2 Minute Medicine Rewind September 28 – October 4, 2015

Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

Although docetaxel is currently used, effective second line chemotherapy agents are limited for patients with non-small cell lung cancer (NSCLC). This study was a randomized, open label, phase 3 clinical trial involving 582 patients with stage IIIB, IV or recurrent NSCLC that examined the use of nivolumab, a PD-L1 inhibitor, versus docetaxel. The primary end point was overall survival, monitored during therapy and for 3 months after discontinuation of treatment. Patients were included if they were >18 years of age, had an ECOG score of 0 or 1 and if they had adequate hepatic, renal and hematologic functions. The analysis showed that overall survival was longer in the 292 patients in the nivolumab group,  (12.2 months, 95% CI: 9.7 to 15.0) compared to the 290 patients in the docetaxel group (9.4 months, 95% CI: 8.1 to 10.7). The difference in overall survival had a hazard ratio of 0.73, 96% CI: 0.59 to 0.89, p=0.002. Furthermore, at 18 months, the survival rate with nivolumab was higher than with docetaxel, specifically 39%( 95% CI: 33 to 45) vs. 23% ( 95% CI: 19 to 28). Subset analysis showed no improvement in survival in patients who did not express PD-L1, the primary target of nivolumab. This subgroup analysis merits further exploration of nivolumab in patients without PD-L1. In conclusion, this study shows the overall superior benefit of nivolumab in extending survival by 2.8 months over docetaxel in patients with advanced, relapsed NSCLC.

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia

Agitation is highly prevalent in patients with Alzheimer’s disease dementia yet pharmacological therapy remains limited. Non-pharmacological approaches are first line therapies but many patients fail to respond. This study was a phase 2 multicenter randomized placebo controlled trial involving 194 patients with Alzheimer’s disease that assessed the efficacy of dextromethorphan-quinidine for Alzheimer’s disease related agitation. The primary endpoint was change from the baseline NPI Agitation/Aggression domain. The study was set in 2 stages. The first stage randomized patients to either dextromethorphan-quindine or placebo and the second stage identified patients assigned to placebo in the first stage without clinical response and rerandomized  these nonresponders to either dextromethorphan-quindine or placebo again. Stage 1 analysis showed reduction in NPI score from 7.1 to 3.8 in the treatment group versus 7.0 to 5.3 in the placebo group, with least squares mean difference of -1.5, 95% CI: -2.3 to -0.7, P<0.001. In stage 2, NPI score were reduced from 5.8 to 3.8 and 6.7 to 5.8 respectively achieving statistical significance, least squares mean difference of -1.6, 95% CI: -2.9 to-0.3, P=0.02. However, the study demonstrated that dextromethorphan-quinidine was associated with increased falls (8.6% vs. 3.9%), diarrhea (5.9% vs. 3.1%) and UTIs (5.3% vs. 3.9%). There was no association with cognitive impairment or clinically significant QTc prolongation. The main limitation of this study was the limited duration of 10 weeks and the lack of evaluation for dose-response relationships. However, this trial demonstrated the clinically efficacy of dextromethorphan-quinidine in controlling Alzheimer’s related agitation.

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

Although 51-81% of older adults with major depressive disorder are resistant to treatment with SSRIs or SNRIs, there is little evidence to guide second-line or augmentation therapy. This study was a randomized double-blind placebo controlled trial involving 468 patients across 3 centers in the US and Canada that examined aripiprazole augmentation in patients >60 years who did not respond to a trial of venlafaxine. The primary efficacy outcome was remission, defined as a MADRS score of ≤10 at both of the final 2 consecutive visits with at least a 2-point drop from the start of the study. The primary cardiometabolic outcome was change in body adiposity quantified with a DEXA scan. The primary neurological tolerability outcome was proportion of patients with akathisia. Of the 468 patients with depression, 181 were deemed to have resistant depression and were assigned to the augmentation phase of a 12-week trial randomized to aripiprazole 2mg daily, titrated to 10mg, versus placebo. Analysis demonstrated greater remission in the aripiprazole group, 44% vs. 29%, OR: 2.0, 95% CI: 1.1 to 3.7, p=0.03. The NNT was 6.6, 95% CI: 3.5 to 81.8. The most common side effect was akathisia reported in 26% of the aripiprazole patients. Parkinsonism was associated in 17% of that group. There was no significant difference in the cardiometabolic risks with aripiprazole. The main limitations of this study included, small sample sizes,  exclusion of patients with dementia and no clear guidelines in regards to appropriate venlafaxine dosing before aripiprazole augmentation. Despite the increase in extrapyramidal side effects, this study does show efficacy of aripiprazole in the remission of treatment-resistant depression in older adults.

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

Psoriasis affects 2-3% of the world‘s population and although a number of therapies are available, many patients remain unresponsive or have toxic side effects from existing treatments. This article investigated the use of brodalumab, an IL-17 antibody, in the treatment of psoriasis. AMAGINE-2 (n=1831) and AMAGINE-3 (n=1881) were two identical phase 3 randomized double-blind, placebo and active comparator–controlled, parallel-group trials each involving 142 sites worldwide. Patients were randomly assigned in a 2:2:1:1 ratio to receive brodalumab 210mg, brodalumab 140mg, ustekinumab or placebo. The primary endpoint was twofold. The first was comparing the two doses of brodalumab with placebo in regards to the proportion of patients who had a 75% or greater reduction from baseline PASI scores (PASI 75) at week 12. The second was to compare brodalumab with ustekinumab in regards to proportion of patients who had a 100% reduction in PASI scores (PASI100) at week 12. The study demonstrated that the PASI75 response rates were higher in 210mg and 140mg groups compared with placebo. In AMAGINE-2 , the response rates were 86% and 67% vs. 8%, and in AMAGINE-3 the response rates were 85% and 69% vs. 6% reaching statistical significance with P<0.001. Furthermore, PASI100 response rates were higher with 210mg of brodalumab vs ustekinumab (44% vs 22% in AMAGINE-2 and 37% vs 19% in AMAGINE-3, P<0.001). However, brodalumab was associated with an increased rate of neutropenia and candida infections when compared to ustekinumab or placebo. This study, although limited in the detection of rare adverse events, succeeded in answering questions of efficacy and in exploring common adverse events. In conclusion, this paper demonstrates the use of brodalumab in controlling the symptoms of moderate to severe psoriasis.

Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial

Age-related macular degeneration is the leading cause of visual impairment in high-income countries. Specifically, wet age-related macular degeneration, stemming from abnormal choroidal blood vessel growth, leads to rapid visual loss and central blindness. Current anti-VEGF methods require frequent intravitreal injections which are associated with vision threatening adverse events. This study, a phase 1 randomized control trial, used gene therapy to transduce retinal cells with rAAV encoding sFLT-1, a potent VEGF inhibitor, in 8 patients. The primary outcome was ocular and systemic safety measured with visual acuity, intraocular pressure, ophthalmoscopy, physical exams and routine laboratory testing. 3 patients received low dose vector genomes, 3 received high dose vector genomes and 2 patients received no vectors. Patients received ranibizumab, a VEGF antibody, at baseline and at week 4, and rescue treatment during follow-up. Analysis revealed no evidence of chorioretinal atrophy and unchanged laboratory assessments. There was transient, mild intraocular inflammation following surgery and no dose-limiting toxic effects were noted. Furthermore, there were encouraging signs of improved clinical outcomes. In the treatment group, 4 of 6 patients no longer required anti-VEGF rescue injection at the 1 year follow up. The primary limitation of this study was that it did not assess efficacy differences between the treatment groups, rather it only establishes the safety of subretinal rAAV.sFLT-1 injection in a small sample of patient with age-related wet macular degeneration.

Image: PD

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