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

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

Cost-effectiveness of lung cancer screening by low-dose CT in China:a micro-simulation study

Background: The effectiveness of lung cancer screening with low-dose computed tomography (LDCT) has been established. The current study evaluates the cost-effectiveness of lung cancer screening with LDCT in a general population in China. Methods: A previously validated micro-simulation model was used to simulate a cohort of men and women on a lifetime horizon in the presence and absence of LDCT screening. The modeling data were collected from numerous national and international sources. Simulated screening scenarios included different combinations of screening intervals and start and stop ages. Additional costs (valued in Chinese Yuan, CNY; 1 USD = 6.8976 CNY, 1 EUR = 7.8755 CNY in 2020), life-years gained (LYG) and mortality reduction due to screening were also determined. The costs and life-years were discounted by 3%. All results were scaled to 1,000 individuals. The average cost-effectiveness ratio (ACER) was calculated. A willingness-to-pay threshold of CNY 217.3k / LYG was considered. A healthcare system perspective was adopted. Results: Compared to no screening, lung cancer screening by LDCT in a general Chinese population yielded 21.0 – 36.7 LYG in men and 9.2 – 16.6 LYG in women across the scenarios. For men, biennial LDCT screening yielded an ACER of CNY 171.4k – 306.3k / LYG relative to no screening. Biennial screening performed between 55 and 75 years of age was optimal at the defined threshold; it resulted in CNY 174.6k / LYG and a lung cancer mortality reduction of 9.1%, and this scenario had a 75% probability of being cost-effective. For women, the ACER ranged from CNY 364.2k to 1193.3k / LYG. Conclusions: In China, lung cancer screening with LDCT in the general population including never smokers could be cost-effective for men with 75% probability, but not for women. The optimal strategy for men would be performing biennial screening between 55 and 75 years of age

Development and Evaluation of a Real-World Outcomes-Based Tool to Support Informed Clinical Decision Making in the Palliative Treatment of Patients With Metastatic NSCLC

PURPOSE: To develop and evaluate a tool for patients with stage IV non-small-cell lung cancer and their thoracic oncologists (TOs) that provides insight into real-world effectiveness of systemic treatments to support informed clinical decision making in the palliative setting. METHODS: A participatory design approach was used to acquire insights from patients and TOs into preferences regarding the content and design of the web-based tool. Implementation was investigated by means of an adoption and usage rate. The appreciation of the tool was evaluated through a telephone survey with patients and a questionnaire for TOs. RESULTS: From clinical data of 2,989 patients with stage IV non-small-cell lung cancer diagnosed in one of the Santeon hospitals, an interface was developed to show treatments plus both real-world outcomes and clinical trial results after selecting patient characteristics (patients like me). This prototype of the tool was finalized after discussion in a focus group with four TOs and semi-structured interviews with six patients. The tool was implemented and used by TOs in three of six Santeon hospitals (50% adoption rate). The tool was used in 48 patients (29% usage rate), of which 17 participated in the telephone survey. Ten TOs responded to the questionnaire. The responses varied from positive reactions on the clear overview of treatment outcomes to statements that the tool rarely changed treatment decisions. Overall, the majority of patients and TOs scored the tool as of added value (71% and 83%, respectively). CONCLUSION: Our real-world data tool in metastatic lung cancer was appreciated in clinical practice by both patients and TOs. However, the efficacy of the implementation can be improved