阿西替尼治疗新诊断的慢性髓性白血病。
Asciminib in Newly Diagnosed Chronic Myeloid Leukemia.
机构信息
From Klinik für Innere Medizin II, Hematology/Oncology, Universitätsklinikum Jena and Comprehensive Cancer Center Central Germany, Campus Jena, Jena (A.H.), and the Department of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin (P.C.) - both in Germany; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (J.W.); Uijeongbu Eulji Medical Center, Geumo-dong, Uijeongbu-si (D.-W.K.), and the Department of Internal Medicine, Seoul National University Hospital, Biomedical Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul (I.K.) - both in South Korea; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto (D.D.H.K.); the Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, and Masaryk University - both in Brno, Czech Republic (J.M.); the Department of Hematology, Singapore General Hospital, Singapore (Y.-T.G.); the Department of Hematology, Akita University, Akita City, Japan (N.T.); the Hematology Department, Institut Bergonié, Bordeaux (G.E.), and Novartis Pharma, Paris (S.I.) - both in France; Rocky Mountain Cancer Centers, Boulder, CO (D.A.); the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston (G.C.I.); the University of Chicago, Chicago (R.A.L.); CML Patients Group, CML Advocates Network, Turin, Italy (F.B.); Novartis Pharmaceuticals, East Hanover, NJ (S.K.); Novartis Pharma, Basel, Switzerland (T.M., K.M., L.Y., M.H.); Georgia Cancer Center at Augusta University, Augusta (J.E.C.); and the South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, SA, Australia (T.P.H.).
出版信息
N Engl J Med. 2024 Sep 12;391(10):885-898. doi: 10.1056/NEJMoa2400858. Epub 2024 May 31.
BACKGROUND
Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).
METHODS
In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.
RESULTS
A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).
CONCLUSIONS
In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).
背景
新诊断的慢性髓性白血病（CML）患者需要长期进行高效且安全的治疗。ASCIMINIB 是一种专门针对 ABL 豆蔻酰口袋的 BCR::ABL1 抑制剂，与目前可用的一线 ATP 竞争性酪氨酸激酶抑制剂（TKI）相比，它可能具有更好的疗效和安全性，且副作用更少。
方法
在一项 3 期临床试验中，新诊断的 CML 患者以 1:1 的比例随机分配接受 ASCIMINIB（每天 80mg，一次）或研究者选择的 TKI，随机分组的依据是欧洲治疗和预后研究的长期生存评分类别（低、中、高危）和研究者在随机分组前选择的 TKI（包括伊马替尼和第二代 TKI）。主要终点是在第 48 周时主要分子学缓解（定义为国际标准[IS]上的转录物水平≤0.1%），比较 ASCIMINIB 与研究者选择的 TKI 以及 ASCIMINIB 与随机分组前选择的伊马替尼分层中的研究者选择的 TKI。
结果
共有 201 名患者被分配接受 ASCIMINIB，204 名患者接受研究者选择的 TKI。ASCIMINIB 组的中位随访时间为 16.3 个月，研究者选择的 TKI 组为 15.7 个月。在第 48 周时，ASCIMINIB 组有 67.7%的患者达到主要分子学缓解，而研究者选择的 TKI 组为 49.0%（差异为 18.9%；95%置信区间[CI]，9.6 至 28.2；调整后的双侧 P<0.001）），在 ASCIMINIB 组中有 69.3%的患者在伊马替尼分层中达到主要分子学缓解，而在伊马替尼组中为 40.2%（差异为 29.6%；95%CI，16.9 至 42.2；调整后的双侧 P<0.001）。在第 48 周时，ASCIMINIB 组有 66.0%的患者达到主要分子学缓解，第二代 TKI 组有 57.8%的患者达到主要分子学缓解（差异为 8.2%；95%CI，-5.1 至 21.5）。ASCIMINIB 组（分别为 38.0%和 4.5%）的 3 级或以上不良事件和导致试验方案停药的事件发生率低于伊马替尼（分别为 44.4%和 11.1%）和第二代 TKI（分别为 54.9%和 9.8%）。
结论
在这项比较 ASCIMINIB 与研究者选择的 TKI 和伊马替尼的试验中，ASCIMINIB 显示出在新诊断的慢性期 CML 患者中优于疗效和良好的安全性。ASCIMINIB 与第二代 TKI 的直接比较不是主要目标。（由诺华公司资助；ASC4FIRST 临床试验.gov 编号，NCT04971226）。
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