Abstract：
Treatment with covalent Bruton tyrosine kinase inhibitors (BTKi) represents an important advance in the management of relapsed or refractory mantle cell lymphoma, but these treatments are not curative and many patients ultimately relapse. Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi, inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies following prior therapy, including covalent BTKi. This phase III, head-to-head, randomized study (NCT04662255) will evaluate whether pirtobrutinib is superior to investigator\'s choice of covalent BTKi in patients with previously treated, BTKi-naive mantle cell lymphoma.
MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a noncovalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor. Clinical Trial Registration: NCT04662255 (ClinicalTrials.gov).
MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a noncovalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor. Clinical Trial Registration: NCT04662255 (ClinicalTrials.gov).
摘要：
共价Bruton酪氨酸激酶抑制剂（BTKi）治疗代表了治疗复发或难治性套细胞淋巴瘤的重要进展。但是这些治疗方法并不能治愈，许多患者最终会复发。皮尔托替尼,一个高度选择性的，非共价（可逆）BTKi，抑制野生型和C481突变型BTK，具有相同的低nM效力，并且具有良好的口服药物学，无论BTK周转的内在速率如何，都可以在整个给药间隔内连续抑制BTK。Pirtobrutinib具有良好的耐受性，并且在先前治疗后预后不良的B细胞恶性肿瘤患者中表现出了有希望的疗效。包括共价BTKi。第三阶段,头对头,随机研究（NCT04662255）将评估吡托布替尼是否优于研究者选择的共价BTKi，BTKi-幼稚套细胞淋巴瘤。
MCL是一种罕见的B细胞非霍奇金淋巴瘤，免疫系统的癌症.它始于淋巴结的一部分，称为地幔区，不寻常的B细胞聚集并排挤淋巴结中健康的B细胞，脾,脾骨髓和/或其他器官。MCL可由不适当的细胞信号传导引起。BTK已被确定为异常细胞信号传导的关键驱动因素，阻断BTK已被证明有助于杀死癌细胞。共价（不可逆的）BTK抑制剂已经促进了MCL的治疗，但是这些治疗的有效性受到副作用和治疗抗性的限制。皮尔托替尼,一种非共价（可逆）BTK抑制剂，已被证明具有可控的副作用，并且在先前治疗后对MCL患者有效，包括用共价BTK抑制剂治疗。BRUINMCL-321研究将pirtobrutinib与三种目前批准的共价BTK抑制剂（ibrutinib，阿卡拉布替尼或扎努布替尼)，从未接受过任何形式的BTK抑制剂的MCL患者。这项试验将研究有多少人患有这种疾病而不会变得更糟。像其他癌症治疗一样，pirtobrutinib可能会影响健康细胞和肿瘤细胞，这可能会导致副作用，这也将在本研究中进行研究。这项研究很活跃，目前正在招募新的患者，他们至少接受过一次MCL治疗，但从未接受过BTK抑制剂治疗。临床试验注册：NCT04662255（ClinicalTrials.gov）。
MCL是一种罕见的B细胞非霍奇金淋巴瘤，免疫系统的癌症.它始于淋巴结的一部分，称为地幔区，不寻常的B细胞聚集并排挤淋巴结中健康的B细胞，脾,脾骨髓和/或其他器官。MCL可由不适当的细胞信号传导引起。BTK已被确定为异常细胞信号传导的关键驱动因素，阻断BTK已被证明有助于杀死癌细胞。共价（不可逆的）BTK抑制剂已经促进了MCL的治疗，但是这些治疗的有效性受到副作用和治疗抗性的限制。皮尔托替尼,一种非共价（可逆）BTK抑制剂，已被证明具有可控的副作用，并且在先前治疗后对MCL患者有效，包括用共价BTK抑制剂治疗。BRUINMCL-321研究将pirtobrutinib与三种目前批准的共价BTK抑制剂（ibrutinib，阿卡拉布替尼或扎努布替尼)，从未接受过任何形式的BTK抑制剂的MCL患者。这项试验将研究有多少人患有这种疾病而不会变得更糟。像其他癌症治疗一样，pirtobrutinib可能会影响健康细胞和肿瘤细胞，这可能会导致副作用，这也将在本研究中进行研究。这项研究很活跃，目前正在招募新的患者，他们至少接受过一次MCL治疗，但从未接受过BTK抑制剂治疗。临床试验注册：NCT04662255（ClinicalTrials.gov）。
