11月 04, 2021
  • Scemblix为接受至少两种酪氨酸激酶抑制剂（TKI）治疗后不耐受或疗效欠佳的慢性髓性白血病（CML）患者提供了新的治疗选择1
  • 在关键III期ASCEMBL试验中，24周时Scemblix与Bosulif®*（博舒替尼）（25% vs. 13%）相比，主要分子学应答（MMR）率具有明显的优效性，因副作用导致的停药率降低了3倍以上（7% vs. 25%）2,3
  • FDA批准的第二个适应症是T315I突变型CML患者4
  • Scemblix是一种STAMP抑制剂，具有新型作用机制，已见于科学文献；而诺华对包括一线治疗在内的不同阶段的患者开展了临床试验。20年来，诺华致力于为CML患者带来变革性治疗，该药获批，必将为CML治疗提供更多选择2-18

2021年10月29日美国食品药品监督管理局（FDA）已批准Scemblix®（Asciminib）用于治疗两种明显不同的CML适应症。基于24周的主要分子学应答（MMR）率，Scemblix获得FDA加速审批，用于既往接受至少两种TKI治疗的费城染色体阳性CML慢性期（Ph+ CML-CP）成人患者，并完全获批用于T315I突变型Ph+ CML-CP成人患者1。Scemblix是FDA批准的首个通过结合ABL肉豆蔻酰口袋发挥作用的CML治疗药物。此药为TKI治疗耐药和/或不耐受患者将提供新的治疗手段1-3。在科学文献中，Scemblix也被称为STAMP抑制剂，正在对CML-CP的多个治疗阶段进行研究，包括评价Scemblix作为一线治疗的ASC4FIRST III期研究2-18。

“20年前TKI的引入彻底改变了CML的治疗；但是仍有许多患者对至少两种可用的治疗应答不足，并且经常出现副作用，给他们的日常生活增加负担，带来困难。”Lee Greenberger（白血病和淋巴瘤协会首席科学官）说，“Scemblix获批可填补对CML治疗的需求，为患者带来希望。”

许多患者可能对现有CML治疗不耐受或发生耐药导致治疗失败，而序贯使用现有TKI与失败率增加有关19-26。对既往接受过两种TKI治疗的CML患者进行分析，发现约55%的患者报告对既往治疗不耐受27。此外，二线治疗背景下的汇集分析显示，高达70%的患者在2年随访期内无法达到主要分子学应答（MMR）28-30。发生T315I突变的患者对大多数现有TKI耐药，这使其疾病进展风险增加4。

“患者接受目前的治疗方法后可能失败或因副作用无法耐受，或者有时两者兼有，这些情况下，CML可能难以治疗。”纪念斯隆-凯特琳癌症中心（MSK）的血液学家和骨髓增殖性肿瘤项目负责人Dr. Michael J. Mauro**表示， “在CML治疗领域引入Scemblix，为我们提供了一种新方法对抗这种血液系统恶性肿瘤，为转换为二线治疗后仍然效果不佳或发生T315I突变的患者带来解决方案。”

FDA对Scemblix的批准是基于III期ASCEMBL试验和I期（NCT02081378）研究的结果，此I期研究纳入了T315I突变的Ph+CML-CP患者。

在对至少两种TKI耐药或不耐受的Ph+CML-CP患者中，ASCEMBL试验显示1-3：

  • 与Bosulif®（博舒替尼）*相比，Scemblix在24周时的MMR率几乎加倍（25% vs. 13%，[P=0.029]）
  • Scemblix组（n = 156）因不良反应终止治疗的患者比例比Bosulif组（n = 76）减少了3倍以上（7% vs. 25%）
  • Scemblix组中最常见（发生率≥ 20%）的不良反应和实验室检查结果异常分别为：上呼吸道感染和肌肉骨骼疼痛；血小板和中性粒细胞计数降低，血红蛋白减少；甘油三酯、肌酸激酶和丙氨酸氨基转移酶（ALT）升高

诺华肿瘤学总裁Susanne Schaffert博士说：“经过二十多年来对CML治疗的重新规划后，我们继续大胆地突破创新界限，革新标准治疗，从而帮助更多罹患这种疾病的患者。我们要感谢所有参与者为实现突破所做出的努力。”

关于Scemblix®（Asciminib）

Scemblix（Asciminib）适用于治疗既往接受过≥两种TKI治疗的Ph+CML-CP成人患者，以及T315I突变型Ph+CML-CP成人患者1。根据第24周的MMR率，第一个适应症获得美国 FDA加速批准；该适应症的继续批准可能取决于对确证性证据中临床获益的验证和描述。

Scemblix是FDA批准的首个与ABL肉豆蔻酰口袋结合的CML治疗药物1。这种新的作用机制在科学文献中也称为STAMP抑制剂，可能有助于解决既往接受过两种或多种TKI治疗的CML患者的耐药，并克服缺陷性BCR-ABL1基因突变（与白血病细胞的过度生成有关）2-11。在临床前研究中，Scemblix也可减少脱靶效应31。

诺华已在全球多个国家和地区启动Scemblix的注册备案。

关于诺华对CML患者的承诺

诺华为CML患者做出了长期的科学承诺。20多年来，我们的科学技术大胆创新，帮助许多患者将CML转变为慢性疾病。尽管取得了这些进展，但我们并没有停下。我们继续研究针对该疾病的方法，为许多患者因治疗耐药和/或不耐受而面临的挑战寻求解决之道。诺华还致力于为患者提供可持续的治疗以及与全球CML社区合作，继续重新规划CML的治疗。

参考文献

  1. Scemblix [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.
  2. Rea D, et al. A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After≥ 2 Prior TKIs. Blood. 2021. DOI: 10.1182/blood.2020009984. PMID: 34407542.
  3. Novartis Data on File, 2021.
  4. Cortes JE, et al. Asciminib, a First-in-Class STAMP Inhibitor, Provides Durable Molecular Response in Patients (pts) with Chronic Myeloid Leukemia (CML) Harboring the T315I Mutation: Primary Efficacy and Safety Results from a Phase 1 Trial. Oral presentation at: ASH Annual Meeting; Dec. 7, 2020
  5. Wylie AA, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature. 2017;543(7647):733-737.
  6. Schoepfer J, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 2018;61(18):8120-8135.
  7. Hughes TP, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019; 381(24):2315-2326.
  8. Hughes TP, et al. Expanded Phase 1 Study of ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Reveals Significant and Durable Responses in Patients with CML-Chronic Phase with Failure of Prior TKI Therapy. Poster presented at: ASH Annual Meeting & Exposition; Dec. 5, 2016.
  9. Ottmann OG, et al. ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Exhibits Safety and Promising Single- Agent Activity in a Phase I Study of Patients with CML with Failure of Prior TKI Therapy. Blood. 2015;126(23):138.
  10. Mauro MJ, et al. Combination of Asciminib Plus Nilotinib (NIL) or Dasatinib (DAS) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
  11. Cortes JE, et al. Combination Therapy Using Asciminib Plus Imatinib (IMA) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
  12. ClinicalTrials.gov. 2017. Study of Efficacy of CML-CP Patients Treated with ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT03106779.
  13. ClinicalTrials.gov. 2021. A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04971226.
  14. ClinicalTrials.gov. 2020. Asciminib in Monotherapy for Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With and WithoutT315I Mutation (AIM4CML). [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04666259.
  15. ClinicalTrials.gov. 2018. Study of Efficacy And Safety Of Asciminib In Combination With Imatinib In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP). [online] Available at: https://clinicaltrials.gov/ct2/show/NCT03578367.
  16. ClinicalTrials.gov. 2021. Study of Efficacy and Safety of CML-CP Patients Treated With Asciminib Versus Best Available Therapy, Previously Treated With 2 or More Tyrosine Kinase Inhibitors. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04795427.
  17. ClinicalTrials.gov. 2014. A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT02081378.
  18. ClinicalTrials.gov. 2021 Asciminib Treatment Optimization in ≥ 3rd Line CML-CP. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04948333.
  19. Flis S, et al. Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities. Drug Des Devel Ther. 2019;13:825-843.
  20. Akard LP, et al. The “Hit Hard and Hit Early” Approach to the Treatment of Chronic Myeloid Leukemia: Implications of the Updated National Comprehensive Cancer Network Clinical Practice Guidelines for RoutinePractice. Clin Adv Hematol Oncol. 2013;11(7):421-432.
  21. Cortes JE, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91(12):1206-1214.
  22. Cortes JE, et al. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: Final 5-yearresults of the phase 2 PACE trial. Blood. 2018;132(4):393-404.
  23. Garg RJ, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114(20):4361-4368
  24. Hochhaus A, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966-984
  25. Cortes JE., et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34:2333-2340.
  26. Steegmann JL., et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648-1671.
  27. Giles FJ, et al. Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy. Leukemia. 2010; 24(7):1299–1301.
  28. Kantarjian HM, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117(4):1141-1145.
  29. Shah NP, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010;95:232-240
  30. Gambacorti-Passerini C., et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014;89:732-742.
  31. Manley P., et al. The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase. Leukemia Research. 2020;98

* Bosulif是Pfizer的注册商标。

**披露：Mauro博士已向诺华提供咨询服务。