Napabucasin Plus FOLFIRI in Patients With Previously Treated Metastatic Colorectal Cancer: Results From the Open-Label, Randomized Phase III CanStem303C Study

IF 4.3 3区材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC

ACS Applied Electronic Materials Pub Date : 2023-03-01 DOI:10.1016/j.clcc.2022.11.002

Manish A. Shah , Takayuki Yoshino , Niall C. Tebbutt , Axel Grothey , Josep Tabernero , Rui-Hua Xu , Andres Cervantes , Sang Cheul Oh , Kensei Yamaguchi , Marwan Fakih , Alfredo Falcone , Christina Wu , Vi K. Chiu , Jiri Tomasek , Johanna Bendell , Marilyn Fontaine , Matthew Hitron , Bo Xu , Julien Taieb , Eric Van Cutsem

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引用次数: 2

Abstract

Purpose

Napabucasin is an investigational, orally administered reactive oxygen species generator bioactivated by intracellular antioxidant NAD(P)H:quinone oxidoreductase 1 that has been evaluated in various solid tumors, including metastatic colorectal cancer (mCRC). Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is hypothesized to predict response in napabucasin-treated patients with mCRC.

Patient and Methods

In the multi-center, open-label, phase III CanStem303C (NCT02753127) study, adults with histologically confirmed mCRC that progressed on first-line fluoropyrimidine plus oxaliplatin ± bevacizumab were randomized to twice-daily napabucasin plus FOLFIRI (napabucasin) or FOLFIRI alone (control). The primary endpoint was overall survival (OS) in the general study population and in patients with pSTAT3-positive tumors (biomarker-positive).

Results

In the general study population (napabucasin, n = 624; control, n = 629), median OS was 14.3 months for napabucasin and 13.8 months for control (hazard ratio [HR], 0.976, one-sided P = .74). Overall, 44% of patients were biomarker-positive (napabucasin, n = 275; control, n = 272). In the biomarker-positive population, median OS was 13.2 months for napabucasin and 12.1 months for control (HR, 0.969; one-sided P > .99). In the control arm, median OS was shorter for biomarker-positive versus biomarker negative patients (12.1 vs. 18.5 months; HR, 1.518; nominal 2-sided P = .0002). The most common treatment-emergent adverse events (TEAEs) were diarrhea (napabucasin, 84.6%; control, 53.9%), nausea (60.5%, 50.5%), vomiting (41.2%, 29.3%), and abdominal pain (41.0%, 25.2%). Grade ≥3 TEAEs occurred in 73.8% of napabucasin-treated and 66.7% of control-treated patients, most commonly diarrhea (21.2%, 7.0%), neutrophil count decreased (13.7%, 19.2%), and neutropenia (13.3%, 15.2%). Safety was similar in biomarker-positive patients.

Conclusion

In patients with previously treated mCRC, adding napabucasin to FOLFIRI did not improve OS. Results from the control arm indicate that pSTAT3 is an adverse prognostic factor in mCRC.

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Nababucasin加FOLFIRI治疗既往治疗的转移性结直肠癌癌症患者：开放标签、随机III期CanStem303C研究结果

目的Nababucasin是一种研究性口服活性氧发生器，由细胞内抗氧化剂NAD（P）H:醌氧化还原酶1生物激活，已在各种实体瘤中进行了评估，包括转移性癌症（mCRC）。磷酸化信号转导子和转录激活子3（pSTAT3）被假设用于预测萘普生治疗的mCRC患者的反应。患者和方法在多中心、开放标签、III期CanStem303C（NCT02753127。主要终点是一般研究人群和pSTAT3阳性肿瘤（生物标志物阳性）患者的总生存率（OS）。结果在一般研究人群中（萘普生，n=624；对照组，n=629），萘普生和对照组的中位OS分别为14.3个月和13.8个月（危险比[HR]为0.976，单侧P=.74）。总体而言，44%的患者生物标志物呈阳性（萘普生：n=275；对照组：n=272）。在生物标志物阳性人群中，萘普生的中位OS为13.2个月，对照组为12.1个月（HR，0.969；单侧P＞0.99），生物标志物阳性患者与生物标志物阴性患者的中位OS更短（12.1个月vs.18.5个月；HR，1.518；标称双侧P=0.002）。最常见的治疗突发不良事件（TEAE）是腹泻（napabucasin，84.6%；对照组，53.9%）、恶心（60.5%，50.5%）、呕吐（41.2%，29.3%），和腹痛（41.0%，25.2%）。73.8%的napabucasin治疗患者和66.7%的对照治疗患者发生≥3级TEAE，最常见的是腹泻（21.2%，7.0%）、中性粒细胞计数下降（13.7%，19.2%）和中性粒细胞减少症（13.3%，15.2%）。生物标志物阳性患者的安全性相似。结论在既往接受mCRC治疗的患者中，在FOLFIRI中加入萘普生并不能改善OS。对照组的结果表明pSTAT3是mCRC的不良预后因素。

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来源期刊

ACS Applied Electronic Materials Multiple-

CiteScore

7.20

自引率

4.30%

发文量

567