Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
Department of Radiology, Netherlands Cancer Institute, Amsterdam, Netherlands.
Lancet Oncol. 2023 Nov;24(11):1219-1228. doi: 10.1016/S1470-2045(23)00446-1. Epub 2023 Oct 13.
The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.
In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.
Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.
Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma.
Merck Sharp & Dohme.
抗 PD-1 抗体帕博利珠单抗与抗血管生成多激酶抑制剂仑伐替尼联合应用在实体瘤的临床前和临床研究中显示出协同作用。我们评估了该联合治疗方案在铂类培美曲塞化疗后进展的胸膜间皮瘤患者中的临床活性。
在荷兰阿姆斯特丹荷兰癌症研究所进行的这项单臂、单中心、2 期研究中，符合条件的胸膜间皮瘤患者（年龄≥18 岁），东部合作肿瘤组体能状态为 0-1 分，化疗后进展（无先前免疫治疗），根据改良实体瘤反应评估标准（mRECIST）1.1 版可测量疾病。患者接受静脉注射 200mg 帕博利珠单抗，每 3 周一次，同时口服仑伐替尼 20mg，每日一次，最长 2 年，或直至疾病进展、出现不可接受的毒性或患者撤回同意。主要终点是根据 mRECIST 1.1 版由当地研究者确定的客观缓解率。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT04287829，正在招募第二队列。
2021 年 3 月 5 日至 2022 年 1 月 31 日，共筛选了 42 名患者，其中 38 名患者纳入主要终点和安全性分析（中位年龄 71 岁[IQR 65-75]，33 名[87%]男性，5 名[13%]女性）。截至 2023 年 1 月 31 日，数据截止时（中位随访 17.7 个月[IQR 13.8-19.4]），38 名患者中有 22 名（58%；95%CI 41-74）有客观缓解。独立审查显示，38 名患者中有 17 名（45%；95%CI 29-62）有客观缓解。10 名（26%）患者发生严重与治疗相关的不良事件，包括 1 例因心肌梗死导致的治疗相关死亡。最常见的与治疗相关的 3 级或更高级别的不良事件是高血压（8 名患者[21%]）和厌食症和淋巴细胞减少症（均为 4 名患者[11%]）。在 38 名患者中，至少有 29 名（76%）需要至少一次减少或停止仑伐替尼的剂量。
帕博利珠单抗联合仑伐替尼在胸膜间皮瘤患者中显示出有希望的抗肿瘤活性，同时伴有相当大的毒性，与之前的研究相似。来自文献的现有证据表明，仑伐替尼的起始剂量较高，以获得最佳的抗肿瘤活性。然而，这需要高标准的支持性护理。帕博利珠单抗和仑伐替尼联合治疗方案值得在胸膜间皮瘤中进一步研究。
默克雪兰诺。
