Combined RAF and MEK Inhibition to Treat Activated Non-V600 BRAF-Altered Advanced Cancers.

BACKGROUND: Cancers with non-V600 BRAF-activating alterations have no matched therapy. Preclinical data suggest that these tumors depend on ERK signaling; however, clinical response to MEK/ERK inhibitors has overall been low. We hypothesized that a narrow therapeutic index, driven by ERK inhibition in healthy (wild-type) tissues, limits the efficacy of these inhibitors. As these mutants signal as activated dimers, we further hypothesized that RAF inhibitors given concurrently would improve the therapeutic index by opposing ERK inhibition in normal tissues and not activate ERK in the already activated tumor. MATERIALS AND METHODS: Using cell lines and patient-derived xenografts, we evaluated the effect of RAF inhibition, alone and in combination with MEK/ERK inhibitors. We then undertook a phase I/II clinical trial of a higher dose of the MEK inhibitor binimetinib combined with the RAF inhibitor encorafenib in patients with advanced cancer with activating non-V600 BRAF alterations. RESULTS: RAF inhibition led to modest inhibition of signaling and growth in activated non-V600 BRAF preclinical models and allowed higher dose of MEK/ERK inhibitors in vivo for more profound tumor regression. Fifteen patients received binimetinib 60 mg twice daily plus encorafenib 450 mg daily (6 gastrointestinal primaries, 6 genitourinary primaries, 3 melanoma, and 2 lung cancer; 7 BRAF mutations and 8 BRAF fusions). Treatment was well tolerated without dose-limiting toxicities. One patient had a confirmed partial response, 8 had stable disease, and 6 had radiographic or clinical progression as best response. On-treatment biopsies revealed incomplete ERK pathway inhibition. CONCLUSION: Combined RAF and MEK inhibition does not sufficiently inhibit activated non-V600 BRAF-mutant tumors in patients.

Refusal of emergency medical care: An analysis of patients who left without being seen, eloped, and left against medical advice.

OBJECTIVE: Emergency department (ED) patients may elect to refuse any aspect of medical care. They may leave prior to physician evaluation, elope during treatment, or leave against medical advice during treatment. This study was undertaken to identify patient perspectives and reasons for refusal of care. METHODS: This prospective study was conducted at an urban Level 1 Trauma Center. This study examined ED patients who left without being seen (LWBS), eloped during treatment, or left against medical advice during September to December 2018. This project included both chart review and a prospective patient survey. RESULTS: Among 298 participants, the majority were female (54%). Most participants were White (61%) or African American (36%). Thirty-eight percent of participants left against medical advice, 23% eloped, and 39% left without being seen by a provider. When compared to the general ED population, patients who refused care were significantly younger (p < 0.001). When comparing by groups, patients who left AMA were significantly older than those who eloped or left without being seen (p < 0.001). Among 68 patients interviewed by telephone, the most common stated reasons for refusal of care included wait time (23%), unmet expectations (23%), and negative interactions with ED staff (15%). CONCLUSION: ED patients who refused care were significantly younger than the general ED population. Common reasons cited by patients for refusal of care included wait time, unmet expectations, and negative interactions with ED staff.