激素受体（HR）阳性乳腺癌是一种无免疫检查点抑制剂显示有效治疗效果的疾病。在临床前研究中，细胞周期依赖性激酶4和6（CDK4/6）抑制剂协同增加了抗程序性细胞死亡蛋白-1（anti-PD-1）/程序性死亡配体-1（PD-L1）抗体的有效性。这项非随机、多组合、2期研究评估了抗PD-1抗体尼伐普（nivolumab）每2周240 mg结合CDK4/6抑制剂阿贝马西尼（abemaciclib）每日两次150 mg以富勒旋（FUL）或来曲唑（LET）作为HR阳性HER2阴性转移性乳腺癌一线或二线治疗的疗效和安全性。主要终点是客观缓解率（ORR），次要终点是毒副作用、无进展生存期和总体生存期。多个时点收集了血液、组织和粪便样本用于相关研究以评估免疫标志物。从2019年6月到2020年7月由于安全问题而提前终止研究期间，共纳入了17例患者（FUL：n=12，LET：n=5）。首次治疗富勒旋组中的1例有治疗史的患者被排除在外。FUL和LET组的ORR分别为54.5%（6/11）和40.0%（2/5）。FUL和LET组中有11例（92%）和5例（100%）患者出现≥3级与治疗相关的不良事件（AEs）。最常见的≥3级治疗与不良事件是中性粒细胞减少症（FUL组为7例（58.3%），LET组为3例（60.0%）），其次为丙氨酸转氨酶升高（FUL组为5例（41.6%），LET组为4例（80.0%））。LET组发生了一例治疗相关性肺间质性肺病导致的死亡。10例患者出现了与肝脏相关的≥3级不良事件。3例患者的肝脏活检标本显示为以CD8+淋巴细胞浸润为主的局灶性坏死性肝炎。在肝毒性患者中观察到肿瘤死亡因子相关的细胞因子和白介素11的显著升高，以及外周调节性T细胞（Tregs）的减少。这些发现表明，与尼伐普疗法相结合的阿贝马西尼的加入导致的治疗相关性毒性是与免疫相关的不良事件，可能是由于促炎性细胞因子的产生和Treg增殖的抑制。尽管尼伐普和阿贝马西尼的联合疗法是有效的，但它引起了严重和持久的与免疫相关的不良事件。JapicCTI-194782, jRCT2080224706, UMIN000036970.©2023作者(或其雇主)。在CC BY-NC下可重新使用。无商业再使用。BMJ出版。

Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies.This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers.From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy.Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs.JapicCTI-194782, jRCT2080224706, UMIN000036970.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.