Nemtabrutinib 是一种口服生物可逆的布鲁顿酪氨酸激酶 (BTK) 和 C481S 突变体 BTK 抑制剂。我们评估了 nemtabrutinib 在复发/难治性血液恶性肿瘤中的安全性、药理学和抗肿瘤活性。 48 名患有慢性淋巴细胞白血病 (CLL)、B 细胞非霍奇金淋巴瘤 (NHL) 或华氏巨球蛋白血症 (WM) 且经过 ≥2 种既往治疗后复发/难治的患者被纳入开放标签、单组、 1 期 MK-1026-001 研究 (NCT03162536) 接受 nemtabrutinib 5 毫克至 75 毫克，每日一次，周期为 28 天。使用 3×3 剂量递增设计进行剂量发现。主要终点是安全性和推荐的 2 期剂量 (RP2D)。在 47 名接受治疗的患者中，29 名患有 CLL，17 名患有 NHL，1 名患有 WM。 37 例（89%）发生了≥3 级治疗相关不良事件，最常见的是中性粒细胞减少症（11 例[23.4%]）、发热性中性粒细胞减少症（7 例[14.9%]）和肺炎（7 例[14.9%]）。 RP2D 为每天 65 毫克。每天服用 65 毫克的 CLL 患者的总体缓解率为 75%。

Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton's Tyrosine Kinase (BTK) and C481S mutant BTK. We evaluated safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenstrom's macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase 1 MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 mg to 75 mg once-daily in 28-day cycles. Dose finding progressed using a 3+3 dose escalation design. Primary endpoints were safety and the recommended phase 2 dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade ≥3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11 [23.4%]), febrile neutropenia (7 [14.9%]), and pneumonia (7 [14.9%]). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily.