Decoding circulating tumor DNA to identify durable benefit from immunotherapy in lung cancer

Objectives: Predicting the outcome of immunotherapy-treated non-small cell lung cancer (NSCLC) patients is challenging. Measuring circulating tumor DNA (ctDNA) in plasma is promising, but its application for outcome delineation needs further refinement. Since most information from the next-generation sequencing (NGS) panel is typically left unused, we aim to integrate more information. Materials and Methods: Patient and ctDNA data were compiled from five published studies involving advanced NSCLC. Plasma samples collected prior (t0) and early during (t1) immunotherapy were selected, tracking the changes of the highest t0 variant per gene. Durable benefit (DB, defined as progression free survival ≥ ½ year) was predicted. Performance was quantified using the integrated receiver operating characteristic curve (ROC AUC) and compared with the traditional molecular response (MR). Results: A total of 365 patients were pooled. Seven recurrently mutated genes were selected which optimally predicted DB (ROC AUC: 0.77-0.11+0.10), outperforming the MR predictor (with a ROC AUC: 0.64-0.11+0.11). Inclusion of patient characteristics led to a slight further improvement (ROC AUC: 0.80-0.10+0.09). The model performed satisfactory across all ctDNA platforms despite differences in panel size and content. Conclusion: Relative to a non-informative classifier (ROC AUC: 0.5), a twofold improvement in predictive value was achieved compared to MR by an integration of changes across seven selected genes in immunotherapy-treated NSCLC patients, whilst being broadly applicable across ctDNA NGS panels

Temporal trends and spatial variation in stage distribution of non-small cell lung cancer in the Netherlands

Introduction To explore regional and temporal variation in clinical stage distribution of non-small cell lung cancer (NSCLC) and link the observations to the introduction of positron emission tomography (PET). Method All NSCLC patients diagnosed between 1989 and 2007 were selected from the Netherlands Cancer Registry (n=126,962). Maps of smoothed percentage distribution of clinical stage NSCLC were conducted by period of diagnosis. Join point regression analyses were performed to detect trends over time. Geographic variation in stage distribution was evaluated using spatial scan statistic. To evaluate the impact of PET in regions proportions of stage IV and Estimated Annual Percentage of Change (EAPC) were calculated for two regions in which PET was introduced between 1995 and 2000 and for two regions without a PET scanner during this period. Results The percentage of stage I and unknown decreased with 7.4% and 13.3% between 1989 and 2007, while the percentage of stage IV increased with 23.4%. The most rapid increase in stage I and IV were observed between 1997 and 2003. In two regions with a PET scan the proportion of stage IV increased annually with 10.3 and 8.5% compared to 5.4 and 6.4% in two regions without a PET scan. Conclusion The most rapid changes towards more stage IV NSCLC diagnoses correspond with the implementation of PET. However, trends were already visible before PET was introduced and regions without PET also showed considerable increases in stage IV diagnose, suggesting other factors or improvements in diagnostics also contributed substantially

Assessing lung cancer screening programs under uncertainty in a heterogeneous population

Background: Lung cancer screening can reduce cancer mortality. Most implementation studies focus only on low-dose computed tomography (LDCT) and clinical attributes of screening and do not include preferences of potential participants. In this study we evaluated the perceived value of screening programs based on LDCT, breath analysis (BA), or blood biomarkers (BB) according to the perspective of the target population. Methods: A multi-criteria decision analysis framework was adopted. The weights of seven attributes of screening (sensitivity, specificity, radiation burden, duration of screening process, waiting time until results are communicated, location of screening, and mode of screening) were obtained from an earlier study that included a broad sample from the Netherlands. Performance data for the screening modalities was obtained from clinical trials and expert opinion. Parameter uncertainty about clinical performances was incorporated probabilistically, while heterogeneity in preferences was analyzed through subgroup analyses. Results: The mean overall values were 0.58 (CI: 0.57 to 0.59), 0.57 (CI: 0.56 to 0.59), and 0.44 (CI: 0.43 to 0.45) for BB, BA, and LDCT, respectively. Seventy-seven per cent of respondents preferred BB or BA. For most subgroups, the overall values were similar to those of the entire sample. BA had the highest value for respondents who would have been eligible for earlier screening trials. Discussion: BB and BA seem valuable to participants because they can be applied in a primary care setting. Although LDCT still seems preferable given its strong and positive evidence base, it is important to take non-clinical attributes into account to maximize attendance.</p

Mutation-tailored treatment selection in non-small cell lung cancer patients in daily clinical practice

Objectives: The number of targeted drugs in non-small cell lung cancer (NSCLC) is ever-expanding and requires testing of an increasing number of predictive biomarkers. We present a comprehensive real-world evaluation of molecular testing and treatment selection in stage IV NSCLC patients in the Netherlands from 2017 to 2019. Materials and methods: Molecular pathology reports of NSCLC patients were collected from the Dutch Pathology Registry in time intervals between Oct-2017 and April-2019 (N = 5,038 patients) to study diagnostic yield. Linkage between the Dutch Pathology Registry and the Netherlands Cancer Registry enabled studying molecular testing rates for stage IV NSCLC initially diagnosed in 2017-Q4 (N = 1,193) and application of targeted therapy in stage IV NSCLC patients with potentially druggable alterations reported between Oct-2017 and June-2018 (N = 401). Results: Predictive molecular testing was performed in 85.0% of adenocarcinomas, 60.4% of NSCLC-not otherwise specified (NOS) and 17.4% of squamous cell carcinomas. Testing rates were highest for EGFR and ALK (adenocarcinoma: 82.7% and 80.7%, respectively). Incidence of molecular driver alterations (i.e. EGFR, KRAS, ALK, ROS1, BRAF, MET, ERBB2, FGFR1) was 61.1% for adenocarcinomas, 42.3% for NSCLC-NOS, and 24.7% for squamous cell carcinomas. Therapeutically relevant alterations were detected at a higher frequency by NGS- versus non-NGS-approaches (adenocarcinoma: 62.4% versus 56.5%, respectively (P = 0.004)) due to a lower failure rate, more comprehensive testing and higher sensitivity. Uptake of treatment with a registered targeted therapy in eligible patients varied per actionable target, i.e. EGFR: 85.8%, ALK: 74.7%, ROS1: 33.7%, BRAF: 51.5%. Treatment with agents in clinical studies/compassionate use was lower, i.e. MET: 22.8%, HER2: 18.9%, RET: 6.7%. Conclusion: Real-world data show NGS-based approaches to be superior to non-NGS. Uptake of molecular testing and the corresponding targeted treatments was less than expected based on guidelines and even more so for trials, off-label use and compassionate use, indicating less than optimal access to rational treatment options

F-18-FDG PET/CT Scans Can Identify Sub-Groups of NSCLC Patients with High Glucose Uptake in the Majority of Their Tumor Lesions

Background: Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (F-18-FDG) positron emission tomography (PET)/computed tomography (CT) scans. Methods: Routine primary diagnostic F-18-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of F-18-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated. Results: The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P = 1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9). Conclusions: F-18-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient

Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study

Contains fulltext : 207334.pdf (publisher's version ) (Open Access

CT characteristics of solid pulmonary nodules of never smokers versus smokers:A population-based study

Purpose: Aim was to assess CT characteristics of lung nodules in never and former smokers compared to current smokers in a population-based setting. Method: We included individuals aged 45–60 years taking part in the ImaLife (Imaging in Lifelines) study, with at least one solid lung nodule (≥30 mm3) on low-dose chest CT. Qualitative (location, shape, margin, nodule type, attached structures) and quantitative (count, diameter, volume) nodule characteristics were evaluated. Based on Fleischner criteria, ‘high risk’ nodules were defined. To examine the association between smoking status and nodule CT characteristics of participants, multi-level multinomial logistic regression corrected for clustering of nodules within participants was performed, where all odds ratios (aORs) were adjusted for age and sex. Results: Overall, 1,639 individuals (median age: 55.0, IQR:50.5–58.5, 50.5% men) were included, with 42.1% never smokers, 35.3% former smokers and 22.6% current smokers. A total of 3,222 solid nodules were identified; 39.7% of individuals had multiple nodules. Nodule size, location, type and attachment were similar for never compared to current smokers. The odds of nodules with an irregular shape and irregular margin was lower in never smokers (aOR:0.64, 95 %CI:0.44–0.93; aOR:0.60, 95 %CI:0.41–0.88, respectively) and former smokers (aOR:0.61, 95 %CI:0.41–0.90; aOR:0.57, 95 %CI:0.38–0.85, respectively) compared to current smokers. The odds of a detected nodule being ‘high risk’ was similar for never versus current smokers (never smokers: aOR = 0.90; 95% CI:0.73–1.11). Conclusions: CT-based characteristics of solid lung nodules in never and former smokers differed only slightly from current smokers. Among individuals with solid nodules, ‘high-risk’ nodules were equally common in never smokers and current smokers

Exploring the Cost Effectiveness of a Whole-Genome Sequencing-Based Biomarker for Treatment Selection in Patients with Advanced Lung Cancer Ineligible for Targeted Therapy

Objective: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. Methods: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient’s disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of €80,000/QALY. Additional scenario and threshold analyses were performed. Results: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (€120,800). The highest QALYs and healthcare costs were 2.00 and €140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (€27,300), followed by strategy B (€26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ €76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ €39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. Conclusions: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy.</p