Department of Paediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Institute, Seoul National University Children's Hospital, Jongno-gu, Seoul, South Korea.
Lancet Oncol. 2020 Jan;21(1):121-133. doi: 10.1016/S1470-2045(19)30671-0. Epub 2019 Dec 4.
Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.
KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.
Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8·6 months (IQR 2·5-16·4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60·0%; 95% CI 32·3-83·7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5·9% (95% CI 2·6-11·3).
Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.
Merck Sharp & Dohme, a subsidiary of Merck & Co.
派姆单抗获批用于治疗成人晚期癌症；然而，尚无该药在儿科患者中的安全性和疗效数据。我们旨在确定派姆单抗在晚期儿科癌症中的推荐 2 期剂量及其安全性和抗肿瘤活性。
KEYNOTE-051 是一项正在进行的 1-2 期开放标签试验。在此次中期分析中，在澳大利亚、巴西、加拿大、法国、德国、以色列、意大利、韩国、瑞典、英国和美国的 30 家医院招募了年龄在 6 个月至 17 岁的儿童患者。患有黑色素瘤或经中心确认的、PD-L1 阳性的、复发或难治性实体瘤或淋巴瘤，且 Lansky 游戏/Karnofsky 体能状态评分为 50 或更高的患者，每 3 周接受 2mg/kg 的静脉注射派姆单抗初始剂量。根据实体瘤反应评价标准 1.1 版或国际神经母细胞瘤反应标准，采用药代动力学和剂量限制毒性来确定推荐的 2 期剂量，并评估该剂量的安全性和抗肿瘤活性。主要终点为确定最大给药剂量下的剂量限制毒性、安全性和耐受性，以及根据实体瘤反应评价标准 1.1 版或国际神经母细胞瘤反应标准，每种肿瘤类型中对派姆单抗有客观反应的患者比例。在至少接受过一次派姆单抗治疗的所有治疗患者中评估安全性和疗效。对复发性或难治性经典霍奇金淋巴瘤患者队列的单独报告是事后决定。此次中期分析的数据截止日期为 2018 年 9 月 3 日。该试验仍在招募患者，并在 ClinicalTrials.gov 上注册，编号为 NCT02332668。
在 2015 年 3 月 23 日至 2018 年 9 月 3 日期间筛选的 863 例患者中，有 796 例患者的肿瘤可评估 PD-L1 表达（278 例[35%]为 PD-L1 阳性）；纳入 155 例符合条件的患者，其中 154 例至少接受过一次派姆单抗治疗。纳入患者的中位年龄为 13 岁（IQR：8-15）。中位随访时间为 8.6 个月（IQR：2.5-16.4）。在 1 期未报告剂量限制毒性，派姆单抗的血浆浓度与先前在成人中报告的浓度一致；因此，确定了 2 期推荐剂量为 2mg/kg，每 3 周一次。在接受治疗的 154 例患者中，69 例（45%）出现 3-5 级不良事件，最常见的是 14 例（9%）患者发生贫血和 9 例（6%）患者发生淋巴细胞计数减少。154 例患者中有 13 例（8%）发生 3-5 级治疗相关不良事件，最常见的是 3 例（2%）患者发生淋巴细胞计数减少和 2 例（1%）患者发生贫血。4 例（3%）患者因治疗相关不良事件而停止治疗，2 例（1%）患者死亡（1 例因肺水肿，1 例因胸腔积液和肺炎）。在 15 例复发性或难治性霍奇金淋巴瘤患者中，2 例完全缓解，7 例部分缓解；因此，9 例患者有客观缓解（60.0%；95%CI：32.3-83.7）。在 136 例实体瘤和其他淋巴瘤患者中，8 例有部分缓解（2 例患者分别患有肾上腺皮质癌和间皮瘤，1 例患者患有恶性神经节胶质瘤、上皮样肉瘤、淋巴上皮癌和恶性横纹肌样瘤）；客观缓解的患者比例为 5.9%（95%CI：2.6-11.3）。
派姆单抗在复发性或难治性霍奇金淋巴瘤的儿科患者中耐受性良好，且抗肿瘤活性令人鼓舞，与成人患者的经验一致。派姆单抗在大多数儿科肿瘤类型中的抗肿瘤活性较低，且仅在少数罕见的 PD-L1 阳性肿瘤类型中观察到应答，这表明 PD-L1 表达本身不足以作为选择可能对 PD-1 检查点抑制剂有反应的儿科患者的生物标志物。预计 2022 年 9 月将公布 KEYNOTE-051 的最终结果，并且可能会扩展，该试验将进一步报告派姆单抗在霍奇金淋巴瘤、微卫星不稳定高肿瘤和黑色素瘤中的活性。
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