Purpose Combination PD-1/CTLA-4 blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600 mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. Methods In a phase III trial, patients with treatment-naïve BRAFV600-mutant metastatic melanoma were randomized to receive either combination nivolumab/ipilimumab (Arm A) or dabrafenib/trametinib (Arm B) in Step 1, and at disease progression were enrolled in Step 2 receiving the alternate therapy, dabrafenib/trametinib (Arm C) or nivolumab/ipilimumab (Arm D). The primary endpoint was 2-year overall survival. Secondary endpoints were 3-year overall survival, objective response rate, response duration, progression-free survival, crossover feasibility and safety. Results 265 patients were enrolled with 73 going onto Step 2 (27 Arm C, 46 Arm D). The study was stopped early by the independent DSMC due to a clinically significant endpoint being achieved. The 2-year overall survival for those starting on Arm A was 71.8% (62.5, 79.1%) and Arm B 51.5% (41.7, 60.4%) (log-rank p=0.010). Step 1 progression-free survival favored Arm A (p=0.054). Objective response rates were: Arm A:46.0%; Arm B:43.0%; Arm C:47.8%; Arm D:29.6%. Median duration of response was not reached for Arm A and 12.7 months for Arm B (p<0.001). Crossover occurred in 52% of patients with documented disease progression. Grade >3 toxicities occurred with similar frequency between arms and regimen toxicity profiles were as anticipated. Conclusion Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

BackgroundPrimary care providers do not routinely follow guidelines for the care of patients with chronic kidney disease (CKD). Multidisciplinary efforts may improve care for patients with chronic disease. Pharmacist based interventions have effectively improved management of hypertension. We performed a pragmatic, randomized, controlled trial to evaluate the effect of a pharmacist based quality improvement program on 1) outcomes for patients with CKD and 2) adherence to CKD guidelines in the primary care setting.MethodsPatients with moderate to severe CKD receiving primary care services at one of thirteen community-based Veterans Affairs outpatient clinics were randomized to a multifactorial intervention that included a phone-based pharmacist intervention, pharmacist-physician collaboration, patient education, and a CKD registry (n = 1070) or usual care (n = 1129). The primary process outcome was measurement of parathyroid hormone (PTH) during the one year study period. The primary clinical outcome was blood pressure (BP) control in subjects with poorly controlled hypertension at baseline.ResultsAmong those with poorly controlled baseline BP, there was no difference in the last recorded BP or the percent at goal BP during the study period (42.0% vs. 41.2% in the control arm). Subjects in the intervention arm were more likely to have a PTH measured during the study period (46.9% vs. 16.1% in the control arm, P <0.001) and were on more classes of antihypertensive medications at the end of the study (P = 0.02).ConclusionsA one-time pharmacist based intervention proved feasible in patients with CKD. While the intervention did not improve BP control, it did improve guideline adherence and increased the number of antihypertensive medications prescribed to subjects with poorly controlled BP. These findings can inform the design of quality improvement programs and future studies which are needed to improve care of patients with CKD.Trial registrationClinicalTrials.gov: NCT01290614.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0052-2) contains supplementary material, which is available to authorized users.

PURPOSE Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting. PATIENTS AND METHODS In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms. RESULTS The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%). CONCLUSION EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

No abstract

No abstract