本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2302299

摘要内容如下：

背景

批准用于治疗ROS1融合阳性非小细胞肺癌（NSCLC）的早期ROS1酪氨酸激酶抑制剂（TKIs）具有抗肿瘤活性，但在肿瘤中产生耐药性，并且颅内活性不理想。Repotrectinib是新一代ROS1 TKI，具有抗ROS1融合阳性癌症的临床前活性，包括ROS1 G2032R等耐药突变。

方法

在该注册1-2期试验中，我们评估了Repotrectinib在晚期实体瘤（包括ROS1融合阳性NSCLC）患者中的疗效和安全性。2期临床试验的主要疗效终点是证实的客观反应；疗效分析包括第1阶段和第2阶段的患者。缓解持续时间、无进展生存期和安全性是第2阶段的次要终点。

结果

根据第1阶段试验的结果，推荐的第2阶段瑞波替尼剂量为每日160 mg，持续14天，随后为每日两次160 mg。71名患者中有56名（79%）出现反应；95%可信区间[CI]，68-88），其中ROS1融合阳性NSCLC既往未接受过ROS1 TKI；中位缓解期为34.1个月（95%CI，25.6至无法估计），中位无进展生存期为35.7个月（95%CI，27.4至无法估计）。56例患者中有21例（38%）出现反应；95%CI，25至52），ROS1融合阳性NSCLC，既往接受过一次ROS1 TKI且从未接受过化疗；中位缓解期为14.8个月（95%CI，7.6至无法估计），中位无进展生存期为9.0个月（95%CI，6.8至19.6）。17例患者中有10例（59%）；95%CI，33至82）对ROS1 G2032R突变有反应。共有426名患者接受了第2阶段剂量；最常见的治疗相关不良事件为头晕（58%的患者）、味觉障碍（50%）和感觉异常（30%），3%的患者因治疗相关不良事件而停用Repotrectinib。

结论

Repotrectinib在ROS1融合阳性NSCLC患者中具有持久的临床活性，无论他们之前是否接受过ROS1 TKI。不良事件主要为低级别且与长期给药相容。（由Bristol Myers Squibb的全资子公司Turning Point Therapeutics资助；Trident-1 ClinicalTrials.gov编号：NCT03093116）。

英文原文如下：

Abstracts

BACKGROUND  The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R.

METHODS  In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2.

RESULTS  On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events.

CONCLUSIONS  Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

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