The Year in Review 2017


We are pleased to bring you the following journal review, part of a project developed by the ITS SpR

Educational Officer Dr Robert Smyth.


Top Reads for 2017

By Dr Ciara Gough, SpR in Respiratory Medicine



FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med. 2017;196(4):438-446


This randomised, double-blind, double-dummy trial compared the effects of once-daily triple therapy (ICS/LAMA/LABA) on lung

function and quality of life scores to those managed with twice-daily ICS/LABA therapy in patients with advanced COPD. 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100/62.5/25μg; ELLIPTA inhaler) (n=911) was compared with twice-daily ICS/LABA therapy (budesonide/formoterol 400/12 μg; Turbuhaler) (n=899). Co-primary endpoints were change from baseline in trough FEV1 and in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 24. In the intention to treat population at week 24, mean change from baseline FEV1 was 142 ml in triple therapy (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13) in standard therapy. Mean change from baseline SGRQ scores were -6.6 units (95% CI,-7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4) respectively. Forboth endpoints, the between-group differences were statistically

significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% relative reduction; 95% CI, 14-51;P = 0.002).


FINAL STATEMENT: Single-inhaler triple therapy offers clinically important benefits in lung function, HRQoL, and reduction in the risk of exacerbations compared to ICS/LABA therapy. This treatment provides a straightforward dosing option for patients with advanced COPD, reducing polypharmacy and may encourage improved adherence.



Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.

New England Journal of Medicine 2016;375:1823-1833


Programmed death one (PD-1) is a negative co-stimulatory receptor expressed primarily on activated T-cells. Binding of PD-1 to PD-L1 enables cancer cells expressing PD-L1 to evade immune surveillance. Pembrolizumab is an IgG4 PD-1 blocking antibody. It binds to PD-1 and prevents engagement with the PD-L1 ligand thereby revealing the cancer cells to the immune system. This trial compared pembrolizumab to the investigator’s choice of platinum based chemotherapy as a first line treatment in patients with advanced NSCLC, and PD-L1 expression of >50%. Patients with EGFR mutations and ALK translocations were excluded. 305 patients were randomised in a 1:1 ratio to receive pembrolizumab 200mg q3 weeks for 35 cycles or the standard of care platinum based regimen. In the intention-to-treat population, treatment with pembrolizumab resulted in significantly longer progression free survival (median PFS 10.3 vs 6.0 months, HR for disease progression or death 0.50, 95% CI, 0.37-0.68; p<0.001) and overall survival at 6 months (80.2% vs 72.4% in the

chemotherapy group, HR for death 0.60, 95% CI, 0.41 to 0.89). Benefits were sustained across all histological subtypes analysed with lower rates of treatment related side effects observed.


FINAL STATEMENT: Though historically lung cancer has been considered a poorly immunogenic malignancy, check point inhibitors such as pembrolizumab have emerged as promising first line agents in the treatment of advanced NSCLC, irrespective of histological subtype.




Tezepelumab in adults with uncontrolled asthma.

New England Journal of Medicine 2017; 377:936-946


This multi-centre, phase 2 randomised, double blind, placebo controlled trial evaluated the efficacy and safety of tezepelumab, a human monoclonal antibody specific for the epithelial-cell–derived cytokine thymic stromal lymphopoietin (TSLP), in patients with

poorly controlled asthma. Tezepelumab given at three dose levels was compared with placebo over a 52-week treatment period. The primary end point was the annual rate of exacerbations at week 52. The use of tezepelumab 70 mg every 4 weeks, 210 mg every 4 weeks, or 280 mg every 2 weeks resulted in asthma exacerbation rates at week 52 of 0.26, 0.19, and 0.22, respectively, as compared with 0.67 in the placebo group. This represents a relative reduction in the exacerbation rate of 61%, 71% and 66% in the respective tezepelumab groups when compared to that observed in the placebo group (P<0.001 for all comparisons).

FEV1 at week 52 was higher in all tezepelumab groups than in the placebo group (difference, 0.12L at low dose [P=0.01], 0.11L at

medium dose [P=0.02], and 0.15L at high dose [P=0.002]). Similar results were observed in patients regardless of blood eosinophil counts.


FINAL STATEMENT: Changes in biomarker levels suggest that inhibition of TSLP may have broader physiological effects than just the targeting of individual Th2 cytokines and may be useful in managing those with difficult to treat, non-eosinophilic disease.



Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis: Results of the INJOURNEY Trial.

Am J Respir Crit Care Med. Epub September 10th 2017


This trial of combination therapy investigated the safety, tolerability, pharmacokinetic properties and and efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. Patients with IPF and FVC ≥50% predicted at screening were randomised to open label nintedanib 150 mg bid with add-on pirfenidone (titrated to 801 mg tid), or nintedanib 150 mg bid alone, for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to week 12. On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Serious adverse events were reported in two patients (3.8%) and five patients (9.8%) in these treatment groups, respectively. Pre-dose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean changes from baseline in FVC at week 12 were −13.3 mL and −40.9mL in patients treated with nintedanib with add-on pirfenidone (n=48) and nintedanib alone (n=44), respectively.


FINAL STATEMENT: This study demonstrates that nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF. The data supports further research into combination regimens in the treatment of this progressive disease.




Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis

New England Journal Medicine 2017; 377:1043-1054


This trial assessed the accuracy of an automated, cartridge-based novel molecular assay, used on the GeneXpert platform, for the detection of Mycobacterium tuberculosis species harbouring resistance to fluoroquinolones, aminoglycosides, and isoniazid. This

was performed directly on sputum samples. Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin (95% CI, 79.0 to 93.7), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI,

54.5 to 83.9). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater.


FINAL STATEMENT: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with M. tuberculosis.