Erasme Hospital, Hopital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
Cliniques Universitaires Saint-Luc, Woluwe-Saint-Lambert, Belgium.
Lancet Oncol. 2024 Jul;25(7):853-864. doi: 10.1016/S1470-2045(24)00263-8. Epub 2024 Jun 1.
Current systemic therapies for metastatic pancreatic ductal adenocarcinoma are associated with poor outcomes with a 5-year overall survival rate under 5%. We aimed to assess the safety and antitumour activity of mitazalimab, a human CD40 agonistic IgG1 antibody, with modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, oxaliplatin, and irinotecan), in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma.
OPTIMIZE-1 was a single-arm, multicentre, phase 1b/2 study which enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and European Cooperative Oncology Group performance status 0 or 1 in 14 university hospitals in Belgium, France, and Spain. The primary endpoint of phase 1b was to determine the recommended phase 2 dose of intravenous mitazalimab (450 μg/kg or 900 μg/kg) when combined with intravenous mFOLFIRINOX (oxaliplatin 85 mg/m, leucovorin 400 mg/m, irinotecan 150 mg/m, fluorouracil 2400 mg/m). In the first 21-day treatment cycle, mitazalimab was administered on days 1 and 10, and mFOLFIRINOX on day 8. In subsequent 14-day cycles mitazalimab was administered 2 days after mFOLFIRINOX. The phase 2 primary endpoint was objective response rate. Activity and safety analyses were conducted on the full analysis set (all patients who received the combination of mitazalimab at the recommended phase 2 dose and mFOLFIRINOX for at least two treatment cycles) and safety set (all patients who received any study treatment), respectively. Enrolment is complete, and data represents a primary analysis of the ongoing trial. The trial is registered at Clinicaltrials.gov (NCT04888312).
Between Sept 29, 2021, and March 28, 2023, 88 patients were screened and 70 patients were enrolled (40 [57%] were female and 30 [43%] were male). In phase 1b, 900 μg/kg mitazalimab was determined as the recommended phase 2 dose. Overall, five patients received 450 μg/kg mitazalimab; 65 received 900 μg/kg mitazalimab. No dose-limiting toxicities were observed at 450 μg/kg, and one dose-limiting toxicity was observed at 900 μg/kg. 57 patients were evaluated for activity, and all 70 patients were included in the safety set. At data cutoff on Nov 14, 2023, median follow-up was 12·7 months (95% CI 11·1-15·7). Of the 57 patients, 29 (51%) remained on study and 18 (32%) remained on treatment. The primary endpoint (objective response rate >30%) was met (objective response rates in 23 [40%]; one-sided 90% CI ≥32 of 57 patients). The most common grade 3 or worse adverse events were neutropenia (18 [26%] of 70 patients), hypokalaemia (11 patients [16%]), and anaemia and thrombocytopenia (eight patients [11%]). Serious adverse events were reported in 29 (41%) of 70 patients, the most common being vomiting (five [7%] of 70 patients), decreased appetite (four [6%]), and diarrhoea and cholangitis (three [4%] of 70 patients for each), none considered related to mitazalimab. No treatment-related deaths were reported.
Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase 3, randomised, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options.
Alligator Bioscience.
目前转移性胰腺导管腺癌的系统治疗效果不佳，5 年总生存率低于 5%。我们旨在评估 mitazalimab（一种人 CD40 激动性 IgG1 抗体）联合改良 FOLFIRINOX（mFOLFIRINOX；氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康）在未经化疗的转移性胰腺导管腺癌患者中的安全性和抗肿瘤活性。
OPTIMIZE-1 是一项单臂、多中心、1b/2 期研究，在比利时、法国和西班牙的 14 所大学医院招募了组织学证实的转移性胰腺导管腺癌和欧洲合作肿瘤组表现状态 0 或 1 的成年人。1b 期的主要终点是确定联合静脉注射 mitazalimab（450μg/kg 或 900μg/kg）和静脉注射 mFOLFIRINOX（奥沙利铂 85mg/m、亚叶酸 400mg/m、伊立替康 150mg/m、氟尿嘧啶 2400mg/m）的推荐 2 期剂量。在第 1 个 21 天治疗周期中，mitazalimab 在第 1 天和第 10 天给药，mFOLFIRINOX 在第 8 天给药。在随后的 14 天周期中，mitazalimab 在 mFOLFIRINOX 给药后 2 天给药。2 期的主要终点是客观缓解率。活性和安全性分析分别在接受推荐的 2 期剂量的 mitazalimab 和 mFOLFIRINOX 治疗至少两个周期的全分析集（所有接受 mitazalimab 和 mFOLFIRINOX 联合治疗的患者）和安全性集（所有接受任何研究治疗的患者）上进行。入组已经完成，数据代表正在进行的试验的初步分析。该试验在 ClinicalTrials.gov 注册（NCT04888312）。
在 2021 年 9 月 29 日至 2023 年 3 月 28 日期间，有 88 名患者接受了筛选，有 70 名患者入组（40%为女性，30%为男性）。在 1b 期，900μg/kg mitazalimab 被确定为推荐的 2 期剂量。共有 5 名患者接受了 450μg/kg mitazalimab；65 名患者接受了 900μg/kg mitazalimab。在 450μg/kg 时未观察到剂量限制毒性，在 900μg/kg 时观察到 1 例剂量限制毒性。57 名患者接受了疗效评估，70 名患者全部纳入安全性集。在 2023 年 11 月 14 日数据截止时，中位随访时间为 12.7 个月（95%CI 11.1-15.7）。在 57 名患者中，29 名（51%）仍在研究中，18 名（32%）仍在治疗中。主要终点（客观缓解率>30%）达到（23 名患者中有 29 名[40%]；57 名患者中有 18 名[32%]符合单侧 90%CI≥32）。最常见的 3 级或更高级别的不良事件是中性粒细胞减少症（70 名患者中的 18 名[26%]）、低钾血症（11 名患者[16%]）和贫血和血小板减少症（8 名患者[11%]）。70 名患者中有 29 名（41%）报告了严重不良事件，最常见的是呕吐（70 名患者中的 5 名[7%]）、食欲下降（4 名[6%]）和腹泻和胆管炎（70 名患者各有 3 名[4%]），均认为与 mitazalimab 无关。没有报告与治疗相关的死亡。
mitazalimab 联合 mFOLFIRINOX 显示出可管理的安全性和令人鼓舞的疗效，值得在 3 期、随机、对照试验中进一步研究。OPTIMIZE-1 的结果为转移性胰腺导管腺癌的一种新型免疫治疗方案的进一步探索和确认铺平了道路，这种癌症具有非常低的生存率和有限的治疗选择，是一种复杂且具有侵袭性的癌症。
Alligator Bioscience。
