Effectiveness of standard treatments in non-small-cell lung cancer with METexon14 skipping mutation: a real-world study.

Aim: To assess real-world clinical outcomes with standard therapies for advanced non-small-cell lung cancer (aNSCLC) with METexon14 skipping mutation (METex14). Methods: In an oncologists-led retrospective review of medical records, data were abstracted and analyzed for patients initiating first-line (1L) systemic therapy after 1 January 2017. Results: In total 287 aNSCLC patients with METex14, the real-world best overall response rate was 73.4% for capmatinib (n = 146), 68.8% for immunotherapy (IO) monotherapy (n = 48), 52.0% for chemotherapy (CT, n = 30), and 54.8% for IO + CT (n = 63). As compared with capmatinib, patients receiving IO (hazard ratio [HR]: 1.57; 95% CI: 0.77-3.20; p = 0.220), CT (HR: 2.41; 95% CI: 1.19-4.85; p = 0.014) and IO + CT (HR: 2.33; 95% CI: 1.35-4.04; p = 0.003) had higher rates of progression. Further, patients receiving CT (HR: 4.43; 95% CI: 1.54-12.75; p = 0.006) and IO + CT (HR: 3.53, 95% CI: 1.41-8.85; p = 0.007) had higher rates of mortality than patients receiving capmatinib. Conclusion: The study showed better clinical outcomes with capmatinib than other standard therapies in 1L setting for aNSCLC harboring METex14.

Real-world study that investigated the outcomes of different therapies used to treat non-small-cell lung cancer patients with mesenchymal-epithelial transition exon 14 skipping mutationWhat is this article about? A real-world study that investigated clinical outcomes in patients with diagnosis of advanced non-small-cell lung cancer (aNSCLC) with mesenchymal-epithelial transition exon 14 (METex14) skipping­a rare form of genetic mutation­who received treatment with one of the commonly used therapies for this disease: immunotherapy, chemotherapy, immunotherapy + chemotherapy combination and capmatinib, which is a highly selective inhibitor of MET tyrosine kinase protein involved in the growth of cancer cells.What were the results? The study showed that, in general, patients treated with capmatinib as the frontline therapy more frequently achieved a clinical response in the form of complete tumor resolution or tumor shrinkage, had a lower risk of disease worsening and lived longer than patients who were treated with immunotherapy, chemotherapy or immunotherapy + chemotherapy combination.What do the results of the study mean? This study suggests that capmatinib is effective in treating patients with aNSCLC with METex14 skipping who have not been treated with another anticancer therapy previously. It provides evidence to support the use of capmatinib in the frontline setting and may inform clinical decision-making in routine practice.

A crossover study to evaluate the pharmacokinetics and bioequivalence of hydroxychloroquine tablets in healthy Chinese subjects.

AIMS: Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. MATERIALS AND METHODS: This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. RESULTS: A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in Cmax, AUC0-72h, and T1/2 between the test and reference preparation (p < 0.05). Food had no significant effect on Cmax and T1/2 (p < 0.05), but AUC0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax and AUC0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. CONCLUSION: The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

Real-world outcomes in non-small-cell lung cancer patients with MET Exon 14 skipping mutation and brain metastases treated with capmatinib.

Aim: To assess real-world clinical outcomes in patients with non-small-cell lung cancer with MET exon 14 skipping mutation and brain metastases (BM) who received capmatinib, a recently approved MET inhibitor, in routine US clinical practice. Materials & methods: Patient data were collected using a retrospective medical record review, led by participating oncologists. Eligible patients initiated treatment with capmatinib in any line, after BM diagnosis, between May 2020 and June 2021. Data on real-world overall response rate (rwORR) and real-world progression-free survival (rwPFS) were descriptively analyzed. Results: 68 eligible patients were analyzed. In patients treated with first-line (1L) capmatinib (n = 55), the rwORR was 90.9% systemically and 87.3% intracranially; median systemic rwPFS was 14.1 months. Among radiation-naive patients on 1L capmatinib (n = 20), rwORR was 85.0%, both systemically and intracranially; median systemic rwPFS was 14.1 months. Conclusion: This study showed substantial systemic and intracranial effectiveness for capmatinib in real-world setting; findings were consistent for RT-naive patients.

[In vitro "benefit-risk" evaluation and network regulation mechanism of Colquhounia Root Tablets and its key material basis].

Colquhounia Root Tablets, prepared from Tripterygium, is effective for rheumatoid arthritis, diabetic nephropathy, and membranous nephropathy. However, the adverse reactions, such as liver injury, nausea, and vomiting, limit its application. This study aims to evaluate the advantages and risk of Colquhounia Root Tablets and its key active components in the treatment of rheumatoid arthritis, diabetic nephropathy, and membranous nephropathy and explore the potential mechanism in treating different diseases based on in vitro efficacy and toxicity assessment and biomolecular network analysis. First, the components of Colquhounia Root Tablets absorbed in blood were detected via ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry, and the influence of Colquhounia Root Tablets and its key components triptolide and celastrol on viability of human hepatocyte L02, human rheumatoid fibroblast-like synovial cell MH7 A, human renal tubular epithelial cell HK-2, and mouse podocyte MPC-5 was detected by cell counting kit 8(CCK8) assay. Then the expression of inflammatory cytokines of MH7 A and HK-2 cells was detected by enzyme-linked immunosorbent assay(ELISA). Moreover, the expression of nephrin and podocin in MPC-5 cells was measured by Western blot, and the expression of cytoskeletal protein by immunofluorence assay. Candidate targets of components from Colquhounia Root Tablets absorbed in blood were retrieved from TCMIP v2.0, and targets of the three diseases from GEO. The "disease-related genes-drug targets" network was constructed based on STRING, followed by pathway enrichment. Finally, molecular docking was performed by AutoDock Vina to explore the binding affinity of triptolide and celastrol with putative targets in the key signaling pathway. RESULTS:: showed that Colquhounia Root Tablets, triptolide, and celastrol can obviously reduce the levels of inflammatory cytokines in supernatant of MH7 A and HK-2 cells and enhance the expression of nephrin and podocin in MPC-5 cells. In addition, triptolide had the strongest toxicity to L02 cells, while Huobahuagen Tablets had the least toxicity to hepatocytes. Network analysis revealed that Colquhounia Root Tablets may intervene the three diseases through PI3 K/HIF1α/NOS signaling pathway. Both triptolide and celastrol had high binding affinities to corresponding targets in this signaling pathway. In conclusion, Colquhounia Root Tablets exerts similar effects on rheumatoid arthritis, diabetic nephropathy, and membranous nephropathy to triptolide and celastrol, but the toxicity was lower. PI3 K/HIF1α/NOS signaling pathway may be the common pathway of Colquhounia Root Tablets in the treatment of the three diseases.

Real-World Treatment Patterns and Clinical Outcomes in Advanced Gastrointestinal Neuroendocrine Tumors (GI NET): A Multicenter Retrospective Chart Review Study.

BACKGROUND: We assessed treatment patterns and outcomes of patients with advanced gastrointestinal (GI) neuroendocrine tumors (NET) at four large tertiary referral centers in the U.S. PATIENTS AND METHODS: We performed a retrospective chart review of patients aged ≥18 years at advanced GI NET diagnosis, treated between July 2011 and December 2014. Index date was the histologically confirmed diagnosis date of locally advanced/metastatic GI NET. Data included baseline characteristics, treatment patterns, progression, death, and GI NET-related health care resource utilization from index date through last contact or death. Time-to-event analyses, including treatment discontinuation, progression, and overall survival (OS), were performed using Kaplan-Meier analysis. RESULTS: We identified 273 patients; 156 (57%) had primary ileum NET, and 174 (64%) had functional NET. First-line treatments included somatostatin analog (SSA) alone (89%) or in combination (2%), liver-directed therapy (LDT; 8%), and cytotoxic chemotherapy or interferon (2%). One hundred fifty-five patients continued with second-line therapy, including SSA alone (17%) or in combination (75%, with 3% combined with peptide receptor radionuclide therapy), LDT (4%), and other treatments (3%). Median time (months) to first-line discontinuation was 154.0 for SSAs and 3.8 for cytotoxic chemotherapy. Overall median time to investigator-assessed progression following treatment initiation was 30.3 months. Median OS (months) following first-line initiation was 151.8 for all patients and 178.9 for first-line SSA. CONCLUSION: Our study illustrates the common use of SSAs in both first-line and subsequent treatment of patients with GI NETs, as well as the relatively long survival durations and multiple additional treatments received by patients with this condition. Treatment pattern assessment at later times, following approval of newer treatments, is warranted. IMPLICATIONS FOR PRACTICE: This study, assessing treatment patterns over a period of up to 30 years, showed that SSAs, LDT, cytotoxic chemotherapy, and interferon are common treatments for advanced GI NETs. SSAs alone or in combination with other treatments were the most frequent therapy in first and subsequent lines. Patients in this study remained on SSAs long-term, with median treatment duration of 12.8 years in first line. Treatment patterns should be assessed beyond this study's time period, given recent U.S. Food and Drug Administration approvals for additional treatments for GI NET, which will likely be incorporated in the continuum of care of patients.

Treatment Patterns and Clinical Outcomes in Advanced Lung Neuroendocrine Tumors in Real-World Settings: A Multicenter Retrospective Chart Review Study.

BACKGROUND: Using data from four tertiary referral centers in the U.S., we assessed real-world treatment patterns and clinical outcomes of patients with advanced lung neuroendocrine tumors (NETs). SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective chart review of adult patients with locally advanced/metastatic (typical/atypical) lung NETs treated between July 2011 and December 2014. Index date was histologically confirmed typical/atypical carcinoid tumor diagnosis date. Data included baseline characteristics, treatment patterns, progression, death, and lung NET-related health care resource use from index date through last contact/death. Time to treatment discontinuation and first progression, time from first to second progression, and overall survival (OS) were estimated using Kaplan-Meier analysis. RESULTS: We identified 83 patients; 19 (23%) had functional NET. First-line treatments included somatostatin analogs (SSAs) alone (56%) or in combination with other therapies (6%), cytotoxic chemotherapy (20%), external beam radiation therapy (EBRT) (9%), liver-directed therapy (LDT) (4%), and everolimus/other (5%). Sixty patients had second-line therapy including SSA alone (18%) or in combination (40%), cytotoxic chemotherapy (17%), everolimus (12%), LDT (7%), EBRT (3%), and other treatments (3%). Median time (months) to first-line discontinuation were as follows: SSAs, 43.3; cytotoxic chemotherapy, 3.6. Overall median time (months) to investigator-assessed progression following treatment initiation was 12.4. Median OS (months) following treatment initiation was 66.4 for all patients and 81.5 for patients receiving SSAs. CONCLUSION: SSAs, alone and in combination, are common treatments for advanced lung NETs. Patients have additional treatment options and relatively long survival compared with patients with other advanced cancers. Treatment pattern assessment following approval of newer treatments is needed. IMPLICATIONS FOR PRACTICE: Somatostatin analogs (SSAs), cytotoxic chemotherapy, EBRT, liver-directed therapy, and targeted therapies are common treatments for locally advanced/metastatic (typical/atypical) lung neuroendocrine tumors (NETs). SSAs alone or in combination with other treatment modalities were the most common first- and second-line therapy, followed by cytotoxic chemotherapy. Patients continued treatment with SSAs long-term with median treatment duration of 43 months. Median overall survival was 66 months following initiation of first-line therapy for all patients. Treatment pattern assessment beyond the time period of this study is needed given recent U.S. Food and Drug Administration approvals for additional treatments for lung NETs that will likely be incorporated in the treatment landscape.

Assessment of change in quality of life, carcinoid syndrome symptoms and healthcare resource utilization in patients with carcinoid syndrome.

BACKGROUND: There is limited information on changes over time in carcinoid syndrome (CS) symptoms and quality of life (QoL). This study assessed change in CS symptoms and QoL in patients treated with somatostatin analogs (SSAs) using the Functional Assessment of Cancer Therapy-General (FACT-G) and Patient-Reported Outcomes Measurement Information System (PROMIS)-29 instruments. METHODS: Patients ≥18 years old with CS symptoms and treated with SSA or non-SSA agents in the United States were recruited through a patient advocacy group to complete a two-part, anonymous online survey. Time point (T) 1 survey was fielded from July-October 2016, and T2 survey followed 6 months later. Clinical characteristics and SSA treatment duration were assessed at T1. FACT-G and PROMIS-29 QoL surveys were administered and CS symptoms were assessed at T1 and T2; proportions of patients not experiencing symptoms were compared by McNemar's test. Healthcare resource utilization (HRU) was assessed for the T1-T2 interval, and mean difference in QoL score from T1 to T2 by SSA duration was calculated. RESULTS: Of 117 participants at T1, 89 (76%) completed the T2 survey and served as the study sample; 11 (13%) were treated with SSAs for > 0-2 years, 37 (42%) for > 2-5 years, and 39 (45%) for > 5 years. A higher proportion of patients at T2 vs. T1 reported the following symptoms as not applicable: diarrhea (16% vs. 7%, p < 0.05), flushing (28% vs. 18%, p < 0.05), wheezing (78% vs 66%, p = 0.008). Most patients (89%) had a physical exam and a mean of 7.2 healthcare provider visits between T1 and T2. Patients treated with SSAs for ≤2 years had a mean positive change of 3.7 in their FACT-G total score between surveys, and 6.0 in an additional set of CS-specific questions. Patients receiving SSAs for > 2 years did not appear to associate with a clinically meaningful improvement in QoL score as assessed by FACT-G between T1 and T2; patients also had no clinically meaningful improvement as assessed by PROMIS-29. CONCLUSIONS: There may be clinically important improvement in QoL as measured by FACT-G in patients in earlier years of receiving SSA, which may not appear in later years of SSA treatment.

Real-World Treatment Patterns for Lung Neuroendocrine Tumors: A Claims Database Analysis.

OBJECTIVE: The aim of this study was to describe real-world lung neuroendocrine tumor (NET) treatment patterns. METHODS: This study examined cytotoxic chemotherapy (CC), somatostatin analogues (SSA), targeted therapy (TT), interferon, and liver-directed therapies in 2 US claims databases. Patients ≥18 years with ≥1 inpatient or ≥2 outpatient claims for lung NET, initiating pharmacologic treatment between July 1, 2009, and June 30, 2014, were identified and followed until the end of enrollment or study end, whichever occurred first. RESULTS: A total of 785 newly pharmacologically treated lung NET patients were identified: mean (SD) age was 58.6 (9.1) years; 54.0% were female; 78.2% started first-line therapy with CC, 18.1% with SSA, and 1.1% with TT. Mean duration of first-line treatment was 397 days for SSA, 142 days for CC, and 135 days for TT. 74.1% of patients received no pharmacological treatment beyond first-line. The most common second-line treatment was SSA. CONCLUSIONS: Most patients received CC as first-line treatment, with SSA being less common. SSA-treated patients remained on therapy for > 1 year, compared to < 5 months for CC. The high proportion of patients using chemotherapy and the low proportion receiving second-line treatment seems consistent with treatment guidelines for small cell lung cancer rather than for NET. Future studies are warranted to describe reasons for treatment choice, discontinuation, and switching.

Incidence and prevalence of neuroendocrine tumors of the lung: analysis of a US commercial insurance claims database.

BACKGROUND: As reported in Surveillance, Epidemiology, and End Results (SEER) data, US incidence and prevalence of neuroendocrine tumors (NET) has increased over recent years. The study objective was to update incidence and prevalence information for lung NET using administrative claims. METHODS: This descriptive epidemiological study used 2009-2014 data from 2 US claims databases: MarketScan and PharMetrics. Patients (18-64 years old) had ≥1 inpatient or ≥ 2 outpatient claims with NET of bronchus or lung, identified by International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes. Prevalence was number of lung NET patients divided by number of enrollees/year. Incidence was number of patients with a first observed NET diagnosis who were disease-free for 2 years prior, divided by number of enrollees. Age and gender adjustments performed. RESULTS: The annual number of patients with lung NET identified from 2009 to 2014 ranged from 435 to 796 (MarketScan) and 419-648 (PharMetrics). In MarketScan, there was a 7.4% (95%CI 2.1-13.0; p = 0.027) annual percent change (APC) in the age-adjusted incidence for males and 6.8% (- 0.2-14.3; 0.052) for females. In PharMetrics, APC was - 2.9% (- 13.8-9.4; 0.395) for males; 14.7% (- 12.9-51.2; 0.165) for females. In MarketScan, APC in age-adjusted prevalence for males was 9.9% (4.7-15.3; 0.006); 16.2% (11.4-21.1; <.001) for females. For PharMetrics, APCs were 9.5% (2.3-17.2; 0.021) for males; 16.3% (9.6-23.5; 0.002) for females. CONCLUSIONS: From 2009 to 2014 there was a statistically significant increase in age-adjusted lung NET incidence for males in MarketScan, and a statistically significant increase in age-adjusted prevalence for both genders in PharMetrics. Incidence and prevalence changes, to the extent they exist, may be due to better diagnostic methods, increased awareness of NET among clinicians and pathologists, and/or an actual increase in US disease occurrence. Differences in rates across databases are difficult to explain. These results suggest the need for awareness of the clinically effective and safe treatment options available for lung NET patients among healthcare providers.

EPIDEMIOLOGY OF GASTROINTESTINAL NEUROENDOCRINE TUMORS IN A U.S. COMMERCIALLY INSURED POPULATION.

OBJECTIVE: To estimate incidence and prevalence of gastrointestinal neuroendocrine tumors (GI NETs) in U.S. commercially insured patients. METHODS: This was a retrospective, cross-sectional study using 2009 to 2014 data from MarketScan and PharMetrics commercial claims databases. Patients were 18 to 64 years old, and had 1 inpatient or 2 outpatient claims with GI NET, identified by International Classification of Diseases, 9th Revision, Clinical Modification codes. Incidence was calculated as number of patients with NET who were disease-free for 2 years prior, divided by number of enrollees and reported as per million person-years (PMPY). Prevalence was calculated as the number of GI NET patients divided by the number of enrollees per year. RESULTS: The annual number of patients with GI NET ranged from 2,014 to 3,413 in MarketScan and 1,436 to 2,336 in PharMetrics. Incidence increased from 2011 to 2014: 67.0 to 79.1 PMPY in MarketScan and 47.4 to 58.2 PMPY in PharMetrics. Incidence increased by 24.3% in females and 10.7% in males in MarketScan, and by 17.6% in females and 29.3% in males in PharMetrics. Incidence increased with age and was highest in the 45 to 54 and 55 to 64 age groups. Prevalence increased from 77.9 to 131.2 per million per year (MarketScan) and 50.8 to 108.9 (PharMetrics) from 2009 to 2014. Prevalence was generally higher in females than males and highest in 55 to 64 year olds. These increases may be due to better diagnostics, increased awareness of NET among clinicians and pathologists, and/or actual increase in disease. CONCLUSION: Clinicians may see GI NET with increasing frequency and should become more familiar with its presentation and treatment. ABBREVIATIONS: GI = gastrointestinal; ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification; NET = neuroendocrine tumor; PMPY = per million person-years; SEER = Surveillance, Epidemiology, and End Results.

Evaluation of the Nutritional Quality of Chinese Processed Meat Products: Comparison of Two Nutrient Profile Models.

Processed meat products are one of the most consumed pre-packaged foods in China. They are also group-1 carcinogens, whose consumption has proved to be positively associated with the risk of noncommunicable diseases (NCDs). The purpose of this study is to analyze the nutrient content on the food label of processed meat products based on the China Standardized Database for the Composition of Pre-packaged Food and the National Open Database of the UK and France. The Chilean front-of-pack warning label (FOPWL) and the Chinese Healthier Choice Logo were used to compare the nutrient content of processed meat products from the three countries. It was found that cured meat products have the highest median energy (483 kcal/100 g), total fat content (38.7 g/100 g), and sodium content (2076 mg/100 g) and dried meat products have the highest median protein content (30.2 g/100 g) and carbohydrate content (38.2 g/100 g). In addition, there were significant differences in energy content and contents of total fat, protein, and carbohydrate across different products of the three countries (p < 0.001). A large number of processed meat products currently collected did not meet the criteria of the Chilean FOPWL and the Chinese Healthier Choice Logo. This study provided information on the healthiness of Chinese processed meat products and provided data for improving food formulations for different categories of processed meat products.

Retrospective Study to Examine Prognostic Value of C-Reactive Protein in Patients With Surgically Resectable Non-Small-Cell Lung Cancer.

BACKGROUND: This study evaluated the association between elevated C-reactive protein (CRP) and clinical outcomes among adults treated with surgery for non-small cell lung cancer (NSCLC) in the US. MATERIALS AND METHODS: Adults with NSCLC who underwent lung cancer surgery and had ≥1 CRP measurement prior to, or >1 month following, index surgery were identified in the Optum Clinformatics claims database. The association between elevated CRP (>10 mg/L) and risk of NSCLC recurrence/death was assessed separately during the 6 months before surgery (pre surgery cohort) and 2 years following surgery (post-surgery cohort) using multivariate regressions and Kaplan-Meier analysis. RESULTS: After adjusting for baseline demographic and clinical characteristics among patients in the pre surgery cohort with index surgery between 2016 to 2020 (n = 104), the incidence rate ratio (IRR) for NSCLC recurrence between elevated vs. non-elevated CRP was 2.17 (95% confidence interval [CI]=1.03-4.60; P = .04). In the post surgery cohort (n = 264), the adjusted IRR for disease recurrence (elevated vs. non-elevated CRP) was 2.22 (95% CI=1.05-4.70; P = .04). In the pre surgery cohort, the odds of death were nearly two-fold (odds ratio [OR]=1.91; 95% CI=1.06-3.42; P = .03) among patients with elevated CRP. In the post surgery cohort, the OR was 1.62 (95% CI=0.88-2.97; P = .12). Among those with persistently elevated CRP prior to surgery, there was a significant overall trend of increased CRP over the 5-year period. CONCLUSION: These results support the association between elevated CRP and a higher risk of NSCLC recurrence/death in pre- and postsurgery cohorts. This study may shed lights on inflammation-suppressing treatments in patients with NSCLC.

Real-world observational study of current treatment patterns and outcomes in recurrent or locally advanced/metastatic non-small cell lung cancer.

BACKGROUND: Treatment for recurrent or advanced/metastatic non-small cell lung cancer (aNSCLC) has advanced in the past 5 years with immunotherapy (IO). This study sought to describe first-line (1L) aNSCLC treatment patterns and clinical outcomes. METHODS: In this retrospective, multisite cohort study, community oncologists reported data for randomly selected stage IIIB/IV, EGFR-/ALK wild-type aNSCLC patients who initiated 1L systemic therapy from 01/01/2016 to 12/31/2019. Follow-up was through November 2020. Demographics, clinical characteristics, treatment patterns, disease response, progression, and death/last follow-up date were described. Overall response rate (ORR) was calculated using tumor measurements applying RECIST v1.1 guidelines. Progression-free survival (PFS) and overall survival (OS) were calculated from 1L initiation by Kaplan-Meier method. RESULTS: 497 patients from 46 sites were included. The most common 1L regimens (%) were platinum-doublet chemotherapy plus IO (PDC+IO) (40.6%), PDC (29.4%), IO monotherapy (20.7%), and PDC+bevacizumab (6.2%). From 2016 to 2019, 1L PDC declined from 63% to 10%, whereas 1L PDC+IO increased from 14% to 58%. The ORRs were 64.9%, 32.9%, 60.2%, and 61.3% for 1L PDC+IO, PDC, IO monotherapy, and PDC+bevacizumab, respectively. Median 1L PFS/OS (months) was 15.6/26.5, 5.3/13.7, 17.8/not reached, 10.8/18.6, respectively, for PDC+IO, PDC, IO monotherapy, and PDC+bevacizumab. Among patients who received only 1L treatment (n = 299), 41.5% had no further therapy and were deceased. CONCLUSIONS: Although the 1L treatment paradigm has recently shifted to IO-based regimens, 41.5% did not survive past 1L. Median 1L PFS did not exceed 1.5 years and median OS remained limited across all 1L treatment groups, illustrating continued unmet aNSCLC therapeutic needs.

Biomarker Testing Patterns and Treatment Outcomes in Patients With Advanced Non-Small Cell Lung Cancer and MET Exon 14 Skipping Mutations: A Descriptive Analysis From the US.

Background: MET exon 14 skipping mutation (METex14) is observed in ~3% of non-small cell lung cancer (NSCLC) cases and has been shown to be an independent poor prognostic factor associated with shorter overall disease-specific survival. Broad molecular testing can identify this biomarker in patients with advanced NSCLC (aNSCLC) and allow patients to be matched with the appropriate targeted therapy. This study examines biomarker testing patterns and clinical outcomes of chemotherapy and immuno-oncology (IO) monotherapy in aNSCLC patients with METex14. Methods: A descriptive retrospective study was conducted using the Flatiron Health-Foundation Medicine Inc. (FMI) clinico-genomic database. Patients with METex14 aNSCLC treated with systemic therapies were included in the biomarker testing analysis. The duration from specimen collection to reported results was assessed for PD-L1- and METex14-tested patients. Clinical outcomes were assessed in patients treated with chemotherapy or IO monotherapy. First-line (1L) and second-line (2L) real-world progression-free survival (rw-PFS) were estimated using Kaplan-Meier analysis. Results: Of 91 METex14 patients eligible for the biomarker testing analysis, 77% and 60% received PD-L1 and FMI next-generation sequencing (NGS) testing within 3 months post aNSCLC diagnosis. Of those assessed for both PD-L1 and METex14 (n=9), the median duration between specimen collection and reporting was 1 week shorter for PD-L1 than for FMI NGS. Median 1L rw-PFS was 5.7 months (95% CI, 4.6-7.1) and 2.4 months (95% CI, 1.4-3.2) in patients receiving 1L chemotherapy (n=59) and IO monotherapy (n=18), with 3-month 1L rw-PFS rates of 78% and 33%. Median 2L rw-PFS was 3.5 months (95% CI, 1.9-11.1) and 4.7 months (95% CI, 2.8-12.9) in patients receiving 2L chemotherapy (n=16) and IO monotherapy (n=23), with 3-month 2L rw-PFS rates of 54% and 67%. Conclusions: The median time from biopsy to test results appears 1 week shorter for PD-L1 than for FMI NGS. Chemotherapy and IO monotherapy were the most common regimens utilized but with limited PFS.

[Construction of HEK293 cell lines expressing hCysLT2 receptor and its application in screening of antagonists].

OBJECTIVE: To construct HEK293 cell lines stably expressing hCysLT(2) receptor, and to evaluate its application in screening of synthetic compounds with antagonist activity. METHODS: The recombinant plasmid pcDNA3.1(+)-hCysLT(2) was transfected into HEK293 cells using Lipofectamin 2000. The transfected HEK293 cells were selected in 96 well plates by limiting dilution with 600 µg/ml C418 for 8 weeks. The expression of human CysLT(2) receptor was detected by RT-PCR and immunofluorescence staining. In HEK293 cells stably transfected with hCysLT(2), the agonist LTD(4)-induced elevation of intracellular calcium concentration ([Ca2(+)]i) was measured as the index for screening compounds with antagonist activity. RESULT: After selection in 96 well plates by limiting dilution, 12 monoclones were obtained and 11 of them highly expressed hCysLT(2) receptor. The positive control ATP at 50 µmol/L and LTD(4) at 100 nmol/L elevated [Ca2(+)]i in hCysLT(2)-HEK293 cells. AP-2100984 inhibited LTD(4)-induced [Ca2(+)]i elevation, but selective CysLT(1) receptor antagonists did not exert such an effect. The newly synthesized compounds DXW2, DXW3, DXW4, DXW5, DXW9, DXW25, DXW26, DXW29 and DXW35 at 1 µmol/L significantly inhibited LTD(4)-induced [Ca2(+)]i elevation. The IC(50) values of DXW4 and DXW5 were 0.25 µmol/L and 7.5 µmol/L. CONCLUSION: HEK293 cell lines stably expressing hCysLT(2) receptor have been successfully constructed, and can be used to screen compounds with CysLT(2) receptor antagonist activity.

[Effects of agonist and antagonist of cysteinyl leukotriene receptors on differentiation of rat glioma C6 cells].

OBJECTIVE: To investigate the role of cysteinyl leukotriene (CysLT) receptors in the differentiation of rat glioma C6 cells. METHODS: Rat glioma C6 cells were treated with the agonist LTD(4), the CysLT(1) receptor antagonist montelukast and the differentiation inducer forskolin. Cell morphology and GFAP protein expression were determined after treatments. RESULT: Forskolin (10 µmol/L) induced morphological changes and GFAP protein expression (cell differentiation) in C6 cells, but LTD(4) (0.1-100 nmol/L) did not induce these changes. Montelukast (1 µmol/L) alone did not affect C6 cell differentiation, while it induced the differentiation when combined with the LTD(4) (100 nmol/L). CONCLUSION: The CysLT(2) receptor may modulate the differentiation of rat glioma C6 cells.

Clinical outcomes and resource utilization after surgical resection with curative intent among patients with non-small cell lung cancer treated with adjuvant therapies in a community oncology setting: A real-world retrospective observational study.

AIMS: Adjuvant chemotherapy has been shown to improve survival in patients with completely resected early-stage non-small cell lung cancer (NSCLC). This study evaluated real-world relapse rates and healthcare resource utilization in patients with stage II-IIIB NSCLC receiving adjuvant therapy in a community oncology setting after complete resection. PATIENTS AND METHODS: The study included patients with stage II-IIIB NSCLC and complete resection receiving any adjuvant therapy during 06/2008-04/2017 at US Oncology Network clinics, with follow-up through 04/2019. Primary endpoints were rate of relapse, time to relapse (TTR), disease-free survival (DFS), overall survival (OS), and monthly emergency department (ED) visits and hospitalizations before and after relapse. RESULTS: The study identified 456 patients; median age was 66 years, 50% were male. In patients with relapse (45.2%), median follow-up was 31.7 months and median TTR was 13.7 months. Median DFS in the overall population was 42.9 months. Median OS was 82.4 months in the overall population and shorter in patients with relapse than without relapse (41.6 months vs. not reached, p < 0.0001). Patients with relapse had significantly more monthly ED visits (mean [SD] 0.10 [0.24] vs. 0.03 [0.08], p < 0.0001) and hospitalizations (mean [SD] 0.20 [0.43] vs. 0.05 [0.10], p < 0.0001) following relapse than before relapse. CONCLUSIONS: Patients with stage II-IIIB NSCLC treated with adjuvant therapy after complete resection had high relapse rates, reduced survival, and significantly increased healthcare resource use when relapse occurred. New therapeutic options to reduce relapse rates in patients with early-stage NSCLC could reduce healthcare utilization and costs.

Budget impact of capmatinib for adults with metastatic non-small cell lung cancer harboring a MET exon 14 skipping mutation in the United States.

AIMS: To estimate the budget impact of adding capmatinib, the first FDA approved MET inhibitor, to a US commercial or Medicare health plan for patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors have a mutation that leads to MET exon 14 (METex14) skipping. METHODS: Target population size was estimated using published epidemiology data. Clinical data were obtained from the GEOMETRY mono-1 capmatinib trial and published trials. Treatments in the market mix included crizotinib, pembrolizumab, ramucirumab, and chemotherapy. Uptake of capmatinib and testing rates were based on market research. All costs (drug acquisition and administration, pre-progression, progression, terminal care, adverse event, and testing) were estimated based on public sources (2020 USD). RESULTS: The number of patients eligible for capmatinib in the first three years was estimated to be 2-3 in a hypothetical 1 million member commercial plan and 34-44 in a hypothetical 1 million member Medicare plan each year. The estimated total budget impact ranged from $9,695 to $67,725 for a commercial plan and $141,350 to $985,695 for Medicare. With capmatinib included, a marginal per member per month budget impact was estimated (commercial: $0.0008 to $0.0056; Medicare: $0.0118 to $0.0821). Capmatinib inclusion resulted in lower medical costs (commercial: -$0.0003 to -$0.0007; Medicare: -$0.0037 to -$0.0106), partially offsetting increased drug costs ($0.0011 to $0.0064; $0.0154 to $0.0928, respectively), and were primarily driven by reductions in progression and terminal care costs (-$0.0003 to -$0.0009; -$0.0037 to -$0.0125, respectively). The results were most sensitive to capmatinib market share, capmatinib price, and treatment duration. LIMITATIONS: Certain assumptions were applied to the model to account for inputs with limited evidence. CONCLUSIONS: The estimated budget impact of including capmatinib for mNSCLC with a METex14 skipping mutation is minimal, and the increased drug costs were partially offset by savings in AEs, and progression-related and terminal care costs.

Healthcare resource use and direct costs in severe aplastic anemia (SAA) patients before and after treatment with eltrombopag.

Purpose: This study evaluated healthcare resource utilization (HCRU), and direct costs among severe aplastic anemia (SAA) patients treated with eltrombopag (EPAG) using US claims data.Methods: This retrospective, real-world claims database study identified SAA patients aged ≥2 years treated with EPAG who initiated any SAA treatment between 1 July 2014 and 31 December 2017 (identification period) using the Truven MarketScan databases. A subset of 82 patients treated with EPAG during the identification period were evaluated for all-cause and SAA-related HCRU and direct costs as well as blood transfusion 1 month before EPAG initiation (baseline) and at Month 6 after EPAG initiation (follow-up period).Results: The average patient age was 50.8 (SD = 20.6) years old, predominantly female (n = 43, 52.4%), and had a mean CCI at baseline of 1.1 (SD = 1.7). Hospitalizations, and ER, office, and outpatient visits were significantly lower at Month 6 after EPAG initiation compared with 1 month before EPAG initiation (p < .05 for all four all-cause HCRU and SAA-related hospitalizations). An almost two-fold decrease in reliance on biweekly blood transfusions was observed: 1.0 at weeks 1-2 to 0.5 at Month 6 after EPAG initiation. Although prescription costs (mean [SD]) were significantly higher at Month 6 after EPAG initiation compared with 1 month before EPAG initiation (difference of $11,045 USD [SD = $18,801]), these increases were offset by savings in direct costs. Overall, a mean reduction in total all-cause costs of $29,391 USD [SD = $137,770] was reported at Month 6 after EPAG initiation due to substantial reductions in hospitalization ($40,060 USD [SD = $123,198]) and outpatient visits ($2,043 USD [SD = $25,264]).Conclusion: All-cause and SAA-related HCRU were reduced following EPAG treatment. Prescription costs were higher following treatment; however, these costs were generally offset by reductions in direct costs. These results provide real-world evidence around the role of EPAG in SAA treatment.

[Construction and identification of eukaryotic expression vector of rat GPR17 gene].

OBJECTIVE: To construct the eukaryotic expression vector of rat GPR17 (rGPR17) cDNA,and to identify its function in HEK293 cells. METHODS: Total RNA was extracted from rat brain tissue; full-length GPR17 cDNA was prepared by RT-PCR, and cloned into pcDNA3.1(+) plasmid. The recombinant plasmid was converted into E.coli DH5alpha and confirmed by PCR, double enzyme digestion analysis and DNA sequencing. The recombinant plasmid pcDNA3.1(+)-rGPR17 was transiently transfected into HEK293 cells using Lipofectamin 2000. Expression of rGPR17 gene was confirmed by RT-PCR and immunofluorescence staining. The exogenous LTD(4) enhanced intracellular calcium was measured using Fluo-4. RESULT: RT-PCR, double enzyme digestion analysis and sequencing showed that the rGPR17 gene was cloned into recombinant vector, and the recombinant rGPR17 was expressed after transfection in HKE293 cells. LTD(4) increased intracellular calcium release in the transfected HEK293 cells. CONCLUSION: The eukaryotic expression vector of rGPR17 cDNA has been constructed; it is functionally expressed in HEK293 cells. This work provides a basis for further research of the GPR17 receptor and its antagonists.