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Adrian G Sacher



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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-24 - Smoking History May Help Predict Immunotherapy Response in PDL1+ Lung Cancer Patients (Now Available) (ID 2688)

      08:00 - 18:00  |  Author(s): Adrian G Sacher

      • Abstract
      • Slides

      Background

      Tumour PD-L1 expression is a key predictor of benefit from anti-PD-1 therapy in NSCLC. Clinical factors associated with benefit include smoking status. We explored the additional predictive impact of smoking status added to tumour PD-L1 expression.

      Method

      A prospective cohort of 125 patients with advanced NSCLC treated at a single institution with anti-PD-1 therapy and outcome data including treatment response was explored. Ordinal logistic regression was performed to test factors associated with treatment response, including age, sex, ethnicity, pathology, PD-L1 expression (>=1%) and smoking status.

      Result

      Median age of the cohort at the time of anti-PD-1 therapy was 65.3 years (range 28-88.2); 55.2% were male, 21.2% were East Asian, 76.8% had adenocarcinoma (11.8% EGFR mutant, 15.2% squamous, 8% other). In univariable analysis, smoking status was associated with higher response rate (current versus never smoker: OR 3.73, 95% CI 1.40-9.97, p=0.004; past versus never: OR 1.09; 95% CI 0.52-2.30, p=0.09). Patients with EGFR mutant lung cancer were unlikely to respond (OR 0.25; 95% CI 0.07-0.83, p=0.02). In multivariable analysis, smoking remained significantly associated with response in patients with positive tumour PD-L1 expression (current vs. never smoker OR 4.01; 95% CI 1.31-12.27, p=0.01).

      Conclusion

      Clinical factors such as smoking status may enrich our ability to select patients with PD-L1 positive lung cancer that respond to immunotherapy.

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    EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.16-05 - Real World Outcomes of Advanced NSCLC Patients with Liver Metastases  (Now Available) (ID 2632)

      08:00 - 18:00  |  Author(s): Adrian G Sacher

      • Abstract
      • Slides

      Background

      Patients with advanced lung cancer represent a heterogenous population with varying patterns of metastasis. Those with liver metastases may represent a unique cohort with differential response to therapy, including immunotherapy in NSCLC. Novel Natural Language Processing (NLP) and Artificial Intelligence (AI) technology enables automated extraction of real-world data to examine these populations at greater scale than current manual chart abstraction processes, helping clinicians make more informed treatment decisions.

      Method

      Patients diagnosed with stage IIIB/IV lung cancer who received first-line systemic therapy at the Princess Margaret Cancer Centre between 2015 and 2018 were reviewed using the DARWEN™ NLP and AI data abstraction platform developed by Pentavere. Data extracted include tumour histology, patient age, sex, ECOG performance status, smoking status, biomarker status, PD-L1 expression, sites of metastases, treatment details and survival.

      Result

      Of 615 patients with accessible electronic pathology records, 540 (87.8%) had NSCLC and 333 (54.1%) received systemic therapy. In those patients treated with first-line therapy (immunotherapy 10.2%, targeted therapy 30.9%, chemotherapy 62.7%), 27.3% (91/333) had liver metastasis at any point from baseline to end of follow up (median follow up 8 months).

      280 patients had NSCLC and received systemic therapy and were included in subsequent analysis. Of these, 69 (24.6%) had liver metastases at any point and overall survival was worse in those patients 544 vs 715 days (p=0.006).

      Liver metastases were more commonly seen in those with more metastatic sites (OR: 1.42, 95% CI: 1.19-1.70, p= < 0.001). By contrast, those with EGFR mutant lung cancer were less likely to develop liver metastasis (OR: 0.45, 95% CI: 0.23-0.87, p=0.02).

      Using Cox regression analyses, after controlling for age, sex, baseline performance status, baseline smoking status, first line treatment, total number of metastatic sites and baseline LDH, presence of liver metastasis remained significantly associated with worse survival (HR: 1.78, 95% CI: 1.14-2.76, p=0.01). Elevated baseline LDH, a known poor prognostic factor, was also associated with worse overall survival (HR: 1.58, 95% CI: 10.6-2.35), p=0.02). No differential effect by type of therapy was seen.

      Conclusion

      The presence of liver metastases confers worse prognosis in advanced non-small cell lung cancer patients. This effect was observed irrespective of treatment type and highlights the need for additional treatment options which are efficacious in this patient population. Larger cohort studies may help identify patients with liver metastases that may benefit from specific therapeutic strategies in the future. NLP and AI technologies like DARWEN™ can rapidly generate population-based datasets and provide clinicians with timely access to previously unavailable information on treatment patterns and outcomes which can lead to improved care.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Adrian G Sacher

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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    MA18 - Advances in Diagnosis of Common Types of NSCLC (ID 145)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      MA18.07 - Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors (Now Available) (ID 1137)

      11:30 - 13:00  |  Author(s): Adrian G Sacher

      • Abstract
      • Presentation
      • Slides

      Background

      Acquired resistance after ALK tyrosine kinase inhibitors treatment has multiple known mechanisms: new mutations or gene amplifications, bypass signaling and rarely neuroendocrine histological transformation. Here we describe results of a program utilizing routine biopsy post-progression in ALK+ patients for clinical and research purposes.

      Method

      Since 2014, ALK+ lung cancer patients treated at the Princess Margaret Cancer Centre have undergone routine biopsies at disease progression time points upon failure of an ALK-tyrosine kinase inhibitor (TKI) for both clinical purposes and research purposes, in particular to obtain tissue for primary derived xenograft (PDX) engraftment.

      Result

      All 9/9 patients consented for research sampling during clinical biopsy procedures (median 2 extra cores/passes); 2 patients were biopsied more than once; 3 PDX models from 2 patients have engrafted; 3 additional models are too early to assess engraftment. Engraftment occurred in patients with clinically aggressive tumors and poor survival outcomes. In this process, we identified 2 patients with neuroendocrine transformation post-second generation ALK TKI: (a) a 59 yo Asian female, never smoker, diagnosed six years prior with metastatic disease, heavily pretreated with crizotinib (12 months), pemetrexed (16 months), ceritinib (25 months), alectinib (6 months) and brigatinib (3 months); post-alectinib biopsy showed no transformation, while post-brigatinib liver biopsy demonstrated transformation to large cell neuroendocrine carcinoma; (b) a 75 yo Caucasian female, never smoker, diagnosed eight months prior and started on alectinib with a partial response, progressed in a single site; endobronchial biopsy demonstrated high grade neuroendocrine transformation. Both biopsies were positive for neuroendocrine markers (chromogranin and synaptophysin), TTF-1 and diffusely co-expressed ALK on immunohistochemistry. Assessment of PDX engraftment of these models is ongoing.

      Conclusion

      Routine combined clinical and research biopsy of ALK+ patients at time of TKI failure helped to identify these recent cases of neuroendocrine transformation as a possible mode of resistance and provide tissue for model development. This is the first time that ALK+ transformation to large cell neuroendocrine carcinoma is reported in the literature. (PP, AFF, SNMF, LN contributed equally).

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-30 - Non-Small Cell Lung Cancer (NSCLC) Next Generation Sequencing (NGS): Integrating Genomic Sequencing into a Publicly Funded Health Care Model (Now Available) (ID 2588)

      09:45 - 18:00  |  Author(s): Adrian G Sacher

      • Abstract
      • Slides

      Background

      Standard of care (SOC) molecular diagnostics for stage IV NSCLC patients in Ontario, Canada includes publicly reimbursed EGFR/ALK, and BRAF/ ROS-1 testing in selected cases. Other genomic alterations are not tested routinely at all institutions; however, enhanced molecular testing may broaden treatment options for patients by identifying actionable targets. This study evaluated costs, identified actionable targets, and determined clinical trial eligibility as a result of using the Oncomine Comprehensive Assay v3 (OCA v3, ThermoFisher) NGS in stage IV NSCLC patients at a single institution.

      Method

      This prospective study of stage IV NSCLC out-patients at Princess Margaret Cancer Centre (Toronto) began in February 2018 and recruitment is ongoing (NCT03558165). NSCLC patients without EGFR/ALK/KRAS/BRAF alteration (unless failure of prior targeted therapy and tissue rebiopsy), had diagnostic samples tested by OCAv3 (ThermoFisher; 161 genes: hotspots, fusions, and copy number variations). Primary endpoints were identification of incremental actionable targets and clinical trial opportunities as a result of broader OCAv3 testing. Secondary endpoints include feasibility and cost from the Canadian public healthcare perspective.

      Result

      From Feb 2018- Jan 2019 65 patients were enrolled [62% (N=40) completed/ 21% (N=14) screen fail/ 17% (N=11) pending], median age of completed cohort was 65, 60% (N=24) female, never/light smokers 68% (N=27), Asian 38% (N=15), previously treated 33% (N=13). Actionable targets beyond SOC were identified in 33% (N=13): ERBB2 (N=8), BRAFV600 (N=3), NRG fusion (N=1), MET exon 14 (N=1). Failure of NGS was secondary to insufficient tissue. 91% (N=10) of screen failures was secondary to tissue exhaustion from prior sequential SOC molecular testing. New clinical trial options were identified in 70% as a result of OCA v3 testing. Incremental costs per case beyond EGFR/ALK are estimated at $540 CAD. If ROS-1 and BRAF testing were publicly reimbursed at current rates, the incremental profiling cost with OCAv3 would be $90 CAD per case.

      Conclusion

      The OCAv3 consolidates genomic testing, identifies additional actionable targets, and substantially increases clinical trial eligibility for patients at a small incremental cost. Sample failures are reflective of exhausted diagnostic tissue as a result of prior sequential genomic testing. The key barrier to implementation of NGS remains funding in the Canadian health care system.

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      P1.01-70 - Dominant Circulating Myeloid Populations Are Associated with Poor Response in NSCLC Treated with 1st Line PD-1 Monotherapy (Now Available) (ID 2295)

      09:45 - 18:00  |  Author(s): Adrian G Sacher

      • Abstract
      • Slides

      Background

      Immune subpopulations within the tumor microenvironment (TME) play a central role in determining response to checkpoint inhibitors. Myeloid derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have a predominantly immunosuppressive role by stimulating T regulatory cells. We hypothesize that elevated myeloid-to-lymphocyte measures in the peripheral blood predict for greater numbers of myeloid derived suppressor cells in the TME and worse outcomes.

      Method

      We identified all advanced NSCLC patients treated with immunotherapy between 2010-2019 at the Princess Margaret Cancer Center. Patients who received first line monotherapy with a PD-1 inhibitor were reviewed for clinical information including age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and tumor genotype. Myeloid cells lines analyzed included neutrophils, monocytes and platelets, expressed as ratios to peripheral lymphocytes. Multivariate analyses were conducted using the cox and logistic regression models to adjust for confounders.

      Result

      We identified 75 patients who were eligible for analysis. Disproportionate increases in the different myeloid cell types were highly correlated with each other (all Pearson’s rho>0.8) and the neutrophil to lymphocyte ratio (NLR) was selected as representative. A high NLR (>5) was associated with shorter time-to-treatment-failure (median TTF 9.7 vs 29.4 months) that remained significant after adjusting for confounders including PD-L1 and presence of liver metastases (p=0.004). High NLR was also an independent predictor of poor OS (median 11.3 vs 56.8 months, HR 3.02, p=0.04). Although NLR was not predictive of radiographic response, there was a trend to association with a rapidly progressive phenotype defined by primary progressive disease and a duration of therapy ≤2 months (p=0.06). Other predictive factors included the presence of liver metastases, which was associated with a worse OS (HR3.37 p=0.05) but not TTF (p=0.14). An association was also seen between NLR and liver metastases (mean NLR 6.6 vs 25.2 in the absence and presence of liver metastases respectively, p<0.001).

      Conclusion

      A disproportionate increase in peripheral immune myeloid populations may represent a systemic, myeloid-driven, immunosuppressive state that is significantly associated with primary refractory disease, rapid progression, and poor survival. A subset of about 50 patients with biobanked tissue are presently being analyzed using multiplex immunofluorescence to assess for MDSCs in the TME to correlate with peripheral blood findings.

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    P1.10 - Prevention and Tobacco Control (ID 175)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Prevention and Tobacco Control
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.10-05 - Tobacco Retail Availability and Tobacco Cessation Among Lung Cancer Survivors (ID 1089)

      09:45 - 18:00  |  Author(s): Adrian G Sacher

      • Abstract

      Background

      Continued smoking after a lung cancer diagnosis is associated with poorer outcomes. Tobacco retail availability is negatively associated with cessation in non-cancer patients but this has not been explored in cancer survivors. We evaluated the impact of tobacco retail availability on tobacco cessation in lung cancer survivors.

      Method

      Lung cancer survivors from Princess Margaret Cancer Centre (Toronto, Canada) completed questionnaires at diagnosis and follow-up evaluating changes in tobacco use with a median of 26 months apart. Validated tobacco retail location data were obtained from Ministry of Health and patient home addresses were geocoded using ArcGIS 10.6.1, which calculated walking time/distance to nearest vendor, and vendor density within 250 meters (m) and 500m from patient residences. Multivariable logistic regression and Cox proportional hazard models evaluated the impact of vendor availability on cessation and time to quitting after diagnosis respectively, adjusting for significant clinico-demographic and tobacco covariates.

      Result

      242/721 lung cancer survivors smoked at diagnosis; subsequent overall quit rate after diagnosis was 66%. Mean distance and walking time to a vendor was 0.8 km (range 0-13) and 10 min (range 0-157). On average, there was one vendor (range 0-19) within 250m and five vendors (range 0-36) within 500m from pts; 40% and 64% of pts lived within 250m and 500m from at least one vendor respectively. Greater distance (aOR 1.28 per 1000m [95% CI 0.97-1.70] p = 0.08) and increased walking time (aOR 1.02 per minute [1.00-1.05] p = 0.08) to a tobacco vendor had a non-significant trend towards increased chances of quitting at one year. Living within 250m (aOR 0.43 [0.25-0.74] p = 0.003) or 500m (aOR 0.50 [0.28-0.88] p = 0.02) to at least one vendor reduced quitting at one year. Living near more vendors within 500m had a non-significant trend towards having an increasing dose effect on reducing cessation rates at one year (aOR 0.97 per vendor [0.94-1.00] p = 0.08). Living within 500m to a vendor reduced chance of quitting at any time (aHR 0.70 [0.50-1.00] p = 0.05).

      Conclusion

      Close proximity to tobacco retail outlets is associated with reduced cessation rates for lung cancer survivors. Reducing density of tobacco vendors is a cessation strategy that could positively impact lung cancer patient outcomes.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-07 - Genomic Profiling of Liquid Biopsies During 2nd/3rd Generation ALK Inhibitor Therapy to Identify Novel Mechanisms of Resistance (ID 804)

      09:45 - 18:00  |  Author(s): Adrian G Sacher

      • Abstract

      Background

      Second- and third-generation ALK inhibitors each have diverse mechanisms of resistance. Only a fraction of resistance is due to secondary mutations of the ALK gene. Altered bypass tracts are likely the case in some other instances. Genomic alterations of other genes and pathways may be a third mechanism of resistance. Repeat liquid biopsies during the course of patients’ treatments can provide a minimally invasive method for sampling cancer-specific genomic information that leads to improved treatment selection.

      Method

      In the Lung Cancer Clinic of the Princess Margaret Cancer Centre, serial plasma samples were collected from six lung cancer patients with ALK rearrangement at multiple serial clinic visits pre- and post- progression on next-generation ALK inhibitors. We focused on next generation agents, as there has been previous focus on crizotinib resistance mechanisms already. Cell-free DNA (cfDNA) was extracted (median: 50 ng; range: 20-2760 ng) and profiled using a next-generation sequencing (NGS) platform with Geneseeq Prime 425-gene panel at a mean coverage depth of 4747X (and a deduplicated mean coverage depth of 2160X).

      Result

      Somatic alterations from plasma cfDNA were detected in all six patients at various time points with three patients having detectable ALK alterations. Systemic progression (2/2 patients) correlated well with the ability of liquid biopsies to detect somatic mutations, while central nervous system (CNS)-predominant progression did not (4/4 patients). One patient, after disease progression on ceritinib, alectinib and brigatinib, exhibited variable allele fractions (AFs) of ALK G1202R mutation in cfDNA. The levels of G1202R decreased and ultimately became undetectable, corresponding to the patient’s clinical response to lorlatinib. In a patient who exhibited significant systemic progression, a massive increase in mutation AFs and many newly acquired mutations were detected in the cfDNA, including NOTCH1, DICER1, BRCA2, TP53, CDKN2A, ERBB3, and FAT1mutations. However, the increase in the number of co-mutations was not related to increases in the amount of extracted cfDNA.

      Conclusion

      Broad panel-based NGS of plasma cfDNA enabled noninvasive detection of systemic (but not CNS-predominant) progression during second and subsequent generation ALK inhibitor treatment, and can identify known and putative mechanisms of resistance for treatment decision-making.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-07 - Real World Evidence of the Impact of Immunotherapy in Patients with Advanced Lung Cancer (Now Available) (ID 2731)

      09:45 - 18:00  |  Author(s): Adrian G Sacher

      • Abstract
      • Slides

      Background

      PD-1 axis inhibitors have become a standard treatment modality in the management of advanced lung cancer. Novel Natural Language Processing (NLP) and Artificial Intelligence (AI) technology enables automated extraction of real-world data at greater scale than current manual chart abstraction processes, which can be used to further explore the impact of these agents in the general population irrespective of PDL1 tumour expression.

      Method

      Patients diagnosed with stage IIIB/IV lung cancer at the Princess Margaret Cancer Centre between 2015 and 2018 were reviewed using the DARWEN™ NLP and AI data abstraction platform developed by Pentavere. Data extracted include patient age, smoking status, ECOG performance status, tumour histology, biomarker status, PDL1 expression, sites of metastases, treatment information and survival.

      Result

      Of 615 patients with accessible electronic pathology records, 540 (87.8%) had NSCLC and 280 (51.8%) of those received systemic therapy and were included in the analysis.

      86 (30.7%) were EGFR sensitizing mutation positive, 18 (6.4%) ALK rearranged, PDL1>50%/1-49/<1/unknown in 21/8/10/61%. Almost one third (31.7%) of those that received treatment received immunotherapy for any line of therapy (12.1% first-line). Chemotherapy was used first-line in 56.1% and targeted therapy in 36.1% of those receiving systemic therapy

      Patients that were more likely to receive immunotherapy any line were smokers (OR: 2.7, 95% CI: 1.43-5.10, p=0.002) with a higher number of metastatic sites (OR: 1.23, 95% CI: 1.06-1.43, p=0.005). Those with EGFR sensitizing mutation and ALK rearrangement were less likely to be given immunotherapy (OR: 0.07, 95% CI: 0.03-0.19, p<0.001 and OR: 0.11, 95% CI: 0.01-0.84, p=0.03 respectively). There was no difference in the rates of immunotherapy being given in those with PDL1>50%/1-49/<1 (52/52/44%, p=0.8).

      Using Cox regression analyses after controlling for ALK, EGFR, PD-L1, age, sex, baseline ECOG, smoking status and number of metastatic sites, patients that received immunotherapy at any point had longer survival (HR: 0.28, 95%CI: 0.12-0.67, p=0.004) in a complete case analysis.

      Conclusion

      Novel NLP and AI technologies like DARWEN™ gives clinicians access to previously unavailable information on real world treatment strategies and outcomes. Increasing uptake of immunotherapy may further improve outcomes for patients with this challenging to treat cancer. This study demonstrates that the benefit of immunotherapy seen in clinical trials can be translated into the general advanced lung cancer population. Larger population studies will be needed to further analyze the impact of new treatments in the real world and will be facilitated by automated data abstraction to rapidly generate large datasets.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-11 - Impact of Ethnicity on Outcome in Never Smokers with EGFR and ALK Wildtype (EGFR/ALK-Wildtype) Lung Adenocarcinomas (ID 2035)

      10:15 - 18:15  |  Author(s): Adrian G Sacher

      • Abstract

      Background

      EGFR-mutations and ALK-rearrangements are frequent in lung adenocarcinoma (LUAD) samples from never smoker patients. Nevertheless, up to a quarter of all LUAD cases in never smokers are EGFR/ALK-wildtype: these patients have limited therapeutic options and few well-established clinical and molecular predictors of outcome. Our main objectives here were to investigate the prognostic impact of ethnicity in never smoker patients with EGFR/ALK-wildtype LUAD and seek for specific somatic events correlated to ethnical background in these patients.

      Method

      We included 85 samples from lifetime never-smoker patients with EGFR/ALK-wildtype LUAD collected from surgical resection with curative intent. Stages 1/2/3 were identified in 56 (66%)/15 (18%)/14 (16%) samples. A subset of those samples (n=46), with similar stage distribution, had snap-frozen tumor and paired-adjacent tissue available and were submitted to paired-end whole-exome sequencing. Fisher’s exact and Chi-squared tests were used to compare specific mutations between Asians vs non-Asians. Recurrence-free-survival (RFS) was calculated based on the Kaplan-Meier method; Cox modeling was used to generate hazard ratios (HR), adjusted for key clinical features.

      Result

      Most patients in the cohort were female (63/85, 74%); the median age was 68 years; median follow-up was 51 months. According to self-reports, 19/85 (22%) and 66/85 (78%) patients identified as Asians and non-Asians, respectively; no major clinical and pathologic differences were identified between these populations. Five-year recurrence free survival was significantly lower for Asians compared to non-Asians (50% vs. 78%, adjusted HR = 2.9; CI = 1.1-7.8, p=0.02), Figure 1. Among somatic events, in-frame deletions in CNPY3 (Toll-like receptor-specific co-chaperone for HSP90B1) were more frequent in Asians (30%) compared to non-Asians (18%). In contrast, DDX11 missense mutations (21% vs 0%; nucleic acid binding protein involved in genome stability), NOTCH2 multi-hits and frame-shift deletions (7% vs 1%), and KRAS missense mutations (7% vs 0%) were more frequently altered in non-Asians than in Asians.

      Conclusion

      In our cohort of never-smoker patients with EGFR/ALK-wildtype LUAD, Asian patients showed higher relapse rates than non-Asians. We identified differentially mutated genes by ethnicity that may partly account for these differences in outcome. (SNMF and AFF contributed equally)

      figure 1.jpg

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      P2.03-37 - Genomic Landscape of EGFR/ALK Wild-Type Lung Adenocarcinomas in Never-Smokers and Importance of Epithelial-Mesenchymal-Transition (ID 1283)

      10:15 - 18:15  |  Author(s): Adrian G Sacher

      • Abstract

      Background

      The molecular landscape of EGFR/ALK wild-type Lung Adenocarcinomas in never-smokers is poorly understood. Never-smokers usually have low PD-L1 expression and low Tumor Mutation Burden, challenging treatment strategies when no known driver-mutations are found. To identify putative driver mutations, we compared whole exome sequencing (WES) results in the EGFR/ALK wild-type Lung Adenocarcinoma in the never smokers Toronto cohort with a corresponding EGFR/ALK wild-type Lung Adenocarcinoma group of smokers from TCGA.

      Method

      For never-smokers with resected EGFR/ALK wild-type Lung Adenocarcinomas, frozen tumor and paired-normal-lung were evaluated by WES at a mean coverage of 238x. The paired-end reads were aligned using BWA and were further processed using the standard GATK pipeline. Somatic mutations and indels were identified using MuTect and VarScan, respectively. We compared mutations from our cohort to the TCGA smokers who had EGFR/ALK wild-type Lung Adenocarcinomas from publicly available data (TCGA) to identify genes at least 10% more frequently mutated in never smokers compared to the TCGA cohort.

      Result

      In our cohort with 45 never-smoker patients, 80% were females; median age was 70y; 29% were Asians; Stage I/II/III+ were 71%/15%/13%; after a median follow-up of 69 months, 24% had recurred. Median non-synonymous Tumor Mutation Burden was 1.3mut/Mb in never-smokers. We identified 39 genes that were more frequently mutated in never-smokers vs smokers, including some known tumor suppressor genes. The most prevalent genes included ADAM21 missense mutations (21% vs 1%; adj p=0.003), NOTCH2 frame-shift deletions and multi-hit mutations (40% vs 17%; adj p=0.04), MST1 missense mutations and in-frame deletions (13% vs 0%; adj p=0.008), ZMIZ2 frame-shift insertions (13% vs 0%; adj p=0.008) and FOXD4 missense mutations (10% vs 0%; adj p=0.02). Many of these differentially mutated genes have been previously associated to epithelial-mesenchymal-transition signaling pathways. Conversely and as expected, KRAS, TP53, STK11 and KEAP1 were more frequently mutated in the TCGA smokers EGFR/ALK wild-type Lung Adenocarcinomas cohort.

      oncoprint wes.png

      Conclusion

      We identified multiple genes, particularly involved in the epithelial-mesenchymal-transition signaling pathways that are over-represented in never-smokers with EGFR/ALK wild-type Lung Adenocarcinomas, when compared to smokers with EGFR/ALK wild-type Lung Adenocarcinomas. This is a novel finding with potential clinical importance. Validation studies, analyzing epithelial-mesenchymal-transition signaling activation pathways on the EGFR/ALK wild-type Lung Adenocarcinomas never smokers population are needed to best identify the actual role in carcinogenesis and metastasis, guiding future treatment strategies. (AFF and SNMF contributed equally).

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-62 - Early, Subclinical SCLC Transformation in Patients with EGFR Mutant Lung Cancer Receiving Osimertinib, Detected Through Cell-Free DNA (ID 812)

      10:15 - 18:15  |  Author(s): Adrian G Sacher

      • Abstract

      Background

      Liquid biopsies provide a convenient approachfor serial sampling and real-time disease monitoring, leading to the early detection of treatment response, disease progression and drug-resistance. Here,we present genomic profiling of serial liquid biopsies from seven lung cancer patients with activatingEGFRmutations receiving osimertinib in clinical practice.

      Method

      At Princess Margaret Cancer Centre, in the Lung Cancer Outpatient Clinics, plasma samples were obtained from each patient at defined clinical visits (between ~1–5 months in-between visits). Cell-free DNA (cfDNA; with a median of 57 ng; range: 3.5 to 3806 ng) was extracted from plasma samples and profiled using targeted capture next-generation sequencing with the Geneseeq Prime 425-gene panel, at a mean coverage depth of 4892X (with a deduplicated mean coverage depth of 2108X).

      Result

      Systemic tumour burden correlated with the detection of genomic alterations in cfDNA: Four of four of the patients with low tumour burden, despite minor disease progression, exhibited minimal EGFR and co-mutation allele frequencies (AFs). Conversely, significant increases in systemic (but not central nervous system) tumour burden led to increases in driver and co-mutation AFs (two our of three patients). EGFR C797S mutation and inactivating mutations in RB1 and TP53 were detected in the cfDNA of one patient nearly four months prior to the development of small cell lung cancer (SCLC) transformation confirmed on tissue biopsy with distinct transformed and untransformed areas. Both of the specific RB1 and TP53 mutations found in cfDNA have been previously associated with SCLC. Subsequent combination cisplatin-etoposide chemoradiation resulted in temporary complete remission of the transformed SCLC, corresponding to loss of RB1 mutation detection by cfDNA testing.

      Conclusion

      Profiling of plasma cfDNA using hybrid capture deep sequencing of a large gene panel can detect early subclinical transformation of EGFR-mutated lung cancer into small cell lung cancer (i.e., neuroendocrine transformation), leading to earlier diagnosis and management of the transformed disease. Serial liquid biopsy profiling can also be used to monitor disease progression. However, detection sensitivity of tumour cfDNA largely depends on systemic tumour burden.