Real-World Outcomes of Patients with Advanced Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer in Canada Using Data Extracted by Large Language Model-Based Artificial Intelligence.

Real-world evidence for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) in Canada is limited. This study's objective was to use previously validated DARWENTM artificial intelligence (AI) to extract data from electronic heath records of patients with non-squamous NSCLC at University Health Network (UHN) to describe EGFR mutation prevalence, treatment patterns, and outcomes. Of 2154 patients with NSCLC, 613 had advanced disease. Of these, 136 (22%) had common sensitizing EGFR mutations (cEGFRm; ex19del, L858R), 8 (1%) had exon 20 insertions (ex20ins), and 338 (55%) had EGFR wild type. One-year overall survival (OS) (95% CI) for patients with cEGFRm, ex20ins, and EGFR wild type tumours was 88% (83, 94), 100% (100, 100), and 59% (53, 65), respectively. In total, 38% patients with ex20ins received experimental ex20ins targeting treatment as their first-line therapy. A total of 57 patients (36%) with cEGFRm received osimertinib as their first-line treatment, and 61 (39%) received it as their second-line treatment. One-year OS (95% CI) following the discontinuation of osimertinib was 35% (17, 75) post-first-line and 20% (9, 44) post-second-line. In this real-world AI-generated dataset, survival post-osimertinib was poor in patients with cEGFR mutations. Patients with ex20ins in this cohort had improved outcomes, possibly due to ex20ins targeting treatment, highlighting the need for more effective treatments for patients with advanced EGFRm NSCLC.

Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

The diversity of inhibitory receptor co-expression patterns of exhausted CD8+ T cells in oropharyngeal carcinoma.

Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Real-World Treatment Patterns and Survival Among Patients with Stage I-III, Non-Squamous, Non-Small Cell Lung Cancer Receiving Surgery as Primary Treatment.

INTRODUCTION: Approximately half of patients with non-small cell lung cancer (NSCLC) present with early-stage disease at diagnosis. Real-world outcomes data are limited for this population but are of interest given recent and impending results from trials evaluating epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immunotherapies in neoadjuvant, adjuvant, and perioperative settings. METHODS: A retrospective, longitudinal, population-level study was conducted in patients diagnosed with resected stage I-III non-squamous NSCLC in Ontario, Canada, between April 2010 and March 2019. Study outcomes included patient characteristics and median overall survival (mOS), with stratification by disease stage and treatment exposure. Patients receiving EGFR-TKIs (assumed EGFR mutation-positive by proxy) were a key population of interest. RESULTS: Among 8255 cases, 4881 had stage I, 2124 had stage II, and 1250 had stage III NSCLC at diagnosis. The mean patient age was 68 years; 53.5% were female. In the overall cohort, 19.6% received adjuvant chemotherapy. Receipt of adjuvant chemotherapy was associated with significantly longer mOS than not receiving such therapy: stage II (7.6 [95% confidence interval: 6.5-8.5] vs. 4.4 [4.0-4.9] years) or stage III (4.4 [3.6-5.1] vs. 2.7 [2.3-3.3] years), both p < 0.0001. Patients receiving treatment (EGFR-TKIs and chemotherapy) were assumed to have experienced disease recurrence/relapse; mOS was longer among those receiving an EGFR-TKI than among those receiving chemotherapy (2.3 [1.8-3.0] vs. 1.1 [1.0-1.3] years). CONCLUSION: In Ontario, between 2010 and 2019, uptake of adjuvant therapy was low among patients with resected NSCLC, despite such therapy being associated with improved survival. Patients assumed to have recurred/relapsed had markedly reduced mOS, regardless of subsequent therapy, compared with those who did not relapse/recur. Novel peri-adjuvant treatment options are needed to enhance outcomes after lung resection.

A pragmatic guide for management of adverse events associated with lorlatinib.

Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. RESULTS: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10-15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10-46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74). CONCLUSIONS: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

The Perceived Value of Liquid Biopsy: Results From a Canadian Validation Study of Circulating Tumor DNA T790M Testing-Patient's Willingness-to-Pay: A Brief Report.

Introduction: Liquid biopsy is recommended to diagnose molecular resistance to targeted therapy in patients with lung cancer. Nevertheless, not all jurisdictions provide funding and patient access. We report patients' perceived value of liquid biopsy in targeted therapy resistance. Methods: Canadian patients participating in a national EGFR T790M liquid biopsy validation study completed structured interviews measuring perceived value and willingness-to-pay for plasma circulating tumor DNA testing as an alternative to tumor biopsy using open-ended and iterative bidding approaches. Results: A total of 60 patients with advanced lung cancer participated with a median age of 64 years (range: 31-87 y); 69% were Asian and 45% female. All had received prior EGFR tyrosine kinase inhibitor; 17% also received chemotherapy. All patients preferred to have plasma testing over repeat tumor biopsy. In the context of the Canadian publicly funded system, patients estimated that a median of 300 (interquartile range: 150-800) Canadian dollars was a reasonable price to pay for liquid biopsy. Patients were personally willing to pay a median 100 (interquartile range: 33-350) Canadian dollars. Conclusions: In a system that covers the cost of standard diagnostic tests, patients with lung cancer indicated high willingness-to-pay out-of-pocket for liquid biopsy in the setting of acquired targeted therapy resistance. Patients have high perceived value of plasma genotyping and prefer it to repeat tumor biopsy.

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. CONCLUSIONS: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. IMPACT: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Radiomics analysis to predict pulmonary nodule malignancy using machine learning approaches.

BACKGROUND: Low-dose CT screening can reduce lung cancer-related mortality. However, most screen-detected pulmonary abnormalities do not develop into cancer and it often remains challenging to identify malignant nodules, particularly among indeterminate nodules. We aimed to develop and assess prediction models based on radiological features to discriminate between benign and malignant pulmonary lesions detected on a baseline screen. METHODS: Using four international lung cancer screening studies, we extracted 2060 radiomic features for each of 16 797 nodules (513 malignant) among 6865 participants. After filtering out low-quality radiomic features, 642 radiomic and 9 epidemiological features remained for model development. We used cross-validation and grid search to assess three machine learning (ML) models (eXtreme Gradient Boosted Trees, random forest, least absolute shrinkage and selection operator (LASSO)) for their ability to accurately predict risk of malignancy for pulmonary nodules. We report model performance based on the area under the curve (AUC) and calibration metrics in the held-out test set. RESULTS: The LASSO model yielded the best predictive performance in cross-validation and was fit in the full training set based on optimised hyperparameters. Our radiomics model had a test-set AUC of 0.93 (95% CI 0.90 to 0.96) and outperformed the established Pan-Canadian Early Detection of Lung Cancer model (AUC 0.87, 95% CI 0.85 to 0.89) for nodule assessment. Our model performed well among both solid (AUC 0.93, 95% CI 0.89 to 0.97) and subsolid nodules (AUC 0.91, 95% CI 0.85 to 0.95). CONCLUSIONS: We developed highly accurate ML models based on radiomic and epidemiological features from four international lung cancer screening studies that may be suitable for assessing indeterminate screen-detected pulmonary nodules for risk of malignancy.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility.

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis. SIGNIFICANCE: The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention.

Analysis of prognostic germline polymorphisms in patients with advanced hepatocellular carcinoma.

Background: The prognosis of hepatocellular carcinoma (HCC) is influenced by both tumor and patient specific factors. Current therapies of advanced HCC target angiogenesis and immune evasion, however there are no clinically useful biomarkers to guide clinicians. Methods: Our aim in this retrospective cohort study was to validate single nucleotide polymorphisms (SNPs) prognostic of outcome in advanced HCC from the literature, and to analyze exploratory SNPs chosen from evaluation of the HCC tumor immune microenvironment. Using a database of patients with HCC treated with sorafenib, blood samples were genotyped, clinical variables were retrospectively collected, and SNPs were analyzed for association with progression-free survival (PFS) and overall survival (OS). A subsequent analysis was conducted to determine if identified SNPs were prognostic in trans arterial chemoembolization (TACE) treated patients. Results: Literature review identified 7 SNPs in vascular endothelial growth factor (VEGF), eNOS, angiopoietin 2 (ANGPT2) and vascular endothelial growth factor receptor 2 (VEGFR2), however none were externally validated in our dataset. Of the 35 exploratory immunomodulatory SNPs, the following were associated with PFS or OS: CCL2 C-C motif ligand 2 (CCL2) (rs1024611), interleukin-10 (IL-10) (rs1800896), cytotoxic T-lymphocyte antigen-4 (CTLA-4) (rs231775) and NFKB1 (rs28362491). Conclusions: SNPs identified by literature review to be prognostic in sorafenib treated patients with advanced HCC were not validated in our dataset. Our findings suggest potentially important prognostic implications of SNPs in VEGFR2, CCL2, IL-10, CTLA-4 and NFKB1 that deserve further study.

Presentation and outcomes of KRASG12C mutant non-small cell lung cancer patients with stage IV disease at diagnosis (de novo) versus at recurrence.

Close monitoring after diagnosis of patients with stage I-III non-small cell lung cancer (NSCLC) may result in fitter patients with lower disease burden at the time of metastatic recurrence or progression compared to patients diagnosed initially as stage IV (de novo). We compared the presentation, treatments, and outcomes of patients with KRASG12C-mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRASG12C-mutated NSCLC who developed stage IV disease at recurrence (n = 38), de novo stage IV patients (n = 71) had worse ECOG performance status (p = 0.007), greater numbers of extra-thoracic metastatic sites (p = 0.001), and were less likely to receive 2nd/3rd line systemic therapy (p = 0.05, p = 0.002) or targeted therapy (p = 0.001). De novo metastatic patients had shorter overall survival than metastatic patients at recurrence (9.1 versus 24.2 months; adjusted-hazard-ratio=1.94 (95% CI: 1.14-3.28; p = 0.01)). There is a critical need for well-tolerated targeted therapies in the first-line setting for metastatic patients with de novo, high-burden, stage IV KRASG12C-mutated NSCLCs.

A Population-Based Outcome-Wide Association Study of the Comorbidities and Sequelae Following COVID-19 Infection.

BACKGROUND: Immense attention has been given to the outcome of COVID-19 infection. However, comprehensive studies based on large populational cohort with long-term follow-up are still lacking. This study aimed to investigate the risk of various short-term comorbidities (within one month) and long-term sequelae (above one month) after COVID-19 infection. METHODS: In this large prospective cohort study with 14 months follow-up information based on UK biobank, we included 16,776 COVID-19-positive participants and 58,281 COVID-19-negative participants matched for comparison. The risk of each comorbidity and sequela was evaluated by multivariable logistic regression analysis and presented as hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: COVID-19-positive individuals had a higher risk of 47 types of comorbidities within one month following COVID-19 infection, especially those who were older, male, overweight/obese, ever-smoked, with more pre-existing comorbidities and hospitalized. About 70.37% of COVID-19 patients with comorbidities had more than one co-occurring comorbidities. Additionally, only 6 high-risk sequelae were observed after one month of COVID-19 infection, and the incidence was relatively low (< 1%). CONCLUSION: In addition to long-term sequelae following COVID-19 infection, plenty of comorbidities were observed, especially in patients with older age, male gender, overweight/obese, more pre-existing comorbidities and severe COVID-19, indicating that more attention should be given to these susceptible persons within this period.

Programmed Cell Death Protein 1 Inhibitors and MET Targeted Therapies in NSCLC With MET Exon 14 Skipping Mutations: Efficacy and Toxicity as Sequential Therapies.

Introduction: NSCLC with MET exon 14 skipping mutation (METex14) is associated with poor outcomes. Integration of novel targeted therapies is challenging because of barriers in testing and drug access. We, therefore, sought to characterize the treatment patterns, outcomes, and emerging issues of treatment sequencing in patients with METex14-mutant NSCLC. Methods: We reviewed all NSCLC cases with METex14 alterations between 2014 and 2020 across four Canadian cancer centers. Demographics, disease characteristics, systemic therapy, overall response rates (ORRs), survival, and toxicity were summarized. Results: Among 64 patients with METex14-mutant NSCLC, the median overall survival was 23.1 months: 127.0 months in stage 1, 27.3 months in resected stage 2 and 3, and 16.6 months in unresectable stage 3 or 4 disease, respectively. In patients with advanced disease, 22% were too unwell for systemic treatment. MET tyrosine kinase inhibitors (TKIs) were administered to 28 patients with an ORR of 33%, median progression-free survival of 2.7 months, and 3.8 months for selective TKIs. Programmed cell death protein-1 (PD-1) inhibitors were given to 25 patients-the ORR was 44% and progression-free survival was 10.6 months. No responses were seen with subsequent MET TKIs after initial TKI treatment. Grade 3 or higher toxicities occurred in 64% of patients who received MET TKI after PD-1 inhibitors versus 8% in those who did not receive PD-1 inhibitors. Conclusions: Many patients with advanced METex14 NSCLC were too unwell to receive treatment. PD-1 inhibitors seem effective as an initial treatment, although greater toxicity was seen with subsequent MET TKIs. Thus, timely testing for METex14 skipping and initial therapy are imperative to improving patient survival.