Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer.
Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer.
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Repotrectinib 治疗 ROS1 融合阳性非小细胞肺癌。
DOI：
10.1056/nejmoa2302299
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发表时间：
2024
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作者：
Drilon,Alexander;Camidge,DRoss;Lin,JessicaJ;Kim,Sang-We;Solomon,BenjaminJ;Dziadziuszko,Rafal;Besse,Benjamin;Goto,Koichi;deLangen,AdrianusJohannes;Wolf,Jürgen;Lee,KiHyeong;Popat,Sanjay;Springfeld,Christoph;Nagasaka,Misako;
研究背景早期的ROS1酪氨酸激酶抑制剂（TKI）已被批准用于治疗ROS1融合阳性的非小细胞肺癌（NSCLC），具有抗肿瘤活性，但在肿瘤中产生耐药性，且颅内活性不理想。Repotrectinib是新一代的ROS1 TKI，对ROS1融合阳性的癌症具有临床前活性，包括那些具有耐药突变的癌症，如ROS1G2032R.MethodsIn这项注册的1 - 2期试验，我们评估了repotrectinib在晚期实体瘤患者中的疗效和安全性，包括ROS1融合阳性的NSCLC。II期试验的主要疗效终点是确认的客观缓解;疗效分析包括I期和II期的患者。反应持续时间、无进展生存期和安全性是2期试验的次要终点。结果根据1期试验的结果，推荐的2期剂量为160 mg每日1次，持续14天，随后为160 mg每日2次。71例患者中有56例出现缓解（79%; 95%置信区间[CI]，68至88）既往未接受过ROS1 TKI的ROS1融合阳性NSCLC;中位缓解持续时间为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例出现缓解（38%; 95% CI，25 - 52）既往接受过一种ROS1 TKI且从未接受过化疗的ROS1融合阳性NSCLC患者;中位缓解持续时间为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例携带ROS1G2032R突变的患者中有10例（59%; 95%CI，33 - 82）有缓解。共有426例患者接受了II期给药;最常见的治疗相关不良事件是头晕（58%的患者）、味觉障碍（50%）和感觉异常（30%），3%的患者由于治疗相关的不良事件而停用repotrectinib。无论他们之前是否接受过ROS1 TKI。不良事件主要为低级别，与长期给药相容。（由布里斯托迈尔斯施贵宝的全资子公司Turning Point Therapeutics资助; TRIDENT-1 www.example.com号码，NCT 03093116。）
BackgroundThe early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment ofROS1fusion–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 againstROS1fusion–positive cancers, including those with resistance mutations such asROS1G2032R.MethodsIn this registrational phase 1–2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, includingROS1fusion–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.ResultsOn 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) withROS1fusion–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) withROS1fusion–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 theROS1G2032R 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.ConclusionsRepotrectinib had durable clinical activity in patients withROS1fusion–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.)