Introduction

The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC.

Methods

Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed.

Results

The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm.

In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0–10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2–11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82–1.18]; P = 0.85).

Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49–0.98]; P = 0.038), from 7.6 to 9.0 months median OS.

With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4–5.3]) and 4.9 months (95%CI:[4.3–5.4]). HR for PFS was 0.97 (95%CI:[0.83–1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS.

Conclusion

In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

中文翻译：

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对两项评估在晚期 NSCLC 标准一线化疗中加入狄诺塞麦的随机试验的患者水平联合分析——ETOP/EORTC SPLENDOR 和 AMGEN-249 试验

介绍

两项独立的随机试验（SPLENDOUR 和 AMGEN-249）评估了在晚期 NSCLC 患者的标准一线化疗中加入狄诺塞麦的疗效。在此汇总分析中，我们将评估最大可用人群中的联合治疗效果，以得出关于狄诺塞麦对 NSCLC 的潜在影响的结论。

方法

纳入本联合分析的两项试验都是随机（SPLENDOUR 1:1，AMGEN-249 2:1）多中心试验，按组织学、骨转移、地理区域和仅针对 SPLENDOR 的 ECOG PS 进行分层。Cox 比例风险模型用于评估总体生存期（OS；主要终点）和无进展生存期（PFS；次要终点）方面的治疗效果。评估了试验之间的异质性，并进行了亚组分析。

结果

汇总分析基于 740 名随机患者 (SPLENDOUR:514; AMGEN-249:226)，其中化疗-狄诺塞麦组 407 名患者，单独化疗组 333 名患者。

在化疗-狄诺塞麦组中，中位随访时间为 22.0 个月，报告了 277 例（68.1%）死亡，中位 OS 为 9.2 个月（95%CI：[8.0-10.7]），而在单独化疗组中，中位随访时间相似，为 20.3 个月，230 人（69.1%）死亡，中位 OS 为 9.9 个月（95%CI：[8.2–11.2]）。未发现显着的狄诺塞麦效应（HR = 0.98；95%CI：[0.82–1.18]；P  = 0.85）。

在亚组中，治疗和组织学亚型之间存在相互作用（P  = 0.020），鳞状组具有统计学显着益处（HR = 0.70；95%CI：[0.49–0.98]；P  = 0.038），从 7.6 到 9.0月中位 OS。

在 PFS 方面，化疗联合狄诺塞麦组和单独化疗组分别报告了 363 (89.2%) 和 298 (89.5%) 次事件，相应的中位数为 4.8 个月 (95%CI:[4.4–5.3]) 和 4.9个月（95% CI：[4.3–5.4]）。PFS 的 HR 为 0.97  （95% CI：[0.83–1.15]；P  = 0.76），表明 PFS 不存在显着的狄诺塞麦益处。

结论

在该汇总分析中，地诺单抗和化疗联合治疗晚期 NSCLC 的 PFS/OS 没有显示出统计学上的显着改善，并且在任何亚组中都没有显着的益处。