Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Barts Cancer Institute, Queen Mary University of London and St Bartholomew's Hospital, London, UK.
Lancet Oncol. 2022 Jun;23(6):758-767. doi: 10.1016/S1470-2045(22)00277-7. Epub 2022 May 16.
Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma.
We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (C), time to C (T), area under the concentration-time curve (AUC) to day 15 (AUC), area under the curve from time 0 extrapolated to infinity (AUC), and the half-life (t) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286.
Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean C was 829 ng/mL (coefficient of variation 56·3%), median T was 2 h (range 1-4), mean AUCwas 3310 h·ng/mL (coefficient of variation 50·4%), mean AUC was 3180 h·ng/mL (46·6%), and the geometric mean t was 3·1 h (13·9%). After a median follow-up of 35·9 weeks (IQR 20·6-85·9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42-67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3-4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred.
Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy.
Epizyme.
恶性胸膜间皮瘤的治疗选择有限。Tazemetostat 是一种选择性口服增强子 Zeste 同源物 2（EZH2）抑制剂，已在几种血液癌症和实体瘤中显示出抗肿瘤活性。我们旨在评估在可测量的复发性或难治性恶性胸膜间皮瘤患者中，tazemetostat 的抗肿瘤活性和安全性。
我们在法国、英国和美国的 16 家医院进行了一项开放标签、单臂 2 期研究。符合条件的患者为年龄在 18 岁或以上、接受过至少一种培美曲塞联合治疗的复发性或难治性恶性胸膜间皮瘤患者，东部合作肿瘤学组（ECOG）表现状态为 0 或 1，预期寿命大于 3 个月。在研究的第 1 部分中，参与者接受口服 tazemetostat 800mg，第 1 天单次给药，然后从第 2 天开始每天两次给药。在第 2 部分中，参与者在第 1 周期的第 1 天开始接受口服 tazemetostat 800mg，每日两次，采用两阶段绿-达尔伯格设计。tazemetostat 以 21 天为一个周期，大约给药 17 个周期。第 1 部分的主要终点是在第 15 天给予 800mg tazemetostat 后，tazemetostat 及其代谢物的药代动力学，通过最大血清浓度（C）、到达 C 的时间（T）、到第 15 天的浓度-时间曲线下面积（AUC）、从时间 0 外推至无穷大的曲线下面积（AUC）和半衰期（t）来评估，所有入组第 1 部分的患者均进行评估。第 2 部分的主要终点是根据免疫组织化学检测 BAP1 失活的协议，在第 12 周时恶性胸膜间皮瘤患者的疾病控制率（完全缓解、部分缓解或稳定疾病的患者比例）。安全性人群包括至少接受过一次剂量后安全性评估的所有患者。这项试验现已完成，并在 ClinicalTrials.gov 上注册，编号为 NCT02860286。
2016 年 7 月 29 日至 2017 年 6 月 2 日期间，共纳入 74 例患者（第 1 部分 13 例，第 2 部分 61 例）并接受 tazemetostat 治疗，其中 73 例（99%）患者的肿瘤存在 BAP1 失活。在第 1 部分中，在稳态下重复给予 tazemetostat 后，在第 1 周期的第 15 天，平均 C 为 829ng/ml（变异系数 56.3%），中位 T 为 2 小时（范围 1-4），平均 AUC 为 3310h·ng/ml（变异系数 50.4%），平均 AUC 为 3180h·ng/ml（46.6%），几何平均 t 为 3.1h（13.9%）。中位随访 35.9 周（IQR 20.6-85.9）后，在存在 BAP1 失活的恶性胸膜间皮瘤患者中，第 2 部分的疾病控制率在第 12 周时为 54%（95%CI 42-67；61 例患者中有 33 例）。没有患者有确认的完全缓解。两名患者有确认的部分缓解：一名患者的部分缓解持续 18 周，另一名患者的部分缓解持续 42 周。最常见的 3-4 级治疗相关不良事件是高血糖（5 例[7%]）、低钠血症（5 例[7%]）和贫血（4 例[5%]）；25 例（34%）患者发生严重不良事件。5 例（7%）患者在研究期间死亡；没有发生与治疗相关的死亡。
除了 BAP1 失活之外，对恶性胸膜间皮瘤中 tazemetostat 活性的生物标志物进行进一步细化，可能有助于确定最有可能从这种治疗中获得长期获益或缩小肿瘤的肿瘤亚群。
Epizyme。
