CD40 激动性单克隆抗体 APX005M（替戈利木单抗）联合化疗，联合或不联合纳武利尤单抗，用于治疗转移性胰腺导管腺癌：一项开放标签、多中心、1b 期研究。
CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study.
机构信息
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
出版信息
Lancet Oncol. 2021 Jan;22(1):118-131. doi: 10.1016/S1470-2045(20)30532-5.
BACKGROUND
Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.
METHODS
This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m intravenous gemcitabine and 125 mg/m intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
FINDINGS
Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).
INTERPRETATION
APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.
FUNDING
Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.
背景
转移性胰腺腺癌的标准化疗仍然不足。在小鼠中，联合使用一种激动型 CD40 单克隆抗体和化疗可诱导 T 细胞依赖性肿瘤消退，并提高生存率。在这项研究中，我们旨在评估在胰腺腺癌患者中联合使用 APX005M（sotigalimab）与吉西他滨加 nab-紫杉醇，联合或不联合 nivolumab 的安全性，以确定推荐的 2 期剂量。
方法
这是一项非随机、开放标签、多中心、四队列、1b 期研究，在美国的七所学术医院进行。入组标准为未经治疗的转移性胰腺腺癌、东部合作肿瘤学组体能状态评分为 0-1 分且根据实体瘤反应评价标准 1.1 可测量疾病的 18 岁及以上成年人。所有患者均接受 1000mg/m2 静脉注射吉西他滨和 125mg/m2 静脉注射 nab-紫杉醇。在队列 B1 和 C1 中，患者接受 0.1mg/kg 静脉注射 APX005M，在队列 B2 和 C2 中接受 0.3mg/kg 静脉注射 APX005M。在队列 C1 和 C2 中，患者还接受 240mg 静脉注射 nivolumab。主要终点包括所有接受至少一剂研究药物的患者的不良事件发生率、所有发生 DLT 或接受至少两剂吉西他滨加 nab-紫杉醇和一剂 APX005M 的患者的剂量限制毒性（DLT）发生率以及确定推荐的 2 期 APX005M 静脉注射剂量。在 DLT 可评估人群中的客观缓解率是关键次要终点。这项试验（PRINCE，PICI0002）在 ClinicalTrials.gov 上注册，NCT03214250，正在进行中。
结果
在 2017 年 8 月 22 日至 2018 年 7 月 10 日期间，对 42 名筛选患者进行了筛查，有 30 名患者入组并接受了至少一剂研究药物；24 名患者可进行 DLT 评估，中位随访时间为 17.8 个月（IQR 16.0-19.4；队列 B1 22.0 个月[21.4-22.7]，队列 B2 18.2 个月[17.0-18.9]，队列 C1 17.9 个月[14.3-19.7]，队列 C2 15.9 个月[12.7-16.1]）。观察到 2 例 DLT，均为发热性中性粒细胞减少症，分别发生在队列 B2（3 级）和 C1（4 级）的 1 例患者中。最常见的 3-4 级治疗相关不良事件为淋巴细胞计数下降（20%[67%]；B1 5 例，B2 7 例，C1 4 例，C2 4 例）、贫血（11%[37%]；B1 2 例，B2 4 例，C1 4 例，C2 1 例）和中性粒细胞计数下降（9%[30%]；B1 3 例，B2 3 例，C1 1 例，C2 2 例）。30 名患者（B1 各 4 例，B2、C1 各 4 例，C2 各 2 例）中有 14 例（47%）发生了与治疗相关的严重不良事件。最常见的严重不良事件为发热（30%[20%]；B2 1 例，C1 3 例，C2 2 例）。因不良事件导致的化疗相关死亡有 2 例：B1 1 例为败血症，C1 1 例为感染性休克。APX005M 的推荐 2 期剂量为 0.3mg/kg。在 24 名可进行 DLT 评估的患者中，有 14 名（58%；B1、C1、C2 各 4 例，B2 各 2 例）观察到了治疗反应。
结论
APX005M 与吉西他滨加 nab-紫杉醇联合或不联合 nivolumab 在转移性胰腺腺癌中是耐受的，并显示出临床活性。如果在后续的试验中得到证实，这种治疗方案可能会取代该人群中的化疗标准治疗。
资金来源
帕克癌症免疫治疗研究所、癌症研究协会和百时美施贵宝公司。
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