Supplementary Material for: Safety of extended pirtobrutinib exposure in relapsed and/or refractory B-cell malignancies

Introduction: Pirtobrutinib, a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment.

Methods: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12-months) drug exposure from the BRUIN trial. Assessments included median-time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs).

Results: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median-time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) was the most common AESI with a median-time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first-year of therapy.

Conclusions: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

引言：吡托布鲁替尼（Pirtobrutinib）是一种高选择性非共价（可逆）布鲁顿酪氨酸激酶（Bruton tyrosine kinase, BTK）抑制剂，在B细胞恶性肿瘤中展现出极具前景的疗效，且停药与剂量降低的发生率较低。该药物需持续给药直至疾病进展或出现毒性反应，因此有必要明确长期治疗患者的安全性特征。
方法：本研究基于BRUIN试验，针对经≥12个月延长药物暴露的复发/难治性B细胞恶性肿瘤患者，报告吡托布鲁替尼的安全性情况。本次评估涵盖不良事件（Adverse Events, AEs）首次发生的中位时间、因治疗突发不良事件（Treatment-Emergent Adverse Events, TEAEs）引发的剂量降低与停药事件，以及选定的关注不良事件（AEs of Interest, AESIs）。
结果：共计纳入773例受试者，其中326例（42%）接受了≥12个月的治疗。在延长暴露队列中，患者的中位治疗时长为19个月。最常见的全因治疗突发不良事件为疲劳（32%）与腹泻（31%）。延长暴露队列中，因TEAEs导致剂量降低的患者有23例（7%），因TEAEs停药的患者有11例（3%）。另有1例患者发生致死性治疗相关不良事件（新型冠状病毒肺炎，COVID-19 pneumonia）。感染（73.0%）是最常见的AESIs，其首次发生的中位时间为7.4个月。绝大多数TEAEs与AESIs均发生在治疗的第一年期间。
结论：吡托布鲁替尼治疗持续展现出优异的安全性特征，可适用于长期给药，且未观察到新的毒性信号或原有毒性加重的迹象。