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Jennifer H Law
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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): Jennifer H Law
- Abstract
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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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- 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): Jennifer H Law
- Abstract
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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P1.14 - 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): Jennifer H Law
- 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): Jennifer H Law
- Abstract
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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P2.14 - 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): Jennifer H Law
- 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.
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P2.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 187)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.16-05 - Population-Based ROS1 Testing in Lung Cancer: Creating Opportunity in a Publicly Funded System (ID 1480)
10:15 - 18:15 | Author(s): Jennifer H Law
- Abstract
Background
ROS1 gene rearrangement is found in 1-2% of all non-small cell lung cancer (NSCLC) and is recommended as standard molecular diagnostic testing. This study models the most efficient ROS1 testing strategy to maximize detection of true positive cases (TP) while minimizing costs and turnaround time (TAT).
Method
A population-based ROS1 testing model was developed from a Canadian (Ontario) public healthcare system perspective examining the use of immunohistochemistry (IHC) and next generation sequencing (NGS) versus fluorescence in situ hybridization (FISH, gold standard), reflex versus molecular or clinical selection (never smokers), and blood- versus tissue-based testing. Model inputs were derived from existing literature and expert opinion. Direct testing costs and TAT were obtained from the Ontario public perspective (University Health Network, Cancer Care Ontario).
Result
The most cost-effective strategy for the outcomes of TAT and TP was reflex testing with IHC and subsequent FISH confirmation; this identified a high proportion of TP within a relatively short TAT. The most costly reflex strategy was NGS, with a greater proportion of missed TP (Table), and long TAT. Clinician selection of never smokers yielded the lowest proportion of TP. Population-based plasma ctDNA testing using commercial assays was the most costly strategy. One-way sensitivity analysis demonstrated that the TP outcome was most sensitive to the population prevalence of ROS1, while cost was most sensitive to the specificity of ROS1 IHC.
Conclusion
Pathologist-initiated reflex testing using IHC with FISH confirmation provides the most cost-effective population-based testing strategy. Clinician-initiated testing significantly lengthens TAT. Selecting only never smokers for testing misses a larger proportion of TP patients who would benefit from targeted therapy despite potential cost savings.
