Repotrectinib 治疗融合阳性非小细胞肺癌。
Repotrectinib in Fusion-Positive Non-Small-Cell Lung Cancer.
机构信息
From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D.) and the NYU Perlmutter Cancer Center (V.V.) - all in New York; the University of Colorado, Anschutz Medical Campus, Aurora (D.R.C.); Massachusetts General Hospital, Harvard Medical School, Boston (J.J.L.); Asan Medical Center (S.-W.K.) and Yonsei Cancer Center, Yonsei University College of Medicine (B.C.C.), Seoul, and Chungbuk National University Hospital, Cheongju-si (K.H.L.) - all in South Korea; the Peter MacCallum Cancer Center, Melbourne, VIC (B.J.S.), and the Chris O'Brien Lifehouse, Camperdown, NSW (S.K.) - both in Australia; the Department of Oncology and Radiotherapy and Early Clinical Trials Center, Medical University of Gdansk, Gdansk, Poland (R.D.); Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif (B.B.), and Centre Hospitalier Universitaire de Grenoble-Alpes, La Tronche (D.M.-S.) - both in France; National Cancer Center Hospital East, Kashiwa, Japan (K.G.); the Netherlands Cancer Institute, Amsterdam (A.J.L.); the Center for Integrated Oncology, University Hospital of Cologne, Cologne (J.W.), and the Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg (C.S.) - both in Germany; the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London (S.P.), and the University of Manchester and the Christie NHS Foundation Trust, Manchester (M.G.K.) - all in the United Kingdom; the University of California, Irvine, School of Medicine, Orange (M.N.), and Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb, San Diego (S.S., M.M., D.T., A.G., G.S.) - both in California; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (E.F.); Hunan Cancer Hospital, Hunan (N.Y.), the Department of Oncology, Shanghai Chest Hospital, Shanghai (S.L.), Sichuan Cancer Hospital and Institute, Chengdu (W.Y.), and Henan Cancer Hospital, Zhengzhou (X.H.) - all in China; the Respiratory Oncology Unit, University Hospitals Leuven, Leuven, Belgium (C.D.); UT Southwestern Medical Center, Dallas (M.S.B.); William Osler Health System, University of Toronto, Toronto (P.C.); and Bristol Myers Squibb, Princeton, NJ (Y.Y.).
出版信息
N Engl J Med. 2024 Jan 11;390(2):118-131. doi: 10.1056/NEJMoa2302299.
BACKGROUND
The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of 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 fusion-positive cancers, including those with resistance mutations such as G2032R.
METHODS
In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including 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 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 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 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 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.).
背景
已获批用于治疗融合阳性非小细胞肺癌（NSCLC）的第一代 ROS1 酪氨酸激酶抑制剂（TKI）具有抗肿瘤活性，但肿瘤会产生耐药性，且颅内活性不佳。Repotrectinib 是一种下一代 ROS1 TKI，具有针对融合阳性癌症的临床前活性，包括具有耐药突变（如 G2032R）的癌症。
方法
在这项注册的 1-2 期试验中，我们评估了 repotrectinib 治疗晚期实体瘤患者的疗效和安全性，包括融合阳性 NSCLC 患者。2 期试验的主要疗效终点为确认的客观缓解；疗效分析包括来自 1 期和 2 期的患者。缓解持续时间、无进展生存期和安全性是 2 期的次要终点。
结果
基于 1 期试验结果，推荐的 repotrectinib 2 期剂量为每日 160mg 连用 14 天，随后每日 160mg 分两次服用。在 71 例未接受过 ROS1 TKI 治疗的融合阳性 NSCLC 患者中，有 56 例（79%；95%置信区间 [CI]，68 至 88）发生了应答；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）。在 56 例接受过一种 ROS1 TKI 治疗且从未接受过化疗的融合阳性 NSCLC 患者中，有 21 例（38%；95%CI，25 至 52）发生应答；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 G2032R 突变的患者中有 10 例（59%；95%CI，33 至 82）有应答。共有 426 例患者接受了 2 期剂量治疗；最常见的与治疗相关的不良事件是头晕（58%的患者）、味觉障碍（50%）和感觉异常（30%），有 3%的患者因治疗相关的不良事件而停止使用 repotrectinib。
结论
Repotrectinib 在融合阳性 NSCLC 患者中具有持久的临床活性，无论其是否接受过 ROS1 TKI 治疗。不良事件主要为低级别，与长期用药相符。（由 Turning Point Therapeutics 公司资助， Bristol Myers Squibb 全资子公司；TRIDENT-1 临床试验.gov 编号，NCT03093116。）
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