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Clinical Trial
. 2019 Dec;24(12):e1409-e1416.
doi: 10.1634/theoncologist.2018-0518. Epub 2019 Aug 16.

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial

David R Spigel  1   2 , Dianna L Shipley  3   2 , David M Waterhouse  3   4 , Suzanne F Jones  3 , Patrick J Ward  3   4 , Kent C Shih  3   2 , Brian Hemphill  3   2 , Michael McCleod  3   5 , Robert C Whorf  3   6 , Ray D Page  3   7 , Joseph Stilwill  3   8 , Tarek Mekhail  9 , Cindy Jacobs  10 , Howard A Burris 3rd  3   2 , John D Hainsworth  3   2
Affiliations
Clinical Trial

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial

David R Spigel et al. Oncologist. 2019 Dec.

Abstract
in English, Chinese

Background: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC).

Methods: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity.

Results: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months.

Conclusion: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

Implications for practice: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

摘要

背景。本次随机双盲 II 期试验对卡铂和培美曲塞联合 Apatorsen[一种反义寡核苷酸靶向热休克蛋白 (Hsp) 27 mRNA]或安慰剂治疗既往未经治疗的非鳞状非小细胞肺癌 (NSCLC) 患者的疗效进行评估。

方法。按照 1:1 的比例将患者随机分配至 A 组(卡铂/培美曲塞联合 Apatorsen)或 B 组(卡铂/培美曲塞联合安慰剂)。治疗以 21 天为一个周期进行，每两个周期重新安排治疗，直至患者出现疾病进展或无法忍受的毒性。在基线和治疗期间对血清 Hsp27 水平进行分析。主要终点为无进展生存期 (PFS)；次要终点包括总生存期 (OS)、客观缓解率和毒性。

结果。试验招募了 155 名患者(中位年龄为 66 岁；44% 的患者的美国东部肿瘤协作组体力状态得分为 0)。2 个治疗组中的毒性相似；血细胞减少、恶心、呕吐和疲劳是最常见的治疗相关不良反应。A 组的中位 PFS 和 OS 分别为 6.0 个月和 10.8 个月，B 组的中位 PFS 和 OS 分别为 4.9 个月和 11.8 个月(差异无统计学意义)。A 组和 B 组的总缓解率分别为 27% 和 32%。在基线时，十六名患者 (12%) 的血清 Hsp27 水平较高。在这个小群体中，使用 Apatorsen 的患者的中位 PFS 为 10.8 个月，使用安慰剂的患者的中位 PFS 为 4.8 个月。

结论。在一线治疗中，卡铂和培美曲塞联合 Apatorsen 治疗的耐受性良好，但是，不能改善转移性非鳞状 NSCLC 患者的预后。

实践意义:本次随机双盲 II 期试验对卡铂和培美曲塞联合 Apatorsen(一种反义寡核苷酸靶向热休克蛋白 27 mRNA)或安慰剂治疗既往未经治疗的转移性非鳞状非小细胞肺癌 (NSCLC) 患者的疗效进行评估。在一线治疗中，卡铂和培美曲塞联合 Apatorsen 治疗的耐受性良好，但是，不能改善转移性非鳞状 NSCLC 患者的预后。

Keywords: Heat‐shock protein 27; Non‐small cell lung cancer; Oligonucleotide.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.
Figure 1.
Treatment schema. Abbreviations: AUC, area under the curve; IV, intravenously.
Figure 2.
Figure 2.
CONSORT diagram. Asterisk (*) indicates inclusion of both related and unrelated adverse events.
Figure 3.
Figure 3.
Progression‐free survival and overall survival on the two study arms. (A): Progression‐free survival. (B): Overall survival. Abbreviations: OS, overall survival; PFS, progression‐free survival.
See this image and copyright information in PMC

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