Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status.
Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status.
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人单克隆抗体dupilumab可阻断白细胞介素（IL）-4和IL-13，这是2型炎症的关键和中心驱动因素。在III期SINUS-52研究（NCT 02898454）中，Dupilumab联合背景糠酸莫米松鼻喷雾剂（MFNS）改善了重度慢性鼻窦炎伴鼻息肉（CRSwNP）患者的结局。SINUS-52的事后分析检查了CRSwNP的嗜酸性粒细胞状态是否是dupilumab疗效的预测因子。患者以1：1：1的比例随机分配至dupilumab 300 mg每2周一次（q2 w），直至第52周; dupilumab 300 mg q2 w，直至第24周，然后300 mg每4周一次，直至第52周;或安慰剂（MFNS），直至第52周。共同主要终点为第24周时鼻息肉评分（NLP）、鼻充血（NC）和CT评估的隆德-麦凯评分（LMK-CT）较基线的变化。根据日本难治性嗜酸性鼻窦炎流行病学调查算法，按嗜酸性慢性鼻窦炎（ECRS）状态对患者（n = 438）进行分层。在所有ECRS亚组中，与安慰剂相比，Dupilumab在第24周时显著改善了ESTA、NC和LMK‐CT评分（p < 0.001），在第52周时保持或增加了改善（p < 0.001）。在第24周和第52周，ECRS亚组（非/轻度或中度/重度）与dupilumab治疗效应之间的所有终点均无显著相互作用（p > 0.05），但第24周的LMK-CT除外（p = 0.0275）。次要终点的结果相似。Dupilumab在所有ECRS亚组中均耐受良好。无论ECRS状态如何，Dupilumab均可持续改善重度CRSwNP的症状。因此，血液嗜酸性粒细胞水平可能不是dupilumab在CRSwNP中疗效的合适生物标志物。根据嗜酸性粒细胞状态（ECRS亚组; JESREC标准）对来自SINUS-52的CRSwNP患者进行分类。尽管中度/重度ECRS显示基线疾病负荷大于轻度/无ECRS，但dupilumab与安慰剂相比，疾病控制、症状负荷、嗅觉和HRQoL的改善不受ECRS状态的影响。嗜酸性粒细胞状态不是符合SINUS-52入选标准的CRSwNP患者中dupilumab疗效的生物标志物。缩略语：CRSwNP，慢性嗜酸性鼻窦炎伴鼻息肉; ECRS，嗜酸性慢性嗜酸性鼻窦炎; EOS，嗜酸性粒细胞; HRQoL，健康相关生活质量; ITT，意向治疗; JESREC，日本难治性嗜酸性鼻窦炎流行病学调查; LMK-CT，CT评估的隆德-Mackay评分; SINUS-52，dupilumab治疗鼻息肉患者的对照临床研究; SNOT-22，22项鼻窦结局试验; VAS，视觉模拟量表。
The human monoclonal antibody dupilumab blocks interleukin (IL)‐4 andIL‐13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS‐52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS‐52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy. Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund‐Mackay score assessed by CT (LMK‐CT) at week 24. Patients (n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm. Dupilumab significantly improved NPS, NC, and LMK‐CT scores versus placebo at week 24 in all ECRS subgroups (p < 0.001), with improvements maintained or increased at week 52 (p < 0.001). There was no significant interaction between ECRS subgroup (non‐/mild or moderate/severe) and dupilumab treatment effect for all endpoints at weeks 24 and 52 (p > 0.05), except LMK‐CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups. Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP. Patients with CRSwNP from SINUS‐52 were classified by eosinophilic status (ECRS subgroup; JESREC criteria). Although moderate/severe ECRS shows greater baseline disease burden than mild/no ECRS, improvements in disease control, symptom burden, sense of smell, and HRQoL with dupilumab versus placebo are unaffected by ECRS status. Eosinophilic status is not a biomarker for dupilumab efficacy in CRSwNP patients meeting SINUS‐52 inclusion criteria. Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyps; ECRS, eosinophilic chronic rhinosinusitis; EOS, eosinophil; HRQoL, health‐related quality of life; ITT, intention‐to‐treat; JESREC, Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis; LMK‐CT, Lund‐Mackay score assessed by CT; SINUS‐52, controlled clinical study of dupilumab in patients with nasal polyps; SNOT‐22, 22‐item sinonasal outcome test; VAS, visual analog scale.
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DOI：
10.1073/pnas.1324022111
发表时间：
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