Liquid biopsy (LB) with plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) leads to more complete molecular profiling with faster turnaround time than tumor tissue (TT) profiling alone and may be cost-effective. The impact of comprehensive LB testing at diagnosis or progression on patient’s quality of life (QOL) in advanced NSCLC has not been previously reported. In this prospective multicentre Canadian study using LB to guide treatment, we tested the hypothesis that by identifying more candidates for targeted therapy, patient-reported QOL outcomes would be improved.

Background: Liquid biopsy (LB) can detect actionable genomic alterations in plasma circulating tumor circulating tumor DNA beyond tissue testing (TT) alone in advanced non-small cell lung cancer (NSCLC) patients. We estimated the cost-effectiveness of adding LB to TT in the Canadian healthcare system. Methods: A cost-effectiveness analysis was conducted using a decision analytic Markov model from the Canadian public payer (Ontario) perspective and a 2-year time horizon in patients with treatment-naïve stage IV non-squamous NSCLC and ⩽10 pack-year smoking history. LB was performed using the comprehensive genomic profiling Guardant360™ assay. Standard of care TT for each participating institution was performed. Costs and outcomes of molecular testing by LB + TT were compared to TT alone. Transition probabilities were calculated from the VALUE trial (NCT03576937). Sensitivity analyses were undertaken to assess uncertainty in the model. Results: Use of LB + TT identified actionable alterations in more patients, 68.5 versus 52.7% with TT alone. Use of the LB + TT strategy resulted in an incremental cost savings of $3065 CAD per patient (95% CI, 2195–3945) and a gain in quality-adjusted life-years of 0.02 (95% CI, 0.01–0.02) versus TT alone. More patients received chemo-immunotherapy based on TT with higher overall costs, whereas more patients received targeted therapy based on LB + TT with net cost savings. Major drivers of cost-effectiveness were drug acquisition costs and prevalence of actionable alterations. Conclusion: The addition of LB to TT as initial molecular testing of clinically selected patients with advanced NSCLC did not increase system costs and led to more patients receiving appropriate targeted therapy.

Liquid biopsy (LB) is an important alternative for advanced lung cancer patients in diagnosing resistance or where tissue genotyping has failed. The VALUE study examines clinical outcomes and utility of LB for molecular diagnosis in treatment naive stage IV lung adenocarcinoma patients. [Preliminary data previously presented at ASCO2020. Final study results will be available for WCLC2021]

CCND2 (12p13) duplications and point mutation BRAF (7q34) p.V600E (c.1799T>A).MLPA analysis of control group showed normal results (fig2).Conclusion: The MLPA technique detected genomic abnormalities in seven MPE-LC samples, when at least 30% of tumor cells were present in the cytological examination.The findings of pathogenic variants in MPE-LC can be valuable to explore new targets for the treatment of lung cancer patients.

Liquid biopsy has been established as an important diagnostic step in identifying EGFR T790M resistance to 1st and 2nd generation EGFR TKIs. This has led to significant interest in exploring the value of liquid biopsy in patients with other oncogene-addicted cancers and acquired resistance to targeted therapy. This study is being conducted at 6 Canadian centres (NCT03576937) using a validated cell-free DNA next-generation sequencing assay that identifies variants in 74 cancer-associated genes, including fusions and copy number gain (Guardant 360TM). In a discovery cohort (N=60), patients that failed targeted therapy for oncogene-addicted lung cancer receive a liquid biopsy (LB), paired with standard tumour tissue (TT) biopsy with molecular profiling if possible. Patients are required to have measurable disease (RECIST version 1.1), and, if failing a 1st or 2nd generation EGFR TKI, must demonstrate the absence of EGFR T790M in tissue (and plasma if standard of care). Exploratory analysis of incremental targetable alterations identified by LB is presented. Genomic alterations are categorized as actionable, (targeted therapy available for indication), potentially actionable (clinical trials available and/or known resistance mechanism) or non-actionable. 56 of 60 patients have been enrolled. Median age of the cohort is 58 years (range 23-86), 36 (64%) are female, 48 (86%) are never smokers and all have adenocarcinoma. Seven (13%) patients have actionable targets and 9 (16%) potentially actionable targets identified through LB. Response data will be presented at the meeting. Liquid biopsy provides a minimally invasive initial approach to the molecular characterization of resistance in patients with oncogene addicted lung cancer failing targeted therapy, yielding actionable or potentially actionable results in 20% of patients beyond EGFR T790M.Table: 1195POncogenic driverNActionable Target in LBPotentially ActionableNo. pts with Non-ActionableALK fusion*92 ALK G1202R1 ALK C1156Y**1 EGFR amp6EGFR T790M-221 CCDC6-RET fusion1 MET amp**2 T790M1 KRAS G12D1 CDK4 amp1 FGFR1 amp**17EGFR T790M+*201 MET amp1 BRAF V600E1 FGFR3-TACC fusion1 BRAF L597R3 EGFR C797S**14ERBB2ins2--2MET ex14skip11 KRAS G12DEGFR ex20ins1--1NRG fusion11 CCND2 amp1 EGFR amp*** ALK fusion+ pts received prior alectinib (median 3 prior TKI); EGFR T790M+ pts received prior osimertinib (median 2 prior TKI).**concurrent aberrations (G1202R+C1156Y; MET amp+ T790M; FGFR1 amp + CDK4 amp; C797S + BRAF; EGFR amp+CCND2 amp) Open table in a new tab

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). 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). 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. 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.

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. 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. 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). 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.

Cell-free DNA (cfDNA) next-generation sequencing (NGS) has emerged as an effective molecular profiling technique that is potentially faster and cost-saving in comparison to standard-of-care (SOC) tumour biopsy and tissue-based profiling. In a public payer system, the added value of cfDNA blood-based profiling compared to SOC remains unknown. This study will determine the incremental clinical utility and cost of cfDNA NGS versus SOC genotyping in patients with advanced non-squamous non-small cell lung cancer (NSCLC). This multicentre, non-randomized, longitudinal study will be conducted at 6 sites across Canada (BC, Alberta, Ontario, Quebec). The Guardant360® assay will be used to perform plasma-based cfDNA testing, and includes mutations, rearrangements and copy number variations in 73 known cancer associated genes. Two patient cohorts will be recruited: (1) treatment naïve patients with ≤10 pack year smoking history; and (2) patients with known abnormalities of EGFR, ALK, ROS-1 or BRAF after disease progression on all standard targeted therapies. SOC tissue profiling will be performed for all patients per institutional standards. The study will begin recruiting in May 2018, with estimated completion in 12 months. The primary endpoints are comparison of response rate (RR), progression-free survival (PFS) and time-to-treatment failure (TTF) using cfDNA versus tissue genomic testing. Secondary endpoints include time to treatment initiation, number of actionable genomic abnormalities identified, result turnaround time, potentially avoidable repeat tissue biopsies, costs, patient-reported quality of life (EQ-5D) and willingness-to-pay. Exploratory analyses of treatment outcomes in selected molecular subgroups will also be undertaken, including response to immunotherapy in those with KRAS/STK11 co-mutations. A decision-analytic model will be developed to perform cost-consequence analyses using a cfDNA versus tissue-based approach. A total of 210 patients will be recruited across Canada, (Cohort 1 N=150, Cohort 2 N=60). Based on testing with either blood-based GUARDANT360TM or tissue-based profiling, the costs and benefits of blood-based profiling either at initial diagnosis or upon TKI progression will be determined versus initial or repeat tumour biopsy and tissue-based profiling. Data from patients accrued until 08/2018 will be presented at the meeting. This study will determine the added value of cfDNA blood-based genotyping compared to SOC from the perspective of a public payer system (Canada).

Osimertinib doubles progression-free survival (PFS) in previously untreated EGFR-positive advanced non-small cell lung cancer (NSCLC) patients, with remarkable intracranial response rates. However, its cost-effectiveness has not been established. We assessed the cost-effectiveness of first-line osimertinib from the perspective of the Canadian public health care payer. A remaining lifetime Markov model was used to project the outcomes and costs of 2 treatment pathways, osimertinib or current standard-of-care (SoC) first-line EGFR TKI gefinitib or afatinib, in previously untreated EGFR-mutant advanced NSCLC patients from the health care system perspective. Clinical, health preference and cost input estimates were informed from the available literature, including second-line osimertinib after SoC failure in those with EGFR T790M mutant cancer. Model outcomes included costs (in 2017 Canadian dollars), quality-adjusted life-years (QALYs), and the incremental cost per QALY gained. The model was fully probabilistic to assess parameter uncertainty. Osimertinib was associated with a gain of 0.70 quality-adjusted life-years (QALYs) at an incremental cost of $58,619 vs SoC (incremental cost-effectiveness ratio [ICER]: $83,164/QALY gained). Unadjusted LY gain was 0.95. Osimertinib had a 7% probability of being cost-effective at a willingness-to-pay threshold of $50,000/QALY, and a 77% probability at a threshold of $100,000/QALY. Deterministic sensitivity analysis showed that health utilities and cost of osimertinib had the largest impact on ICER results. First-line osimertinib use in patients with advanced EGFR mutant lung cancer was found to involve a trade-off between improved PFS, QALYs and LYs versus increased cost.