Anti-IL-4R versus Anti-IL-5/5R after Anti-IL-5/5R failure in asthma: an emulated target trial.

BACKGROUND: Switching biologics is now common practice in severe eosinophilic asthma. After insufficient response to anti-interleukin 5 or 5 receptor (anti-IL-5/5R), the optimal switch between an anti-IL-4R monoclonal antibody (mAb) (inter-class) or another anti-IL-5/5R drug (intra-class) remains unknown. OBJECTIVE: We compared the effectiveness of these two strategies on asthma control in patients with severe eosinophilic asthma and insufficient response to an anti-IL-5/5R mAb. METHODS: We emulated a target randomized trial using observational data from the RAMSES Cohort. Eligible patients were switched to an anti-IL-4R mAb or another anti-IL-5/5R drug after insufficient response to an anti-IL-5/5R mAb. The primary outcome was the change in Asthma Control Test (ACT) score at 6 months. RESULTS: Among the 2046 patients in the cohort, 151 were included in the study: 103 switched to an anti-IL-4R mAb and 48 to another anti-IL-5/5R. At 6 months, the difference in ACT score improvement was not statistically significant (mean difference groups, 0.82 [-0.47,2.10], p=0.213). The inter-class group exhibited greater cumulative reduction in oral corticosteroids dose (Pinter-intra -1.05g [-1.76, -0.34], p=0.041). The inter-class group had a better effect, although not significantly, on reducing exacerbations (Δinter-intra -0.37 [-0.77, 0.02], p=0.124) and increasing lung function (FEV1) (126.8 ml [-12.7, 266.4], p=0.124). CONCLUSION: After anti-IL-5/5R mAb insufficient response, switching to dupilumab demonstrated similar improvement in ACT scores compared to intra-class switching. However, it appeared more effective in reducing oral corticosteroid use. Larger studies are warranted to confirm these results.

Articular manifestations related to anti-interleukin-5 therapies in severe asthma: a case series.

Articular manifestations should be screened before and during anti-IL-5/5R biologic treatment in severe asthma. Rigorous multidisciplinary team discussion should be carried out to assess the risk-benefit balance of withholding effective treatment. https://bit.ly/3vfPn4k.

Real-world super-response to biologics in severe asthma: A French monocentric retrospective cohort study.

BACKGROUND: Biologics have dramatically improved outcomes in severe T2-high asthma. Although the identification of patients with the best response is key to understand the efficacy of these agents and select the best target populations, the definition and predictors of super-response are not fully established yet. METHODS: This study aimed to describe super-response and to identify predictors of super-response to biologics in a French severe eosinophilic asthma cohort followed in a severe asthma tertiary care center between January 2005 and December 2020. Super-response was defined a priori as no oral corticosteroids intake and no exacerbations over 12 months. Collected data at baseline and after 12 months included asthma history, comorbidities, clinical characteristics, lung function, T2-biomarkers, baseline asthma-related treatments, and asthma control. RESULTS: Among 157 patients assessed for eligibility, 108 were included, corresponding to 166 treatments with biologics. Overall response rate was 63.2 % (105/166) and super-response rate was 39.7 % (66/166). In omalizumab group (n = 67), lower dose of oral corticosteroids in maintenance was the only factor associated with super-response (p = 0.008). In the anti-IL-5/anti-IL-5R group (n = 99), absence or lower dose of oral corticosteroids in maintenance and absence of eosinophilic granulomatosis with polyangiitis were statistically associated with super-response (p = 0.009, p = 0.001 and p = 0.02 respectively). CONCLUSION: In this real-life study in severe T2-high asthma patients, a lower dose or absence of daily oral corticosteroids and absence of eosinophilic granulomatosis with polyangiitis were the only identifiable predictors of super-response to biologics. Physicians should not wait for maintenance oral corticosteroids to be required before considering the initiation of a biologic in severe asthma.

Derivation and validation of a simple multidimensional index incorporating exercise capacity parameters for survival prediction in idiopathic pulmonary fibrosis.

INTRODUCTION: The gender-age-physiology (GAP) index is an easy-to-use baseline mortality prediction model in idiopathic pulmonary fibrosis (IPF). The GAP index does not incorporate exercise capacity parameters such as 6 min walk distance (6MWD) or exertional hypoxia. We evaluated if the addition of 6MWD and exertional hypoxia to the GAP index improves survival prediction in IPF. METHODS: Patients with IPF were identified at a tertiary care referral centre. Discrimination and calibration of the original GAP index were assessed. The cohort was then randomly divided into a derivation and validation set and performance of the GAP index with the addition of 6MWD and exertional hypoxia was evaluated. A final model was selected based on improvement in discrimination. Application of this model was then evaluated in a geographically distinct external cohort. RESULTS: There were 562 patients with IPF identified in the internal cohort. Discrimination of the original GAP index was measured by a C-statistic of 0.676 (95% CI 0.635 to 0.717) and overestimated observed risk. 6MWD and exertional hypoxia were strongly predictive of mortality. The addition of these variables to the GAP index significantly improved model discrimination. A revised index incorporating exercise capacity parameters was constructed and performed well in the internal validation set (C-statistic: 0.752; 95% CI 0.701 to 0.802, difference in C-statistic compared with the refit GAP index: 0.050; 95% CI 0.004 to 0.097) and external validation set (N=108 (C-statistic: 0.780; 95% CI 0.682 to 0.877)). CONCLUSION: A simple point-based baseline-risk prediction model incorporating exercise capacity predictors into the original GAP index may improve prognostication in patients with IPF.

Paclitaxel-bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel-bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19-82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2-9.6] and 10.8 [IQR: 5.3-19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI-): 7.0 [IQR: 4.2-11.0] versus 5.2 [IQR: 2.9-8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0-1. Only a performance status of 0-1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.