Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer

ObjectivesIn randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression.MethodsPatients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring).ResultsIn the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction—the most suitable method based on published guidelines and trial characteristics—produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction.ConclusionsAfter adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis

Assessment of statin therapy, LDL-C levels, and cardiovascular events among high-risk patients in the United States

BackgroundStatins have demonstrated significant benefit in reducing cardiovascular disease (CVD) risk.ObjectiveTo evaluate statin treatment patterns by intensity, elevated low-density lipoprotein cholesterol (LDL-C) levels, and cardiovascular (CV) events in high-risk CVD patients.MethodsPatients included were aged ≥18 years, with a coronary heart disease (CHD; Jan 1, 2007–Dec 31, 2011, index date) or CHD risk equivalent (CHD RE) diagnosis (Jan 1, 2007–Dec 31, 2010, index date), in the Truven MarketScan claims database, continuously enrolled for 2 years pre- and up to 1 (CHD) or 2 (CHD RE) years post-index. Patients with CHD, CHD RE, rhabdomyolysis, or chronic kidney disease any time pre-index were excluded. Statin therapy was assessed at baseline, 30, 90, and 365 days post-index. LDL-C values were captured in patients with available data at 30-day intervals up to 1 year. CV events were evaluated up to 1 year post-index. Descriptive statistics were used to report results.ResultsThere were 175,103 CHD and 68,290 CHD RE patients; 3333 CHD RE patients had post-index CV events. At 1 year, 38.7% of CHD patients and 44.3% of CHD RE patients with post-index CV events were not prescribed statins. Most patients who were prescribed statins, received a moderate-intensity statin. The percentage of patients with LDL-C ≥ 100 mg/dL reduced over time, but at 1 year, 29.3% of CHD and 30.0% of CHD RE patients with post-index CV events had LDL-C ≥ 100 mg/dL. At 1 year post-index, 9.9% CHD and 7.3% CHD RE patients had at least 1 CV event.ConclusionThere is room for better LDL-C management among high-risk CVD patients to reduce their overall CV risk

A systematic review to assess adherence and persistence with statins

<p><b>Objective:</b> To identify and assess studies published over a 10 year period up to February 2016 which measure adherence or persistence with statins, to summarize their methods, strengths and weaknesses and to summarize evidence linking statin adherence/persistence with risk of cardiovascular events.</p> <p><b>Methods:</b> Electronic databases and abstracts from four major cardiovascular disease conferences were searched from January 2005 to February 2016. The study selection process was performed by two reviewers working independently. Studies were included if they reported data regarding patient adherence or persistence with statins in adults with primary hypercholesterolemia, using any type of study design or length of follow-up. One reviewer extracted the study data and assessed study quality, which was checked by a second reviewer independently. Given the heterogeneity between the included studies a narrative critique and summary is presented.</p> <p><b>Results:</b> We report on 84 real world studies which aimed to assess adherence or persistence with statins. The majority of studies concluded that good adherence/persistence was associated with reduction in cardiovascular events and mortality. In two studies high intensity statin regimens were associated with poorer patient adherence when compared to low intensity statins. Adherence and persistence with statin therapy also has an impact on hospitalization costs and other cardiovascular disease (CVD) related costs.</p> <p><b>Conclusions:</b> Adherence and persistence are associated with a reduction in CVD events and mortality. There was limited evidence to suggest that high intensity statin regimens are associated with poorer treatment adherence when compared to lower intensity regimens. Hence, more robust studies are required to establish this association. As recommended by the 2013 ACC/AHA, 2016 ESC and several other clinical guidelines, clinicians and pharmacy managers should regularly monitor statin therapy adherence.</p

Outcomes in clinically relevant patient subgroups from the EMBRACA study: Talazoparib vs physician’s choice standard-of-care chemotherapy

Background: Talazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations.Methods: EMBRACA (NCT01945775) was a randomized phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician's choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) or triple-negative breast cancer (TNBC) subgroups.Results: Of 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/UHER2-: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71; TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/UHER2- and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia.Conclusions: Across all patient subgroups with gBRCA-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT