Awad Mark M, Le Bruchec Yvan, Lu Brian, Ye Jason, Miller JulieAnn, Lizotte Patrick H, Cavanaugh Megan E, Rode Amanda J, Dumitru Calin Dan, Spira Alexander
Lowe Center for Thoracic Oncology and Dana-Farber Cancer Institute, Boston, MA, United States.
Bristol Myers Squibb, Princeton, NJ, United States.
Front Oncol. 2021 Sep 6;11:696512. doi: 10.3389/fonc.2021.696512. eCollection 2021.
Histone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer (NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.
The orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.
A total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3 T cells was observed following treatment.
The study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC.
https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).
组蛋白去乙酰化酶（HDAC）过表达已在多种癌症中得到证实，可能与更差的预后相关。晚期非小细胞肺癌（NSCLC）早期研究的数据表明，HDAC抑制剂与铂类化疗或EGFR抑制剂联合使用具有令人鼓舞的抗肿瘤活性；然而，毒性是泛HDAC抑制剂使用的限制因素。选择性抑制HDAC6可能是一个潜在的治疗靶点，临床前研究显示抑制HDAC6具有免疫调节作用，提示其与免疫检查点抑制剂联合使用的潜力。这项Ib期、多中心、单臂、开放标签、剂量递增研究，在既往接受过治疗的晚期NSCLC患者中，研究了HDAC6抑制剂ACY-241（西他司他）联合纳武利尤单抗，这些患者未接受过先前的HDAC或免疫检查点抑制剂治疗。
口服给予的ACY-241剂量递增（每日一次180、360或480mg）。纳武利尤单抗在第1周期第15天给予240mg，此后每2周一次。主要终点是确定ACY-241联合纳武利尤单抗的最大耐受剂量（MTD）。次要终点包括安全性、耐受性和初步抗肿瘤活性。药效学是一个探索性终点。
共纳入18例患者，17例接受治疗。180mg或360mg的ACY-241未发生剂量限制性毒性（DLT）；480mg时发生2例DLT。ACY-241的MTD为360mg。最常见的≥3级治疗中出现的不良事件是呼吸困难（n=3；18%）和肺炎（n=3；18%）。在180mg剂量时，观察到1例完全缓解和2例部分缓解（PR）。在360mg剂量时，观察到3例PR；1例患者疾病稳定（SD），1例疾病进展（PD）。在480mg剂量时，未观察到缓解；1例患者达到SD，3例患者出现PD。乙酰化分析显示治疗后组蛋白和微管蛋白乙酰化水平短暂升高。治疗后观察到浸润的总CD3 T细胞增加。
该研究确定了ACY-241联合纳武利尤单抗的MTD，数据表明该联合方案在晚期NSCLC患者中可能可行。在晚期NSCLC患者中观察到了缓解。
https://clinicaltrials.gov/ct2/show/NCT02635061（标识符，NCT02635061）
