Yap Timothy A, Nakagawa Kazuhiko, Fujimoto Nobukazu, Kuribayashi Kozo, Guren Tormod Kyrre, Calabrò Luana, Shapira-Frommer Ronnie, Gao Bo, Kao Steven, Matos Ignacio, Planchard David, Chatterjee Arkendu, Jin Fan, Norwood Kevin, Kindler Hedy L
Drug Development Unit, Royal Marsden Hospital, London, UK.
Department of Medical Oncology, Kindai University Hospital, Osaka, Japan.
Lancet Respir Med. 2021 Jun;9(6):613-621. doi: 10.1016/S2213-2600(20)30515-4. Epub 2021 Apr 6.
Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study.
The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067.
Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation.
Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated.
Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
恶性胸膜间皮瘤（MPM）的治疗选择有限。帕博利珠单抗在程序性死亡配体1（PD-L1）阳性的MPM中显示出初步的临床获益。在KEYNOTE-158研究中，我们评估了帕博利珠单抗单药治疗既往接受过治疗的MPM患者的疗效和安全性，无论其PD-L1状态如何。
正在进行的开放标签、多队列、单臂2期KEYNOTE-158研究纳入了符合条件的成年（≥18岁）MPM患者，这些患者在标准治疗中出现进展或不耐受，东部肿瘤协作组体能状态为0-1，且有可进行生物标志物评估的肿瘤样本。个体来自澳大利亚、北美、欧洲和亚洲14个国家的35个学术机构和社区机构。参与者每3周静脉注射200mg帕博利珠单抗，最多35个周期。主要疗效终点是根据实体瘤疗效评价标准（RECIST）1.1版的客观缓解，在研究的第一年每9周进行一次放射学成像评估，此后每12周进行一次，并由独立中央审查进行评估。对所有接受至少一剂帕博利珠单抗的患者进行疗效和安全性分析。该试验已在ClinicalTrials.gov注册，编号为NCT02628067。
患者于2016年2月9日至2016年8月16日纳入MPM队列。截至2019年6月27日，118例患者已入组并接受了至少一剂帕博利珠单抗。10例（8%[95%CI 4-15]）患者有客观缓解。客观缓解的中位持续时间为14.3个月（范围4.0至33.9+），60%的客观缓解在12个月时仍在持续。在77例PD-L1阳性的MPM患者中有6例（8%）出现客观缓解（中位缓解持续时间17.7个月[范围5.8至33.9+]），在31例PD-L1阴性的MPM患者中有4例（13%）出现客观缓解（10.2个月[4.0-16.6]）。中位总生存期为10.0个月（95%CI 7.6-13.4），中位无进展生存期为2.1个月（2.1-3.9）。118例患者中有82例（69%）发生了治疗相关不良事件，118例患者中有14例（12%）发生了被认为与治疗相关的严重不良事件。19例（16%）患者发生3-4级治疗相关事件，其中最常见的是结肠炎（3例患者）、低钠血症（3例）和肺炎（2例）。1例患者死于治疗相关的呼吸暂停。在试验结束时，113例（96%）患者停止使用帕博利珠单抗，疾病进展是停药的最常见原因。
无论PD-L1状态如何，帕博利珠单抗在晚期MPM患者中显示出持久的抗肿瘤活性和可管理的毒性。我们的数据支持程序性死亡1（PD-1）和PD-L1通路作为一些既往治疗的间皮瘤患者的潜在治疗靶点，但尚未阐明能有效识别这类患者的生物标志物。
美国新泽西州肯尼沃思默克公司的子公司默克雪兰诺公司。
