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.

Burden of illness in carbapenem-resistant Acinetobacter baumannii infections in US hospitals between 2014 and 2019.

BACKGROUND: Carbapenem-resistant (CR) Acinetobacter baumannii is a concerning pathogen in the USA and worldwide. METHODS: To assess the comparative burden of CR vs carbapenem-susceptible (CS) A. baumannii, this retrospective cohort study analyzed data from adult patients in 250 US hospitals from the Premier HealthCare Database (2014-2019). The outcomes analyzed included hospital length of stay (LOS), intensive care unit (ICU) utilization, discharge status, in-hospital mortality, readmission rates and hospital charges. Logistic regression was used for univariate and multivariable assessment of the independent relationship between relevant covariates, with a focus on CR status, and in-hospital mortality. RESULTS: 2047 Patients with CR and 3476 patients with CS A. baumannii infections were included. CR A. baumannii was more commonly isolated in respiratory tract infections (CR 40.7% and CS 27.0%, P < 0.01), whereas CS A. baumannii was more frequently associated with bloodstream infections (CS 16.7% and CR 8.6%, P < 0.01). Patients with CR A. baumannii infections had higher in-hospital (CR 16.4% vs CS 10.0%; P < 0.01) and 30-day (CR 32.2% vs CS 21.6%; P < 0.01) mortality compared to those with CS infections. After adjusting for age, sex, admission source, infection site, comorbidities, and treatment with in vitro active antibiotics within 72 h, carbapenem resistance was independently associated with increased mortality (adjusted odds ratio 1.42 [95% confidence interval 1.15; 1.75], P < 0.01). CR infections were also associated with increases in hospital length of stay (CR 11 days vs CS 9 days; P < 0.01), rate of intensive care unit utilization (CR 62.3% vs CS 45.1%; P < 0.01), rate of readmission with A. baumannii infections (CR 17.8% vs CS 4.0%; P < 0.01) and hospital charges. CONCLUSIONS: These data suggest that the burden of illness is significantly greater for patients with CR A. baumannii infections and are at higher risk of mortality compared with CS infections in US hospitals.

Burden of illness in US hospitals due to carbapenem-resistant Gram-negative urinary tract infections in patients with or without bacteraemia.

BACKGROUND: Urinary tract infections (UTIs) are the most common infections caused by Gram-negative bacteria and represent a major healthcare burden. Carbapenem-resistant (CR) strains of Enterobacterales and non-lactose fermenting pathogens further complicate treatment approaches. METHODS: We conducted a retrospective analysis of the US Premier Healthcare Database (2014-2019) in hospitalised adults with a UTI to estimate the healthcare burden of Gram-negative CR UTIs among patients with or without concurrent bacteraemia. RESULTS: Among the 47,496 patients with UTI analysed, CR infections were present in 2076 (4.4%). Bacteraemia was present in 24.5% of all UTI patients, and 1.7% of these were caused by a CR pathogen. The most frequent CR pathogens were Pseudomonas aeruginosa (49.4%) and Klebsiella pneumoniae (14.2%). Patients with CR infections had a significantly longer hospital length of stay (LOS) (median [range] 8 [5-12] days vs 6 [4-10] days, P < 0.001), were less likely to be discharged home (38.4% vs 51.0%, P < 0.001), had a higher readmission rate (22.6% vs 13.5%, P < 0.001), and had greater LOS-associated charges (mean US$ 91,752 vs US$ 66,011, P < 0.001) than patients with carbapenem-susceptible (CS) infections, respectively. The impact of CR pathogens was greater in patients with bacteraemia (or urosepsis) and these CR urosepsis patients had a significantly higher rate of mortality than those with CS urosepsis (10.5% vs 6.0%, P < 0.001). CONCLUSIONS: Among hospitalised patients with UTIs, the presence of a CR organism and bacteraemia increased the burden of disease, with worse outcomes and higher hospitalisation charges than disease associated with CS pathogens and those without bacteraemia.

Clinical Features and Outcome of Sickle Cell Disease in a Tertiary Center in Northern Lebanon: A Retrospective Cohort Study in a Local, Hospital-Associated Registry.

Sickle cell disease affects more than 30 million people worldwide, including 0.1% of the population in Lebanon. It is characterized by unpredictable and painful vaso-occlusive crises (VOCs) that may lead to serious complications. This study describes the clinical burden of sickle cell disease in a cohort of patients treated at a comprehensive sickle cell disease referral center in Tripoli, Northern Lebanon. Patient demographics, clinical events, treatment, and survival were evaluated from a local, hospital-based registry of 334 sickle cell disease patients treated at the Nini Hospital, Tripoli, Lebanon, between 2009 and 2019. Mean age at sickle cell disease diagnosis and at first clinic visit was 2.9 and 8.5 years, respectively. Pain was the most common clinical event observed among all patients. Over the 10-year follow-up period, 15 (4.5%) patients died. Hydroxyurea (HU) and red blood cell (RBC) transfusions were the most commonly used therapies. One hundred and thirty-one (39.0%) patients were diagnosed with sickle cell disease at the Nini Hospital; the remaining patients were referred to and subsequently followed-up at the Nini Hospital. Eighty-seven (66.0%) Nini Hospital-diagnosed patients experienced a VOC. Seventy-four (85.0%) of these patients with a VOC event required HU during follow-up. Patients with a VOC required more RBC transfusions, cholecystectomy, and splenectomy than non-VOC patients. The high disease burden observed in this population of sickle cell disease patients illustrates a continued, unmet need to both prevent and manage VOC events and other sickle cell disease-associated complications.

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer.

BACKGROUND: The BYLieve trial (NCT03056755) confirmed efficacy and safety of alpelisib with fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC), after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with an aromatase inhibitor (AI) as immediate prior therapy. Further analyses were performed to compare efficacy from BYLieve with effectiveness of standard treatment in the real-world setting. MATERIALS AND METHODS: Patients who progressed on a CDK4/6i plus AI and were treated with alpelisib with fulvestrant in BYLieve were matched with a real-world patient cohort who received standard-of-care from a deidentified clinico-genomics database (CGDB). Primary and secondary endpoints were to compare progression-free survival (PFS), estimated by the Kaplan-Meier method, and the proportion of patients remaining progression-free at 6 months, respectively, between the two cohorts. RESULTS: A total of 855 patients with PIK3CA-mutant disease who had prior CDK4/6i plus hormone therapy were selected from the CGDB; further matching to 120 patients from BYLieve selected 95 patients without exposure to HER2-targeting agents, clinical study drug, or alpelisib. In unadjusted and postmatching results, primary and secondary endpoints favored treatment with alpelisib with fulvestrant in BYLieve more than standard treatments in the real-world cohort. Postadjustment, median PFS for patients treated with alpelisib in BYLieve was 7.3 versus 3.7 months in the real-world cohort, and 6-month PFS was 54.6% versus 40.1%, respectively. CONCLUSION: Matched/weighted analysis comparing BYLieve with the real-world setting further supports the clinical benefit of alpelisib with fulvestrant for treatment of HR+, HER2-, PIK3CA-mutant ABC after CDK4/6i treatment. IMPLICATIONS FOR PRACTICE: Approximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) have PIK3CA-mutated tumors, which have been associated with endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol-3-kinase inhibitor, demonstrated significantly improved progression-free survival in SOLAR-1 and demonstrated clinical efficacy in BYLieve when combined with fulvestrant. Data are limited in comparing the efficacy of alpelisib combined with fulvestrant with effectiveness of standard therapy after CDK4/6i treatment. Using real-world data, this is the first analysis comparing alpelisib combined with fulvestrant with standard treatments for HR+, HER2-, PIK3CA-mutant ABC in the post-CDK4/6i setting.

Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.

BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. FINDINGS: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. FUNDING: Novartis Pharmaceuticals.

No increase in incidence or risk of recurrence of breast cancer in ospemifene-treated patients with vulvovaginal atrophy (VVA).

OBJECTIVE: To estimate the incidence and recurrence of breast cancer (BC) in patients with vulvovaginal atrophy (VVA) treated with ospemifene and matched untreated VVA patients using real-world data. STUDY DESIGN: Retrospective matched cohort study. MAIN OUTCOME MEASURES: VVA patients were identified from the 2011-2018 US MarketScan® insurance claims database. For incidence, ospemifene-treated VVA patients without evidence of BC prior to index treatment were matched to two untreated VVA controls similarly without history of BC on age, index VVA year, geographic region, Charlson Comorbidity categories, and follow-up time. BC after the index treatment was identified by BC diagnosis codes, mastectomy, chemotherapy, or radiation procedure. Incidence rate, rate ratio (RR) and their 95 % confidence intervals (CI) were calculated. The process was repeated to estimate BC recurrence in patients with a history of BC in 1:1, 1:2 and 1:3 matches. RESULTS: 1728 ospemifene users and 3456 untreated patients met the inclusion and matching criteria for assessing incidence. The average number of days for which ospemifene was supplied was 314 (standard deviation [SD] = 340). Average follow-up time from index treatment was 937 days (SD = 392) for treated patients and 915 days (SD = 396) for controls. BC incidence rates per 1000 person-years was 2.03 (95 % CI: 1.06-3.91) for treated patients and 3.53 (95 % CI: 2.49-4.99) for controls (RR = 0.58, 95 % CI: 0.28-1.21). No difference in recurrence was observed between ospemifene-treated and matched untreated patients. Ten (32.3 %) treated vs. 25 (40.3 %) controls in the 1:2 matched analysis had a recurrence. CONCLUSION: No differences were observed in the BC incidence and recurrence rates in ospemifene users compared with matched controls.

Impact of Incremental Delays in Appropriate Therapy on the Outcomes of Hospitalized Adult Patients with Gram-negative Bloodstream Infections: "Every day matters".

BACKGROUND: Serious bloodstream infections (BSIs) are often caused by Gram-negative (GN) bacteria in hospitalized patients. Treatment of these infections has been further complicated by the continued rise and spread of drug-resistant pathogens, including carbapenem resistant (CR) strains of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa. METHODS: This retrospective cohort analysis used real-world data from a large United States hospital-based database to examine the association between key clinical outcomes and different lengths of time to appropriate treatment between October 2010 and September 2015. RESULTS: Of 40,549 patients with GN-BSIs who were identified, 1117 (2.8%) had a CR GN-BSI. Overall, outcomes of hospitalized adult patients with GN-BSIs incrementally worsened the longer appropriate therapy was delayed. Patients with CR GN-BSIs had a median infection-associated length of stay (LOS) of 8, 9, 10, and 13 days, whereas patients with CS GN-BSIs had a median infection-associated LOS of 6, 7, 8, and 11 days for patients with days to appropriate therapy of 0, 1-2, 3-4, and ≥ 5 days, respectively. Among patients with CR GN-BSIs, the percentage of patients discharged home was 38%, 33%, 35%, and 31%, whereas in patients with CS GN-BSIs, the percentage of patients discharged home was 58%, 53%, 48%, and 43% for patients with days to appropriate therapy of 0, 1-2, 3-4, and ≥ 5 days, respectively. CONCLUSION: The findings from this study highlight the clear need to deliver appropriate therapy more expeditiously in patients with CS and CR GN-BSIs.