Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.

Pembrolizumab 治疗晚期黑色素瘤或 PD-L1-positive 、晚期、复发或难治性实体瘤或淋巴瘤的儿科患者 (KEYNOTE-051): 开放标签、单臂、 1-2 期试验。

  • 影响因子:10.07
  • DOI:10.1016/S1470-2045(19)30671-0
  • 作者列表:"Geoerger B","Kang HJ","Yalon-Oren M","Marshall LV","Vezina C","Pappo A","Laetsch TW","Petrilli AS","Ebinger M","Toporski J","Glade-Bender J","Nicholls W","Fox E","DuBois SG","Macy ME","Cohn SL","Pathiraja K","Diede SJ","Ebbinghaus S","Pinto N
  • 发表时间:2020-01-01

BACKGROUND: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. METHODS: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. FINDINGS: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). INTERPRETATION: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. FUNDING:Merck Sharp & Dohme, a subsidiary of Merck & Co.


背景: Pembrolizumab 被批准用于治疗成人晚期癌症; 然而,没有关于儿科患者安全性和有效性的信息。我们旨在确定 pembrolizumab 的推荐 2 期剂量及其在晚期儿科癌症中的安全性和抗肿瘤活性。 方法: KEYNOTE-051 是一项正在进行的 1-2 期开放标签试验。在此中期分析中,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。黑色素瘤或中央确诊、 PD-L1-positive 、复发或难治性实体瘤或淋巴瘤患者,Lansky Play/Karnofsky 性能状态评分 ≥ 50 分, 每 3 周接受静脉注射 pembrolizumab,初始剂量为 2 mg/kg。采用药代动力学和剂量限制性毒性确定推荐的 2 期剂量,并评估该剂量的安全性和抗肿瘤活性。主要终点是确定最大给药剂量时的剂量限制性毒性、安全性和耐受性, 以及根据实体瘤 1.1 版或国际神经母细胞瘤疗效标准的疗效评价标准,对每种肿瘤类型对 pembrolizumab 客观疗效的患者比例。在接受至少一剂 pembrolizumab 治疗的所有患者中评估安全性和有效性。单独报告复发或难治性经典型霍奇金淋巴瘤患者队列是一项事后决定。本中期分析的数据截止日期为 2018。该试验仍在招募患者,并在 ClinicalTrials.gov 注册,编号为 nct02332668。 结果: 在 2015年3月23日和 9 月 3 日期间筛查的 863 例患者中,2018 例肿瘤可评价 PD-L1 表达 (796 [278] 为 PD-L1-positive); 入组 155 例合格患者,154 例至少服用 1 剂 pembrolizumab。入组患者的中位年龄为 13 岁 (IQR 8-15)。中位随访时间为 8 · 6 个月 (IQR 2 · 5-16 · 4)。1 期未报告剂量限制性毒性,pembrolizumab 血浆浓度与成人既往报告的浓度一致; 因此,推荐的 2 期剂量确立为每 3 周 2 mg/kg。在接受治疗的 154 例患者中,69 例 (45%) 出现 3-5 级不良事件,14 例 (9%) 患者最常见贫血,9 例 (6%) 患者淋巴细胞计数降低。8% 例患者中有 13 例 (154) 发生 3-5 级治疗相关不良事件,最常见的是 3 例 (2%) 患者淋巴细胞计数下降,2 例 (1%) 患者贫血。14 例 (9%) 患者出现严重的治疗相关不良事件,最常见的是发热 (4 例 [3%]),以及高血压和胸腔积液 (各 2 例 [1%])。4 例 (3%) 患者因治疗相关不良事件停止治疗,2 例 (1%) 死亡 (1 例因肺水肿,1 例因胸腔积液和肺炎)。15 例复发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,9 例获得客观缓解 (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 (肾上腺皮质癌和间皮瘤各 2 例,恶性神经节细胞瘤、上皮样肉瘤、淋巴上皮癌各 1 例, 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)。 解读: Pembrolizumab 耐受性良好,在儿童复发性或难治性霍奇金淋巴瘤患者中显示出令人鼓舞的抗肿瘤活性,与成人患者的经验一致。Pembrolizumab 在大多数儿科肿瘤类型中具有较低的抗肿瘤活性,并且仅在少数罕见的 PD-L1-positive 肿瘤类型中观察到反应, 提示单独 PD-L1 表达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。KEYNOTE-051 的最终结果,预计到 2022年9月,有延长的可能性,将进一步报告 pembrolizumab 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。



作者列表:["Abrahamsson H","Jensen BV","Berven LL","Nielsen DL","Šaltytė Benth J","Johansen JS","Larsen FO","Johansen JS","Ree AH"]

METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.

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作者列表:["Suvina V","Kokulnathan T","Wang TJ","Balakrishna RG"]

METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.

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来源期刊:Cancer letters
作者列表:["Zhou Z","Zhou Q","Wu X","Xu S","Hu X","Tao X","Li B","Peng J","Li D","Shen L","Cao Y","Yang L"]

METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.

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