately 10-30% of adenocarcinomas.

      A panel of chromogranin A, synaptophysin and CD56 is the best combination for the diagnosis of NE tumors. There is no consensus on how many markers should be used for the diagnosis of NE, most cases of NE tumors are positive for ≥2 out of the 3 NE markers. Positivity for at least one NE marker is necessary for the diagnosis of Large Cell Neuroendocrine Carcinoma (LCNEC) in association with histological features (chromatin pattern, palisading etc). The diagnosis of LCNEC in a biopsy or cytology specimen is not recommended but can be suggested if a combination of histological features and NE markers positivity is encountered.

      A proliferative marker such as Ki-67 is very useful for the classification of NE tumors in small biopsy specimens, especially in samples with significant crush artifact. In small biopsies Ki-67 stains can separate a low-grade NE tumor (carcinoid) from a high grade tumor such as small cell carcinoma. Ki-67 is not recommended in the classification of typical from atypical carcinoid in excision specimens. In cytology samples, the marker does not work well in alcohol-fixed specimen and can lead to misclassification of NE tumors.

      Suggested reading:

      Sauter JL, Grogg KL, Vrana JA, et al. Young investigator challenge: Validation and optimization of immunohistochemistry protocols for use on cellient cell block specimens. Cancer Cytopathol 2016;124:89-100

      Rekhtman N, Kazi S. Nonspecific reactivity of polyclonal napsin a antibody in mucinous adenocarcinomas of various sites: a word of caution. Arch Pathol Lab Med 2015;139:434-436.

      Rekhtman N, Ang DC, Sima CS, et al. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 2011;24:1348-1359

      Thunnissen E et al. The use of Immunohistochemistry improves the diagnosis of Small Cell Lung Cancer and its Differential Diagnosis. An International reproducibility Study in a demanding set of cases. J Thorac Oncol. 2017;12:334-46.

      Moreira AL, Travis WD. Histologic Classification and its need for Treatment of Lung Cancer. In Diagnosing Non-Small Cell Lung Cancer in Small Biopsy and Cytology. Edited By Moreira AL and Saqi A. 2014. Springer Science Business Media, New York. Pages 1-14. Doi 10.1007/978-1-4939-1607-8_1.

      Moreira AL, Mino-Kenudson M. Update on Histologic Classification of Non-Small Cell Lung Cancer. Diagnostic Histopathology, 2014. 20: 385-91.

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    MS15 - Disruptive Technology and Lung Cancer Risk (ID 794)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 201 BD
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      MS15.01 - Just Water Vapor? Toxicology Perspectives on Electronic Cigarettes (Now Available) (ID 11463)

      10:30 - 10:45  |  Presenting Author(s): Maciej Lukasz Goniewicz

      • Abstract
      • Presentation
      • Slides

      Abstract

      Electronic cigarettes (e-cigarettes) were introduced to the global market in the mid 2000’s. While it is common to hear the term “e-cigarettes”, this label is a broad term referring to a heterogeneous class of devices that differ in shape, size, and functional characteristics. Common features of e-cigarettes include a heating element that heats a propylene glycol and/or vegetable glycerin based solution (“e-liquid” /“e-juice”) that contains stabilizers, flavorings and often, nicotine. Numerous flavors are available, including tobacco, menthol, fruit, and sweet flavors. Heating of e-liquids produces an aerosol, which is then inhaled by the user. Due to their relatively short existence, data on the long-term health effects of e-cigarette use are not currently available. In the interim, evidence from animal studies, in vitro and in vivo laboratory studies, observational studies, and small-scale clinical trials may provide important information on the potential harms of e-cigarette use [1].

      Many studies conducted on e-cigarettes have focused on the measurement of potentially harmful chemicals that may be produced by these products. Chemicals identified in e-cigarette aerosol include nicotine, tobacco‑specific nitrosamines (TSNAs), metals, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and aldehydes. Within these classes, there are several respiratory irritants and toxicants, as well as carcinogenic substances linked to the development of respiratory cancers. In our work, we have tested emissions from numerous e-cigarette brands [2] and identified the presence of formaldehyde, acetaldehyde, and acrolein in e-cigarette emissions. Overall, concentrations of toxicants identified in e-cigarette aerosols were 9 to 450 times lower than in tobacco smoke [2]. Concerns have also been raised about the presence of metal particles in e-cigarette aerosol (particularly nickel and chromium, two main elements in heating coils).The inhalation of these metals in larger quantities may cause respiratory diseases, bronchitis, and pneumonia [3], however, these effects have not been definitively elucidated.

      The size of particulate matter generated from e-cigarettes affects pulmonary nicotine absorption and determines settlement of particulate matter into various parts of the upper or lower airways. There is likely substantial variation across generations of e‑cigarette devices, and across brands. Results from laboratory studies indicate that e-cigarettes may expose users to small particles and lower amounts of particulate matter in general. While inhalation of high levels of particulate matter has been linked to greater mortality risk from cardiopulmonary illnesses, the available data indicate that e-cigarette particulate emissions expose users at a level akin to WHO guidelines and are far lower than those of conventional cigarettes.

      Issues raised about toxicological effects mostly question effects on cells, with a special interest in lung epithelial cells. For instance, many flavorings used in e‑cigarettes (e.g. cinnamaldehyde, benaldehyde, diacetyl) are already approved for use in food, yet their impact on respiratory health via repeated inhalation is currently unknown. Several studies have shown that e-cigarette flavorings could lead to lung cell damage (mostly by releasing free radicals) and inflammation in lung tissue [4]. Studies on cytotoxic effects of e-cigarette constituents have also identified negative effects on DNA. In one in vitro research, e-cigarette liquids aerosolized at biologically relevant doses induced increased DNA strand breaks and apoptosis while decreasing survival in both normal epithelial and head and neck squamous cell carcinoma cell lines [5]. Moreover, in experiments conducted by Yu et al. [6] e-cigarettes aerosol has shown cytotoxic effects on epithelial cell lines and acted as a DNA-breaking agent.

      Given multiple potential etiologic mechanisms related to incident case development coupled with the long latency period in developing illness, there is currently no definitive evidence to commenting on the role of e-cigarettes in increasing lung cancer risk. As an intermediate assessment, cross-sectional biomarker data can be suggestive of possible carcinogen exposures related to cancer development. For instance, Shahab et al. [7] examined a large panel of biomarker data among e-cigarette users, cigarette users, and users of both products (“dual users”). The e-cigarette–only users had significantly lower metabolite levels for tobacco-specific nitrosamines (TSNAs), particularly NNAL, a metabolite of potent lung carcinogen NNK. Several observational longitudinal studies also showed a substantial reduction in exposure to NNK and several VOCs, including respiratory toxicants like acrolein, acrylamide, acrylonitrile, 1,3-butadiene (human carcinogen), and ethylene oxide among smokers who switched to e-cigarette [8]. Although evidence from biomarker studies are insufficient to evaluate causative mechanisms, but show users of e-cigarettes display lower levels of exposure to biomarkers of lung carcinogens when compared to smokers, such as NNK.

      Since e-cigarettes have only been on the market for a decade, it is presently not possible to assess all potential long-term harmful effects of e-cigarette use. To date, findings from clinical studies have demonstrated that e-cigarettes are likely less harmful compared to conventional tobacco cigarettes, and any harmful side effects are noticeably milder compared with regular cigarettes. Furthermore, it is also clear that e-cigarette aerosols are not “a harmless water vapor”, as claimed by manufacturers and retailers, and potential health effects from vaping may emerge after long-term use.

      References

      1. National Academies of Sciences, Engineering and Medicine. Public health consequences of e-cigarettes. Washington, DC: The National Academies Press; 2018.

      2. Goniewicz et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control. 2014;23:133-139

      3. Lerner et al. Environmental health hazards of e cigarettes and their components: oxidants and copper in e-cigarette aerosols. Environ Pollut. 2015;198:100-107

      4. Leigh et al. Flavourings significantly affect inhalation toxicity of aerosol generated from electronic nicotine delivery systems (ENDS). Tob Control. 2016;25(Suppl 2):ii81-ii87.

      5. Welz et al. Cytotoxic and genotoxic effects of electronic cigarette liquids on human mucosal tissue cultures of the oropharynx. J Environ Pathol Toxicol Oncol. 2016;35:343-354.

      6. Yu et al. Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines. Oral Oncol. 2016;52:58-65.

      7. Shahab et al. Nicotine, carcinogen, and toxin exposure in long-term e-cigarette and nicotine replacement therapy users: a cross-sectional study. Ann Intern Med. 2017;166:390-400.

      8. Goniewicz et al. Exposure to nicotine and selected toxicants in cigarette smokers who switched to electronic cigarettes: a longitudinal within-subjects observational study. Nicotine Tob Res. 2017;19:160-167.

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      MS15.02 - PRO- Electronic Cigarettes: A Cessation Tool (Now Available) (ID 11464)

      10:45 - 11:00  |  Presenting Author(s): K. Michael Cummings

      • Abstract
      • Presentation
      • Slides

      Abstract

      Should clinicians recommend electronic cigarettes (e-cigarettes) to their lung cancer patients who continue to smoke? For many clinicians the answer to this question is a resounding NO WAY. However, I hope to persuade you that there are good reasons why clinicians should strongly consider recommending e-cigarettes to at least some of their patients who smoke. No one disputes the enormous health risks posed by cigarette smoking, or the need to find better treatments to help smokers overcome addiction to cigarettes. In theory, a product that can deliver nicotine like a cigarette without the toxins found in smoke could be used instead of cigarettes would be a welcome invention. E-cigarettes were first introduced into the marketplace in 2003 and were initially promoted as an aid to help smokers to stop smoking. However, concerns have been raised about whether e-cigarettes are an effective cessation aid or if they would actually reduce successful quitting by adult smokers, whether they are safe to use, and if they may be a gateway into smoking for youth. Admittedly, the science is in a state of flux and evolving rapidly. The National Academy of Sciences, Engineering, and Medicine (NASEM) report on the public health consequences of e-cigarettes, and a new evidence review on e-cigarettes and heated tobacco products commissioned by Public Health England (PHE) both come to similar conclusions. Both reports acknowledge that available evidence indicates that e-cigarette use is less risky than use of combustible tobacco cigarettes; that e-cigarettes may be helpful to smokers who are trying to stop smoking cigarettes, and that e-cigarettes should not be used by non-smokers, especially youth. However, both reports also state that e-cigarettes contain constituents that are not inert and are likely to have some negative health effects on their own. Given uncertainties regarding e-cigarettes, clinicians should advise cigarette smokers seeking to stop smoking to use evidence-based, FDA-approved, safe, and effective smoking cessation pharmacotherapies as first-line treatments in preference to e-cigarettes. So why consider e-cigarettes as a treatment option? First, many patients have already tried the evidence based methods and have found them not to be helpful. We need better treatments and e-cigarettes, in theory, might work for some patients. Second, nicotine seeking is the primary motivation for continued smoking so providing addicted smokers with an alternative that delivers nicotine without most of the harmful toxins in smoke makes sense. Nicotine is not the problem, it is the smoke. E-cigarettes are not lit, they do not burn, and do not produce cigarette smoke. Finally, many smokers simply prefer e-cigarettes over other aids to quitting. It is great to have government approved stop smoking treatments, but if smokers are unwilling to use them, they don’t do much good. Sales of e-cigarettes have grown exponentially over the past decade, and they have become the most popular quitting aid used by smokers in many countries. For those smokers and ex-smokers who are already using the e-cigarettes, clinicians need to be informed and prepared to answer questions regarding potential harms and benefits and to advise patients about use.

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      MS15.03 - CON- Electronic Cigarettes: Not Evidence Based Cessation (Now Available) (ID 11465)

      11:00 - 11:15  |  Presenting Author(s): Alison Wallace

      • Abstract
      • Presentation
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      Abstract not provided

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      MS15.04 - The Rise of Heat-Not Burn Tobacco in Japan: A “Hot” Issue for Tobacco Control (Now Available) (ID 11466)

      11:15 - 11:30  |  Presenting Author(s): Junji Yoshida

      • Abstract
      • Presentation
      • Slides

      Abstract

      Just like in other developed countries, public health has been of major public interest in Japan. Reduced-risk tobacco alternative that exposes smokers who cannot quit and non-smokers around them to lower levels of harmful and potentially harmful constituents (HPHC) has long been a goal. In many countries, electronic nicotine delivery systems (ENDS) have been introduced into the market for that purpose. However, there is a high hurdle for ENDS in Japan. Nicotine is classified as a medicinal drug, and devices using nicotine require governmental approval under the pharmaceutical affairs law. Although Japanese citizens can privately import ENDS as an unapproved pharmaceutical product for private use, bureaucratic formalities are troublesome, and the monthly amount able to be imported is limited.

      In 1997, Japan Tobacco (JT) started to sell AIRS®, the R.J. Reynolds’ Premia® product but with a slight modification. AIRS® had a charcoal heat source at one end, and heated air was inhaled through tobacco leaves. This product did not sell well and was discontinued in 2004. Then in 2010, the next alternative was ZERO STYLE STIX®, also by JT. This product has no heat source. It is a snuff variant, and ambient air is simply inhaled through tobacco leaf powder. When its nicotine was measured by ISO metrics, the amount of inhaled nicotine was shown to be less than a half of low nicotine cigarette.

      Following these alternatives, heat-not burn tobacco (HNBT) came into the market. Tobacco manufacturers aimed at public tobacco harm reduction in total by reducing HPHC emissions from their products and encouraging public acceptance of such products. The tobacco manufacturers understood that Japanese value cleanliness and physical fitness. Most Japanese people are very anxious about their reputation within their community. An American anthropologist Ruth Benedict described it as “Shame Culture” in her book “The Chrysanthemum and the Sword” in 1946. Many Japanese smokers feel shame at releasing HPHC and ash. The manufacturers also know Japan is a country of electric gadget geeks.

      The first of the updated or more recent heated tobacco products was Ploom® from JT in 2013, which was updated to Ploom TECH® in 2016. These were bought from a Californian company Ploom Inc. They are not HNBT but aerosol-not burn or e-cigarette, to be precise. Glycerin, propylene glycol and water vapor passes through a tobacco capsule at the maximum temperature of 30. Philip Morris International introduced their true HNBT, iQOS®, to the Japanese market in 2015, and British American Tobacco product named glo® in 2016. All these HNBT’s were sold in limited areas of Japan at first and gradually extended to nation-wide sales, in response to the demand for HNBT, expanding their production lines. HNBT sales increased rapidly, and heated tobacco category usage among all tobacco users grew up to over 30% in early 2018 from about 4% in late 2015.

      Cigarette ads on TV, radio, or Internet have been allowed in Japan if it is technically possible to restrict access only to the adults, and this is true for the HNBT ads. According to the guidelines set down by the Ministry of Finance, access to HNBT advertising/information web sites and purchase at virtual/real shops have been strictly restricted, requiring proof of age such as a driving license. In their web sites and on product packages, there are always some messaging to the effect of reduced HPHC, but not necessarily guaranteeing less harm to health, which is in accordance with the Ordinance for Enforcement of the Tobacco Business Act.

      Reduction in HPHC exposure and lower levels of biomarker responses have been vigorously reported in peer-reviewed journals, but many of them are funded, studied and reported by the tobacco manufacturing companies themselves. There have been several contradictory articles and in media coverage suggesting that some HPHC are released more from HNBT than from cigarettes. However, manufacturers refute the findings by pointing out inappropriate methods, evaluation and data presentation in these reports. The truth will need to wait for the academic and public health community to sort out the reality of the potential for HNBT to reduce the morbidity and mortality caused by tobacco product use.

      Currently, it seems reasonable to understand that HNBT is likely to expose users and bystanders to lower levels of most HPHC. Although the extent of the reduction found so far varies between studies, reduced exposure to some HPHC is reported to be associated with less short-term harm. To this extent, HNBT might be beneficial for smokers who cannot quit and non-smokers around them. However, less is not zero. It will take 15-20 years to confirm long-term health harm caused by reduced HPHC, such as clinical carcinogenesis. It requires tremendous effort to maintain and watch a large cohort of HNBT users for that long period of time. It is questioned which party ought to do and publish the study. Another question is who pays the cost and whether the study is worth the cost. Because zero is zero, tobacco products including HNBT are desired to be completely abandoned in the future, eliminating the need for long-term harm studies.

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      MS15.05 - Heat-Not-Burn Tobacco: Real Risk Reduction or Industry’s Next Promise (Now Available) (ID 11467)

      11:30 - 11:45  |  Presenting Author(s): Carolyn Dresler

      • Abstract
      • Presentation
      • Slides

      Abstract

      So, the question is: what are we to think about the products emerging from the global tobacco manufacterers that are being marketed in upper income countries? To be clear the topic is not about electronic nicoitne delivery systems (ENDS) that have been sweeping the world’s marketplaces - those arise from a multitude of mostly small companies. ENDS are an interesting topic that is quickly changing also - but, not the topic of this dissertation.

      Rather the topic for this paper will discuss the current market-disrupters which are the so-called ‘heat not burn’ cigarettes (HNB). The tobacco control community tends to call them ‘heated tobacco products’ (HTP), as some of them do come close to ‘burning’ (combusting) the tobacco, so, HTP is a more accurate, broad term for the category. The question to be addressed is whether they are less harmful than cigarettes or are they the usual ‘oversell’ or untrue marketing claims that have been the usual practice of the global tobacco manufacturers.

      A brief review: the global tobacco manufacturers are: Philip Morris, International. (PMI-Switzerland); British American Tobacco (BAT-UK); Imperial Tobacco (UK); Altria (USA) and Japan Tobacco International (JTI- Japan).(see: https://www.statista.com/statistics/259204/leading-10-tobacco-companies-worldwide-based-on-net-sales/). Altria is really just a spin-off from Philip Morris International who sells their products in the USA, including trying to do so for their HNB product (iQOS). Each of them have their own offerings in the HNB category: PMI/Altria is the current leader with iQOS, quipped as standing for: I quit ordinary smoking; BAT has ‘glo’; and Imperial has not embraced/marketed a HNB product but had thought to stay with their ENDS (blu) product. Reportedly, Imperial is considering getting their own HNB, as this category appears to be growing (commerically renumerative). JTI has PloomTECH.

      IQOS and glo use a lithium battery to heat compressed/powdered tobacco to around 300 Celsius which creates an aerosol for inhalation. PloomTech heats a liquid that has nicotine in it (closer to an ENDS)

      A recent paper by Farsalinos et, tested iQOS, an ENDS and a regular cigarette for emitted carbonyls, like formaldehyde and acrolein. (1) They found that iQOS emitted 82-98% less carbonyls compared to smoking 20 tobacco cigarettes. The ENDS emitted 92-99.8% less carbonyls. So, iQOS were better than cigarettes by alot, but the ENDS was better still.

      In a webpage hosted by RIVM (National Institute for Public Health and the Environment, misistry of Health, Welfare and Sport), their research to date is quoted as:

      “Heated tobacco products are newly available on the market. An example of such a product is the heatstick which is heated with an iQOS, a device that looks like an e-cigarette. Heating the heatstick leads to the formation of carcinogenic and other harmful substances. The use of heatsticks with the iQOS is harmful to health, but probably less harmful than smoking tobacco cigarettes. This is RIVM’s conclusion, based on its research into heated tobacco products (HTPs).”(2)

      In another recent paper from Japan, HTPs (iQOS, glo and Ploom TECH) were compared with ‘reference cigarettes’(research cigarettes that are well-defined and not for human consumption (as if any should ever be)). (3) Chemists interested in these findings should check out this paper. For the rest of us - it just demonstrates the tremendous variability in the products. Cigarettes deliver nicotine better than the other tested products, and iQOS does better than glo which does better than PloomTech. Since users are going for the nicotine, it seems that the order of preference will be cigarettes, iQOS, glo and PloomTech. However, the manufacturers are constantly changing their products, so they could be different next month. (This is the problem of unregulated products)

      Most of the published/available research is by the tobacco industry. For the hardy, there is a very large amount of scientific information from PMI on their iQOS submission to the USA FDA. (4) This is all publicly available information - and actually, a very interesting read. The question always remains when reviewing tobacco industry research - can it be verified?

      Overall, however, it does seem that heated tobacco products (or, ENDS) deliver lower levels of most toxicants to the human lung. Low enough to prevent disease is a different question. BUT, cigarettes kill more than half of the people who use them, cause a huge amount of morbidity and healthcare costs - and, are addictive. So, the question facing society - or, public health - is it possible or probable that if people who are already addicted to nicotine and using cigarettes switch (completely) to HTP products - would there be lower morbidity and mortality than we currently experience from cigarttes? No one knows the answer at present - and, we are unlikely to know for a few decades the real answer.

      However, are we horrified enough at the currently greater than 7 million deaths globally per year from cigarettes to radically alter our passionless inactivity and push, by regulation (and social pressure) for people to quit cigarettes. If they use HTPs (or ENDS) to quit the unacceptably deadly cigarettes, so be it. I don’t know how they could be worse than what we currently allow.

      {Disclaimer: I am still passionate about the standard tobacco control measures that are working in some countries, per the Framework Convention for Tobacco Control. I do not trust the global tobacco manufacturers that they are willing to help everyone in the world to quit cigarettes, particularly in low income countries, where these HTP products would be more expensive (unaffordable?) for their current customers. I believe the industry is still intersted in maintaining tobacco addiction - I want to ultimately reduce it as far as possible. First however, I want people who are nicotine addicted to stop dying from that addiction.}

      1. Farsalinos KE at al. Addiction 2019 June 19. doi: 10.1111/add 14365

      2. https://www.rivm.nl/en/Documents_and_publications/Common_and_Present/Newsmessages/2018/Addictive_nicotine_and_harmful_substances_also_present_in_heated_tobacco (accessed 6/29/2018)

      3. Uchiyama S. et al. Simple Determination of gaseous and particulate compounds generated from heated tobacco products. Chem. Res. Toxicol 2018.

      4. https://www.fda.gov/tobaccoproducts/labeling/marketingandadvertising/ucm546281.htm (accessed 6/29j/2018)

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    MS19 - Pulmonary Dilemmas with Immunotherapy (ID 798)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 201 BD
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      MS19.01 - Drug-Induced Pneumonitis with IO: How worried should we be for our Lung Cancer Patients (Now Available) (ID 11481)

      13:30 - 13:50  |  Presenting Author(s): Desiree Hao

      • Abstract
      • Presentation
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      Abstract

      In recent years, indications for the use of immune checkpoint inhibitors (ICI) in the treatment of non-small cell lung cancer (NSCLC) have been rapidly expanding. With the increased use of ICI comes concern about monitoring and managing rare, but serious, side effects including pulmonary toxicities. Pneumonitis is a general term typically used to describe non-infectious causes of focal or diffuse inflammation of the lung parenchyma and may encompass analogous terminology including acute interstitial pneumonitis, interstitial lung disease, and pulmonary fibrosis. Several meta-analyses and larger scale systematic or institutional reviews have illustrated that across clinical trials of ICI in various cancer types, pneumonitis has only been reported at low frequencies and has generally been of low grade [1-6]. Serious cases including death from pneumonitis are rare.

      ICI-related pneumonitis can be challenging to diagnose as there are no pathognomonic clinical or radiographic findings that define this condition. The symptoms of pneumonitis, including dyspnea and cough, may be subtle and, particularly among lung cancer patients, these symptoms may be difficult to distinguish from other common conditions such as chronic obstructive pulmonary disease, infection or simply the patient’s underlying malignancy. Up to one third of cases of pneumonitis are asymptomatic [4] and documented solely on imaging hence a high index of suspicion is required to make the diagnosis. Most commonly pneumonitis has been reported to occur within the first few months of initiating ICI therapy, however pneumonitis can occur as early as the first dose or may even emerge after ICI treatment has been discontinued [4, 6, 8]. Often, the onset of pneumonitis coincides with other immune related adverse events (irAEs) [4]. Concurrent or sequential use of CTLA-4 and PD-1 blockade appears to increase the risk of pneumonitis [1, 2, 4], while age, ethnicity, and chemotherapy do not [9]. The influence of smoking history [4, 9], tumour type [1-2] and radiation [7, 9] on developing ICI-related pneumonitis is less clear as various groups have reported differing observations. There is also considerable variability in radiographic presentation [4, 6, 8] thus bronchoscopy and lung biopsy may be valuable tools to exclude alternate diagnoses. Even on pathology though, there are no definitive findings characterizing pulmonary irAEs [4]; histopathological findings ranging from diffuse alveolar damage to sarcoid granulomas have been described [4, 6]. In small series, a correlation has been noted between anti-tumour activity with ICI and the occurrence of irAEs [3], but this too remains unproven and is not specific to pneumonitis.

      At present, there are no validated treatment recommendations for pneumonitis resulting from treatment with ICI. Management of ICI pneumonitis follows the same general guidelines as other irAEs namely, withholding ICI, starting steroids, and if needed, using additional immunosuppressants such as mycophenolate mofetil or infliximab [10]. Like most irAEs, pneumonitis is generally steroid-responsive and usually resolves within 4-6 weeks [10]. The prolonged half-life of the antibodies necessitates the protracted period of corticosteroid treatment and slow tapering. Only very limited data is available regarding re-challenge with ICI after development of pneumonitis. Again, in small series - all involving 10 or fewer patients - 25-30% of patients re-challenged with ICIs developed recurrent pneumonitis [1, 4, 9].

      In conclusion, immune-related pneumonitis is a rare, but potentially fatal, side effect of ICI for which vigilance in monitoring is required in order to ensure timely diagnosis and treatment. As pneumonitis is usually a diagnosis of exclusion, multidisciplinary input is often required to make the diagnosis. The results from meta-analyses and several large reviews on irAEs provide reassurance that for the vast majority of NSCLC patients, ICIs can safely be administered and are well tolerated treatments.

      SELECTED REFERENCES:

      1. Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol 2016; 2(12):1607-1616.

      2. Abdel-Rahman O, Fouad M. Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Ther Adv Respir Dis 2016; 10(3):183-193.

      3. Costa R, Carneiro BA, Agulnik M, et al. Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumours: a systematic review and meta-analysis of randomized clinical trials. Oncotarget. 2017; 8(5): 8910-8920.

      4. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol 2017; 35:709-717.

      5. Nishijima TF, Shachar SS, Nyrop KA et al. Safety and tolerability of PD-1/PDL-1 inhibitors compared with chemotherapy in patients with advanced cancer: a meta-analysis. The Oncologist. 2017; 22:470-479.

      6. Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J 2017; 50:1700050 DOI: 10.1183/13993003.00050-2017.

      7. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. NEJM 2017; 377(20): 1919-29.

      8. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 2016; 22:6051-6060.

      9. Ahn MJ, Gandhi L, Hamid O, et al. Risk of pneumonitis in patients with advanced NSCLC treated with pembrolizumab in KEYNOTE-001. Ann Oncol 2015; 26:Suppl9:459P.

      10. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncol 2017; 28(Suppl 4):iv119-iv142.

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      MS19.02 - What Are the Clinical Features of IO Progression/Pseudoprogression and Radiation Fibrosis vs Recurrence (Now Available) (ID 11482)

      13:50 - 14:10  |  Presenting Author(s): Chong-Kin Liam

      • Abstract
      • Presentation
      • Slides

      Abstract

      IO Progression vs Pseudoprogression

      The patterns of response to treatment with immunotherapy differ from those with molecularly targeted agents or cytotoxic chemotherapy where responses can take appreciably longer to become apparent. In addition, a unique response pattern termed "pseudoprogression" may be encountered with immunotherapy with checkpoint inhibitors in which patients appear to have a transient worsening of disease, manifested either by progression of known lesions or the appearance of new lesions, before disease stabilizes or regresses.

      While pseudoprogression is rare in lung cancer with reported rates of < 5%, it is a worrying situation for both clinicians and patients on immunotherapy.1,2 It can be difficult to differentiate pseudo-progression from true disease progression, but close monitoring of the following clinical features may help identify pseudoprogression

      - Pseudoprogression is often asymptomatic, whereas true progression is more likely to be associated with clinical decline.

      - The patient’s performance status remains stable or improves if it is pseudoprogression while the performance status may deteriorate in true disease progression

      - Systemic symptoms may or may not improve in pseudoprogression while systemic symptoms often worsen in disease progression

      - Symptoms of tumour enlargement may or may not be present in pseudoprogression whereas true progression may be associated with symptoms of tumour enlargement

      - There is an initial increase in baseline tumour burden followed by a response in pseudoprogression while there is an increase in baseline tumour burden in true progression. New lesions that appear in pseudoprogression remain stable and/or subsequently respond while in true progression, new lesions appear and increase in size.

      Biopsy may reveal evidence of immune cell infiltration in pseudoprogression3,4 and evidence of tumour growth in true progression. However, histological confirmation is not always possible.

      Smaller deposits of tumour may continue to grow or new lesions appear in the first few months of effective immunotherapy during this period of immune priming and appear as progressive disease on restaging scans. These areas of apparent pseudoprogression should be carefully followed to distinguish nonresponding patients with progressive disease from those with delayed response. Distinguishing treatment-induced imaging changes from progressive disease has important implications to avoid premature and inappropriate discontinuation of a treatment regimen.

      Radiation Fibrosis vs Recurrence

      Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiation therapy (SBRT), is a recommended treatment for stage 1 non–small-cell lung cancer (NSCLC) in patients who are medically inoperable or refuse surgery. Most patients treated for NSCLC with SABR develop post-treatment radiographic changes due to radiation-induced lung injury (RILI) which can occur in the acute phase (within six months) as radiation pneumonitis and in the late phase (after six months) as radiation fibrosis. With SABR, the incidence of acute- and late-onset RILI is high with acute benign computed tomography (CT) changes in 54-79% of patients and late changes in 80–100% of patients.5 Radiation pneumonitis may appear as ground-glass opacities, consolidation or both. The late phase of radiation fibrosis frequently appears as a well-defined area of volume loss with a linear scar or consolidation, parenchymal distortion and traction bronchiectasis that conforms to the treatment portals which may either stabilize or evolve up to 24 months. Shrinkage of the region of fibrotic consolidation or a more sharply defined demarcation between normal and irradiated lung parenchyma may occur as the process progresses.

      Such benign CT changes can mimic tumour recurrence, especially when they develop as mass-like patterns.6 Distinguishing radiological changes due to radiation-induced fibrosis after SABR and local tumor recurrence can be quite challenging.7

      A systematic review by Huang et al.7 identified several high-risk radiologic features on CT scan to discriminate between SABR-induced fibrosis and tumor recurrence. These include an enlarging mass-like lesion at the primary site, sequential enlarging opacity, enlarging opacity after 12 months, bulging margins, disappearance (loss) of linear margins, craniocaudal growth, disappearance (loss) of air bronchograms, ipsilateral pleural effusion, or lymph node enlargement. While some sources caution against the use of PET scans to differentiate between post-SBRT fibrosis and recurrence, others have postulated a SUVmax of > 5 can be a useful discriminator.a,b,d Due to a high number of false-positive findings on PET, patients suitable for salvage therapy should undergo a biopsy, whenever possible.8

      The optimal follow-up schedule for patients treated with SABR for early stage NSCLC is unclear, although clinical practice guidelines of the European Society for Medical Oncology recommend CT imaging every 6 months for a period for at least 3 years in those patients suitable for salvage therapy.8The timing of local recurrence after SABR, as well as a persistent risk of second primary lung cancer with an annual rate of 2% to 5%, suggests that long-term radiological follow-up using CT scans is needed, especially in patients fit enough to undergo any radical treatment. Others recommend a post SABR follow-up strategy similar to that of postsurgical cases, i.e. all patients eligible for any type of salvage undergo 6 months follow-up CT scans for a period of 3 years post-SABR, followed by annual CT scans thereafter.9,10 With suspicion of progressive disease, recommendations include a multidisciplinary team discussion with consideration for biopsy and/or surgical or nonsurgical salvage therapy if safe and when further investigations are non-reassuring.10

      References

      1. Fehrenbacher L, Spira A, Ballinger M, et al. Lancet. 2016; 387(10030):1837-1846.

      2. Borghaei H, Paz-Ares L, Horn L, et al. N Engl J Med. 2015; 373(17): 1627–1639.

      3. Wolchok JD, Hoos A, O’Day S, et al. Clin Cancer Res. 2009; 15(23):7412-7420.

      4. Ribas A, Chmielowski B, Glaspy JA. Clin Cancer Res. 2009; 15(23):7116-7118.

      5. Park KJ, Chung JY, Chun MS, Suh JH. Radiographics 2000; 20:83-98.

      6. Linda A, Trovo M, Bradley JD. Eur J Radiol 2011; 79(1):147-154.

      7. Huang K, Dahele M, Senan S, et al. Radiother Oncol 2012; 102(3):335- 342.

      8. Postmus PE, Kerr KM, Oudkerk M, et al. Annals of Oncology 2017; 28 (Supplement 4):iv1–iv21

      9. Verstegen NE, Lagerwaard FJ, Hashemi SM, et al. J Thorac Oncol 2015; 10(8):1195-1200.

      10. Huang K, Palma DA, et al. J Thorac Oncol. 2015; 10:412-419.

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      MS19.03 - Diagnostic Approaches Suspected IO Progression/Pseudoprogression and What/When to Rebiospy for TT Progression (Now Available) (ID 11483)

      14:10 - 14:30  |  Presenting Author(s): Kasia Czarnecka-Kujawa

      • Abstract
      • Presentation
      • Slides

      Abstract

      The 2000’s marked the beginning of precision medicine era with treatment of NSCLC becoming increasingly personalized. This was driven by effective therapies in biomarker-defined populations, most notably treatments targeting the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1) pathways (1) testing for which is now the standard of care for majority of patients with NSCLC, both, at the time of diagnosis and with recurrent disease (2-4). In addition, testing indications emerged for other proto-oncogenes, many of which are actively investigated as therapy targets (3, 5). In addition, given development of effective treatments for recurrent NSCLC in setting of acquired resistance (AR) to targeted therapies (TT), the minimally-invasive tumor sampling to identify resistance mutations has become increasingly attractive, given frailty of population with metastatic lung cancer (4, 6).

      Imaging and clinical patient status are used to diagnose cancer progression, pseudoprogression and recurrence. Conventional tumor response criteria serve as standardized measures for treatment response in NSCLC. However, given unique tumor behaviour upon exposure to immunotherapy, immune response criteria have been developed to assess treatment response in patients on immunotherapy (7).

      While preparing to obtain a diagnostic sample in setting of suspected disease recurrence/progression one should consider: 1) procedural safety and convenience; 2) size of tissue sample, 3) proportion of tumor cells in the sample; 4) fixative used to preserve tissue; 5) tumor heterogeneity; 6) difference in genetic make up of the primary and metastatic tumor(4).

      The choice of diagnostic procedure to confirm disease recurrence/progression must be guided by the procedure safety and diagnostic yield. Percutaneous or surgical lung biopsies, are often not possible for patients with advanced lung cancer. The minimally-invasive techniques have become an attractive alternative for tissue acquisition in this setting. The most common, minimally-invasive techniques utilized by interventional pulmonologists are: 1) transbronchial biopsy (TBBx) or transbronchial needle aspiration (TBNA); 2) Endoscopic techniques: Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) and Esophageal Ultrasound- guided Fine Needle Aspiration (EUS-FNA); 3) and pleural fluid sampling. Studies show that endoscopic techniques provide tissue of comparable quantity and quality material for molecular testing compared to surgical or conventional needle biopsy. Reported adequacy of EBUS-TBNA samples for molecular diagnosis ranges from 77% to 98% (8). EBUS samples have one of the lowest insufficiency rates (4%) for EGFR and KRAS mutational analysis (compared with CT-FNA – 7.5%; ultrasound guided/superficial FNA- 10%) and can provide sufficient tissue quantity for multigene testing (i.e. p53 mutation, BRAF and PIK3CA) (8). EBUS-TBNA samples have been shown to yield a higher number of viable cells with less crush artifact and better concordance with the primary tumor for expression of the PD-L1 than TBBx (9). TBNA has been shown to improve diagnostic yield in NSCLC when added to conventional TBBx.

      High concordance has been reported for detection of EGFR mutation and PD-L1 expression between primary and metastatic tumors. Some authors suggest that either of the two sites can be used for molecular testing. However, there is a significant heterogeneity in PD-L1 expression within tumors (10). Additionally, AR to Tyrosine Kinase Inhibitors (TKI) develops almost invariably within 8–16 months on TKI use, resulting in disease progression. The T790M mutation is the most common mechanism of AR with TT available for patients baring this EGFR aberration. During workup of recurrence, some of the patients will be diagnosed with transformation into a new primary lung cancer, which warrants different treatment than metastatic NCSLC. For these reasons, an attempt should be made to obtain a fresh tissue sample if disease progression/relapse are suspected. Pleural fluid cytology has been shown to be an excellent source of tumor cells with high yield in detection of both EGFR and ALK mutations(5). In all instances, bronchoscopist should work closely with cytopathologists seeking feedback on tissue quality, quantity for ancillary testing (5).

      1. Thai AA, Solomon BJ. Treatment of ALK-positive nonsmall cell lung cancer: recent advances. Current opinion in oncology. 2017.

      2. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. The Journal of molecular diagnostics : JMD. 2013;15(4):415-53.

      3. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for molecular pathology guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(32):3673-9.

      4. Kim E, Feldman R, Wistuba, II. Update on EGFR Mutational Testing and the Potential of Noninvasive Liquid Biopsy in Non-Small-cell Lung Cancer. Clinical lung cancer. 2018;19(2):105-14.

      5. Czarnecka-Kujawa K, Yasufuku K. Molecular alterations in non-small-cell lung cancer: perspective for targeted therapy and specimen management for the bronchoscopist. Respirology (Carlton, Vic). 2014;19(8):1117-25.

      6. Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17(5):1169-80.

      7. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;15(23):7412-20.

      8. Billah S, Stewart J, Staerkel G, Chen S, Gong Y, Guo M. EGFR and KRAS mutations in lung carcinoma: molecular testing by using cytology specimens. Cancer cytopathology. 2011;119(2):111-7.

      9. Sakakibara R, Inamura K, Tambo Y, Ninomiya H, Kitazono S, Yanagitani N, et al. EBUS-TBNA as a Promising Method for the Evaluation of Tumor PD-L1 Expression in Lung Cancer. Clinical lung cancer. 2017;18(5):527-34.e1.

      10. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-Small-Cell Lung Cancer. JAMA oncology. 2016;2(1):46-54.

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    MS27 - Therapeutic Implications of Staging Issues (ID 805)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 5
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 201 BD
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      MS27.01 - Staging of Lymph Nodes in Early Stage NSCLC: Therapeutic Implications (Now Available) (ID 11515)

      10:30 - 10:45  |  Presenting Author(s): Raymond U. Osarogiagbon

      • Abstract
      • Presentation
      • Slides

      Abstract

      For patients with potentially curable non-small cell lung cancer (NSCLC), typically those without evidence of distant metastasis, the status of lymph node involvement is one of the most powerful prognostic factors: 5-year survival for patients with clinical N0, N1, N2 and N3 is estimated at 60%, 37%, 23% and 9%, respectively. Because clinical nodal status also determines optimal treatment modality, clinical nodal staging, performed with the combination of radiologic studies (CT and PET/CT scans) and invasive nodal biopsy techniques (bronchoscopy, endobronchial ultrasound/endoscopic ultrasound, mediastinoscopy, and other minimally invasive surgical methods which extend access to the mediastinum), is highly recommended for most patients being considered for curative-intent therapy.

      The minority of patients who undergo curative-intent surgical resection for NSCLC provide the vast majority of long-term survivors of lung cancer. Patients with amenable primary tumors, clinical N0 and N1 and adequate physiologic function typically undergo primary surgical resection or definitive radiation therapy (with use of chemotherapy in the setting of node-positivity), those with N2 or N3 typically undergo combined-modality chemotherapy and radiation therapy. Irrespective of the clinical staging approach, because of the residual inaccuracy of clinical staging even when adequately applied, thorough pathologic nodal staging is also strongly recommended as the most accurate determinant of stage in patients who undergo attempted resection. Estimated 5-year survival rates are 75%, 49%, 36% and 20%, for patients with pathologic N0, N1, N2 and N3 respectively.

      The pathologic nodal stage also has therapeutic implications: patients with pN1-3 benefit from adjuvant chemotherapy; those with pN2 or 3 may also benefit from radiation therapy (which is harmful to patients with pN0 or pN1). Accurate pathologic nodal staging requires surgical retrieval of lymph nodes from certain specific hilar and mediastinal stations depending on the location of the primary tumor (the pathologist has no access to these nodes without surgical retrieval) and examination of all lymph nodes provided in the resection specimen (including intrapulmonary lymph nodes which are present within the anatomic resection specimen and therefore available to the pathologist, irrespective of surgical practice).

      Gaps in the quality of nodal staging. Although there is no universal definition of clinical or pathologic nodal staging quality, multiple organizations have made recommendations for nodal staging. The American College of Surgeons Oncology Group provided an anatomically-precise definition of ‘systematic sampling’ and ‘mediastinal lymph node dissection’ which was used in the landmark Z0030 trial. Although this trial revealed survival equivalence between the two extents of surgical nodal retrieval in patients undergoing resection for clinical T1 or T2 and N0 or non-hilar N1 NSCLC, the quality of nodal staging in ‘real world practice’ falls well short of these definitions.

      The use of PET/CT scans has increased in the US with greater willingness of insurers to cover testing, but invasive mediastinal nodal staging remains severely underused, with penetration rates below 20% in many institutions. Large US database analyses reveal that up to 18% of ‘node-negative’ resections have no lymph nodes (pNX); 40-60% of pN0 or pN1 resections have no mediastinal lymph nodes; and less than 20% of pN0 resections have up to 10 lymph nodes, despite multiple studies showing that a minimum of 14 to 20 lymph nodes are associated with the lowest hazard for death. In a population-based cohort of over 2300 resections within a high lung cancer mortality region of the US, only 15% of patients had the combination of preoperative PET/CT scan, invasive mediastinal nodal staging and pathologic examination of any mediastinal lymph nodes; 17% had no attempted histologic examination of mediastinal lymph nodes before, during or after surgical resection.

      Survival implications. The nodal staging quality gap has profound survival impact. For example, the survival of patients with pNX resections mirrors that of patients with pN1, not pN0; pN0 and pN1 patients without pathologic mediastinal nodal examination have a 5% lower 5-year survival rate than those with any mediastinal nodes; patients without attempted histologic examination of mediastinal lymph nodes (lacking both invasive preoperative biopsy and mediastinal nodal examination in the resection specimen) have 14% to 37% higher hazard for death within 5 years, compared to those who do. Unsurprisingly, eligibility for adjuvant therapy is significantly more likely when histologic examination of mediastinal lymph nodes is attempted. Furthermore, when large sets of surgically resected NSCLC patients are ordered according to stringency of pathologic nodal staging quality, a strong direct association with survival is revealed.

      Quality improvement. The near-universality of the nodal staging quality gap, its profound survival impact, and the negative impact on clinical trial eligibility, accrual, balanced randomization and accurate determination of intervention-related outcomes, suggest the need for corrective intervention. The urgency of this need is heightened by the predicted increase in the proportion of candidates for curative-intent treatment with deeper penetration of low dose CT screening and more organized management of patients with incidentally-detected lung nodules; the widening array of candidate novel adjuvant treatments; the opportunity to develop stage-independent biologic prognostic markers; and the intensifying interest in comparative effectiveness studies of surgical versus non-surgical treatment modalities.

      Sustainable quality improvement will require simple, rationally-designed and empirically-proven interventions because of the complexity of lung cancer care and the multiplicity of providers involved. We can conceptualize accurate pathologic nodal staging as involving a chain of responsibility from surgical retrieval during the operation (surgeon and scrubbed assistants), accurate specimen labeling (nodal mapping by members of the operating team, often the 'circulating nurse'), secure specimen transfer from the operating room to the pathology laboratory, complete retrieval of all provided lymph node material (pathologic specimen gross dissector, often a pathology technician), thorough examination of all material (pathologist) and accurate reporting in a standardized format (pathologist and transcriptionist). A breach in quality at any of these steps in the chain of responsibility could, in theory, impair the accuracy of pathologic nodal staging. To be sustainably successful, corrective interventions must secure quality across all links in the chain of responsibility, which is only as strong as its weakest link.

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      MS27.02 - Invasive Staging in Medically Inoperable Patients Treated with SBRT: Is It Necessary? (Now Available) (ID 11516)

      10:45 - 11:00  |  Presenting Author(s): Anand Swaminath

      • Abstract
      • Presentation
      • Slides

      Abstract

      Patients with stage I, medically inoperable non-small cell lung cancer (NSCLC) who are treated with stereotactic body radiation therapy (SBRT) are typically not routinely subjected to invasive mediastinal or hilar staging. In an era of combined positron emission tomography (PET) and computed tomography (CT) staging, the presence of clinically node negative disease in a patient ineligible for surgery usually justifies use of SBRT, although there are a proportion of patients who harbor subclinical nodal disease. For instance, in large SBRT series (with long followup) using PET/CT clinical staging only, the rates of regional recurrence (defined as hilar or mediastinal failure) were estimated at up to 15%1,2, with other smaller prospective and retrospective series suggesting higher or lower regional rates.

      Yet all of this occurs in the face of excellent long term local control that is consistently high among studies using SBRT. Therefore, there exists a double- edged sword in answering the question of whether there is a strong desire to consider routine invasive mediastinal staging in this population. On one hand, there is the possibility of undertreating patients who already harbor occult regional nodal disease; on the other hand the chances of detecting nodal failure appear modest at best, and implications exist with respect to use of potentially more prolonged courses of radiotherapy and/or systemic therapy in a medically frail population where significant competing risks for survival exist.

      To put things in perspective, rates of regional nodal failure following surgical resection in medically operable patients appear similar - in the ACOSOG Z0030 trial, 18% of patients with resected clinical stage I disease were found to have regional nodal upstaging, with the majority (13%) having occult N1 disease3. Other comparative retrospective studies of SBRT and surgery have shown varying differences in rates of regional nodal failure; however these sorts of studies are fraught with bias in terms of definitions of regional failure, rates of histological diagnosis (in the case of SBRT), patient selection, and duration of follow-up. Within SBRT series themselves, there is less data available, but some indication may exist that at least local control and survival is unchanged in patients who have invasive mediastinal staging versus those who do not4, likely largely owing to competing risks of mortality. Other series have shown that incidental low SBRT dose to the hilum may or may not reduce the chance of regional nodal recurrence5,6, and so at this time at least should not be considered a factor in determining whether to consider invasive nodal staging upfront.

      Other important factors such as tumor size and location however have been fairly consistently reported in both surgical and SBRT series as indications to consider invasive mediastinal staging. In fact, the high false negative rates of CT and PET/CT in detecting nodal disease in central (defined as within the inner third of the hemithorax) tumors would lend argument to the fact that all patients (whether treated with SBRT or surgery) should undergo invasive staging7,8. To attempt to answer this question further, the STAGE trial was a prospective study that evaluated the role of endobronchial ultrasound (EBUS) nodal staging in patients with high risk (T2 lesion, centrally located via RTOG definition, and/or suspicion of N1/2 disease on PET/CT) NSCLC suitable for SBRT. Initial results suggested that in patients with cN0 disease on PET/CT, the rate of upstaging using EBUS was approximately 11%9. Therefore there are a small but significant proportion of patients who do have occult nodal disease in high risk subgroups that may warrant routine evaluation of the hilum/mediastinum, however long term outcome data is required.

      Until we have definitive answers from STAGE and other ongoing prospective trials (NCT02719847, NCT01786590), the decision to consider invasive mediastinal staging in a medically inoperable stage I NSCLC patient will largely be an individualized one; yet we are at least fortunate to know that even in a clinical N0 scenario, the chances of nodal failure appear modest at best, and that perhaps with appropriate patient selection (at least for the time being), we can slowly begin to avoid the harm of the double-edged sword that we wield.

      1. Marwaha G, Stephans KL, Woody NM, Reddy CA, Videtic GM. Lung stereotactic body radiation therapy: regional nodal failure is not predicted by tumor size. J Thorac Oncol. 2014;9(11):1693-1697.

      2. Senthi S, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, Senan S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol. 2012;13(8):802-809.

      3. Su S, Scott WJ, Allen MS, et al. Patterns of survival and recurrence after surgical treatment of early stage non-small cell lung carcinoma in the ACOSOG Z0030 (ALLIANCE) trial. J Thorac Cardiovasc Surg. 2014;147(2):747-752: Discussion 752-743.

      4. Corso CD, Lloyd S, Harder E, Mancini BR, Rutter CE, Decker RH. Invasive Mediastinal Staging Does Not Improve Outcomes Over PET Alone in Early-Stage NSCLC Treated With SBRT. Int J Rad Oncol Biol Phys;90(1S):S216-217.

      5. Lao L, Hope AJ, Maganti M, et al. Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis. Int J Radiat Oncol Biol Phys. 2014;90(1):209-215.

      6. Rwigema JC, Chen AM, Wang PC, Lee JM, Garon E, Lee P. Incidental mediastinal dose does not explain low mediastinal node recurrence rates in patients with early-stage NSCLC treated with stereotactic body radiotherapy. Clin Lung Cancer. 2014;15(4):287-293.

      7. Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA, American College of Chest P. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):202S-220S.

      8. Gao SJ, Kim AW, Puchalski JT, et al. Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT. Lung Cancer. 2017;109:36-41.

      9. Crombag LMMJ, Annema J, Dieleman E, et al. Complete endosonographic nodal staging of lung cancer in patients eligible for stereotactic ablative radiotherapy (STAGE study NCT02997449). Eur Respir J. 2017;50(Suppl 61).

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      MS27.03 - Multiple Lung Nodules: M1, T4 or T3? Are They Really Different? (Now Available) (ID 11517)

      11:00 - 11:15  |  Presenting Author(s): Frank Detterbeck

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS27.04 - Therapeutic Implications of AJCC 8th Edition T1 Subsets (Now Available) (ID 11518)

      11:15 - 11:30  |  Presenting Author(s): Laura Donahoe

      • Abstract
      • Presentation
      • Slides

      Abstract

      In January 2018, the American Joint Committee on Cancer (AJCC)/International Union for Cancer Control (UICC) introduced the 8thedition of the tumor, node, and metastasis (TNM) staging system for lung cancer. In the 7thedition, T1a tumors were defined as <2cm and T1b tumors were defined as 2-3cm. In preparation for the 8thedition, an analysis was done of the International Association for the Study of Lung Cancer (IASLC) database and statistically significant differences in survival based on tumor size in increments of 1cm were found (1). Thus, the 8thEdition T-stage was divided into three subgroups: T1a, tumor 1cm or less; T1b, tumor more than 1cm but not larger than 2cm; T1c, tumor more than 2cm but not larger than 3cm. Currently, the standard of care for early stage lung cancer is surgical resection by lobectomy, based on the results of the 1995 Lung Cancer Study Group trial showing improved survival compared with sublobar resection (2). With improvements in imaging technology and clinical staging, the question of whether sublobar resection, in the form of wedge resection or segmentectomy, can provide an oncologically equivalent treatment remains to be answered (3). In a comparison of survival between lobectomy and sublobar resection, it was found that the survival benefit from lobectomy was only present for patients before 1997 and not for the newer cohorts (4). This suggests that early stage lung cancer patients of the present era are different from the era by which our current standards of care were established. Similarly, in comparing outcomes after lobectomy with sublobar resection using the T-stage from the AJCC/UICC 7thedition, there was no difference in survival based on the type of resection for T1a and T1b ground glass-predominant nodule groups, although there was a higher rate of lymph node metastases in the T1b group (5). Additionally, Okada et al found that there was no difference in survival between lobectomy or segmentectomy for T1a tumors based on the AJCC/UICC 7thedition classification (6). Thus, even when using the prior classification of T-stage, there is evidence to suggest that these early tumors should be managed differently than larger, more advanced non-metastatic tumors. With the introduction of the AJCC/UIC 8thedition of the staging system, further studies will be able to better delineate the question of whether sublobar resection is appropriate for early stage lung cancer and whether a specific size cutoff within the T1 stage can guide the extent of resection.

      1. Rami-Porta R, Bolejack V, Crowley J, Ball D, Kim J, Lyons G, et al. The IASLC 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.

      2. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1995;60(3):615-22; discussion 22-3.

      3. Van Schil PE. Non-small cell lung cancer: the new T1 categories. F1000Res. 2017;6:174.

      4. Yendamuri S, Sharma R, Demmy M, Groman A, Hennon M, Dexter E, et al. Temporal trends in outcomes following sublobar and lobar resections for small (≤ 2 cm) non-small cell lung cancers--a Surveillance Epidemiology End Results database analysis. J Surg Res. 2013;183(1):27-32.

      5. Tsutani Y, Miyata Y, Nakayama H, Okumura S, Adachi S, Yoshimura M, et al. Appropriate sublobar resection choice for ground glass opacity-dominant clinical stage IA lung adenocarcinoma: wedge resection or segmentectomy. Chest. 2014;145(1):66-71.

      6. Okada M, Mimae T, Tsutani Y, Nakayama H, Okumura S, Yoshimura M, et al. Segmentectomy versus lobectomy for clinical stage IA lung adenocarcinoma. Ann Cardiothorac Surg. 2014;3(2):153-9.

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      MS27.05 - The Future of Precision Therapy for Localized Lung Cancer (Now Available) (ID 11519)

      11:30 - 11:45  |  Presenting Author(s): Takashi Seto

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE10 - Emerging Technologies for Small and Smaller Lesions - Update on Ablation via Endoscopy vs Percutaneous (Ticketed Session) (ID 820)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 201 BD
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      MTE10.01 - Emerging Technologies for Small and Smaller Lesions - Update on Ablation via Endoscopy vs Percutaneous (Now Available) (ID 11563)

      07:00 - 08:00  |  Presenting Author(s): Felix JF Herth

      • Abstract
      • Presentation
      • Slides

      Abstract

      A solitary pulmonary nodule (SPN) is a round or oval opacity smaller than 3 cm in diameter that is completely surrounded by pulmonary parenchyma.

      Workup of these nodules is rather expensive and emotionally burdensome, especially when the patient has risk factors for bronchial carcinoma.

      SPNs are noted in up to 0.2% of chest radiograph, whereas 27.3% of patients undergoing the national lung screening trial (NLST) had at least one SPN with a diameter of more than 4mm on their CT examination.

      Numerous articles/papers have been published addressing the optimal strategy of evaluating individuals with lung nodules, including the published ACCP guideline for the diagnosis and management of lung cancer. Those strategies are generally based on the individuals’ risk of developing lung cancer, the pulmonary nodule characteristics and the capability of the current diagnostic and therapeutic approaches.

      Standard bronchoscopy has been limited in the evaluation of the peripheral pulmonary nodules, with diagnostic yields ranging from 19% to 68%. The addition of tools such as electromagnetic navigational bronchoscopy (ENB), radial endobronchial ultrasound (r-EBUS), and several other navigation technologies have been used and increased the diagnostic yield. Actual, The Transbronchial Parenchymal nodule access (TPNA) has shown the best results.

      Radiofrequency ablation (RFA) and Microwaves (MW) are promising alternative treatment method for early-stage lung cancer in non-surgical patients. They can also be used for oligometastasis from distant cancer or as a therapy for the local control

      of tumors.

      Compared to their percutaneous approach, in the lung, percutaneous ablation is associated with severe complications, including pneumothorax, hemothorax, bronchopleural fistulas, and pleural effusions.

      Therefore a bronchoscopic approach seems to be as effective with reduced complications.

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    MTE13 - Clonal Evolution and Targeted Therapy (Ticketed Session) (ID 823)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Targeted Therapy
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 201 BD
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      MTE13.01 - Clonal Evolution and Targeted Therapy (Now Available) (ID 11568)

      07:00 - 07:30  |  Presenting Author(s): Ramaswamy Govindan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MTE13.02 - Clonal Evolution and Targeted Therapy (Now Available) (ID 11569)

      07:30 - 08:00  |  Presenting Author(s): Janessa Laskin

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE23 - Surgical Considerations Following Induction Therapy for Stage IIIA Disease (Ticketed Session) (ID 833)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 07:00 - 08:00, Room 201 BD
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      MTE23.01 - Surgical Considerations Following Induction Therapy for Stage IIIA Disease (Now Available) (ID 11587)

      07:00 - 07:30  |  Presenting Author(s): Eric Vallieres

      • Abstract
      • Presentation
      • Slides

      Abstract

      Considerations following Induction Therapy for Stage IIIA Disease

      Surgery after induction therapy can at times be very challenging. From my own observations, this may particularly be an issue when the patient had nodal involvement at presentation and experienced a good response to the induction treatment (induction chemoradiation (CRT) or induction chemotherapy (C) alone) where fibrosis of the responding lymph nodes may make the hilar vascular mobilization more difficult. (Induction immunotherapy as well in limited reported series) The following lines will describe some tips on how to minimize the risks of such resections.

      Preoperatively:

      One should always take advantage of the induction therapy period (12 weeks or more) to achieve absolute smoking cessation in these patients. After induction therapy, one should obtain a fresh set of PFTs including a DCO measurement as both radiation and some of the induction chemotherapy agents may have caused significant pneumonitis with resulting altered lung function. If there is a possibility that a pneumonectomy will be required, prepare yourself. (QVQ, stress echo). Radiation esophagitis may have brought some nutritional issues, consider an alimentary “boost” when a significant weight loss has occurred during the induction phase of therapy. If there may be a risk that the SVC will be clamped, repaired or replaced, discontinue the port-o-cath preoperatively. Finally, make sure to review all imaging, particularly the pre-induction therapy CT: the MTD is a good format for such review in our institution.

      Surgery

      Personally, I approach these cases via open thoracotomy, though some have reported successful resections on MIS platforms. All patients get an epidural catheter preop. If one anticipates, issues with the SVC with a R upper lobar resection, get infra diaphragmatic IV access preop. Emphasize w anesthesia, in the preoperative area, the absolute need to keep these patients dry: an irradiated mediastinum cannot handle excess fluid.

      At entry, I prepare/ harvest the intercostal muscle, without dividing it. (I now keep the omentum for later if needed to manage a complication, and spare the serratus anterior in all cases). If accessible, I usually clear zone 7 first, with frozen section read. (The frozen section information/ feedback during this type of surgery can be very useful to have when one gets into a tough surgical corner…) If one is attempting a lobectomy and anticipates possible difficulties in the hilum, one should consider obtaining early circumferential control of the main veins and main PA (if possible), and do so intrapericardially if needed. Similarly, early division of the azygos vein on the right, may help when one anticipates difficulties accessing the main R PA and surrounding structures.

      One may have to alter their usual sequence of dividing the central structures. With both upper lobes, when bulky fibrotic changes are present in the suprahilar areas, proceeding retrograde, from the fissures up is often very helpful. As well, dividing open the upper lobe bronchi from the back can help access and control the often fibrosed and foreshortened proximal lobar PA upper lobar branches.

      On the left, I will identify the vagus nerve low down, away from the fibrotic field and follow it up into the AP window to minimize the risks of inadvertently injuring the recurrent nerve. During the case, I constantly remind anesthesia to keep these patients dry. For pneumonectomies, we give a steroid bolus before dividing the main PA, similarly we initiate amiodorone prophylaxis by infusion during surgery. In high R pneumonectomies, when we have stapled the bronchial stump and a portion of the tracheal wall, I add an additional non resorbable monofilament stitch to reinforce both ends of the bronchial stapled line. Finally, we cover all of our bronchial stumps after induction CRT, and selectively after induction C alone, with the intercostal muscle flap.

      POSTOP AND DC

      Remember to keep the patient dry. Consider maintaining amiodorone prophylaxis for 72 hours after pneumonectomies or with other patients deemed at elevated risk of going into atrial fibrillation post op.

      Beware of a possible left vocal cord palsy after L pneumonectomy and difficult left upper lobectomy: we keep these patients NPO until we are confident that their cords are OK. If there are any concerns, we get an immediate laryngoscopy. If the left cord is found to be paretic, we immediately get VC medicalization. (not negotiable)

      In addition to having a high Caprini DVT Risk Score by virtue of their diagnosis, age and magnitude of surgery, patients who have received induction C or CRT may potentially be at higher risk of post op TBE as some of the C agents are thrombogenic. Unless contraindicated, we will discharge them home on continued TBE chemical prophylaxis for one month after surgery, longer if the recovery lags.

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      MTE23.02 - Surgical Considerations Following Induction Therapy for Stage IIIA Disease (Now Available) (ID 11588)

      07:30 - 08:00  |  Presenting Author(s): Jonathan David Spicer

      • Abstract
      • Presentation
      • Slides

      Abstract

      Seeking new solutions through the windows of opportunity offered by induction therapy for locoregional disease.

      The predominant model of care for locally advanced solid organ malignancies involves a shotgun approach. Indeed, the full range of “omic” strategies are currently insufficiently exploited when assigning treatment regimens to patients with IIIA non-small cell lung cancer (NSCLC). Despite the advent of precision oncology, management strategies for stage IIIA NSCLC remain relatively untargeted despite such successes as those described in the PACIFIC trial [1]. Indeed, the workhorses of curative intent therapy for IIIA NSCLC and their various permutations (surgery, radiation and chemotherapy) remain essentially unchanged over the last 25 years since the first trials of induction chemotherapy were performed in the early 1990s [2-3]. The paradigm of multimodality therapy combining local and systemic treatments holds true today and offers the best available oncological outcomes recorded to date.

      After decades of debate, emerging data seem to conclude that induction therapy with chemotherapy alone or concurrent chemoradiation offer essentially identical results when planned prior to surgery [4]. However, these data remain largely retrospective with few randomized head to head comparisons in this most heterogeneous of stage groupings. Hence, not only has stage IIIA remained a highly heterogenous cohort with a wide spectrum of disease burden, but its relative rarity has hampered the execution of innovative randomized trials. Thus, most centers have adopted a preferred institutional approach based on expert readings of the available literature. These variations in care have led to heated debates over what is essentially a game of musical chairs, arranging various permutations of conventional therapeutics for which the outcomes are largely identical.

      In this respect, the old debate of whether to give induction chemotherapy or concurrent chemoradiation misses the point and overlooks a tremendous opportunity for discovery. Years of clinical trials have taught us that approximately 15 to 20% of patients will experience a major pathological response after induction chemotherapy [5] and approximately one third will have a pathological complete response after concurrent chemoradiation [6]. Yet, we are no closer to selecting those patients most likely to benefit most from these conventional therapeutics. The windows of opportunity offered by induction therapy in surgically resectable IIIA NSCLC are numerous and vastly powerful. Properly exploited, these opportunities make IIIA NSCLC the perfect pivot point for discovery that will inform both the metastatic setting and novel approaches to early stage disease.

      As NSCLC patients are offered more therapeutic options, the ability to tailor induction therapeutics based on predictive analyses up-front remains under-exploited in IIIA disease. Current trials exploring the value of checkpoint inhibition prior to surgical resection for locally advanced NSCLC assign patients randomly to the available combinations. This again is a key moment to provide improved selection through the extensive correlative science pipelines offered by these window of opportunity trials [7]. The surrogate measure of major pathological response and its close association with long term survival outcomes provides a powerful incentive to rapidly adopt new regimens into the corpus of available therapeutic options.

      Our program capitalizes on the availability of large tissue samples offered by patients treated with multimodality therapy in surgically resectable IIIA NSCLC, to establish lab-based patient avatars. These living and highly personalized biobanks provide the necessary materials to profile and generate a lab-proven first line therapeutic regimen. While such programs would be highly inefficient in early stage disease where cure rates are much higher, patients with stage IIIA have high rates of recurrence and generally benefit from a sufficiently long disease-free interval. This luxury of time offers yet another window of opportunity where patient-derived xenograft models and organoids are generated from the surgical specimen to create the necessary patient avatar to execute a predictive analysis and establish the optimal next step for the significant number of patients who will experience progressive disease. Moreover, the sensitivity of liquid biopsy protocols is easily tested in this setting where a significant proportion of patients are placed into remission with no radiological evidence of disease [8]. Such opportunities provide the ideal setting to revisit our surveillance strategies which have become so resource intensive, yet offering so little measurable benefit [9].

      Finally, a dedicated research program centred on locally advanced NSCLC provides a desirable clinical entity to rapidly establish predictors of response and failure to conventional and emerging biologicals by leveraging all “omic” platforms, from clinical to radiological and from pathological to deep sequencing, metabolomics, immunoprofiles and beyond. Such research provides the pipeline to generate the true essence of personalized medicine in NSCLC, which can easily be translated to both early and late stage disease.

      References

      Antonia SJ, et al. Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer. N Engl J Med, 2017 377(20): 1919-1929

      Roth JA, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst, 1994 86(9): 673-80.

      Rosell R, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med, 1994 330(3): 153-8

      Spicer J, et al. Multimodality therapy for N2 Non-small cell lung cancer: An evolving paradigm. Under review at Ann Thorac Surg.

      Hellman MD, et al. Pathological response after neoadjuvant chemotherapy in resectable non-small cell lung cancers: Proposal for the use of major pathological response as a surrogate endpoing. Lancet Oncol, 2014 15(1): e42-50.

      Eberhardt WEE, et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol, 2015 33(35): 4194-4201.

      Forde P, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med, 2018 378(21): 1976-1986.

      Chaudhuri AA, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov, 2017 7(12): 1394-1403.

      Colt HG, et al. Follow-up and surveillance of the patient with lung cancer after curative-intent therapy: Diagnosis and management of lung cancer. Chest, 2013 143(5 Suppl): e437S-e454S.

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