Real-world effectiveness of HPV vaccination against cervical neoplasia among birth cohorts ineligible for routine vaccination

Human papillomavirus (HPV) vaccine effectiveness may differ between settings. Here we present the first real-world effectiveness study of HPV vaccination on high-grade cervical lesions from Norway, among women who received HPV vaccine outside the routine program. We performed an observational study of all Norwegian women born 1975 to 1996 and retrieved individual data from nationwide registries on HPV vaccination status and incidence of histologically verified high-grade cervical neoplasia during 2006 to 2016. We estimated the incidence rate ratio (IRR) and 95% confidence intervals (CI) for vaccination vs no vaccination by Poisson regression stratified by age at vaccination <20 years and ≥20 years. The cohort consisted of 832 732 women, of which 46 381 (5.6%) received at least one dose of HPV vaccine by the end of 2016. The incidence rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increased with age regardless of vaccination status and was highest at age 25 to 29, at 637/100 000 among unvaccinated women, 487/100 000 among women vaccinated before age 20 and 831/100 000 among women vaccinated at age 20 or older. The adjusted IRR of CIN2+ between vaccinated and unvaccinated women was 0.62 (95% CI: 0.46-0.84) for women vaccinated below age 20, and 1.22 (95% CI: 1.03-1.43) for women vaccinated at age 20 or older. These findings indicate that HPV vaccination among women too old to be eligible for routine HPV vaccination is effective among women who are vaccinated below age 20 but may not have the desired impact among women who are vaccinated at age 20 or older.     

Real-World Palbociclib Use in HR+/HER2− Advanced Breast Cancer in Canada: The IRIS Study

Background: Palbociclib is a selective cyclin-dependent kinase (CDK) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer (ABC/MBC). Palbociclib was the first CDK 4/6 inhibitor approved for HR+/HER2− ABC/MBC treatment in Canada in combination with letrozole (P+L) as an initial endocrine-based therapy (approved March 2016), or with fulvestrant (P+F) following disease progression after prior endocrine therapy (approved May 2017). The Ibrance Real World Insights (IRIS) study ({"type":"clinical-trial","attrs":{"text":"NCT03159195","term_id":"NCT03159195"}}NCT03159195) collected real-world outcomes data for palbociclib-treated patients in several countries, including Canada. Methods: This retrospective chart review included women with HR+/HER2− ABC/MBC receiving P+L or P+F in Canada. Physicians reviewed medical records for up to 14 patients, abstracting demographic and clinical characteristics, treatment patterns, and clinical outcomes. Progression-free rates (PFRs) and survival rates (SRs) at 6, 12, 18, and 24 months were estimated via Kaplan–Meier analysis. Results: Thirty-three physicians examined medical records for 247 patients (P+L, n = 214; P+F, n = 33). Median follow-up was 8.8 months for P+L and 7.0 months for P+F. Most patients were initiated on palbociclib 125 mg/d (P+L, 90.2%; P+F, 84.8%). Doses were reduced in 16.6% of P+L and 14.3% of P+F patients initiating palbociclib at 125 mg/d. The PFR for P+L was 90.3% at 12 months and 78.2% at 18 months; corresponding SRs were 95.6% and 93.0%. For P+F, 6-month PFR was 91.0%; 12-month SR was 100.0%. Conclusions: Dose reduction rates were low and PFR and SR were high in this Canadian real-world assessment of P+L and P+F treatments, suggesting that palbociclib combinations are well tolerated and effective.     

Effectiveness,safety and quality of life of trifluridine/tipiracil in pretreated patients with metastatic colorectal cancer: Real-world data from the noninterventional TACTIC study in Germany

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.     

Is weight-based IV dosing of trastuzumab preferable to SC fixed-dose in some patients? A systematic scoping review

Trastuzumab, a key treatment for HER2-positive breast cancer, is available in weight-based IV and fixed-dose (600 mg) SC formulations. While the Phase 3 HannaH trial indicated non-inferiority of the SC formulation, there is some concern that the target plasma concentration may not be reached in overweight/obese patients whereas low-body-weight patients may be at risk of toxicity.This scoping review evaluated whether overweight/obese patients are at risk of below-target exposure with fixed-dose SC trastuzumab, whether low-body-weight patients are at risk of increased toxicity, especially cardiotoxicity, and whether IV and SC trastuzumab are equivalent in terms of treatment-emergent adverse events (TEAEs) (e.g. infections). Thirty-seven publications that met the eligibility criteria were included.Body weight is not an important determinant of exposure to trastuzumab at steady state (i.e. pre-dose cycle 8); however, real-world evidence suggests that the target concentration (20 μg/mL) may not be reached with the first SC dose in overweight/obese patients. There is no evidence that low-body-weight patients are at increased risk of cardiotoxicity with SC trastuzumab, although this may be confounded by the higher rate of cardiovascular comorbidities in overweight patients. In Phase 3 trials, SC trastuzumab was associated with higher rates of ISRs, ADAs and SAEs, the latter often requiring hospitalization and occurring during adjuvant treatment when patients are not burdened by chemotherapy.The route of administration of trastuzumab (IV vs SC) in different treatment settings should be discussed with the patient, taking into account the risks and benefits associated with each route.     

Economic Burden of Checkpoint Inhibitor Immunotherapy for the Treatment of Non–Small Cell Lung Cancer in US Clinical Practice

PurposeThe efficacy of checkpoint inhibitor (CPI) immunotherapy in patients with non–small cell lung cancer (NSCLC) is limited by a lack of strongly predictive response markers, subjecting patients to potential underutilization of alternative effective treatments, increased risk for futile care, and unnecessary costs. Here, we characterize the extent to which basic molecular tumor-marker testing has been performed for NSCLC therapy selection in the United States, and compare medical resource utilization and costs in CPI-treated patients versus CPI-eligible patients treated with other therapies.MethodsWe identified a cohort of CPI-treated patients with NSCLC and a propensity score–matched cohort of CPI-eligible patients with NSCLC treated with non-CPI therapies (3095 patients in each group), using US administrative claims data covering the pre- and postinitial FDA-approval period for nivolumab, pembrolizumab, and atezolizumab (October 2012 to September 2017). We describe the utilization of recommended baseline molecular testing for CPI selection (pre–index date for CPI or other anticancer therapy), including programmed death ligand 1 (PD-L1) immunohistochemistry, ALK rearrangement and EGFR mutation testing, and pre- and postindex treatment patterns. All-cause medical resource utilization and semiannual total reimbursement (costs) were compared between CPI-treated and non-CPI–treated patients.FindingsAt baseline, in the propensity score–matched CPI- and non–CPI-treated patient cohorts, mean PD-L1 immunohistochemistry test utilization for CPI selection was moderate (0.6 vs 0.7 per patient, respectively). However, we observed much lower mean utilization of testing for EGFR mutations (0.1 vs 0.1 per patient) and ALK rearrangements (0.1 vs 0.2 per patient). Postindex, the use of both chemotherapy and ALK- and EGFR-targeted therapies were decreased in both cohorts. The CPI-treated group had significantly higher mean medical resource utilization in nearly all categories in the postindex period, and total per-patient semiannual costs, than did the CPI-eligible patients who received other therapies (141,537 vs 75,429 US dollars [USD]; P < 0.0001), driven by CPI drug reimbursement. Median (interquartile range) time on CPI was longest with pembrolizumab (113 [106–127] days), followed by nivolumab (105 [97–106] days) and atezolizumab (64 [50–85] days). Despite being associated with the lowest drug cost and the shortest treatment duration, atezolizumab was associated with the highest mean total per-patient semiannual costs (160,540 USD) compared with pembrolizumab (153,003 USD) and nivolumab (138,542 USD).ImplicationsThe advent of CPI treatment for NSCLC has added substantial care-related costs for patients and payers, concurrent with underutilization of minimum recommended molecular testing for therapy selection. Broad uptake of panel-based comprehensive targeted-therapy and immunotherapy profiling can promote optimal treatment selection and sequencing, reduce the likelihood of futile treatment, and further improve patient outcomes.     

Trends in U.S. Ambulatory Cardiovascular Care 2013 to 2017: JACC Review Topic of the Week

The National Cardiovascular Data Registry PINNACLE (Practice Innovation and Clinical Excellence) Registry is the largest outpatient cardiovascular practice registry in the world. It tracks real-world management and quality of 4 common cardiovascular conditions: heart failure, coronary artery disease, atrial fibrillation, and hypertension. In 2013, the PINNACLE Registry contained information on 2,898,505 patients, cared for by 4,859 providers in 431 practices. By 2017, the registry contained information on 6,040,996 patients, cared for by 8,853 providers in 724 practices. During this time period, care processes for PINNACLE patients generally improved. Among patients with heart failure, combined beta-blocker and renin-angiotensin antagonist medication rates increased from 60.7% to 72.8%. Among patients with coronary artery disease, statin medication rates increased from 66% to 80.1%. Among patients with atrial fibrillation, oral anticoagulation rates increased from 52.7% to 65.2%. In contrast, blood pressure control rates among patients with hypertension were largely stable. PINNACLE data also fueled a variety of quality measurement programs and 51 peer-reviewed publications.     

达格列净治疗84例糖尿病肾病的临床疗效观察

目的：描述在真实世界中达格列净对于糖尿病肾病治疗的疗效和安全性。方法： 在我院服用达格列净的84例糖尿病肾病患者中,回顾性分析达格列净对于血糖、血压、体重、血脂、蛋白尿、肾功能的疗效,比较治疗前后临床治疗的差异性,并记录治疗过程中的副作用以评价其安全性。结果：84例患者平均年龄52.47岁,男性56 例(66.7%),平均糖尿病病史8年,合并肥胖或超重34例(40.4%),合并糖尿病视网膜病变患者47 例(56.0%),高血压69 例(82.1%),平均24小时蛋白尿3.1 g/天,平均eGFR 87.1 ml/min/m²。在随访过程中,共有12例(14.3%)停用达格列净(男性4例、女性8例)。女性更容易发生泌尿系感染(p=0.024,OR=10.0)。达格列净显著降低糖化血红蛋白(p<0.001),空腹血糖(p<0.001)、胰岛素用量(p<0.001)、体重(p=0.02)、BMI(p=0.02)、收缩压(p=0.04)、蛋白尿(p=0.05)。结论：本研究依据真实世界的观察性数据,支持达格列净相对安全,是糖尿病肾病治疗的一个良好选择。     

现实世界研究生态圈的构建与发展

现实世界证据（real-world evidence，RWE）由现实世界数据（real-world data，RWD）产生，经现实世界研究（real-world study，RWS）转化而来。科学的RWE可为决策提供参考依据，其产生有赖于系统性地构建和发展良性生态圈。本文梳理了RWD、RWS在产生RWE中的角色及转化机制，试图探讨构建现实世界研究良性生态系统的必要性及构成要素，并简要展望生态圈的发展趋势、机遇及挑战。