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    MA13 - Interventional Pulmonology

    • Type: Mini Oral Abstract Session
    • Track: Interventional Diagnostics/Pulmonology
    • Moderators:
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      MA13.01 - CT-Guided Transthoracic Needle Biopsy for Evaluation of PD-L1 Expression: Comparison of 22C3 and SP263 Assays

      10:30 - 10:35  |  Presenting Author(s): Kyongmin Sarah Beck  |  Author(s): Kyo Young Lee, Su Jin Hong

      • Abstract

      Background

      Although there are a few studies about concordance of different assays testing PD-L1 expression using surgical specimens, there hasn’t been any such concordance study using real-world biopsy specimens. However, many of the patients requiring immunotherapy and thus PD-L1 testing have unresectable lung cancer and have to rely on small biopsy results. Although phase 2 of Blueprint phase 2 does include core biopsy specimens, they are mixed with bronchial biopsy specimens and the absolute number is very small (n=20). We sought to evaluate the concordance of 22C3 and SP263 assays in a larger number CT-guided transthoracic needle biopsy (TNB) specimens.

      The purpose of this study was to assess the concordance of two commercially available diagnostic assays (22C3 and SP263) in evaluating programmed cell death ligand-1 (PD-L1) expression using specimens from CT-guided TNB in a routine clinical setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This retrospective analysis reviewed 202 non-small cell lung cancer (NSCLC) patients who underwent CT-guided TNB at our institution from April 2017 to February 2018. Among these, biopsy specimens tested with both 22C3 and SP263 assays were included for review. Concordance of PD-L1 expression levels determined by the two assays was assessed using intraclass correlation coefficient, and the agreement of dichotomized values at various cut-offs (1%, 25%, and 50%) were assessed using Cohen’s κ coefficient of agreement. Clinical characteristics and biopsy-related factors were also assessed for the association of concordance of PD-L1 expression detected by different assays

      4c3880bb027f159e801041b1021e88e8 Result

      In total, 80 patients (M:F =47:33, mean age: 68.0 years) were included in the study. Concordance of PD-L1 expression levels was high (intraclass coefficient: 0.892) between 22C3 and SP263 assays. Agreements at cut-off levels of 1%, 25%, and 50% were also good, with κ values of 0.878, 0.698, and 0.790 respectively. Positive percent agreement was 93.2%, 100.0%, and 95.2% for agreements at 1%, 25%, and 50%. At multivariate analysis, the presence of emphysema was significantly related to discordant PD-L1 results (odds ratio: 0.059, p= 0.005).

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is a high concordance of PD-L1 expression evaluated with 22C3 and SP263 assays using CT-guided TNB specimens.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.02 - PD-L1 Expression in EBUS-Guided Cytology Specimens of Non-Small Cell Lung Cancer is Not Affected by Type of Fixation: A Study of Matched Pairs

      10:35 - 10:40  |  Presenting Author(s): Alexander Haragan  |  Author(s): John Roy Gosney, Claire Chadwick, Tom Giles, Seamus Grundy, Victoria Tippett, Krishna Gumparthy, Andrew Wight, Hock Tan

      • Abstract

      Background

      No previous trials of immune modulators (IMs) to treat non-small cell lung cancer (NSCLC) have included ‘cytology’ specimens, dispersed cells aspirated from a tumour deposit or body cavity, for immunochemical assessment of PD-L1, a useful complementary or compulsory companion diagnostic test. This has led to the widely-held view that, in the absence of such ‘validation’, cytology specimens cannot be used to assess it. In many centres, endobronchial ultrasound (EBUS)-guided aspiration of the tumour or intra-thoracic lymph nodes is the preferred means of diagnosis and staging of NSCLC and such specimens account for the majority received for analysis. Failure to asses them has serious implications for appropriate management and might deny patients effective therapy. Much of this reluctance centres on the alleged effect of fixation in alcohol-based fixatives, the preferred method of cytopathologists, rather than formalin, the standard fixation medium for tissue specimens, on the expression of PD-L1 on the cell surface.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We compared expression of PD-L1 in 50 paired specimens of NSCLC, one fixed in an alcohol-based fixative and one in neutral-buffered formalin, taken from the same tumour deposit or lymph node during the same procedure. All were spun down and formed into a cell block before assessment for PD-L1 expression, which was by two appropriately-trained pathologists with extensive experience in its interpretation.

      4c3880bb027f159e801041b1021e88e8 Result

      In none of the 50 pairs studied was there any significant difference, qualitative or quantitative, in the pattern or extent of PD-L1 expression and, in the great majority, it was identical irrespective of fixation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is no evidence from this study that the use of alcohol-based fixatives has any effect on the expression of PD-L1 or its interpretation. Notwithstanding the general challenges in accurately assessing such expression, which are common to specimens of tissue as well as dispersed cells, pathologists should feel able to interpret cytology specimens with confidence and clinicians able to rely on the results.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.03 - Heterogeneity Analysis of EBUS-TBNA-Derived Specimens for Evaluation of PD-L1 Expression and Copy Number Alterations in Patients with NSCLC

      10:40 - 10:45  |  Presenting Author(s): Katsuhiro Yoshimura  |  Author(s): Yusuke Inoue, Kazuo Tsuchiya, Masato Karayama, Yuji Iwashita, Tomoaki Kahyo, Akikazu Kawase, Masayuki Tanahashi, Hiroshi Ogawa, Koshi Yokomura, Naoki Inui, Kazuhito Funai, Kazuya Shinmura, Hiroshi Niwa, Takafumi Suda, Haruhiko Sugimura

      • Abstract

      Background

      Most patients with non-small cell lung cancer (NSCLC) are diagnosed at advanced stages and only small biopsy specimens are available for diagnosis in the majority of the patients. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a useful diagnostic modality and is becoming more relevant and essential procedure in the real-world clinical setting. However, it is poorly elucidated whether EBUS-TBNA-derived small specimens are suitable for evaluation of biomarkers such as PD-L1 alterations, because heterogeneity of PD-L1 expression limits the power as a guide to select patients who are likely to benefit from the PD-1/PD-L1 blockade therapy. In addition, PD-L1 copy number alterations (CNAs) have been proposed to potentially complement the predictive performance of PD-L1 expression. We here evaluated the utility of EBUS-TBNA-derived specimens in the assessment of PD-L1 protein and CNAs focusing on the heterogeneity with other biopsy/resected samples.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PD-L1 protein expression and CNAs in 71 EBUS-TBNA specimens of NSCLC were assessed. Corresponding 68 transbronchial biopsy (TBB) specimens, 13 resected primary tumors, and 6 resected metastases were comparatively analyzed. PD-L1 expression on tumor cells was assessed by immunohistochemistry (E1L3N). Positivity of ≥1% was used as the cut-off. PD-L1 CNAs were assessed with fluorescent in situ hybridization, and were classified into three categories: amplification, polysomy, and disomy. Concordance between EBUS-TBNA and other specimens were calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      The median age was 68 years (38-90 years). The cohort comprised 48 men (67.6%), 15 never-smokers (21.1%), and 39 adenocarcinomas (54.9%). The concordance of PD-L1 positivity between EBUS and the other specimens was moderate; κ=0.63 for EBUS vs TBB, κ=0.68 for EBUS vs the resected primary tumors, and κ=1.00 for EBUS vs the resected metastases. The concordance of PD-L1 CNA statuses was comparable with that of PD-L1 expression: κ=0.60 for EBUS vs TBB, and κ=0.74 for EBUS vs the resected primary tumors. When the PD-L1 copy number was assessed as a continuous variable, the correlation was also good/moderate: ρ=0.60 for EBUS vs TBB specimens, ρ=0.56 for EBUS vs the resected primary tumors, and ρ=0.80 for EBUS vs the resected metastases. Intratumorally, PD-L1 expression was significantly heterogeneous in whole sections of resected tumors, but PD-L1 CNAs was less heterogeneous than protein expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      EBUS-TBNA-derived specimens can be used for the assessment of PD-L1 alterations including CNAs. The concordance of PD-L1 CNAs between EBUS-TBNA and TBB/resected specimens were comparable with that of PD-L1 expression. However, spatial heterogeneity should be taken into account to interpret both PD-L1 protein expression and CNAs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.04 - Discussant - MA 13.01, MA 13.02, MA 13.03

      10:45 - 11:00  |  Presenting Author(s): John Roy Gosney

      • Abstract

      Abstract not provided

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      MA13.05 - The Canada Lymph Node Sonographic Score: National Validation of a Sonographic Score to Determine Mediastinal Lymph Node Malignancy

      11:00 - 11:05  |  Presenting Author(s): Danielle Alexandria Hylton  |  Author(s): Julie Huang, Simon Turner, Daniel French, Chuck Wen, James Masters, Biniam Kidane, Jonathan David Spicer, Jenelle Taylor, Christian Finley, Yaron Shargall, Christine Fahim, Forough Farrokhyar, Kazuhiro Yasufuku, John Agzarian, Waël C. Hanna

      • Abstract

      Background

      At the time of endobronchial ultrasound (EBUS) staging for Non-Small Cell Lung Cancer (NSCLC), 6 ultrasonic criteria (Fig. 1) are used to assign a Lymph Node Sonographic Score (LNSS) that is predictive of malignancy. The LNSS has not gained widespread use due to lack of research demonstrating its validity and reliability among endoscopists. We hypothesized that LNSS correlates well with the probability of malignancy, potentially guiding decisions for lymph node (LN) biopsy.

      iaslc abstract lnss - figure 1_jpg.jpg

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a prospective study to assess the validity and reliability of the LNSS. The validation cohort comprised LN that were video-recorded from patients with NSCLC, and assigned a LNSS by an experienced endoscopist. Videos were then circulated to thoracic surgeons and interventional respirologists across Canada, who were asked to assign a score to each LN. All raters had demonstrated proficiency using our online education module, were blinded to staging information, and to each other. Each LN was scored by at least 3 independent raters. Pathological specimens were used as the gold standard for determination of malignancy. Regression, receiver operator curve (ROC), and Gwet’s AC1 analyses were used to test LNSS score performance, discriminatory capacity, and inter-rater reliability.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 300 LNs (18% malignant) from 140 patients were analyzed by 11 endoscopists across 7 Canadian centres. LNSS=0 was strongly predictive of benign LN (NPV= 95.69%, OR=49.2, p=0.001). LNSS ≤2.5 (OR=44, p=0.001) was determined as the cutoff for malignancy based on ROC analysis (c= 0.7757, 95%CI: 0.70281-0.84853). Inter-rater reliability for LNSS=0 was 0.8553 (95%CI:0.8158-0.8947, p=0.0001) and 0.46 for LNSS ≤2.5 (95%CI=0.3521-0.5012, p=0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The Canada LNSS shows excellent performance in identifying benign LN at the time of EBUS. A cutoff ≤2.5 has the potential to inform decision-making regarding biopsy or repeat biopsy/mediastinoscopy if the initial results are inconclusive. Further teaching and education are required to improve inter-rater reliability.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.06 - Endosonography with Lymph Nodes Sampling for Restaging the Mediastinum in Lung Cancer: A Systematic Review and Pooled-Data Analysis

      11:05 - 11:10  |  Presenting Author(s): Long Jiang  |  Author(s): Jun Liu, Wenlong Shao, Kassem Harris, Lonny Yarmus, Weizhe Huang, Jianxing He

      • Abstract

      Background

      Mediastinal restaging after induction treatment is still a difficult and controversial issue. We aimed to investigate the diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for restaging the mediastinum after induction treatment in patients with lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Embase and PubMed databases were searched from conception to July 2017. Data from relevant studies were analyzed to assess sensitivity and specificity of EBUS-TBNA and EUS-FNA, and to fit the Hierarchical Summary Receiver-Operating Characteristic curves.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of nine studies consisting of 542 patients fulfilled the inclusion criteria. All patients were restaged by EBUS-TBNA, EUS-FNA or both. Negative results were confirmed by subsequent surgical approaches. There were no complications reported during any endosonography approaches reviewed. The pooled sensitivities of EBUS-TBNA and EUS-FNA were 66%(95% CI, 60%-72%) and 73%(95% CI, 52%-87%), respectively; and specificities were 100%(95% CI, 98%-100%) and 99%(95% CI, 90%-100%), respectively. The area under the HSROC curves(AUC) were 0.84(95% CI, 0.81-0.87) for EBUS-TBNA and 0.99(95% CI, 0.98-1) for EUS-FNA. Moreover, for patients who received chemotherapy alone, the pooled sensitivity of endosonography with lymph node sampling for restaging was 69% (95% CI, 63%-75%), and specificity was 100% (95% CI, 97%-100%); and for patients who received chemoradiotherapy, the results seemed similar with sensitivity of 65% (95% CI, 50%-78%) and specificity of 100% (95% CI, 96%-100%).

      Variables

      No. of patients

      Pooled sensitivity (95% CI)

      Pooled specificity (95% CI)

      Negative Likelihood Ratio

      AUC

      In all mediastinal stations

      Overall

      543

      0.70 (0.65-0.75)

      1.00 (0.98-1.00)

      0.30 (0.21-0.43)

      0.93 (0.91-0.95)

      EBUS-TBNA

      424

      0.66 (0.60-0.72)

      1.00 (0.98-1.00)

      0.38 (0.26-0.54)

      0.84 (0.81-0.87)

      EUS-FNA

      226

      0.73 (0.52-0.87)

      0.99 (0.90-1.00)

      0.27 (0.14-0.53)

      0.99 (0.90-1.00)

      Combine

      106

      0.67 (0.53–0.79)

      0.96 (0.86–0.99)

      N/A

      0.81 (0.73–0.87)

      Subgroup analysis

      Chemo alone

      365

      0.69 (0.63-0.75)

      1.00 (0.97-1.00)

      0.35 (0.26-0.48)

      0.90 (0.88-0.94)

      Chemo radiotherapy

      130

      0.65 (0.50-0.78)

      1.00 (0.96-1.00)

      0.25 (0.06-1.02)

      0.97 (0.95-0.98)

      If negative Likelihood Ratio(LR-) is smaller: essentially a definite diagnosis when negative result.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Endosonography with lymph node sampling is an accurate and safe technique for mediastinal restaging of lung cancer. For nondiagnostic results, a further more invasive approach should be thoroughly considered.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.07 - Diagnostic Yield of N3 Hilar Staging by Endobronchial Ultrasonography (EBUS) in Lung Cancer

      11:10 - 11:15  |  Presenting Author(s): Antoni Rosell  |  Author(s): Jaume Bordas Martinez, Jose Luis Vercher Conejero, Guillermo Rodriguez Gonzalez, Cristina Martin Cabeza, Noelia Cubero De Frutos, Rosa-Maria Lopez Lisbona, Marta Diez Ferrer, Paula Notta, Roger Llatjos Sanuy, Jordi Dorca Sargatal

      • Abstract

      Background

      Systematic lung cancer staging with EBUS has proven to be equivalent to cervical mediastinoscopy. Nevertheless, in the daily practice it is common to explore and sample negative PET-CT hilar N3 lymph nodes (LN). This study aims to explore if there is enough evidence to support this clinical practice.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective study from our database including 1,013 explorations over the last 5 years. Including criteria were patients with lung cancer staged by PET-CT and EBUS-TBNA. Mediastinal and hilar N3 LN with a short axis ≥ 5 mm were sampled with a 21G needle and assessed by rapid on site evaluation (ROSE). A single nuclear medicine expert reviewed blindly all PET-CT scans and determined the SUVmax of every LN. Those that were ≥ 5 SUVmax by PET-CT and/or ≥ 10mm in short axis by EBUS were considered abnormal.

      4c3880bb027f159e801041b1021e88e8 Result

      87 patients were included, of which 87% were male with a mean age of 66 years (SD 12.6). The final histopathology diagnoses were adenocarcinoma (46%), squamous cell carcinoma (39%) and other histology (14%). EBUS-TBNA was performed 30 days (SD 16.9) after PET-CT. None of the 61 normal hilar and normal mediastinum N3 LN, and none of the 7 normal N3 hilar LN with abnormal mediastinal LN (3 by PET-CT, 3 by EBUS and 1 for both) resulted positive for lung cancer. Of the 19 patients with abnormal N3 hilar LN (6 by PET-CT, 8 by EBUS and 6 for both) malignancy was found in 16.7% , 25% and 60% for both techniques, respectively.ryywawmo--450186-1-any.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      In absence of abnormal N3 hilar LN (PET: SUVmax<5; EBUS<10mm in short axis) it seems there is not enough evidence to sample them, regardless of N3 mediastinal status.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.08 - Discussant - MA 13.05, MA 13.06, MA 13.07

      11:15 - 11:30  |  Presenting Author(s): Nicole Bouchard

      • Abstract

      Abstract not provided

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      MA13.09 - Electromagnetic Navigation Bronchoscopy as an Integrated Approach to Aid in Diagnosis and Treatment of Pulmonary Lesions

      11:30 - 11:35  |  Presenting Author(s): Sandeep Khandhar  |  Author(s): Septimiu Murgu, Kyle Hogarth, William Krimsky, Javier Flandes, Otis Rickman, Momen Wahidi, Eric Sztejman, Philip Linden, Sadia Benzaquen, Sandeep Bansal, Erik Folch

      • Abstract

      Background

      Electromagnetic navigation bronchoscopy (ENB) is an image-guided localization approach to guide endoscopic tools to lung targets. In a single procedure, ENB aids in localizing lung lesions for biopsy or molecular profiling, fiducial placement for stereotactic body radiation therapy (SBRT), or dye marking for surgical resection. The multidisciplinary utility of ENB in a large, prospective, multicenter study is unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      NAVIGATE (clinicaltrials.gov, NCT02410837) is a prospective, multicenter, observational cohort study of ENB using the superDimension™ navigation system. From April 2015 to August 2016, 1,215 consecutive subjects were enrolled at 29 United States sites. Two-year follow-up is ongoing. A prespecified 1-year interim analysis is presented.

      4c3880bb027f159e801041b1021e88e8 Result

      ENB was used to aid in lung lesion biopsy (n=1157 subjects), fiducial placement (n=258), pleural dye marking (n=23), and/or lymph node biopsy (n=30). EBUS-guided lymph node staging was conducted in the same procedure in 448 subjects. The median lesion-to-pleura distance was 9mm. The median lesion size was 20mm; most were in the middle (30%) and peripheral (67%) thirds of the lung. Pathology results were malignant in 44.3% (484/1092) (54.1% Stage I, 11.1% Stage II, 17.0% Stage III, 17.7% Stage IV). Molecular testing was attempted in 30.7% (80/261) of adenocarcinoma or NSCLC-not-otherwise-specified cases overall and 57.9% (33/57) of Stage IIIB/IV cases. Tissue was adequate in 87.5% (70/80) of cases. EGFR mutations (14.7%) and ALK translocations (4%) were the most frequently observed genetic alterations. The ENB procedure was well-tolerated; 2.9% of subjects had procedure-related pneumothorax requiring hospitalization or intervention, lower than published rates for CT-guided core biopsy (25%) and CT-guided fine needle aspiration (19%). Subject-reported impact of ENB on daily activities was 0.9 out of 10 (0 = no impact).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the largest prospective, multicenter study to date, ENB aided in lesion biopsy in the middle and periphery of the lung and tissue collection for molecular testing, with a very low morbidity. ENB facilitates a multidimensional approach to lung biopsy and mediastinal/hilar staging, offering the opportunity for multiple sites/tissues to be safely sampled in one anesthetic event.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.10 - Comparison of Pulmonary Nodule Location Between Preprocedural CT and Intra-Procedural Cone-Beam CT During Guided Bronchoscopy

      11:35 - 11:40  |  Presenting Author(s): Michael A. Pritchett

      • Abstract

      Background

      Electromagnetic navigation bronchoscopy relies on pre-procedural CT scans to create a virtual airway reconstruction that is used as a roadmap during bronchoscopy. These systems assume similarity between the position of the nodule during bronchoscopy and the pre-procedure CT scan. However, there are multiple factors that suggest that such assumption maybe inaccurate. These include differences in positioning, breathing motion, and the presence of atelectasis. In this study, we evaluated the lung nodule position between pre-procedural CT to interprocedural cone-beam CT (CBCT). In addition, we assessed the ability of a novel augmented endobronchial fluoroscopic guidance system (LungVision, Body Vision Medical Ltd, Israel) to overcome those differences in real-time.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was a prospective study of 21 patients with 23 peripheral pulmonary nodules. CT scans were imported into the planning software and the physician identified the nodule and navigation pathway. CBCT (Philips Allura Xper FD20) was used to scan the patient during the procedure. LungVision was used for real-time navigation and guidance during biopsy. The divergence in nodule location between the pre-procedural CT and the interprocedural CBCT was measured.

      4c3880bb027f159e801041b1021e88e8 Result

      The average patient age was 69 ± 8.6, median nodule size was 18mm with 74% of the nodules in the upper lobes. The average divergence of the nodule was 14.11 ± 9.9mm. Successful navigation was verified by CBCT in 91% of cases. Malignancy was diagnosed in 20 of 23 nodules for a diagnostic yield of 87%. No adverse events were reported.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study demonstrates a significant divergence in lesion location between pre-procedural CT and intra-procedural CBCT during guided bronchoscopy. This finding indicates that the change in nodule position between the CT and bronchoscopy could have a great impact on the diagnostic success of the procedure. This movement, sometimes greater than the size of the nodule itself, can lead to an inaccurate localization when relying solely on virtual bronchoscopic or electromagnetic navigation.

      CT to patient divergence does not appear to influence the accuracy of this novel navigation platform. The system is capable of tracking the nodules dynamically and can compensate for changes in patient positioning and respiratory motion during both navigation and biopsy which leads to a high diagnostic yield.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.11 - Photodynamic Therapy for Peripheral-Type Lung Cancer in a Multi-Center Clinical Trial

      11:40 - 11:45  |  Presenting Author(s): Jitsuo Usuda

      • Abstract

      Background

      Photodynanic therapy (PDT), is a treatment modality for many cancers, and uses a tumor-specific photosensitizer and laser irradiation. Recently, we have developed a new minimally invasive laser device using a 1.0 mm in diameter composite-type optical fiberscope (COF), which could transmit laser energy and images for observation in parallel.In this study, we aimed to develop a new endobronchial treatment for peripheral cancer using PDT and a COF, and we evaluated the feasibility of PDT using COF for peripheral lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This phase I study enrolled 3 patients with peripheral lung cancers (primary tumor< 20 mm, stage IA), which were definitively diagnosed by bronchoscopic modalities such as EBUS-GS and brocnhoscopic navigation system. We conducted irradiation using a diode laser (664 nm) and a COF 4 hours after the administration of NPe6 40 mg/m2. We evaluated the tumor lesions using EBUS, and then we introduced the COF into the peripheral lung cancer, and irradiated of red light 664 nm (120 mW, 50 J/cm2 or 100J/cm2). 

      4c3880bb027f159e801041b1021e88e8 Result

      We performed PDT for 3 patients with c-stage IA peripheral lung cancer, using a laser dose (120mW, 50J/cm2), and confirmed the feasibility of the dose. We escalated the laser dose and performed 4 patients using a laser dose (120mW, 100J/cm2).

      Seven patients met our criteria, and 5 cases were adenocarcinoma and 2 case squamous cell carcinoma. We were able to observe the cancer lesions at the peripheral lung by the COF, and feasibly irradiated. Two weeks and 3 months after NPe6-PDT, complications such as pneumonia and pneumothorax were not found, but one mildly found light skin-photosensitivity. Six months later, we found CR in 3 cases and SD in 4 cases.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The 1.0 mm COF was a very useful device of NPe6-PDT for peripheral lung cancers, and PDT was a feasible and non-invasive treatment for a peripheral type early lung cancer. In the future, for non-invasive adenocarcinoma such as AIS, NPe6-PDT will become a treatment modality.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA13.12 - Discussant - MA 13.09, MA 13.10, MA 13.11

      11:45 - 12:00  |  Presenting Author(s): Antoni Rosell

      • Abstract

      Abstract not provided

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    MA14 - Survivorship, Socioeconomic and End-of-Life Considerations

    • Type: Mini Oral Abstract Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Moderators:
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      MA14.01 - Life Sustaining Procedures, Palliative Care and Hospital Cost Trends in Dying Lung Cancer Patients in U.S. Hospitals: 2005-2014

      10:30 - 10:35  |  Presenting Author(s): Jinwook Hwang  |  Author(s): Ji won Yoo, Jay Shen, Sun Jung Kim, Sung Youn Chun

      • Abstract

      Background

      Little is known about the extent to which dying patients with lung cancer receive life-sustaining treatments and palliative care services at the end-of-life in U.S. hospitals. We examine hospital cost trends and the impact of palliative care utilization on the use of life-sustaining procedures in this population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective nationwide cohort analysiswas performed using National Inpatient Sample (NIS) data from 2005 and 2014. We examined the receipt of both palliative care and life-sustaining procedures, defined as systemic procedures, local procedures, or surgeries using the International Classification of Diseases, 9th revision (ICD-9-CM).

      4c3880bb027f159e801041b1021e88e8 Result

      Figure 1.

      스크린샷 2018-05-05 05.44.27.png

      We used compound annual growth rates (CAGR) to determine temporal trends and multilevel multivariate regressions to identify factors associated with hospital cost. Among 77,394,755 hospitalizations, 120,144 patients were examined. During 10 years, the CAGR of hospital cost was 7.05% (p<.0001). In contrast, the CAGR of hospital lengths of stay was -3.77% (p<.0001). The CAGRs of palliative care was over ten percentage (13.30 %, p<.0001). However, the CAGRs of systemic procedures, local procedures, and surgeries were less than around one percentage (-1.13%, -1.07% and 1.42%, each p<.0001). Systemic procedures, local procedures and surgeries were associated with increased hospital cost and lengths of stay by 50.6%, 74.4%, 68.5%, and 7.4%, 50.6%, 4.6% respectively (each p<.001). Palliative care was associated with decreased hospital cost and length of stay by 28.6% and 4.6% (each, p<.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The volume of life-sustaining treatments is the biggest driver of cost increase although there is a cost-saving effect from greater palliative care utilization at the end-of-life in dying lung cancer patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA14.02 - Use and Impact of A Systematic Advanced Care Planning in Hospitalized Lung Cancer Patients: A Prospective Study.

      10:35 - 10:40  |  Presenting Author(s): Anne Claire Toffart  |  Author(s): Natacha Denis, Matteo Giaj Levra, Linda Sakhri, Michaël Duruisseaux, Julian Pinsolle, Léonie Ferrer, Denis Moro-Sibilot, Jean-François Timsit

      • Abstract

      Background

      End-of-life communication is crucial, particularly for cancer patients. In usual practice, advanced care planning discussions with the patients are uncommon and rarely documented. The aim of this study was to investigate the impact of advanced care planning on intensity of care in cases of organ failure in lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This prospective study was performed at the Grenoble University Hospital in France. Consecutive patients hospitalized in thoracic oncology unit between 01/28/2014 and 03/31/2016 were included and followed up to 12/31/2016. At each hospital admission, lung cancer patients benefited from advanced care planning. We defined 3 intensities of care: intensive care, maximal medical care and exclusive palliative care. The propositions of care could be modified during the hospitalization. Patients’ wishes should be received.

      4c3880bb027f159e801041b1021e88e8 Result

      Data of 715 hospitalizations corresponding to 473 patients were studied. Hundred fifty nine patients had a second hospitalization and 69 a third. At first admission, 247 (52%) patients had a performance status of 0 to 2, 186 (39%) were not yet treated for the cancer and 165 (35%) in progression. Main reasons of admission were an acute disease (n=208, 44%) and supportive care of cancer symptoms (n=167, 35%).

      During the three first admissions, 173 (25%) patients developed an organ failure. Among them, 56 (32%) had intensive care proposition, 104 (61%) maximal medical care, and 13 (7%) exclusive palliative care. Median time between admission and organ failure was 9 days [IQR 25%-75%, 3-13]. All patients benefited from intensity of care equal or lower than the proposed intensity of care. Among patients planed for intensive care, 17 (30%) patients received intensive care, 22 (39%) maximal medical care and 17 (30%) exclusive palliative care. Thirteen of the 39 patients not admitted in ICU despite organ failure and previous proposition of intensive care were considered too well by the oncologist. Patients’ wishes were recorded for 158 (91%) patients, and a discussion about end of life conditions was led with 116 (73%) patients or families.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In case of organ failure, an advanced care planning appears helpful to provide reasonable intensity of care. The proposition of care seems to be adapted to the patient’s general condition and cancer characteristics. 3/4 of the patients with an organ failure benefited from a discussion about end of life conditions.

      ClinicalTrials.gov Identifier: NCT02852629

      Funding from the publicly funded nonprofit organization Cancéropole Lyon Auvergne Rhône-Alpes (CLARA).

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      MA14.03 - Aggressiveness of Cares on the Month Before Death of Patients with Lung Cancer: A French National Database Survey

      10:40 - 10:45  |  Presenting Author(s): Olivier Bylicki  |  Author(s): Charlène Tournier, florence Canoui-Poitrine, Cecile Blein, Christos Chouaid

      • Abstract

      Background

      Prior studies have demonstrated that high-intensity end of life (EOL) cares improves neither survival nor quality of life for cancer patients. The National Quality Forum endorses markers of poor EOL care for cancer patients but there is little data’s concerning lung cancer patients (1). The aim of this study was to assess, the quality of management during the last month of life of lung cancer patients managed in France and factors associated EOL aggressiveness.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using a French hospital discharge database (PMSI, Programme de Médicalisation des Systèmes d’Information), all patients with lung cancer who died between January 1, 2010 and December 31, 2011 (cohort 1) and between January 1, 2015 and December 31, 2016 (cohort 2) were identified through the International Classification of Diseases 10th version (ICD-10). Aggressiveness of EOL cares was assessed by the following criteria’s 1) chemotherapy administrated within last 14 days of life (DOL); 2) > 1 hospitalization within 30 DOL; 3) ICU admission within 30 DOL; and 4) Palliative care < 3 days before death. Multivariate analysis was performed to identify individual determinants EOL aggressiveness.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 90,827 incident adult patients were identified (cohort 1: 43,862, cohort 2: 46,965): men: 74%, median age: 67 years], metastatic at diagnosis: 70%; 57% have at least one marker of aggressiveness of EOL cares (repeated hospitalizations: 49%, ICU admissions: 12%, chemotherapy within 14 DOL: 9%, palliative care < 3 days before death: 5%). A significant increase was observed between 2010/2011 and 2015/2016 for repeated hospitalizations (48% vs 51%, p<.001) and ICU admissions (11% vs 13%, p<.001); the two other markers have remained stable. In multivariate analysis of cohort 2, the risk of aggressiveness of care in EOL was increased by the presence of COPD (OR: 1.08, 95%CI: 1.02-1.14) and a management in an anti-cancer center (OR: 2.32,95%CI 2.05-2.61) while advanced age (OR: 0.51, 95%CI 0.47-0.55), female sex (OR: 0.86 95%CI: 0.82-0.90), malnutrition (OR: 0.72, 95%CI:0.68-0.76) were protective factors for EOL aggressiveness of cares.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite growing focus on providing appropriate EOL cares, in this analysis 57% of deceased lung cancer patients in France received aggressive EOL cares. Research must be undertaken to better identify patients at risk of aggressive EOL cares and to improve the quality of cares of last days of life these patients.

      1.McNiff KK, . Measuring supportive care in medical oncology practice: lessons learned from the quality oncology practice initiative. JCO 2008;

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      MA14.04 - Discussant - MA 14.01, MA 14.02, MA 14.03

      10:45 - 11:00  |  Presenting Author(s): Gouri Shankar Bhattacharyya

      • Abstract

      Abstract not provided

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      MA14.05 - Social Isolation Increases Psychological Distress in Patients With NSCLC

      11:00 - 11:05  |  Presenting Author(s): Cheryl Ho  |  Author(s): Bonnie Leung, Jonn Wu, Janessa Laskin, Heather Rennie, Alan Bates

      • Abstract

      Background

      The Psychosocial Screen for Cancer (PSSCAN-R) questionnaire is a validated screening tool used to identify the psychosocial needs of patients with cancer. The questionnaire assesses patients’ perceived social supports and identifies patients at risk for developing psychological distress. The study goal was to examine patients with NSCLC who reported risk factors for social isolation and their risk for developing psychological distress.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients with NSCLC referred to BC Cancer from 2011-2015 who completed a prospective PSSCAN-R questionnaire at the time of first visit were included in the study. Perceived social support questions include: if patients live alone, lost a life partner recently, have no help with IADLs, have no regular contact with friends and family or have no emotional support from others. Demographics were collected retrospectively. Chi-squared test and logistical regression were used to compare patient groups based on age, gender and perceived social support factors.

      4c3880bb027f159e801041b1021e88e8 Result

      The study cohort was comprised of 4428 patients who completed the PSSCAN-R questionnaire. Female 50%, patients ≥65 years 69%, live alone 29%, lost life partner 13%, no help with IADLs 9%, no regular contact 3% and no emotional support 5%.table1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Female patients and patients younger than 65 are more at risk for developing moderate to severe anxiety and depression. Lack of perceived social support also contributes to the risk of developing psychological distress. In addition to developing gender and age-based resources for patients addressing their psychosocial needs, greater efforts in assessing patients’ perceived social supports and allocating community and institutional resources to isolated patients should also become an important part of the patients’ comprehensive and holistic care.

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      MA14.06 - Predictors of Financial Toxicity, an Under-Recognized Patient-Reported Outcome

      11:05 - 11:10  |  Presenting Author(s): Doreen Anuli Ezeife  |  Author(s): Josh Morganstein, Sally C Lau, Jennifer Law, Lisa Le, Penelope Bradbury, Geoffrey Liu, Frances A Shepherd, Natasha B Leighl

      • Abstract

      Background

      In contemporary cancer care, financial distress has been established as a clinically relevant patient-reported outcome (PRO) associated with worse mortality and quality of life, but remains under-recognized by health care providers. Our goal was to define predictors of patient financial toxicity (FT) in a public healthcare system.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FT was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, an 11-item survey scored from 0-44 with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP) and extended insurance coverage (EIC) were collected. Associations between variables and COST score were evaluated using multivariable regression analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 249 patients approached, 200 (80%) participated. Median age of the cohort was 65 years; 44% were male, 36% immigrants, 67% employed or on pension, with median OOP between $1000-5000 CAD. Median COST score was 21 (range 0-44). FT was associated with age, with patients <65 years reporting greater FT than older patients (COST 18 vs. 25; P<0.0001). Employed patients or those receiving pension income reported less FT than unemployed patients (22 vs. 19; P=0.01). Less FT occurred in patients with EIC compared to those without (23 vs. 19; P=0.03). Patients with higher OOP reported more FT (P<0.0001). Patients on clinical trials reported less FT than others (25 vs. 20; P=0.04). In multivariable linear regression, younger age was a predictor of higher FT, when adjusting for income, employment status, OOP and EIC (P<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Age is a predictor of FT in the Canadian (Ontario) public healthcare system, with younger lung cancer patients reporting greater financial distress. This study highlights priority patient populations where FT should be routinely assessed and appropriate resources for support offered.

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      MA14.07 - The Impact of Socioeconomic Status and Geographic Location on Palliative Chemotherapy Uptake in Patients with Metastatic NSCLC 

      11:10 - 11:15  |  Presenting Author(s): Zamzam Salam Al-Hashami  |  Author(s): Bonnie Leung, Janessa Laskin, Jonn Wu, Heather Rennie, Alan Bates, Cheryl Ho

      • Abstract

      Background

      Socioeconomic status (SES) and geographic factors may impact patient treatment choices. Canada has a publically funded health care system and in BC, there are 35 community oncology network sites that delivery treatment in patients’ local communities. We studied the impact between SES and geographic location upon delivery of chemotherapy/survival in metastatic NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients with metastatic NSCLC referred to BC Cancer centres from 2011-2015, who completed a prospective Canadian Problem Checklist questionnaire at the time of their first visit and for which chemotherapy data was available were included in the study. The CPC assesses patient distress in 6 domains including practical aspects of cancer care. The Postal Code Conversion File Plus uses data from Statistics Canada 2011 census to determine population size and income quintiles. Baseline characteristics and chemotherapy treatments were collected retrospectively. Univariate analysis using the Chi-squared test and Fisher’s exact test were used for analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      1113 patients were included with median age of 69 years, 54% female and 77% were former/current smoker and 47% received palliative chemotherapy. Uptake of chemotherapy did not differ between lowest + mid-lowest 44%, middle 51% /mid-highest + highest 49% income quintiles (p=0.18). Chemotherapy use was also similar between patients reporting financial concerns 50% versus none 47% (p=0.51). Uptake of chemotherapy was lower in patients who lived in rural communities population<10 37% (P 0.00), 10K-1.5M 41%, >1.5 million 53% (p<0.001). Chemotherapy use was lower for patients with concerns about getting to appointments (39% vs 49%, p=0.008) or accommodations (33% vs 48%, p=0.012).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This dataset provide evidence that patients from rural communities were less likely to receive palliative chemotherapy treatment for metastatic NSCLC in BC despite the availability of multiple local community oncology services. SES did not appear to impact the proportion of patients treated, congruent with a government funded health care system. An in depth assessment of distances to local cancer services and treatment delivery is warranted to investigate these differences and their effect on mortality.

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      MA14.08 - Discussant - MA 14.05, MA 14.06, MA 14.07

      11:15 - 11:30  |  Presenting Author(s): Christos Chouaid

      • Abstract

      Abstract not provided

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      MA14.09 - Mortality of Lung Cancer as a Second Primary Malignancy among Cancer Survivors: A Study of Surveillance, Epidemiology, and End Results Database

      11:30 - 11:35  |  Presenting Author(s): Lei Deng  |  Author(s): Huan Song, Zhengrui Xiao, Changchuan Jiang, Qian Wang, Haiying Cheng, Donghao Lu

      • Abstract

      Background

      Cancer survivors are at increased risk of developing a second primary malignancy, including lung cancer. However, the prognosis of lung cancer as a second primary malignancy (lung-2) remains largely unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Primary lung cancer patients diagnosed from 1988 to 2014 in the SEER program were included. Lung-2 was ascertained by a previous diagnosis of primary malignancy in SEER. Hazard ratios (HRs) of overall and lung cancer specific mortality were estimated among patients with lung-2 compared to lung-1.

      4c3880bb027f159e801041b1021e88e8 Result

      679,541(88.8%) and 85,758 (11.2%) patients were identified as lung-1 and lung-2, respectively. The median time from first primary malignancy to lung-2 diagnosis was 4.8 years. Compared to lung-1, patients with lung-2 were more likely to be diagnosed at localized stage, with smaller primary tumor, and treated with surgery. Lung-2 patients were at lower risk of lung cancer specific mortality in the first five years (HR 0.77, 95% CI 0.76 - 0.78 at < 1 year; HR 0.87, 95% CI 0.86 - 0.89 from 1 to < 5 years) but at higher risk thereafter. Patients with lung-2 were associated with reduced risk of overall mortality during the first year after diagnosis (HR 0.91, 95% CI 0.91 - 0.92), but with significantly increased risks thereafter.

      Table Hazard ratios (HRs) of overall and lung cancer specific mortality among patients with lung-2

      N (%) of patients

      From 0 to <1 year after diagnosis

      From 1 year to < 5 years after diagnosis

      From 5 years to 10 years of follow-up after diagnosis

      N (IR)

      HR (95% CI) *

      N (IR)

      HR (95% CI)*

      N (IR)

      HR (95% CI)*

      Overall mortality

      First primary lung cancer

      679,541

      383,208 (99.9)

      1.00

      135,513 (29.3)

      1.00

      16,821 (9.8)

      1.00

      Second primary lung cancer

      85,758

      44,288 (84.1)

      0.91 (0.91-0.92)

      20,073 (29.4)

      1.10 (1.08-1.12)

      3,133 (14.6)

      1.32 (1.27-1.37)

      Lung cancer specific mortality

      First primary lung cancer

      679,541

      325,633 (84.9)

      1.00

      111,348 (24.1)

      1.00

      8,147 (4.7)

      1.00

      Second primary lung cancer

      85,758

      31,247 (59.3)

      0.77 (0.76-0.78)

      12,485 (18.3)

      0.87 (0.86-0.89)

      1,158 (5.4)

      1.10 (1.03-1.17)

      N, number of deaths; IR, incidence rate per 100 person-years

      * HR was adjusted for age and calendar period at diagnosis, sex, race, cohabitation status, percentile of cost of living and high-school education in county of residence, tumor stage, histology, tumor grade, surgery, radiation therapy, and chemotherapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung-2 is associated with favorable lung cancer specific and overall survival within early period of diagnosis. Inferior overall survival afterwards cannot be attributed to aggressiveness of lung-2, highlighting the importance of managing first malignancy and comorbidities.

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      MA14.10 - QTc Interval-Prolonging Medications in Lung Cancer: Implications for Clinical Trial Eligibility and Routine Clinical Care

      11:35 - 11:40  |  Presenting Author(s): David E Gerber

      • Abstract

      Background

      Concomitant medication use, including agents that prolong the QTc interval, may exclude cancer patients from clinical trials. To estimate potential impact on accrual, we determined the prevalence of QTc-prolonging medication prescriptions in a national patient cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified adult patients in the United States Veterans’ Affairs system diagnosed with lung cancer 2003-2016. QTc-interval prolonging medications and risk category were obtained from CredibleMeds®. We calculated prevalence of prescriptions for QTc-prolonging medications with known or possible risk of torsades de pointes (the most common criteria employed as trial exclusion criteria) in the 3 months up to and including date of cancer diagnosis. Rates across patient groups and time periods were compared using Chi-square test.

      4c3880bb027f159e801041b1021e88e8 Result

      280,068 patients were included in the study. Mean age was 70 years, 98% were male, and 72% were white. Overall, 29.7% were prescribed a QTc-prolonging medication. Patients receiving QTc-prolonging medications were marginally younger (mean age 68.9 years versus 70.9 years; P<0.001) and more likely to be black (14.1% versus 11%; P<0.001). The most commonly prescribed QTc-prolonging medications were antimicrobials (14.0%), psychiatric agents (10.2%), antiemetics (2.6%), and cardiovascular medications (1.7%). Seven percent of patients were prescribed two or more QTc-prolonging medications. Over the period of study, the rate of QTc-prolonging medication use increased 20% (25% in 2004 versus 31% in 2016; P<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      A substantial and growing proportion of individuals with lung cancer are prescribed QTc-prolonging medications. These prescriptions may limit eligibility for clinical trials and complicate the administration of standard cancer therapies. Given the prevalence of chronic and/or multiple QTc-prolonging medication prescriptions, it may be challenging to address this obstacle to trial enrollment simply through prescription substitution or discontinuation. Further research into the actual clinical risks and optimal management of QTc-prolonging medications in cancer populations is warranted.

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      MA14.11 - Factors Associated with Early Mortality in Non-Small Cell Lung Cancer Patients Following Systemic Anti-Cancer Treatment

      11:40 - 11:45  |  Presenting Author(s): Amanda Jane Williams Gibson  |  Author(s): Haocheng Li, Adrijana D'Silva, Roxana A. Tudor, Anifat A. Elegbede, Shannon Mary Otsuka, Winson Y Cheung, Gwyn Bebb

      • Abstract

      Background

      To determine a 30-day mortality rate benchmark and assess factors associated with early mortality of non-small cell lung cancer (NSCLC) patients following receipt of systemic anti-cancer therapies (SACT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In a 10-year population-based analysis, NSCLC patients receiving SACT in 2005-2014, with or without other treatments, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data were reviewed. 30-day mortality after most recent SACT cycle was calculated, and end-of life (EOL) regimen changes in the last 14 days of life were identified. Univariate analysis and multivariable logistic regression were used to identify demographic, tumor or treatment-related factors that correlated with mortality risk.

      4c3880bb027f159e801041b1021e88e8 Result

      1044 eligible NSCLC patients receiving at least one cycle of SACT in 2005-2014 were identified. 51% were female, 62% adenocarcinoma, 79% current/former smokers, 83% advanced stage at diagnosis, and 77% receiving palliative-intent treatment. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt, and 32 (13.7%) EOL regimen changes identified. Risk of early mortality decreased for never-smokers and those receiving SACT between 2010-2014, and increased in association with male gender, advanced disease at diagnosis, palliative-intent treatment, and use of EGFR-targeting agents. No factors were associated with a decreased risk of EOL regimen change. (Table 1). The predominant SACT-modality among those experiencing 30-day mortality was EGFR-targeting agents (54%).
      abstract #12790 table.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings from a real-world population identify several factors which affect the risk of early mortality in NSCLC patients following SACT, and establish a 30-day mortality benchmark for Canadian NSCLC populations. Evolving SACT modalities may facilitate an increased use of SACT at EOL and associated early mortality; however, in this cohort, decreased early mortality risk in the 2010-2014 timeframe suggests concomitant evolution of decisions regarding EOL SACT and/or palliative and EOL care may be underway at our centre, but represents an area for ongoing investigation.

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      MA14.12 - Discussant - MA 14.09, MA 14.10, MA 14.11

      11:45 - 12:00  |  Presenting Author(s): Amanda Tufman

      • Abstract

      Abstract not provided

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    MS13 - Novel Mediators of Lung Cancer Metastasis

    • Type: Mini Symposium
    • Track: Biology
    • Moderators:
    • +

      MS13.01 - Liquid Biopsy-mediated Identification of Metastatic Variants

      10:30 - 10:45  |  Presenting Author(s): Philip Christopher Mack

      • Abstract

      Abstract not provided

    • +

      MS13.02 - Capicua Inactivation Drives Lung Cancer Metastasis

      10:45 - 11:00  |  Presenting Author(s): Trever G Bivona

      • Abstract

      Abstract not provided

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      MS13.03 - Ubiquilin as a Novel Mediator of Lung Cancer Invasion and Metastasis

      11:00 - 11:15  |  Presenting Author(s): Levi J. Beverly

      • Abstract

      Abstract

      Data from large, publicly available datasets indicate multiple somatic non-synonymous recurrent mutations in Ubiquilin (UBQLN) family genes or loss of either UBQLN1 or UBQLN2 loci in over 50% of human lung adenocarcinoma patient samples. The UBQLN family consists of 5 related proteins (UBQLN1-4 and UBQLNL) that all contain ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains. Our work was the first to show that UBQLN proteins regulate processes involved in tumorigenesis. In fact, our work now conclusively demonstrates that Ubiquilin1 is a bona fide metastasis suppressors in human lung adenocarcinoma. Importantly, since the vast majority of patients that succumb to lung cancer, die from the metastatic disease and not from the primary tumor burden the combination of these data suggest that nearly 700,000 people die world-wide every year from lung cancers that have decreased or altered UBQLN function. The exact mechanism by which loss of UBQLN proteins leads to metastatic progression remains unclear, however metastatic cancer progression requires cells to acquire new aggressive properties, such as increased migration, invasion, survival and growth at the metastatic site. The identification of regulators of these properties will be crucial for our future success in decreasing metastatic progression and thus cancer mortality rates. The goal of our lab is to understand the detailed mechanisms by which disruption of UBQLN proteins contributes to the metastatic progression of hLAC. We demonstrate that (i.) loss of UBQLN1 or UBQLN2 increases proliferation, EMT, migration and invasion of hLAC cells, in vitro; (ii.) loss of UBQLN1 activates multiple signaling pathways known to regulate cell motility, such as IGF1R and Integrin/FAK; (iii.) inhibition of SRC kinase blocks migration, but not proliferation of cells lacking UBQLN1; (iv.) and finally, loss of UBQLN1 increases metastasis of hLAC cells in vivo. By understanding how UBQLN1 functions to protect cells from tumor progression and metastatic dissemination we may be able to use UBQLN1 status as a predictive biomarker for disease staging or as an indicator for which patients will respond to a given therapeutic. Further, by understanding how UBQLN1 alters signaling pathways that contribute metastatic progression, we may be able to target these downstream pathways specifically in tumors with altered UBQLN1 function to block metastasis, thus potentially affecting millions of lung cancer patients in the coming decades.

      e353dbe42c8654f33588d4da0b517469

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      MS13.04 - Tracking the Evolution of Non-Small-Cell Lung Cancer

      11:15 - 11:30  |  Presenting Author(s): Charles Swanton  |  Author(s):

      • Abstract

      Abstract

      Increasing evidence supports complex subclonal relationships in solid tumours, manifested as intratumour heterogeneity. Parallel evolution of subclones, with distinct somatic events occurring in the same gene, signal transduction pathway or protein complex, suggests constraints to tumour evolution that might be therapeutically exploitable. Emerging data from TRACERx, a longitudinal lung cancer evolution study will be presented. Drivers of tumour heterogeneity change during the disease course and contribute to the temporally distinct origins of lung cancer driver events. APOBEC driven mutagenesis appears to be enriched in subclones in multiple tumour types. Oncogene, tumour suppressor gene and drug induced DNA replication stress are found to drive APOBEC mutagenesis. Evidence that intratumour heterogeneity and chromosomal instability is finely tuned will be presented, to create sufficient diversity for adaptation mitigating the risks of excessive genome instability resulting in cell autonomous lethality. On-going chromosomal instability, manifested as Mirrored Subclonal Allelic Imbalance (MSAI) is found to be a major driver of intratumour heterogeneity in non-small cell lung cancer, contributing to parallel evolution and selection. The finding of subclonal driver events, evidence of ongoing selection within subclones, combined with genome instability driving cell-to-cell variation is likely to limit the efficacy of targeted monotherapies, suggesting the need for new approaches to drug development and clinical trial design and integration of cancer immunotherapeutic approaches. The clonal neo-antigenic architecture may act as a tumour vulnerability, targeting multiple clonal neo-antigens present in each tumour to mitigate resistance and treatment failure. The role of cancer genome instability driving immune evasion and HLA/MHC loss and immune escape will be presented.

      e353dbe42c8654f33588d4da0b517469

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      MS13.05 - Discussant

      11:30 - 11:45  |  Presenting Author(s): David Beer

      • Abstract

      Abstract not provided

    • +

      MS13.06 - Q&A

      11:45 - 12:00

      • Abstract

      Abstract not provided

  • +

    MS14 - IO in Early Stage NSCLC

    • Type: Mini Symposium
    • Track: Immunooncology
    • Moderators:
    • +

      MS14.01 - Basic Science Rationale of IO in Early Stage NSCLC?

      10:30 - 10:45  |  Presenting Author(s): Johan F. Vansteenkiste  |  Author(s): Christophe A. Dooms

      • Abstract

      Abstract

      The 5-year overall survival (OS) of patients with surgically treated early stage NSCLC ranges from 92% (stage IA) to 36% (stage IIIA). Numerous clinical trials over the last decades tried to improve on these results by either adding adjuvant therapy (i.e. in addition after a radical local therapy) or neoadjuvant therapy (i.e. cytoreductive before a radical local therapy).

      Adjuvant setting

      Adjuvant therapy for resected NSCLC came into place in 2004, when the large International Adjuvant Lung cancer Trial (IALT) demonstrated OS benefit with cisplatin-based chemotherapy. No further progress with other types of adjuvant therapy has been made since then. The progress in patients with advanced NSCLC in stage IV with pemetrexed, bevacizumab and EGFR-directed TKIs was not translated in the adjuvant setting [1].

      As for immunotherapy, the MAGRIT trial assessed antigen-specific immunotherapy directed to the MAGE-A3 antigen in completely resected MAGE-A3 positive NSCLC [2]. The adjuvant setting – where the aim is to eliminate sparse tumor cells remaining after surgery – was judged to be the ideal setting for this approach. Unfortunately, the trial did not improve survival. One of the hypotheses why is that the generated MAGE-A3 directed T-cells with cancer killing properties did not travel nor enter easily in tumors, and even if they did, they encountered checkpoints that blocked their potential benefit.

      Immune checkpoint inhibitor (ICI) immunotherapy, which revolutionized the approach to metastatic NSCLC, is now tested in the post-surgical setting with micrometastatic disease and low tumor burden. In contrast to directly cytotoxic chemotherapy, however, agents blocking the PD-1/PD-L1 axis require an interaction between antigen-presenting cells, CD8+ T cells, and tumor cells. It is far from certain that these intercellular interactions will occur sufficiently in patients with micrometastatic disease, where low tumor (mutation) burden may not sufficiently incite the tumor microenvironment. Because of the adjuvant setting, without detectable disease, no early effectiveness read-outs of efficacy nor translational tissue research is feasible. The results of the different ongoing trials with adjuvant ICI therapy in early stage NSCLC needs to be awaited.

      Neoadjuvant setting

      Because of the aforementioned limitations, the neoadjuvant use of PD-1/PD-L1 blockade is of greater interest for several reasons.

      From a biologic perspective, PD-1/PD-L1 blockade before surgery, when the tumor mass and intact locoregional lymph nodes with ongoing activation of T cells may be present, might be more rational. In a breast cancer model in mice, it has been suggested that neoadjuvant ICI is more effective than adjuvant ICI [3]. In the neoadjuvant setting, there was a stronger systemic antitumor T-cell response with maintenance of tumor specific CD8+ T cells in the blood early after immunotherapy. High levels of CD8+ T cells predicted long-term survival in this mouse model. Moreover, induction of this systemic immune response could lead to immune memory that may prevent metastatic relapse over time.

      From a clinical perspective, the neoadjuvant strategy has advantages, as we learned from the chemotherapy era. The systemic therapy has better distribution because of the intact vascularization, which may reduce the locoregional tumor extension. There is an early attack microscopic metastatic disease and the effectiveness can be evaluated in vivo with pre- and post-imaging.

      From a clinical trial perspective, a big advantage is the possibility to study surrogate endpoints. The crucial outcome in this setting is OS, but this endpoint requires many years of follow-up. Here as well, lessons learnt from neoadjuvant chemotherapy followed by surgical resection are of use. Tumor-free lymph nodes and pathological response in the primary tumor have been associated with significantly better outcome. In a dedicated study on the prognostic impact of morphometric tissue analysis of tumor regression, the latter was graded in I: no regression; II: remaining vital tumor tissue ≥10% (grade IIa) or <10% (grade IIb); and III: no evidence of vital tumor tissue [4]. Patients with tumors of regression grades IIb or III showed significantly longer OS than the others (3-year OS 52% vs 9%, P=0.02). These findings, however, do not help to select patients for surgery, as they are post-hoc analyses on the resection specimen. Ideally, one should have pre-surgical (pre-hoc analysis) predictors, but the standard clinical restaging with repeat CT after neoadjuvant only is a raw tool for this purpose. Our group first demonstrated that morphometric tissue analysis of mediastinal lymph nodes after induction was a strong prognosticator in that setting [5]. This was then validated in a prospective multi-center setting, using the first video-mediastinoscopy after neoadjuvant chemotherapy [6]. Patients with a grade IIA or III regression (<10% viable tumor) had much better outcome than the others: 5-year OS 43% versus 19%.

      A recent pilot study evaluated the clinical, pathological, and immunologic effects of short-term neoadjuvant PD-1 blockade in NSCLC [7]. Here again, major pathological response was defined as ≤10% residual viable tumor on sections of the resected tumor. With this criterion, 45% of the patients had a major pathological response, with clear infiltration of CD8+ T cells in regressing tumors. Moreover, a systemic immune response with T-cells of similar T-cell receptor repertoire as in the tissue were described. Even with its small sample (N=21), this strategy has a strong mechanistic principle, both in the tumor and on distant sites, and has resulted in a promising surrogate endpoint effect. Whether this will translated in better 5-year OS now needs to be defined in larger multi-center phase 3 trials, several of which are currently started.

      References

      1. Deslypere G. et al. Ther Adv Med Oncol 2018; 10: 1-11.

      2. Vansteenkiste J. et al. Lancet Oncol 2016; 17: 822-35.

      3. Liu J et al. Cancer Discov 2016; 6: 1382-99.

      4. Junker K et al. Chest 2001; 120: 1584-91.

      5. Dooms C et al. J Clin Oncol 2008; 26: 1128-34.

      6. Dooms C et al. J.Thorac.Oncol. 12 Suppl 1, 460S. 2017.

      7. Forde P et al. N Engl J Med 2018; 378: 1976-86.

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      MS14.02 - Adjuvant / Neoadjuvant IO Therapy

      10:45 - 11:00  |  Presenting Author(s): Julie R. Brahmer

      • Abstract

      Abstract not provided

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      MS14.03 - Concerns About IO for the Thoracic Surgeon?

      11:00 - 11:15  |  Presenting Author(s): Bernward Passlick

      • Abstract

      Abstract

      Perioperativ immunotherapy is a relative new field in thoracic oncology. Although several studies are ongoing, there are until now only two publications describing the effect of preoperative immunotherapy and the intraoperative and the postoperative course of patients with thoracic malignancies.

      The first study is a publication by Forde and colleagues (1), dealing with patients with resectable lung cancer who received one or two preoperative doses of PD-1-inhibitior Nivolumab. The immunotherapy was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The authors described an acceptable side-effect profile and no delays in surgery. Treatment-related adverse events of any grade occurred in 5 of 22 patients (23%) an only one event was a 3 grades side effect. This was a patient with a pneumonitis who could be resected thereafter that without any complications. The median interval between the administration of the second dose of Nivolumab and surgery was 18 days (range 11 to 29). Twenty of 21 eligible patients underwent a complete resection. The preoperative imaging showed that the majority of the patients (86 %) had stable disease.

      The other report (2) deals with the safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors. This is a retrospective study on 19 patients treated between 2012 and 2016. The majority of them had lung cancer (47 %) followed by metastatic melanoma. Various types of immunotherapeutic agents were used. Anatomic resections (lobectomy or greater) were performed in 11 patients. Complications occurred in 32 % but the majority of them were again only minor. One patients developed postoperative pneumonitis in the contralateral lung approximately 2 weeks after VATS-resection on the other side.

      In summary, preoperative immunotherapy seems to be applicable with only minor side effects. However, there are only few reports and theoretically other complications might occur. Especially if the side effect spectrum in patients with metastatic disease and immunotherapy is considered (3). Frequent side effects are pneumonitis, hepatitis or even myocarditis. The development of such side effects should be excluded in each patient undergoing surgery after immunotherapy.

      References

      1. Forde PM, Chaft JE, Smithe KN et al. Neoadjuvant PD-1-Blockade in Resectable Lung Cancer. N Engl J MED 2018 378;21.

      2. Matthew JB, Cools-Lartigue J, Tan KS et al. Safety and Feasibility of Lung Resection after Immunotherapy for Metastatic or Unresectable Tumors. Ann Thorac Surg 2018; …..

      3. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med 2018 378;22.

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      MS14.04 - IO - New Standards in Stage III NSCLC

      11:15 - 11:30  |  Presenting Author(s): Rafal Dziadziuszko

      • Abstract

      Abstract not provided

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      MS14.05 - Do Biomarkers used in Metastatic Setting Apply in Earlier Stages

      11:30 - 11:45  |  Presenting Author(s): Naiyer A Rizvi

      • Abstract

      Abstract not provided

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      MS14.06 - Q&A

      11:45 - 12:00

      • Abstract

      Abstract not provided

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    MS15 - Disruptive Technology and Lung Cancer Risk

    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Moderators:
    • +

      MS15.01 - Just Water Vapor? Toxicology Perspectives on Electronic Cigarettes

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

      • Abstract

      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

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

      • Abstract

      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

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

      • Abstract

      Abstract not provided

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

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

      • Abstract

      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

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

      • Abstract

      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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      MS15.06 - Q&A

      11:45 - 12:00

      • Abstract

      Abstract not provided

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    OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships

    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Moderators:
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      OA10.01 - Patient Preferences for Tyrosine Kinase Inhibitor Treatments for EGFR Mutation Positive Metastatic NSCLC

      10:30 - 10:40  |  Presenting Author(s): John F.P. Bridges  |  Author(s): Marie De La Cruz, Melissa Pavilack, Emuella Flood, Ellen Janssen, Nabil Chehab, Ancilla W. Fernandes

      • Abstract

      Background

      EGFR mutation positive (EGFRm) NSCLC responds to EGFR-tyrosine kinase inhibitors (TKIs). First-, second-, and third-generation EGFR-TKI treatment attributes vary in efficacy, side effects, and dosing regimen. We used two different methods to explore treatment preferences among patients with EGFRm metastatic NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with EGFRm metastatic NSCLC were recruited in the US to participate in an online survey containing two complimentary preference elicitation methods. First, preferences were assessed through direct elicitation exercises where participants chose between competing treatment profiles. The first exercise compared two profiles with a large difference in progression-free survival (PFS) (6 vs 18 months). The second exercise compared two profiles with a smaller difference (10 vs 18 months). Both exercises compared the same side effect risks (0–1% vs 2–16% risk). Second, a discrete choice experiment (DCE) was used to assess preferences for variation in treatments in terms of PFS, severity of side effects (mild/moderate/severe), and mode of administration. These attributes and levels were varied based on a D-efficient design. Participants completed 10 DCE choice tasks where they saw pairs of hypothetical treatments with different attribute levels and selected their preferred treatment. A choice model was estimated using conditional logit regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Between 10/2017 and 03/2018, 90 patients with EGFRm metastatic NSCLC were recruited and completed the survey: 42% female; 79% white; 76% taking first-line or second-line EGFR-TKIs at time of survey. Median time since diagnosis: 2.1 years (inter-quartile range: 1.1–2.7). In the direct elicitation exercise, participants opted for shorter PFS in exchange for more favorable side effects, but were less likely to do so for a large difference in PFS (52% of participants) vs a smaller difference (66%; p<0.001). Participants who chose shorter PFS when difference in PFS was large were more likely to be taking EGFR-TKIs (odds ratio: 21.4; 95% confidence interval: 2.24, 204.88). No relationship between choice and treatment characteristic was observed when difference in PFS was small. In the DCE, conditional logit regression indicated that to avoid severe levels of nausea/vomiting, diarrhea, rash, or fatigue, participants on average would accept reductions in PFS of 13, 11, 9, and 8 months, respectively. Participants would accept reduction in PFS of 7 months for oral treatment taken with/without food vs IV.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this online survey of patients with EGFRm metastatic NSCLC, some patients were willing to accept shorter PFS for a better safety profile and dosing convenience; however, PFS remained an important attribute in treatment choice.

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      OA10.02 - Oncogene-Driven Patient Groups: A New Era For Research Partnerships

      10:40 - 10:50  |  Presenting Author(s): Janet Freeman-Daily  |  Author(s): Ivy Elkins, Laura Greco, Marcia K Horn, Bonnie Addario, David LeDuc, Robert C. Doebele, Christine Lovly

      • Abstract

      Background

      Genomic alterations drive more than 60% of non-small cell lung cancer (NSCLC). About 20% of NSCLC cases (EGFR, ALK, ROS1, BRAF) will have an oncogenic driver that can be treated with approved targeted therapy drugs, and more have clinical trial options. In some cases, patients on targeted therapies will have years of good quality of life. However, targeted therapies do not cure, and these patients will eventually see their cancer progress. Patients and caregivers dealing with cancers driven by EGFR, ALK, ROS1 and Exon20 oncogenes have organized globally into online groups and are building partnerships that seek to provide support, increase awareness and education, accelerate and fund research, and improve access to effective diagnosis and treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Each patient-caregiver group forms using social media, patient blogs, websites, fliers, newsletters, and contacts with clinicians. Each has a private Facebook group or other network to inform and educate patients and caregivers of approved and experimental treatments, share common experiences, provide information and tips from expert clinicians and researchers, and enable real-life connections. Each group sets its own priorities such as creating websites, raising funds for research, donating tissue, developing studies of demographics and treatment sequences, and creating biorepositories with annotated specimens that will be made widely available. These projects are accomplished in patient-driven partnership with researchers, clinicians, advocacy groups, and industry. None of the patient-caregiver groups are corporations or other types of legal entities.

      4c3880bb027f159e801041b1021e88e8 Result

      The ROS1ders focus on ROS1+ cancers of all types and include over 275 members from 21 countries across 8 cancer types. They have partnered in two studies to create ROS1+ cancer models. ALK Positive focuses on ALK+ NSCLC and other cancers, and includes over 1000 members from 38 countries. They have raised nearly $400,000 for research and will announce two grants in May. Exon 20 Group focuses on EGFR and HER2 insertions in Exon 20, and includes 110 members from 19 countries. They created an Exon 20 molecular tumor board and awarded two grants. The EGFR Resisters focus on EGFR+ NSCLC and cancers that develop resistance to EGFR targeted therapies, and include over 450 members from 20 countries.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Oncogene-driven patient-caregiver groups are creating a new paradigm in cancer research and have demonstrated that their partnerships with advocacy organizations, clinicians, researchers and industry, combined with social media outreach, can increase available patient data, specimens, cancer models and research funding for geographically distributed, oncogene-driven cancer populations.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA10.03 - Discussant - OA 10.01, OA 10.02

      10:50 - 11:05  |  Presenting Author(s): Zofia Piotrowska

      • Abstract

      Abstract not provided

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      OA10.04 - Afatinib With or Without Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Safety and Efficacy Results from SWOG S1403

      11:05 - 11:15  |  Presenting Author(s): Sarah B Goldberg  |  Author(s): Mary W. Redman, Rogerio Lilenbaum, Katerina Politi, Thomas E. Stinchcombe, Leora Horn, Everett H. Chen, Sandeep Mashru, Scott N. Gettinger, Mary Ann Melnick, Jieling Miao, James Moon, Karen Kelly, David R. Gandara

      • Abstract

      Background

      Several EGFR tyrosine kinase inhibitors (TKIs) are used for the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), however resistance inevitably develops. The combination of the irreversible ErbB family TKI afatinib and the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to first-line EGFR TKIs. To attempt to delay resistance, we conducted a randomized trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with previously-untreated EGFR-mutant NSCLC were randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks or afatinib 40mg PO daily. The study was designed to accrue a total of 212 patients, comparing progression-free survival (PFS) between the arms at the 1-sided 0.025 level when 134 PFS events had been observed. Secondary objectives included comparison of overall survival (OS), time to treatment discontinuation (TTD), and toxicity. An interim analysis evaluating early stopping for futility occurred when at least 64 PFS events were reported.

      4c3880bb027f159e801041b1021e88e8 Result

      Between March 26, 2015 and April 23, 2018, 170 eligible patients were accrued: 86 to afatinib/cetuximab and 84 to afatinib. Median age was 66.4 years, 66% were female, 64% had an EGFR exon 19 deletion mutation and 36% had an L858R point mutation. With 109 events observed, there was no improvement in PFS with the combination compared to single-agent (HR 1.17, 95% CI 0.80-1.73, P = 0.42, median 10.6 months vs 13.1 months). OS was also not improved with the addition of cetuximab (HR 1.23, 95% CI 0.62-2.44, P = 0.55, median 26.9 months vs not reached). TTD was similar between the two groups (HR 0.95, 95% CI 0.64-1.39, P = 0.79, median 12.5 months vs 12.2 months). Grade > 3 treatment-related adverse events (AEs) were more common among patients treated with afatinib/cetuximab, and more patients in the combination arm required at least 1 dose reduction of afatinib (57% vs 26%). However, treatment discontinuations due to AEs were similar between the two groups (11.6% vs 10.7%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      There was no difference in PFS, OS or TTD with the addition of cetuximab to afatinib for treatment-naïve patients with EGFR-mutant NSCLC. The trial was closed to accrual at the interim analysis having met the criteria for futility. Correlative analysis of tumor tissue and blood from patients is ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA10.05 - An Open-Label, Multicenter, Phase II Single Arm Trial of Osimertinib in NSCLC Patients with Uncommon EGFR Mutation(KCSG-LU15-09)

      11:15 - 11:25  |  Presenting Author(s): Jang Ho Cho  |  Author(s): Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Keon Uk Park, Eun Joo Kang, Yoon Hee Choi, Ki Hwan Kim, Ho Jung, An An, Hyun Woo Lee, Myung-Ju Ahn

      • Abstract

      Background

      Approximately 10% of EGFR mutants harbor uncommon mutations, which represent a heterogeneous group of rare molecular alterations within exons 18-21 and the sensitivity to EGFR TKIs is variable. Osimertinib is a potent irreversible inhibitor of both sensitizing EGFR mutation and T790M. In preclinical data, osimertinib was found to be active against most uncommon EGFR mutants, apart from the exon 20 insertion variant. Here we present the efficacy and safety of osimertinib in patients with uncommon EGFR mutation positive NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with histologically confirmed metastatic or recurrent NSCLC with activating EGFR mutation other than exon 19 deletion, L858R, T790M and insertion in exon 20 were eligible. Patients received 80mg of osimertinib orally, once daily until progression or unacceptable toxicity. Response was assessed every 8 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT03424759.

      4c3880bb027f159e801041b1021e88e8 Result

      Between Mar 2016 and Oct 2017, 35 patients were enrolled. Median age was 59, 63% male, 43% never smoker, 97% adenocarcinoma. 63% of patients were treated as first-line therapy. The mutations identified were G719A/C/D/S/X (19, 54.3%) followed by L861Q (9, 25.7%), S7681 (8, 22.9%), and others (3, 8.6%). The overall response rate was 50.0% (95% CI 32.8-67.2) and DCR was 88.9% (95% CI 78.1-99.7). Seven patients (77.8%) with L861Q mutation achieved partial response; 10/19 (52.6%) with G719A/C/D/S/X mutation; 3/8 (37.5%) with S768I mutation. At data cutoff (Apr, 2018), the median PFS was 8.2 months (95% CI 1.9- 14.4) and median duration of response was 9.8 months (95% CI 7.6-12.0). The most common adverse events were rash (n=11, 31.4%), anorexia (n=8, 22.9%), and diarrhea (n=7, 20.0%). Grade 3 or 4 AEs were reported in 8 of 35 patients (23%), but all of AEs were manageable.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib showed highly active in NSCLC patients harboring uncommon EGFR mutation with manageable safety profile, consistent with previous reports. Further analysis will be provided.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA10.06 - A First-in-Human Phase 1 Trial of the EGFR-cMET Bispecific Antibody JNJ-61186372 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)

      11:25 - 11:35  |  Presenting Author(s): Keunchil Park  |  Author(s): Myung-Ju Ahn, Se-Hoon Lee, Hye Ryun Kim, Min Hee Hong, Dawn Millington, Martin Curtis, Spyros Triantos, Sandra Chaplan, Nahor Haddish-Berhane, Roland Knoblauch, Zuleima Aguilar, Sylvie Laquerre, Matthew V. Lorenzi, Byoung Chul Cho

      • Abstract

      Background

      JNJ-61186372 (JNJ-372) is a bispecific antibody targeting both EGFR and cMET. In preclinical studies, JNJ-372 demonstrated efficacy in EGFR and cMET driven tumor xenograft models (including EGFR T790M and MET-amplified/HGF secretion), consistent with inhibition of ligand binding, receptor degradation, and ADCC activity. The goal of Part 1 of this study (reported here) was to assess the safety, pharmacokinetics (PK), and preliminary efficacy of JNJ-372 and to identify the recommended phase 2 dose(s) to be explored in Part 2.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with previously treated, advanced NSCLC were enrolled at two sites and treated with escalating doses of JNJ-372 administered IV weekly for the first 4-week cycle, then biweekly for each subsequent cycle. PK sampling was taken at multiple time points within cycle 1 and 2. Disease assessments were performed every 8 weeks. Tumors were characterized at baseline through next-generation sequencing of circulating tumor DNA (Guardant 360).

      4c3880bb027f159e801041b1021e88e8 Result

      25 patients were treated with JNJ-372 during dose escalation: 140mg (n=3), 350mg (n=3), 700mg (n=9), 1050mg (n=7), 1400mg (n=3). Median age was 63y, 48% were male, 100% were Asian, 84%/12%/4% had adenocarcinoma/squamous/other histology, and median prior therapies was 4. No dose-limiting toxicities were observed at any dose level tested. The most frequent treatment-emergent AEs were infusion-related reactions (76%), rash/acneiform dermatitis (40%), dyspnea (24%), paronychia (24%), pruritus (20%), fatigue (20%), and nausea (20%); incidence of peripheral edema (cMET-related toxicity) was 12%. Infusion-related reactions were grade ≤2 severity, observed primarily with the first dose. The worst severity of rash/acneiform dermatitis was grade 2 (16%). One treatment-related AE of grade ≥3 severity was reported (neutropenia grade 3, possibly related). JNJ-372 demonstrated linear PK at dose levels 350 mg and above with non-linear PK at lower concentrations, suggesting target-mediated drug disposition. Doses ≥700mg resulted in average steady-state concentrations at or above the preclinically established therapeutic target level. Preliminary evidence of efficacy (maximum change from baseline in sum of target lesion diameters) was observed in a patient with squamous cell carcinoma (-20%), a patient with wtEGFR adenocarcinoma (-20%), and 4 patients with EGFR-mutant adenocarcinoma (≥-30%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      JNJ-372 is a novel EGFR-cMET bispecific antibody. The manageable safety profile and preliminary evidence of clinical activity support active accrual of patients with previously treated EGFR-mutant NSCLC. The first recommended dose of 1050mg is being evaluated in Part 2.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA10.07 - Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer Patients: Analysis from AURA17 Trial

      11:35 - 11:45  |  Presenting Author(s): Caicun Zhou  |  Author(s): Min Hu, Xuehua Zhu, Yun Sun, Xuesong Lu, Jia Wang, Mengzhao Wang, Ying Cheng, Yuan Chen, Yanqiu Zhao, Yuan-Kai Shi, You Lu, Meiqi Shi, He-Long Zhang, Xiangning Huang, Zheng Wang, Zhijie Ding, Heyan Li, George Chen, Yi-Long Wu

      • Abstract

      Background

      Osimertinib is approved for metastatic NSCLC patients with EGFR T790M mutation after progression from TKI therapy. Despite impressive tumor responses, drug resistance usually develops. The resistance mechanisms of osimertinib are emerging but studies with large cohorts of Chinese patients and association with clinical outcomes are lacking. Here we report a biomarker study of osimertinib using plasma samples from 107 Chinese patients who had progressed by 24 months after LSFD (Oct. 2017) of AURA17 (NCT02442349), the 2nd-line pivotal trial in China.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Serial plasma cell-free DNA (cfDNA) were collected from baseline until progressive disease (PD) by investigator assessment. Capture-based 75-gene NGS panel with unique molecular index (UMI) system was used to identify resistance mechanisms to osimertinib by comparing paired cfDNA at baseline and PD. Droplet digital PCR (ddPCR) was used to dynamically monitor EGFR mutation changes (L858R, Ex19Del, T790M and C797S) during treatment course. Association of cfDNA biomarkers based on valid test results with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) from DCO3 (Mar. 20, 2018) was analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      The 107 patients were with ORR of 68.2%, median PFS of 8.2 months, and median OS of 21.5 months. Eight-two had detectable EGFR sensitizing mutations (L858R or Ex19Del) in their PD cfDNA samples. Among them, 15 had acquired EGFR C797S, all in cis with T790M, and with no enrichment for L858R or Ex19Del (6 and 9, respectively). The median time of C797S detection from plasma was 2.8 (1.2-8.4) months prior to PD. EGFR L718Q, I744T, C775Y, G796S/D, T854I mutations, or amplification were found in 11 patients. Aberrations in bypass tracks including AKT2, ALK, DDR2, ERBB2/3, HRAS, JAK1/2, KRAS, MET, NTRK1, PIK3CA, RIT1, etc. were observed in 45 patients.

      Clearance of EGFR sensitizing mutations at weeks 3 of treatment was associated with favorable ORR (78.7% vs. 33.3%), PFS (9.6 vs. 4.0 months, p<0.001) and OS (21.5 vs. 11.7 months, p<0.001). Clearance of EGFR sensitizing mutations at weeks 6 of treatment was also associated with favorable ORR (80.0% vs. 36.8%) and PFS (8.3 vs. 4.2 months, p<0.001). Presence of T790M at PD was correlated with longer PFS (12.3 vs. 5.5 months, p<0.001) and OS (21.3 vs. 13.2 months, p=0.045). Acquired or enriched TP53 alterations at PD were associated with worse PFS (4.2 vs. 8.3 months, p=0.008).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study revealed diverse resistance mechanisms to osimertinib in Chinese NSCLC patients and urged for new drug discovery or combination strategies to overcome this clinical challenge.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA10.08 - Discussant - OA 10.04, OA 10.05, OA 10.06, OA 10.07

      11:45 - 12:00  |  Presenting Author(s): Linda Coate

      • Abstract

      Abstract not provided

  • +

    PC05 - Optimizing Clinical Trial Design in NSCLC

    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Moderators:
    • +

      PC05.00 - Introduction with Poll Questions

      10:30 - 10:35  |  Presenting Author(s): Pilar Garrido, Luis Ubillos

      • Abstract

      Abstract not provided

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      PC05.01 - Debate 1: Which is Most Important Efficacy Endpoint in First Line Trials in Advanced NSCLC PFS or OS - Point of View: PFS

      10:35 - 10:50  |  Presenting Author(s): Mary O’brien

      • Abstract

      Abstract

      This is an old chestnut. The debate has gone on for years and for first line trials in advanced NSCLC it is always OS that wins.

      So why do I think I will win this time?. Well maybe it is because (I was given the task and I like a challenge) we are in a new era of medicine and we are in such a hurry to get new drugs to our patients to prolong our lives and cure them.

      A PFS (DFS) endpoint in a clinical trial is all about the activity of that drug or intervention, it is reported at a point when crossover to other treatments has not happened. It is the standard endpoint for treatments for advanced breast cancer and other disease where there are many treatment options and in general patients will live to get all those treatments options.

      An OS endpoint in advanced lung cancer in the past has been quite similar to PFS – both of them short ie. less than one year. An OS endpoint suggests that a treatment has truly modified the natural history of a disease and therefore this new treatment should be given as early as possible.

      In this era of new treatments it is gratifying to see that an improved PFS has predicted an improved OS e.g. Keynote 024 and it is a gratifying to see that the trial did not report until PFS and OS were available at the same time as in coprimary endpoints. So in these trials of very active treatment PFS reported one year earlier than OS could have cut down the expense of the trial and got the drug to patients earlier.

      Looking at drugs that target the EGFR mutation gefitinib, erlotinib and Afatinib – all positive for PFS and all negative for OS because of crossover. If OS had been the only endpoint, all these drugs would still not be on our pharmacy shelves.

      So I believe if you have a great treatment that should activity very early on then PFS should be the endpoint.

      However if the benefit is small but still significant then OS must be the endpoint.

      But surely at this point in time we only want very active treatments that give us big differences in PFS as we know that these will be the treatments that can change lives.

      e353dbe42c8654f33588d4da0b517469

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      PC05.02 - Debate 1: Which is Most Important Efficacy Endpoint in First Line Trials in Advanced NSCLC PFS or OS - Point of View: OS

      10:50 - 11:05  |  Presenting Author(s): Yu Shyr

      • Abstract

      Abstract not provided

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      PC05.03 - Discussion

      11:05 - 11:10

      • Abstract

      Abstract not provided

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      PC05.04 - Debate 2: Patient Reported Outcomes Should Be the Most Important Endpoint in Trials in the Palliative Setting - YES

      11:10 - 11:25  |  Presenting Author(s): Maurice Pérol

      • Abstract

      Abstract

      The aim of an anticancer treatment in palliative setting, i.e. when there is no curative intent, is to improve the quantity and the quality of life. The evaluation of a treatment effect is mainly based on randomized clinical trials which are meant to provide a correct assessment of the effect size. Therefore, the selection of the primary endpoint is critical not only for the sample size calculation but mainly to judge the relevance and the meaning of the treatment results which define the treatment utility from both the patient perspective and the healthcare system in terms of cost-effectiveness. Two categories of endpoints are used in clinical trials: some are patient-centered, clinical endpoints including overall survival (OS), health-related quality of life (HRQoL) assessment and tolerance profile whereas other are tumor-centered as progression-free survival (PFS), response rate, disease control rate. OS is a universally accepted measure of the treatment benefit in oncology, directly reflecting the quantity of life gained and is still the preferred endpoint of Phase III clinical trials. However, OS as a primary endpoint has some limitations: it usually requires a longer follow-up and a large sample size leading to an increase in the cost of trials. Moreover, especially in cancer with an improved prognosis as for lung cancer depending on an oncogenic driver, OS can be confounded by the effect of crossover and subsequent treatments with small expected OS differences between treatment sequences. These reasons make increasingly difficult to demonstrate an OS benefit especially for first-line therapy. These limitations have led to consider tumor-centered endpoints, mainly PFS, as surrogate endpoints for patient benefit in a clinical trial. PFS provides results earlier than OS and is not influenced by subsequent treatments. However, selecting PFS as primary endpoint assumes that there is a statistical validation of PFS as a surrogate endpoint for OS, which is not the case in advanced NSCLC, especially in palliative setting: many trials have demonstrated a PFS benefit without improvement of OS. Furthermore, there is a lack of consensus for PFS definition or tumor progression (i.e. taking or not into consideration symptomatic progressions), blinding or independent review is required to provide more robust evidence of a PFS benefit and its assessment is dependent on the schedule of tumor evaluations. In this context, HRQoL may constitute an alternative endpoint, which ensures earlier assessment of direct clinical benefit for the patient and takes into account the impact of potential treatment-related toxicities; HRQoL is therefore more recognized as a component endpoint for assessment of the benefit coming from cancer therapy by the American Society of Clinical Oncology and the European Society of Medical Oncology and for drug approval by Regulatory Agencies. It appears obvious that a delay in the time to symptom deterioration, or improvements in symptoms and in HRQoL might be more meaningful to the patient with an advanced lung cancer than the RECIST criteria or PFS, not necessarily reflecting a clinically meaningful benefit.

      HRQOL is a multidimensional concept representing the patient's perception of the effect of illness and treatment on physical, psychological, and social aspects of life. QoL measurement in clinical trials is based upon patient reported outcome (PROs) which are reports of the status of a patient's health condition coming directly from the patient, without any interpretation by a clinician. Many validated self-completion QoL questionnaires for cancer patients are available, taking into consideration the multidomain aspect of QoL; the EORTC QLQ-C30 with its specific module for lung cancer (LC-13), the FACT-L are the most frequently used for assessment of patients HRQL, physical functioning, or tumor related symptoms in lung cancer. HRQoL evaluated with PROs has been shown to be an independent prognostic factor in advanced lung cancer. However, the complexity and heterogeneity of QoL data reports and numerous methodological issues for QoL analyses make the PROs difficult to understand for clinicians and limit their utility to help for therapeutic decisions. Indeed, HRQoL is challenging to assess and raises many methodological issues, including missing data and patient drop-out rate, multiplicity, longitudinal analysis and lack of standardization making impossible to perform cross trials comparisons. These issues as well as the usual deferred publication of QoL results after tumor-centered endpoints communication have led the scientific community and the clinicians to give little attention to PROs.

      Nevertheless, there is a greater awareness that a similar degree of scientific rigor should be applied to the PRO strategy to make it a key component of treatment effect, likely more sensitive to assess therapy's effect on the disease and the patient than conventional measures. Different approaches have been underscored to improve the use of PROs in clinical trials. Recent extensions of the CONSORT have suggested recommendations for PROs analysis and report in clinical trials, with the need to define PROs as a primary or secondary endpoint with a specific statistical defined hypothesis, including approaches to deal with missing data; it is then possible to consider HRQoL as a co-primary endpoint. New statistical methods have also been suggested for longitudinal analyses of PROs as linear mixed model for repeated measures or time until definitive deterioration for symptoms or QoL score deterioration. Other approaches suggest focusing on three well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms which are easier to assess and are key components of a treatment effect. Information after the treatment and during subsequent treatment should also be collected to take into consideration the impact of a delayed disease progression on QoL or those of subsequent treatment or residual toxicities.

      As tremendous advances have been made in the field of lung cancer treatment, especially in advanced disease with its transformation into a chronic disease for some patients, the treatment focus has shifted to improve or preserve the patients QoL. It is therefore mandatory to develop new and validated endpoints that better indicate a clinical benefit rather than small variations in tumor size. PROs should not be viewed anymore as a surrogate endpoint, but regarded as an important patient-centered endpoint, needing an optimization of trials design and methods to analyze HRQoL.

      e353dbe42c8654f33588d4da0b517469

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      PC05.05 - Debate 2: Patient Reported Outcomes Should Be the Most Important Endpoint in Trials in the Palliative Setting - NO

      11:25 - 11:40  |  Presenting Author(s): Rathi N Pillai

      • Abstract

      Abstract not provided

    • +

      PC05.06 - Discussion

      11:40 - 11:45

      • Abstract

      Abstract not provided

    • +

      PC05.07 - Let's Not Forget Chemo-Regret

      11:45 - 11:55  |  Presenting Author(s): Patricia J. Hollen

      • Abstract

      Abstract

      Background: Although thousands of patients annually receive treatment for advanced non-small cell lung cancer (NSCLC), little is known about their views on the decision to receive that treatment. Even with encouraging newer treatments, survival rates continue to be low in NSCLC. With potential treatment toxicities and with modest response rates, there are many risks for regret by both patients and their supporters. The highly symptomatic nature of NSCLC, coupled with pressures to decide rapidly on therapy, creates challenges that affect quality decision making. In a recent review of 59 studies dealing with regret (Becerra Perez et al, Med Decis Making; 2016;36:777-790), no study focused on lung cancer, even with 66% of the studies in oncology settings, none reported reduced regret over time during the study, and only 2 studies reported delayed regret several months after the decision. In this review, risk factors for regret seemed to be able to be affected by clinicians, according to the opinion of the authors of this systematic review. In a large survey (Morse et al, J Psychosocial Oncol, 2014;32:112-123) results including more than 3500 patients with cancer. More than 90% of these individuals rated "making decisions about care" as being important to them, out of 26 issues. The patients with lung cancer, ranked decision making as the third most important issue of the 26 surveyed. In a recent article in the New England Journal of Medicine (Groopman and Hartzband 2017;377:1507-1509), the authors state that the risk of regret is in almost every medical decision a patient makes and the impact of regret is underestimated in patient decision making. They observe that regret and its impacts are not sufficiently considered by physicians as part of the decision-making process. A profile of the extent of regret, and factors contributing to that regret, is lacking for those undergoing systemic therapy for lung cancer, and for their supporters. Identifying patients early and predicting patients at high risk for regret during treatment could assist in early intervention, which may decrease eventual regret.

      Methods: We sought to investigate prospectively the incidence, extent, and associated factors concerning regret in patients receiving systemic treatment for advanced NSCLC. All patients were enrolled into a phase III trial which included 164 patients. All patients were monitored using the LCSS PRO assessment questionnaire. Patients were randomized 1:1 to either usual care or to enhanced care. In the enhanced care group, all patients also completed the DecisionKEYS decision aid, and their oncologists were aware of the ongoing LCSS results. Also, in the enhanced care group, the results of the LCSS symptomatic and quality of life scores over time, and the results of the decision aid were discussed with the patient and supporter. The LCSS was completed every 3 weeks using the electronic LCSS (eLCSS-QL). The LCSS analysis included using the 3-Item Global Index (“3-IGI,” assessing: distress, activities, and quality of life). All patients, in both arms of the study, completed the Decision Regret Scale (Brehaut et al, Med Decis Making 2003;23:281-292) at 3 months after starting treatment, and at the conclusion of treatment.

      Results: 164 patients signed consent and 160 received treatment (the modified intent to treat group). Patient characteristics included: 43% women; 92% Stage IV; median PS = 1; mean age 63, and 46% of patients represented minority groups. 86% of patients alive at 3 months completed the Decision Regret Scale. Results combined the 2 top categories indicating the greatest extent of regret. By this criterion, 13% of patients (95% CI: 7.4% - 19.2%) expressed regret at the 3-month timepoint after starting chemotherapy. Of note, nearly all patients expressing regret at this point could be identified at the 6-week LCSS evaluation. Of the patients expressing regret at the 6- week mark after starting treatment, nearly all of the patients had a 20% decline or greater by 6 weeks in the 3-IGI score compared with baseline. Specifically, when asked if they would make the same decision again, only 1% not having the 20% 3-IGI decline had regret, as contrasted to 15% with 20% or greater 3-IGI decline (p = 0.01). Results were similar in both randomization groups. Additionally, the supporters of these patients were also asked to complete the Decision Regret Scale. Only a subset of the supporters filled out the regret scale; of those 41 supporters, 3 (7%, 95% confidence interval: 1.5% to 19.9%) expressed regret. This indicates a similar extent of regret among both patients and their supporters.

      Conclusions: Regret is not common in patients receiving systemic therapy for NSCLC or their supporters. It is a positive finding that regret is found in only about one of eight patients undergoing systemic treatment or their supporters; however, it should be acknowledged that this regret is unfortunate for those individuals, and steps taken to modify this regret could contribute to enhanced care. Our findings clearly demonstrate that nearly all patients ultimately having regret could be identified much earlier using the 3-IGI of the LCSS measure. Identifying patients at high risk for regret allows for interventions which could address potential regret in patients and their supporters.

      Support: NIH/NCI R01 CA157409

      e353dbe42c8654f33588d4da0b517469

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      PC05.08 - Discussion

      11:55 - 12:00

      • Abstract

      Abstract not provided

  • +

    ISS14 - Symposium Supported by Novartis: Expert Perspectives on the Management of NSCLC in Clinical Practice: Are Novel Approaches Realistic? (Not IASLC CME Accredited)

    • Moderators:
    • +

      Symposium Supported by Novartis: Expert Perspectives on the Management of NSCLC in Clinical Practice: Are Novel Approaches Realistic?

      12:00 - 13:30  |  Presenting Author(s): Daniel S.W. Tan, Scott A. Laurie, Laura Q Chow

      • Abstract

      Abstract not provided

  • +

    EXH02 - Thermo Fisher Exhibit Showcase Session - The Way We Test Matters for Patient Outcomes (Not IASLC CME Accredited)

    • Type: Exhibit Showcase
    • Track:
    • Moderators:
    • +

      EXH02.01 - Thermo Fisher Exhibit Showcase Session - The Way We Test Matters for Patient Outcomes

      12:15 - 13:15  |  Presenting Author(s): Anagh Vora

      • Abstract

      Abstract not provided

  • +

    MA15 - Colliding Approaches - EGFR and Immunotherapy

    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Moderators:
    • +

      MA15.01 - Strong PD-L1 Expression Predicts Poor Response and de Novo Resistance to EGFR TKIs Among Non-Small Cell Lung Cancer Patients with EGFR Mutation

      13:30 - 13:35  |  Presenting Author(s): Shan Su  |  Author(s): Zhong-Yi Dong, Xie Zhi, Jian Su, Zhi-Hong Chen, Jin-Ji Yang, Hai-Yan Tu, Qing Zhou, Wen Zhao Zhong, Xu-Chao Zhang, Yi-Long Wu

      • Abstract

      Background

      This study evaluated whether tumor expression of programmed death-ligand 1 (PD-L1) predicted the response of EGFR-mutated non-small cell lung cancer (NSCLC) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC between April 2016 and September 2017 at the Guangdong Lung Cancer Institute. None of them were enrolled in clinical studies, and their EGFR and PD-L1 statuses were simultaneously evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 101 eligible patients, strong PD-L1 expression significantly decreased the objective response rate (ORR) compared with those with weak or negative PD-L1 expression (35.7% vs 63.2% vs 67.3%, P=0.002) as well as shortened progression-free survival (PFS, 3.8months vs 6.0months vs 9.5months, P<0.001), regardless of EGFR mutation types (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% vs 30.2%, P=0.009). Notably, patients with de novo resistance had a high proportion of dual positive for PD-L1 and CD8 (46.7%, 7/15). Finally, one patient with de novo resistance to EGFR-TKIs and dual positivity for PD-L1 and CD8 experienced a favorable response to anti-PD-1 therapy.1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study uncovered the adverse impact of PD-L1 expression on the efficacy of EGFR- TKIs, especially in those with de novo resistance NSCLC, which inclined to reshape an inflamed immune phenotype of dual positive for PD-L1 and CD8 and showed potential therapeutic sensitivity to PD-1 blockade.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.02 - Long-Term Safety and Clinical Activity Results from a Phase Ib Study of Erlotinib Plus Atezolizumab in Advanced NSCLC

      13:35 - 13:40  |  Presenting Author(s): Charles M. Rudin  |  Author(s): Andres Cervantes, Afshin Dowlati, Benjamin Besse, Brigette Ma, Daniel B Costa, Peter Schmid, Rebecca Heist, Victoria M. Villaflor, Indrani Sarkar, Genevive Hernandez, Paul Foster, Jessica Spahn, Carol O'Hear, Scott N. Gettinger

      • Abstract

      Background

      Patients with EGFR mutation–positive non-small cell lung cancer (NSCLC) achieve favorable outcomes with EGFR tyrosine kinase inhibitors (TKIs); however, the long-term efficacy of these agents is limited by development of acquired resistance. Atezolizumab (anti–PD-L1 mAb) monotherapy has shown tolerability and durable clinical activity in NSCLC. By selectively targeting PD-L1 to block its interaction with receptors PD-1 and B7.1, atezolizumab can reinvigorate anti-cancer T-cell activity. Thus, combining atezolizumab and erlotinib could result in improved anti-tumor immunity and durable anti-tumor effects. Safety and preliminary clinical activity from a Phase Ib study of erlotinib plus atezolizumab in locally advanced or metastatic NSCLC have been previously reported (Rudin, et al. WCLC 2016). Here we describe updated findings from this study (NCT02013219).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFR TKI-naive patients with NSCLC were enrolled into a safety-evaluation stage (Stage 1) regardless of EGFR status, and an expansion stage (Stage 2) enrolled patients with EGFR-mutant NSCLC who were previously untreated or treated with 1 prior non–EGFR TKI therapy. A 7-day run-in period with erlotinib 150 mg PO QD was followed by addition of atezolizumab 1200 mg IV q3w. The primary endpoint was safety/tolerability of the combination; secondary endpoints included clinical activity per RECIST v1.1.

      4c3880bb027f159e801041b1021e88e8 Result

      At data cutoff (August 18, 2017), 28 patients (Stage 1, n = 8; Stage 2, n = 20) were evaluable for safety, and the median survival follow-up was 26.0 months (range, 7.8-32.9; Stage 2). The median age was 61 years (range, 47-84), and the most common EGFR mutation was exon 19 deletion (44%). Grade 3 treatment-related AEs (TRAEs) were reported in 43% of patients; no Grade 4 or 5 TRAEs occurred. The most common TRAEs were increased ALT, pyrexia, rash and diarrhea (2 patients each). Serious AEs occurred in 54% of patients; treatment-emergent AEs led to atezolizumab discontinuation in 18% and erlotinib discontinuation in 11%. Clinical activity was evaluated in Stage 2 patients. ORR was 75% (95% CI: 50.9, 91.3), with a median DOR of 16.7 months (range, 4.2-26.0+). Median PFS was 15.4 months (95% CI: 8.4, not estimable [NE]), and median OS was 32.7 months (95% CI: 32.7, NE).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Atezolizumab plus erlotinib demonstrated a tolerable safety profile and compared favorably with prior reports of efficacy with erlotinib monotherapy. OS data are expected to mature and improve with longer follow-up; updated clinical and biomarker data will be presented. Further investigation of the combination is warranted to assess its full potential.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.03 - PD-L1 Expression in Untreated EGFRm Advanced NSCLC and Response to Osimertinib and SoC EGFR-TKIs in the FLAURA Trial

      13:40 - 13:45  |  Presenting Author(s): Suresh S. Ramalingam  |  Author(s): Helen Brown, Johan F. Vansteenkiste, Kazuhiko Nakagawa, Manuel Cobo Dols, Thomas John, Craig Barker, Alexander Kohlmann, Alexander Todd, Matilde Saggese, Juliann Chmielecki, Aleksandra Markovets

      • Abstract

      Background

      In the Phase III FLAURA trial (NCT02296125), osimertinib significantly improved PFS relative to SoC EGFR-TKIs (gefitinib/erlotinib) in patients with untreated Ex19del/L858R positive (EGFRm) NSCLC. EGFRm NSCLC tumors can exhibit high PD-L1 expression, an important biomarker for immunotherapy treatment decisions. The frequency and clinical relevance of exhibiting both biomarkers prior to treatment are unclear. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following EGFR-TKI treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue samples from 994 patients with advanced NSCLC were screened for EGFR Ex19del/L858R mutations for enrolment in FLAURA; 556 were randomized to treatment. 197 tissue-blocks from the screened population (including EGFR mutation-positive and -negative samples) were tested for PD-L1 using the SP263 (Ventana) immunohistochemical assay; positive tumour cell (TC) staining PD-L1 TC≥25% and TC≥1% thresholds were applied. PFS was investigator-assessed, per RECIST 1.1, according to PD-L1-expressers (TC≥1%) or -negatives (TC<1%) in randomized patients.

      4c3880bb027f159e801041b1021e88e8 Result

      193/197 blocks had sufficient tumor tissue for staining. 65/193 patients were EGFR mutation-negative. 128/193 patients were EGFR mutation-positive: 106/128 were randomized to treatment (osimertinib: 54; SoC: 52). The table presents PD-L1 expression according to EGFR mutation status. For PD-L1-expressers (TC≥1%), median PFS was 18.4 months for osimertinib and 6.9 months for SoC (HR 0.30 [95% CI 0.15, 0.60]). For PD-L1-negative patients (TC<1%), median PFS was 18.9 months for osimertinib and 10.9 months for SoC (HR 0.37 [95% CI 0.17, 0.74]).

      PD-L1 TC≥1%, n (%)

      PD-L1 TC≥25%, n (%)

      EGFR mutation-negative (n=65)

      Screened population (n=65)

      44 (68)

      23 (35)

      EGFR mutation-positive (n=128)

      Screened population (n=128)

      65 (51)

      10 (8)

      Randomized to treatment (n=106)

      52 (49)

      8 (8)

      Randomized to osimertinib (n=54)

      28 (52)

      3 (6)

      Randomized to SoC EGFR-TKI (n=52)

      24 (46)

      5 (10)

      8eea62084ca7e541d918e823422bd82e Conclusion

      There was PFS benefit with osimertinib versus SoC regardless of whether tumors were PD-L1-expressers (TC≥1%) or -negatives (TC<1%). Using the TC≥25% threshold, PD-L1 prevalence was lower in EGFR mutation-positive than mutation-negative samples; there were insufficient patients with TC≥25% tumors for PFS assessment.

      These results support the efficacy of EGFR-TKIs, including osimertinib, as first-line treatment of EGFRm advanced NSCLC, irrespective of PD-L1 expression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.04 - Discussant - MA 15.01, MA 15.02, MA 15.03

      13:45 - 14:00  |  Presenting Author(s): Adrian Sacher

      • Abstract

      Abstract not provided

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      MA15.05 - The Mutational Profiles of EGFR 19 Exon Deletion and 21 Exon L858R Mutation and Their Association with Primary Response to EGFR-TKIs

      14:00 - 14:05  |  Presenting Author(s): Wenhua Liang  |  Author(s): Caichen Li, Yi Zhao, Jianxing He

      • Abstract

      Background

      In addition to the known resistant genetic alterations, such as de novo T790M and TP53 mutations, some recent studies suggested that other concomitant mutations might also compromise the efficacy of EGFR-TKIs. Meanwhile, it has been widely observed that EGFR 19 exon deletion (19del) was associated with better outcomes in treatments with EGFR-TKIs than L858R mutation (L858R). It is of interest to explore whether the respective mutational profiles of 19del and L858R may explain their different sensitivity to EGFR-TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We obtained individual patient data from 7 studies (including 1 from our center) using next generation sequencing to comprehensively determine the mutational profile of EGFR mutated patients. As different panels were used by different studies, we analyzed T790M, TP53 and the loci that were reported by at least 4 studies (half of the included ones).

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 250 19del and 279 L858R patients were included. We found similar prevalence of all co-mutations (19del 65.2% vs. L858R 64.2%), TP53 (19del 36.8% vs. L858R 40.9%), APC, BRAF, PIK3CA, STK11, PDGFRA, PTEN, AKT1 and KIT between the two types, except for de novo T790M (19del 34.4% vs. L858R 50%, P=0.07), CDKN2A (19del 10.5% vs. L858R 3.4%, P=0.03) and KRAS (19del 0.5% vs. L858R 4.0%, P=0.01). In addition, the number of co-mutations was equivalent between the two types (19del 0.95±0.95 vs. L858R 0.93±0.90, P=1.00). Through multivariate logistic regression, we found that EGFR mutation type, de novo T790M, TP53 and other co-mutations, all had independent adverse effects on primary response rate. Consistently, we found that in those without co-mutations, 19del still showed better outcomes compared with L858R (pure EGFR mutations: 19del 88.0% vs. L858R 68.4%), and that the response rates in both mutation types decreased in the same extent when contaminated with other mutations (EGFR mutations with co-mutations: 19del 53.1% vs. L858R 30.0%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study demonstrated that the presence of T790M, TP53 and other concomitant mutations indicated poor response to EGFR-TKIs, but most of them showed similar prevalence between 19del and L858R. Patients with L858R showed significantly less response than those with 19del regardless of the co-mutation status, indicating that some intrinsic factors and potentially de novo T790M, rather than other co-mutations, might underlie the different sensitivity of 19del and L858R to EGFR-TKIs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.06 - Circulating Tumor DNA Portrays the Resistance Landscape to a Novel Third Generation EGFR Inhibitor, AC0010

      14:05 - 14:10  |  Presenting Author(s): Yi-Chen Zhang  |  Author(s): Qing Zhou, Zhi-Hong Chen, Chong-Rui Xu, Jin -Ji Yang, Xu-Chao Zhang, Xiao-Yan Bai, Hong-Hong Yan, Zhi Xie, Wen -Feng Li, Shannon Chuai, Jun-Yi Ye, Han Zhang-Han, Zhou Zhang, Yi-Long Wu

      • Abstract

      Background

      In a Phase I/II dose-escalation and expansion study conducted at Guangdong Lung Cancer Institute, AC0010 demonstrated promising efficacy and good tolerability in advanced NSCLC patients with EGFR T790M-mediated resistance to previous EGFR TKIs, (NCT02330367). As disease progression (PD) with EGFR T790M-directed therapy also emerges over time, we investigated the resistance mechanisms to AC0010 in this study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Serial ctDNA samples obtained from patients who developed PD with AC0010 were analyzed using ultra-deep sequencing capturing 295 cancer-related genes. Alterations that were absent before treatment and acquired at PD or that increased in abundance during treatment were identified as putative resistance mechanisms.

      4c3880bb027f159e801041b1021e88e8 Result

      Longitudinal plasma samples were obtained from 23 patients who progressed on AC0010 (data cut-off October 14, 2016; figure1). Putative resistance mechanisms to AC0010 were identified in 19/23 patients (>1 putative resistance mechanism was detected in some patients). EGFR amplification was the predominant resistance mechanism (21.1% [4/19 patients]), followed by TP53 loss of heterozygosity (15.8% [3/19]). EGFR C797S mutation, Met amplification and mutations in the PI3KCA pathway each occurred in 10.5% of patients (2/19). SCLC transformation, ERBB2 amplification, CD79A_A32G mutation, CDKN2A_R80 mutation, CRLF2 amplification, MLH1 amplification, Rb1 loss, and concurrent rise in the allelic fraction of tumor suppressor gene TP53 and Rb1 were each detected in 5.3% of patients (1/19). In a patient with PD following single-agent AC0010 and EGFR amplification as the putative resistance mechanism to AC0010, subsequent treatment with AC0010 plus nimotuzumab (EGFR monoclonal antibody) successfully overcame resistance, resulting in a response that lasted for 7.7 months.

      fig 1_study profile.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The resistance landscape to AC0010 appears to differ from that described previously with osimertinib. In this cohort of patients in China, EGFR amplification was the predominant resistance mechanism to AC0010 and could be potentially overcome by EGFR dual inhibition.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.07 - Different Responses to Osimertinib in Primary and Acquired EGFR T790M-Mutant NSCLC Patients

      14:10 - 14:15  |  Presenting Author(s): Shuyuan Wang  |  Author(s): Bo Zhang, Baohui Han

      • Abstract

      Background

      Primary EGFR T790M could be occasionally identified by routine molecular testing in tyrosine kinase inhibitor TKI-naive non-small cell lung cancer (NSCLC) patients. This study was aimed to compare clinical characteristics of primary and acquired T790M mutations and their responses to Osimertinib in NSCLC patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We collected clinical characteristics of patients diagnosed with epidermal growth factor receptor (EGFR) mutation from 2012 to 2017 in Shanghai Chest Hospital. For patients with primary and acquired T790M mutations, the responses to Osimertinib were analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      Primary T790M was identified in 1.03% (61/5900) of TKI-naive patients. Acquired T790M was detected in 45.50% (96/211) of TKI-treated patients. T790M always coexisted with sensitizing EGFR mutations. Primary T790M was always coexisted with 21L858R (45/61) whereas acquired T790M was coexisted with 19del (61/96). Among them, 18 patients with primary T790M mutation acquired Osimertinib and 75 patients with acquired T790M mutation received Osimertinib. The median progression-free survival (mPFS) of Osimertinib in primary T790M group was greatly longer than that in acquired T790M group (18.0 months:95% CI:15.0-21.0 VS 10.0months:95% CI:8.3-11.7, P=0.016). The DCR of both groups were 89.3% and 100%. In primary T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 15.7m and 24.0 m, respectively. In acquired T790M group, the mPFS of concomitant occurrence of 20 T790M and 21 L858R or 19del were 11.0m and 10.0m, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Primary and acquired T790M-mutation patients showed different molecular characteristics. Both of them may respond to Osimertinib. However, primary T790M patients showed greater survival benefits from Osimertinib than acquired T790M patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.08 - Discussant - MA 15.05, MA 15.06, MA 15.07

      14:15 - 14:30  |  Presenting Author(s): Charu Aggarwal

      • Abstract

      Abstract not provided

    • +

      MA15.09 - Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR Mutant Advanced NSCLC Patients Treated with First-Line EGFR-TKIs

      14:30 - 14:35  |  Presenting Author(s): Chunxia Su  |  Author(s): Tao Jiang, Jing Zhao, Xuefei Li, Caicun Zhou

      • Abstract

      Background

      We proposed a non-invasive, folate receptor (FR)-based circulating tumor cell (CTC) assay counts to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutant non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients were enrolled and three milliliter (mL) of blood were obtained prior to initial treatment, after one month, and follow-up every two months hereafter. CTCs were isolated based on negative enrichment by immunomagnetic beads and detected by a ligand-targeted polymerase chain reaction (LT-PCR) method.

      4c3880bb027f159e801041b1021e88e8 Result

      232 patients with EGFR mutations treated with first-line EGFR-TKIs were included. The objective response rate (ORR) of patients with low baseline CTC level (<20.5 FU/3 mL) were significantly higher than those with high baseline CTC level (≥20.5 FU/3 mL) (55.8% vs 38.5%, P = 0.030). Moreover, patients with low baseline CTC level had a markedly longer progression-free survival (PFS) than those with high baseline CTC level (HR = 0.50, P < 0.001). This difference remained significant after multivariate analysis (P = 0.003). Dynamic change of CTC value was significantly associated with partial response (PR) (P = 0.042) and stable disease (SD)/progression disease (PD) (P = 0.032). Of note, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before CT scanning, median: 113 days; range: 45 to 169 days.

      Table 1. Clinical and molecular characteristics of included patients.

       

      CTC < 20.5 (n = 165)

      %

      CTC > 20.5 (n = 52)

      %

      P value

      Age, years

       

       

       

       

       

      Median

      61

       

      63

       

       

      Range

      27-85

       

      40-83

       

       

      Sex

       

       

       

       

       

      Male

      79

      47.88

      28

      53.85

      0.453

      Female

      86

      52.12

      24

      46.15

       

      Smoking status

       

       

       

       

       

      Never-smoker

      122

      73.94

      35

      67.31

      0.351

      Current/ever Smoker

      43

      26.06

      17

      32.69

       

      Pathological type

       

       

       

       

       

      ADC

      150

      90.91

      47

      90.38

      0.909

      ADS

      4

      2.42

      1

      1.92

       

      NOS

      13

      7.88

      4

      7.69

       

      Clinical stage

       

       

       

       

       

      Ⅲb

      9

      5.45

      3

      5.77

      0.794

      156

      94.55

      49

      94.23

       

      Distant metastases

       

       

       

       

       

      Brain

      43

      26.06

      15

      28.85

      0.953

      Bone

      78

      47.27

      21

      40.38

       

      Liver

      10

      6.06

      1

      1.92

       

      Other sites

      109

      66.06

      34

      65.38

       

      No metastases

      12

      7.27

      3

      5.77

       

      Mutation type

       

       

       

       

       

      19DEL

      76

      46.06

      24

      46.15

      0.012

      L858R

      79

      47.88

      19

      36.54

       

      Rare mutations

      10

      6.06

      9

      17.31

       

      Response rate

       

       

       

       

       

      Complete response

      0

      0.00

      0

      0.00

       

      Partial response

      92

      55.76

      20

      38.46

       

      Stable disease

      48

      29.09

      21

      40.38

       

      Progressive disease

      25

      151.50

      11

      21.15

       

      Disease control rate

      140

      84.85

      41

      78.85

      0.310

      Objective response rate

      92

      55.76

      20

      38.46

      0.030

      ADC, adenocarcinoma; ADS, adenosquamous carcinoma; CTC, circulating tumor cell.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The current evidences suggest that FR-positive CTCs can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutant NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to CT scanning.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.10 - Loss of T790M Mutation is Associated with Early Progression to Osimertinib in Chinese Advanced NSCLC Patients Harboring EGFR T790M

      14:35 - 14:40  |  Presenting Author(s): Sha Zhao  |  Author(s): Tao Jiang, Xuefei Li, Chao Zhao, Chunxia Su, Shengxiang Ren, Caicun Zhou

      • Abstract

      Background

      Osimertinib has demonstrated striking superior efficacy in non-small cell lung cancer (NSCLC) patients detected acuqired T790M mutation as resistant mechanism to upfront early-generation EGFR-TKIs. However, not all the T790M positive tumors are homogeneously sensitive to osimertinib, and the duration of response often varies. Previous studies suggest that loss of T790M mutation upon progression is related to decreased therapeutic benefit from osimertinib. The aim of this study is to investigate the association of T790M-mutant status and clinical outcomes after osimertinib treatment in Chinese NSCLC patients harboring acquired EGFR T790M mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed the electric medical records of all patients receiving osimertinib monotherapy after detected acquired T790M mutation in rebiopsy after resistant to prior EGFR-TKIs, and underwent re-rebiopsy again upon progression to osimertinib at our hospital. Detailed clinicopathologic characteristics and response data were collected for all patients.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 2014 to December 2016, 230 patients were confirmed T790M mutation positive for acquired resistance to early-generation EGFR-TKIs (gefitinib, erlotinib, afatinib and icotinib). Among them, 90 patients received osimertinib monotherapy as subsequent treatment. Out of the patients, 84 (93.3%) were eligible for osimertinib-resistance analysis, and 31 (34.4%) patients underwent T790M detection in biopsy after disease progression to osimertinib. The most commonly used biopsy sample were tumor tissue, peripheral blood and hydrothorax. 16 patients remained T790M positive, while 15 patients lost T790M mutation in their re-rebiopsy samples. Loss of T790M upon progression was significantly associated with shorter duration of response to osimertinib (median time 5.93 vs 11.87 m, HR:0.325, 95%CI: 0.087 to 0.45, p=0.0005), while overall survival (OS) was not statistically different between T790M-loss and -remain groups. The objective response rates were also similar in two groups (85% and 100%, respectively). In multivariate analysis, T790M mutation loss remained significantly associated with early progression to osimertinib.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Loss of T790M mutation was associated early progression to osimertinib in Chinese NSCLC patients harboring acquired T790M mutation. Dynamic detection during osimertinib treatment may be a potential strategy to timely reveal disease progression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.11 - Real World Biomarker Testing and Treatment Patterns in Patients with Advanced NSCLC Receiving EGFR-TKIs

      14:40 - 14:45  |  Presenting Author(s): Anne Chiang  |  Author(s): Ancilla W. Fernandes, Melissa Pavilack, Jennifer W. Wu, Francois Laliberté, Mei Sheng Duh, Nabil Chehab, Janakiraman Subramanian

      • Abstract

      Background

      In patients who progress on treatment with first- or second-generation EGFR-TKIs, 50–60% will have an EGFR T790M resistance mutation. Osimertinib, a third-generation EGFR-TKI, is FDA approved for use in patients with metastatic EGFR T790M-positive NSCLC and disease progression on or after prior EGFR-TKI therapy, and recently gained additional approval for first-line treatment for patients with EGFR Ex19del/L858R positive advanced NSCLC. We sought to observe how many patients in the real world underwent biomarker testing on progression and subsequently received osimertinib, when T790M positive.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Flatiron Health EHR-derived database was used to identify adult patients with NSCLC treated with a first- or second-generation EGFR-TKI from 11/2015–09/2017, with the start of first EGFR-TKI defined as the index date. Patients were stratified by EGFR-TKI use as a first (1L) or later line (2L+) treatment. EGFRm status, including T790M testing and subsequent treatments received after initiating first- or second-generation EGFR-TKI, were described. Chart review was conducted on patients who received a subsequent therapy to confirm disease progression.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients in this study (n=782; 1L: n=435; 2L+: n=347) had a median age of 69 years, 64% were female, 56% were white, 87% were seen in the community, with a median follow-up of 307 days. During the study period, 30% (235/782; 1L: 96/435 [22%]; 2L+: 139/347 [40%]) of patients died without receiving a subsequent therapy, and 38% (294/782; 1L: 160/435 [37%]; 2L+: 134/347 [39%]) received subsequent therapies. From post-index date to initiation of subsequent therapies, 30% (88/294; 1L 63/160 [39%]; 2L+ 25/134 [19%]) of patients were tested for EGFR mutations including T790M. Among patients who received subsequent therapies, treatments included chemotherapies (1L=23%; 2L+=37%), immunotherapies (1L=16%; 2L+=43%), and targeted therapies (1L=64%; 2L+=30%). On progression, 25% (1L 40/160) and 5% (2L+ 7/134) of the patients received osimertinib. Of those tested for EGFR mutation post-index date (n=88), 28% (n=25) were positive for T790M and 96% of these (n=24) received osimertinib. Most patients (251/294 [85%]; 1L: 136/160 [85%]; 2L+: 115/134 [86%]) on subsequent therapies were confirmed to have disease progression at chart review.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, a third of patients were tested for subsequent EGFR mutations including EGFR T790M following treatment with first- or second-generation EGFR-TKI. Of these, a third were positive for T790M and nearly all of the T790M positive patients received osimertinib. These findings highlight low rates of biomarker testing at progression, and the need for optimal treatments that maximize benefits for patients with EGFRm NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA15.12 - Discussant - MA 15.09, MA 15.10, MA 15.11

      14:45 - 15:00  |  Presenting Author(s): Joel W. Neal

      • Abstract

      Abstract not provided