A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.

BACKGROUND: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). METHODS: Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. RESULTS: Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. CONCLUSIONS: Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.

Factors Associated With Blood Pressure Control Among Patients in Community Health Centers.

INTRODUCTION: Understanding the multilevel factors associated with controlled blood pressure is important to determine modifiable factors for future interventions, especially among populations living in poverty. This study identified clinically important factors associated with blood pressure control among patients receiving care in community health centers. METHODS: This study includes 31,089 patients with diagnosed hypertension by 2015 receiving care from 103 community health centers; aged 19-64 years; and with ≥1 yearly visit with ≥1 recorded blood pressure in 2015, 2016, and 2017. Blood pressure control was operationalized as an average of all blood pressure measurements during all the 3 years and categorized as controlled (blood pressure <140/90), partially controlled (mixture of controlled and uncontrolled blood pressure), or never controlled. Multinomial mixed-effects logistic regression models, conducted in 2022, were used to calculate unadjusted ORs and AORs of being in the never- or partially controlled blood pressure groups versus in the always-controlled group. RESULTS: A total of 50.5% had always controlled, 39.7% had partially controlled, and 9.9% never had controlled blood pressure during the study period. The odds of being partially or never in blood pressure control were higher for patients without continuous insurance (AOR=1.09; 95% CI=1.03, 1.16; AOR=1.18; 95% CI=1.07, 1.30, respectively), with low provider continuity (AOR=1.24; 95% CI=1.15, 1.34; AOR=1.28; 95% CI=1.13, 1.45, respectively), with a recent diagnosis of hypertension (AOR=1.34; 95% CI=1.20, 1.49; AOR=1.19; 95% CI=1.00, 1.42), with inconsistent antihypertensive medications (AOR=1.19; 95% CI=1.11, 1.27; AOR=1.26; 95% CI=1.13, 1.41, respectively), and with fewer blood pressure checks (AOR=2.14; 95% CI=1.97, 2.33; AOR=2.17; 95% CI=1.90, 2.48, respectively) than for their counterparts. CONCLUSIONS: Efforts targeting continuous and consistent access to care, antihypertensive medications, and regular blood pressure monitoring may improve blood pressure control among populations living in poverty.