A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.

BACKGROUND: Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens. METHODS: The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (Cavg) and trough concentration (Cmin) at steady state (ss). Safety was bridged by ensuring that concentrations were below those at 10 mg/kg dose every 2 weeks (Q2W), the maximum clinical dose. RESULTS: The 400 mg Q6W dose had similar predicted exposure (Cavg,ss, geometric mean âˆ¼1% higher) as the 200 mg Q3W dose. Fewer than 1% of subjects had transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (∼65%) lower than the 10 mg/kg Q2W dose. CONCLUSIONS: Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types. CLINICAL TRIAL REGISTRATION NUMBERS: NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.

Anti-angiogenic-specific adverse events in patients with non-small cell lung cancer treated with nintedanib and docetaxel.

OBJECTIVES: LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib+docetaxel versus placebo+docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib+docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents. MATERIALS AND METHODS: The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication (N=1307) and for the two main histologies: adenocarcinoma (n=653) and squamous cell carcinoma (SCC; n=553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders. RESULTS AND CONCLUSION: The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perforations was 1.2% with nintedanib+docetaxel versus 0.2% with placebo+docetaxel. The incidence of some events was higher with nintedanib+docetaxel versus placebo+docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1-2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib+docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatment differences in the SCC subpopulation; most events were Grade 1-2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib+docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile.

A success story: HIV prevention for injection drug users in Rhode Island.

BACKGROUND: New HIV diagnoses related to injection drug use (IDU) have declined in the United States. Access to clean syringes and decreasing HIV transmission among injection drug users have been HIV prevention priorities of the Rhode Island (RI) HIV community. To examine trends in IDU-related new HIV diagnoses in RI, we performed a retrospective analysis of new HIV diagnoses according to HIV risk factor from 1990-2003. RESULTS: There has been an 80% absolute reduction in IDU-related new HIV diagnoses in RI coincident with IDU-specific prevention efforts. CONCLUSION: There has been a greater decline in IDU-related new HIV diagnoses in Rhode Island compared to national data reported by the Centers for Disease Control and Prevention. We hypothesize that this dramatic decline in Rhode Island is related to extensive HIV prevention efforts targeting IDUs. Further research is needed to examine the impact of specific HIV prevention interventions for injection drug users.

Prevalence and predictors of night sweats, day sweats, and hot flashes in older primary care patients: an OKPRN study.

PURPOSE: We wanted to estimate the prevalence of night sweats, day sweats, and hot flashes in older primary care patients and identify associated factors. METHODS: We undertook a cross-sectional study of patients older than 64 years recruited from the practices of 23 family physicians. Variables included sociodemographic information, health habits, chronic medical problems, symptoms, quality of life, and the degree to which patients were bothered by night sweats, daytime sweating, and hot flashes. RESULTS: Among the 795 patients, 10% reported being bothered by night sweats, 9% by day sweats, and 8% by hot flashes. Eighteen percent reported at least 1 of these symptoms. The 3 symptoms were strongly correlated. Factors associated with night sweats in the multivariate models were age (odds ratio [OR] 0.94/y; 95% confidence interval [CI], 0.89-0.98), fever (OR 12.60; 95% CI, 6.58-24.14), muscle cramps (OR 2.84; 95% CI, 1.53-5.24), numbness of hands and feet (OR 3.34; 95% CI, 1.92-5.81), impaired vision (OR 2.45; 95% CI, 1.41-4.27), and hearing loss (OR 1.84; 95% CI, 1.03-3.27). Day sweats were associated with fever (OR 4.10; 95% CI, 2.14-7.87), restless legs (OR 3.22; 95% CI, 1.76-5.89), lightheadedness (OR 2.24; 95% CI, 1.30-3.88), and diabetes (OR 2.19; 95% CI, 1.22-3.92). Hot flashes were associated with nonwhite race (OR 3.10; 95% CI, 1.60-5.98), fever (OR 3.98; 95% CI, 1.97-8.04), bone pain (OR 2.31; CI 95%: 1.30-4.08), impaired vision (OR 2.12; 95% CI, 1.19-3.79), and nervous spells (OR 1.87; 95% CI, 1.01-3.46). All 3 symptoms were associated with reduced quality of life. CONCLUSION: Many older patients are bothered by night sweats, day sweats, and hot flashes. Though these symptoms are similar and related, they have somewhat different associations with other variables. Clinical evaluation should include questions about febrile illnesses, sensory deficits, anxiety, depression, pain, muscle cramps, and restless legs syndrome.