Epidemiology and Outcomes of Non-Small Cell Lung Cancer in South Korea.

Importance: Valuable evidence regarding clinical characteristics, treatments, and outcomes for non-small cell lung cancer (NSCLC) is limited to individual hospital databases or national-level registries. The common data and federated analysis framework developed through the Extensible Platform for Observational Research in Lung Cancer (EXPLORE-LC) initiative allows for research across multiple high-quality data sources, which may provide a deeper understanding of the NSCLC landscape and identification of unmet needs of subpopulations. Objective: To describe clinical characteristics, initial treatment patterns, subsequent treatment, and overall survival (OS) of patients with NSCLC in South Korea. Design, Setting, and Participants: This multicenter cohort study included patients aged 18 years and older who were diagnosed with NSCLC between 2014 and 2019 and followed up until March 2020 at 3 tertiary hospitals in South Korea. Clinical data were collected using a common data model and clinical data warehouse. Patients who had an initial diagnosis of nonsquamous (NSQ) or squamous (SQ) NSCLC and who had received at least 1 treatment for NSCLC were included in the study. Data were analyzed from June through November 2022. Main Outcomes and Measures: The primary outcome was clinical OS for patients with NSCLC. Secondary outcomes were clinical characteristics and treatment patterns subsequent to the diagnosis of NSCLC. Results: Among 22 101 patients with NSCLC who received anticancer treatment analyzed in this study, 17 350 patients (78.5%) had NSQ and 4751 patients (21.5%) had SQ NSCLC. Clinical characteristics and outcomes and treatment patterns were assessed for 13 084 patients with NSQ cancer who had known EGFR and ALK status (75.4%; mean [SD] 62.2 [10.5] years; 6552 males [50.1%]) and all 4751 patients with SQ cancer (mean [SD] age, 67.1 [8.6] years; 4427 males [93.2%]). More than half of patients with NSQ cancer were never smokers (7399 patients [56.6%]). Patients with SQ cancer were mostly males and former or current smokers (4235 patients [89.1%]) and were diagnosed at a later clinical stage than patients with NSQ cancer (eg, stage I: 1165 patients [24.5%] vs 5388 patients [41.2%]). Patients with EGFR-positive and ALK-positive NSQ cancer diagnosed between 2017 and 2019 had better median OS than similar patients diagnosed between 2014 and 2016 (EGFR-positive: not reached [95% CI, 35.9 months to not reached] vs 28.4 months [95% CI, 25.8 to 30.0 months]; P < .001; ALK-positive: not reached [95% CI, not reached] vs 49.5 months [95% CI, 35.1 months to not reached]; P < .001). No significant difference was observed in OS from first-line treatment for patients with SQ cancer. Conclusions and Relevance: This study, which pooled medical data from multiple clinical data warehouses to produce a large study cohort, may provide meaningful insights into the clinical practice of NSCLC and underscores the value of a common data model approach. The analyzable dataset may hold great promise for future comprehensive identification of subpopulations and unmet needs.

Initial treatment and survival in Danish patients diagnosed with non-small-cell lung cancer (2005-2015): SCAN-LEAF study.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005-2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0-60.6%) but not squamous NSCLC (44.9-47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23-31%) but not squamous NSCLC (22-25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.

Epidemiology and Survival Outcomes for Patients With NSCLC in Scandinavia in the Preimmunotherapy Era: A SCAN-LEAF Retrospective Analysis From the I-O Optimise Initiative.

INTRODUCTION: SCAN-LEAF, part of the I-O Optimise initiative, is a retrospective, longitudinal study investigating the epidemiology, clinical care, and outcomes for patients with NSCLC in Scandinavia. We report overall survival (OS) trends for patients diagnosed with NSCLC in Sweden and Denmark between 2005 and 2015. METHODS: Swedish and Danish cohorts were established by linking national registries. Data on all adults diagnosed with incident NSCLC from January 1, 2005, to December 31, 2015, were included. For temporal analyses of OS trends, patients were stratified by TNM stage and histology. RESULTS: Between 2005 and 2015, a total of 30,067 and 31,939 patients from Sweden and Denmark, respectively, were diagnosed with NSCLC; the most common histological subtype was nonsquamous cell carcinoma (56.9% and 53.0%) and 48.4% and 51.6% were diagnosed at stage IV. Over the study period, significant improvements in short-term survival (1 y) were observed for patients with nonsquamous cell carcinoma in both countries, regardless of disease stage at diagnosis; however, improvements in longer-term survival (5 y) were limited to patients with stage I and II disease only. Conversely, among patients with squamous cell histology, improvements in short-term survival were only observed for stage I disease in Sweden and stage IIIA disease in Denmark, while significant improvements in longer-term survival were seen only for stage IIIA NSCLC in both countries. CONCLUSIONS: Despite some survival improvements between 2005 and 2015, an unmet need remains for patients with advanced NSCLC, particularly those with squamous cell histology. Future analyses will evaluate the impact of newer treatments on OS in NSCLC.

Use of External Comparators for Health Technology Assessment Submissions Based on Single-Arm Trials.

BACKGROUND: Single-arm trial (SAT) data is increasingly reviewed for drug approvals by regulators and Health Technology Assessment (HTA) bodies. Supplementary data in the form of external comparators (ECs) can be used to provide clinical context to support these drug evaluations. In this study we characterized HTAs for SAT-based submissions, the use of supplementary EC data and outcomes from HTA review. METHODS: HTA Accelerator database was used to describe SAT-based HTA submissions with decisions (2011-2019). RESULTS: A total of 433 SAT-based HTA submissions were identified between 2011 and 2019 with a 13-fold increase during this period. Around 65%(283/433) were in oncology or hem-oncology. Around 52%(226/433) of submissions contained some type of EC data, including prior clinical trials (24%, 104) and real-world data (RWD) (20%, 87), but 40%(175) contained no EC data. The overall acceptance rate for SAT-based submissions was 48% and with RWD EC data acceptance was 59%. In the latest 5-year period (2015-2019), use of RWD ECs increased 22% as a proportion of submissions per year, whereas, prior trial ECs decreased (-14%) and use of no EC remained stable (-2%). Between 2015 to 2017 and 2018 to 2019, acceptance rate for RWD ECs increased by 20% (41% in 2015-2017 to 61% in 2018-2019) whereas prior trial EC use decreased by 10% and no EC submissions decreased 16%. Of 226 submissions using ECs, only 29%(66) used an adjusted indirect treatment comparison method. CONCLUSIONS: SAT-based submissions to HTA bodies are rapidly evolving in terms of composition and acceptance. Types of EC and methodological approach used are important determinants of positive outcomes.

Treatment and outcomes for early non-small-cell lung cancer: a retrospective analysis of a Portuguese hospital database.

AIM: This observational study evaluated treatment patterns and survival for patients with stage I-IIIA non-small-cell lung cancer (NSCLC). MATERIALS & METHODS: Adults newly diagnosed with NSCLC in 2012-2016 at IPO-Porto hospital were included. Treatment data were available for patients diagnosed in 2015-2016. RESULTS: 495 patients were included (median age: 67 years). The most common treatments were surgery alone or with another therapy (stage I: 66%) and systemic anticancer therapy plus radiotherapy (stage II: 54%; stage IIIA: 59%). One-year OS (95% CI) for patients with stage I, II and IIIA NSCLC (diagnosed 2012-2016) were 92% (88-96), 71% (62-82) and 69% (63-75), respectively; one-year OS (95% CI) for treated patients with stage I-II or stage IIIA NSCLC (diagnosed 2015-2016) were 89% (81-97) and 86% (75-98) for non-squamous cell and 76% (60-95) and 49% (34-70) for squamous cell NSCLC. CONCLUSION: Treatment advances are strongly needed for stage I-IIIA NSCLC, especially for patients with squamous cell histology.

Real-world treatment patterns and survival outcomes for advanced non-small cell lung cancer in the pre-immunotherapy era in Portugal: a retrospective analysis from the I-O Optimise initiative.

BACKGROUND: As part of the multinational I-O Optimise research initiative, this retrospective cohort study of patients with advanced non-small cell lung cancer (NSCLC) evaluated real-world treatment patterns and survival prior to immunotherapy reimbursement in Portugal. METHODS: This study utilized a database held by IPO-Porto, Portugal's largest oncology hospital. Adult patients diagnosed with stage IIIB or IV NSCLC from January 2012 to December 2016 at IPO-Porto, with follow-up to June 2017, were included. Treatment analyses were performed from 2015 onwards. Kaplan-Meier methods were used for overall survival (OS). Factors associated with OS and systemic anti-cancer therapy (SACT) treatment were assessed using multivariate statistical models. RESULTS: Of 1524 patients diagnosed with NSCLC at IPO-Porto, 1008 patients had advanced disease (stage IIIB: 10.1%, 154/1524, stage IV: 56.0%, 854/1524). For those with advanced disease, median age was 65 years (range: 21-92) and 75.6% (762/1008) were male. Median OS (interquartile range [IQR]) was 11.4 (5.2-26.9) months for stage IIIB and 6.3 (2.4-15.0) months for stage IV. Factors associated with decreased risk of death included female sex and epidermal growth factor receptor gene (EGFR)/anaplastic lymphoma kinase gene (ALK) mutations/rearrangements; factors associated with increased risk of death included older age and stage IV disease. Among patients diagnosed in 2015 or 2016, 75.8% (297/392) received ≥1 line of SACT. Platinum-based chemotherapy was the most common first-line therapy (non-squamous cell carcinoma [NSQ]: 72.9%; squamous cell carcinoma [SQ] 87.3%, 55/63; patients with EGFR/ALK mutations/rearrangements primarily received tyrosine kinase inhibitors). The likelihood of receiving SACT was lower in older patients and those diagnosed with stage IV disease. Patients not receiving SACT had poor survival outcomes (median OS [IQR]: NSQ, 1.8 [1.1-3.1] months; SQ, 2.3 (1.3-3.4) months), while median OS (IQR) in SACT-treated patients was 12.6 (6.1-24.5) months for NSQ and 10.3 (5.7-15.9) months for SQ. CONCLUSIONS: This real-world data analysis from a large Portuguese oncology hospital demonstrates a high disease burden for advanced NSCLC in the pre-immunotherapy era, with nearly one-quarter of patients not receiving SACT. Even in patients receiving SACT, median survival was only about 1 year.

The burden of systemic juvenile idiopathic arthritis for patients and caregivers: an international survey and retrospective chart review.

OBJECTIVES: To investigate the burden of systemic juvenile idiopathic arthritis (SJIA) on health-related quality of life (HRQOL) and resource use of patients and caregivers (families) on biologic therapy. METHODS: This international study assessed SJIA burden in patients on biologics, using a caregiver questionnaire and retrospective chart review. Validated measures included: Child Health Questionnaire Parent-Form 50 (CHQ-PF50), 36-Item Short-Form Health Survey (SF-36v2) and Work Productivity and Activity Impairment questionnaire: Specific Health Problem (WPAI:SHP). Caregivers completed function, treatment satisfaction and resource utilisation questions. RESULTS: Sixty-one biologic treated patients participated (12 anakinra, 25 canakinumab, 24 tocilizumab). Mean age at diagnosis and survey completion was 6.4 and 11.3 years, respectively. Mean (±SD: standard deviation) CHQ-PF50 physical (PhS) and psychosocial (PsS) summary scores were significantly lower in SJIA patients than a normative population (PhS: 40.0±18.2 vs. 53.0±8.8; PsS: 46.6±11.3 vs. 51.2±9.1) as was caregivers' mean SF-36v2 mental component score (MCS; 46.2±10.7 vs. 50.0±10). Assistive devices were required by 54%; 20% required home/car alterations. According to caregivers, biologic treatment completely improved SJIA symptoms in 48% on canakinumab or tocilizumab and 32% on anakinra. Over 2 months, patients missed 2.9 school days due to SJIA (10% yearly loss). Caregivers lost 25 work days annually and 27.5 days of productivity (WPAI-SHP: mean absenteeism 10%; presenteeism 11%). Yearly SJIA travel/treatment costs averaged $1,130. CONCLUSIONS: SJIA patients on biologic therapy experience HRQOL impairment, caregivers' mental well-being suffers and productivity losses and expenses are incurred. Therapeutic interventions that reduce the burden of SJIA are required.

Management of Factor Xa inhibitor-associated life-threatening major hemorrhage: A retrospective multi-center analysis.

BACKGROUND: Factor Xa (FXa) inhibitors, used for stroke prevention in atrial fibrillation and venous thromboembolism treatment and prevention, are the dominant non-Vitamin K oral anticoagulants on the market. While major bleeding may be less common with these agents compared to warfarin, it is always a risk, and little has been published on the most serious bleeding scenarios. This study describes a cohort of patients with FXa inhibitor-associated life-threatening bleeding events, their clinical characteristics, interventions and outcomes. METHODS: We performed a retrospective, 5-center review of FXa inhibitor-treated major bleeding patients. Investigators identified potential cases by cross-referencing ICD-9/10 codes for hemorrhage with medication lists. Investigators selected cases they deemed to require immediate reversal of coagulopathy, and reviewed charts for characteristics, reversal strategies and other interventions, and outcomes. RESULTS: A total of 56 charts met the inclusion criteria for the retrospective cohort, including 29 (52%) gastrointestinal bleeds (GIB), 19 (34%) intracranial hemorrhages (ICH) and 8 (14%) others. Twenty-four (43%) patients received various factor or plasma products, and the remainder received supportive care. Thirty-day mortality was 21% (n=12). Re-anticoagulation within 30-days occurred in 23 (41%) patients. Thromboembolic events (TEEs) occurred in 6 (11%) patients. No differences were observed in outcomes by treatment strategy. CONCLUSIONS: This cohort of FXa inhibitor-associated major bleeding scenarios deemed appropriate for acute anticoagulant reversal illustrates the variable approaches in the absence of a specific reversal agent.

Characteristics and outcomes of ALK+ non-small cell lung cancer patients in Korea.

AIM: This study aimed to describe characteristics, treatment patterns and survival among Korean patients diagnosed with locally advanced or metastatic anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC). METHODS: A retrospective patient chart review was conducted in major cancer centers in Korea in 2014-2015. Participating physicians reviewed patient charts and reported characteristics, treatment patterns, clinician-defined progression-free survival (PFS) and overall survival (OS) of ALK+ locally advanced or metastatic NSCLC patients. PFS and OS were estimated using Kaplan-Meier analysis. RESULTS: Physicians reported on 55 ALK+ NSCLC patients. Median age at locally advanced or metastatic NSCLC diagnosis was 60 years. Most patients (82%) received initial chemotherapy; 13% received an ALK inhibitor in the first line; 62% received an ALK inhibitor by the end of follow-up. Of the 30 patients who received crizotinib, 83% discontinued and 13% died during crizotinib therapy. Median PFS on crizotinib was 6.7 months. Of those who discontinued, 32% switched to chemotherapy, 16% switched to a different ALK inhibitor and 52% received no further therapy. After discontinuing crizotinib, median OS was 6.0 months overall, and 3.4 months among patients who did not receive a second-generation ALK inhibitor. CONCLUSION: In this study of locally advanced or metastatic ALK+ NSCLC patients in Korea, roughly one-third did not receive an ALK inhibitor. Among patients who discontinued crizotinib, over half received no further antineoplastic therapy and OS was poor, particularly among patients without second-generation ALK inhibitor use. These findings suggest a need for greater access to effective treatments following crizotinib discontinuation for ALK+ NSCLC patients in Korea.

International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome.

OBJECTIVE: Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). METHODS: PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de-identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. RESULTS: A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute-phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8-year delay in FMF patients. An equal proportion of TRAPS patients first received anti-interleukin-1 (anti-IL-1) and anti-tumor necrosis factor (anti-TNF) biologic agents, whereas IL-1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti-TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. CONCLUSION: Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real-world treatment assessment supports the need for further refinement of treatment practices.

Characteristics, treatment patterns, and survival among ALK+ non-small cell lung cancer (NSCLC) patients treated with crizotinib: A chart review study.

OBJECTIVES: Second-generation ALK inhibitors are recently available for ALK+ non-small cell lung cancer (NSCLC) patients previously treated with crizotinib. This study described characteristics, treatment sequencing, and outcomes among locally advanced/metastatic crizotinib-experienced ALK+ NSCLC patients. MATERIALS AND METHODS: From July 2014 to June 2015, a retrospective patient chart review was conducted among physicians from the US, EU, Korea, and Latin America. Participating clinicians identified their ALK+ NSCLC patients who received crizotinib and reported on their clinical characteristics, treatments, and survival using a pre-defined case report form. Kaplan-Meier analyses were used to describe overall survival (OS) and clinician-defined progression-free survival (PFS). RESULTS: Participating clinicians reviewed charts of 158 ALK+ NSCLC patients treated with crizotinib during the study period. Crizotinib was most commonly received in the second-line setting (41% of patients), though this varied across geographical regions. Roughly half (53%) of the patients who discontinued crizotinib received further antineoplastic therapy; second-generation ALK inhibitors (44%) and chemotherapy (42%) regimens were used most frequently. Following crizotinib discontinuation, median OS was 8.2 months. Among patients who did not initiate a second-generation ALK inhibitor following crizotinib, median OS was 4.9 months; among those who did, median OS was not reached. Among patients who received chemotherapy immediately following crizotinib discontinuation, time to clinician-defined PFS from post-crizotinib chemotherapy initiation was 3.6 months. CONCLUSION: Following crizotinib discontinuation, many patients received no further antineoplastic therapy, and OS was poor among patients who did not receive a second-generation ALK inhibitor. Recently available second-generation ALK inhibitors may provide important treatment options for ALK+ NSCLC patients.

Effective inhibitors of the essential kinase PknB and their potential as anti-mycobacterial agents.

PknB is an essential serine/threonine kinase of Mycobacterium tuberculosis with possible roles in a number of signalling pathways involved in cell division and metabolism. We screened a library of >50,000 compounds for inhibitors of the in vitro phosphorylation of GarA (Rv1827) by PknB and identified a number of inhibitors. A program of synthetic medicinal chemistry was subsequently conducted around one class of inhibitors and was successful in generating ATP competitive inhibitors with potency in the nanomolar range. Compounds in this class showed cross-reactivity with the related M. tuberculosis kinase, PknF, but not with PknG in an in vitro autophosphorylation assay. These synthesised inhibitors were able to prevent the growth of M. tuberculosis in an Alamar blue assay and in an intracellular model of infection, but only in the micromolar range. We attempted to determine if cell wall permeability was an explanation for the discrepancy between the potent in vitro compared with relatively poor in vivo activity, but found no evidence that the activity of the inhibitors could be improved by weakening the cell wall. Despite a number of drug discovery efforts attempting to develop inhibitors against PknB, it is yet to be reported that any such inhibitors prevent mycobacterial growth at submicromolar concentrations.

Structural and functional analysis of phosphothreonine-dependent FHA domain interactions.

FHA domains are well established as phospho-dependent binding modules mediating signal transduction in Ser/Thr kinase signaling networks in both eukaryotic and prokaryotic species. Although they are unique in binding exclusively to phosphothreonine, the basis for this discrimination over phosphoserine has remained elusive. Here, we attempt to dissect overall binding specificity at the molecular level. We first determined the optimal peptide sequence for Rv0020c FHA domain binding by oriented peptide library screening. This served as a basis for systematic mutagenic and binding analyses, allowing us to derive relative thermodynamic contributions of conserved protein and peptide residues to binding and specificity. Structures of phosphopeptide-bound and uncomplexed Rv0020c FHA domain then directed molecular dynamics simulations which show how the extraordinary discrimination in favor of phosphothreonine occurs through formation of additional hydrogen-bonding networks that are ultimately stabilized by van der Waals interactions of the phosphothreonine γ-methyl group with a conserved pocket on the FHA domain surface.

An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium tuberculosis.

Forkhead-associated (FHA) domains have gained considerable prominence as ubiquitous phosphothreonine-dependent binding modules; however, their precise roles in serine and threonine kinase (STK) pathways and mechanisms of regulation remain unclear. From experiments with Rv1827, an FHA domain-containing protein from Mycobacterium tuberculosis, we derived a complete molecular description of an FHA-mediated STK signaling process. First, binding of the FHA domain to each of three metabolic enzyme complexes regulated their catalytic activities but did not require priming phosphorylation. However, phosphorylation of a threonine residue within a conserved amino-terminal motif of Rv1827 triggered its intramolecular association with the FHA domain of Rv1827, thus blocking its interactions with each of the three enzymes. The solution structure of this inactivated form and further mutagenic studies showed how a previously unidentified intramolecular phosphoswitch blocked the access of the target enzymes to a common FHA interaction surface and how this shared surface accommodated three functionally related, but structurally diverse, binding partners. Thus, our data reveal an unsuspected versatility in the FHA domain that allows for the transformation of multiple kinase inputs into various downstream regulatory signals.