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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
    • 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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

      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      a9ded1e5ce5d75814730bb4caaf49419 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).

      4c3880bb027f159e801041b1021e88e8 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%).

      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA02.04 - Discussant - MA 02.01, MA 02.02, MA 02.03 (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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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).

      4c3880bb027f159e801041b1021e88e8 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

      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA02.07 - Aprepitant for Cough Suppression in Advanced Lung Cancer: A Randomized Trial (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. a9ded1e5ce5d75814730bb4caaf49419 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). 4c3880bb027f159e801041b1021e88e8 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. 8eea62084ca7e541d918e823422bd82e 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. 6f8b794f3246b0c1e1780bb4d4d5dc53

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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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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).

      4c3880bb027f159e801041b1021e88e8 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

      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA02.09 - Discussant - MA 02.05, MA 02.06, MA 02.07, MA 02.08 (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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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

      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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 (ID 14577)

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

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      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
    • 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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 (ID 14639)

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

      • Abstract
      • Presentation
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      Abstract not provided

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

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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 (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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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 (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
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
    • +

      MA26.01 - Accumulation of Concomitant Mutations Involved in Drug Resistance in the Sequential ALK TKI Treatments of ALK-Positive NSCLC (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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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      • 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.

      a9ded1e5ce5d75814730bb4caaf49419 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).

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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 (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.
      a9ded1e5ce5d75814730bb4caaf49419 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.
      4c3880bb027f159e801041b1021e88e8 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.
      8eea62084ca7e541d918e823422bd82e 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 (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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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
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      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.

      a9ded1e5ce5d75814730bb4caaf49419 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).

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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
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      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).

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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).

      8eea62084ca7e541d918e823422bd82e 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 (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 (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)

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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.

      4c3880bb027f159e801041b1021e88e8 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.

      8eea62084ca7e541d918e823422bd82e 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 (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.

      a9ded1e5ce5d75814730bb4caaf49419 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).

      4c3880bb027f159e801041b1021e88e8 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]).

      8eea62084ca7e541d918e823422bd82e 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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

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

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    MS05 - Diagnostic Dilemma in Lung Cancer (ID 784)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Pathology
    • Presentations: 4
    • 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 (ID 11419)

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

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

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

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

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

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

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

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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
    • 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 (ID 11463)

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

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      Abstract not provided

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

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

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

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

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

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

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

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

      • Abstract
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      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)

      e353dbe42c8654f33588d4da0b517469

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    MS19 - Pulmonary Dilemmas with Immunotherapy (ID 798)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 3
    • 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 (ID 11481)

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

      • Abstract
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      Abstract not provided

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

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

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

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

      • Abstract
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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
    • 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 (ID 11515)

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

      • Abstract
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      Abstract not provided

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

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

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

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

      • Abstract
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      Abstract not provided

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

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

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

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

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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
    • 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 (ID 11563)

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

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      Abstract not provided

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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
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 201 BD
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      MTE13.01 - Clonal Evolution and Targeted Therapy (ID 11568)

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

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

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

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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
    • 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 (ID 11587)

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

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

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

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