Tjulandin Sergey, Demidov Lev, Moiseyenko Vladimir, Protsenko Svetlana, Semiglazova Tatiana, Odintsova Svetlana, Zukov Ruslan, Lazarev Sergey, Makarova Yuliya, Nechaeva Marina, Sakaeva Dina, Andreev Aleksey, Tarasova Anna, Fadeyeva Natalya, Shustova Mariia, Kuryshev Ivan
N. N. Blokhin National Cancer Research Medical Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.
Saint Petersburg Clinical Research and Practice Center for Specialized Medical Care (Oncology), Saint Petersburg, Russia.
Eur J Cancer. 2021 May;149:222-232. doi: 10.1016/j.ejca.2021.02.030. Epub 2021 Apr 17.
Prolgolimab is an IgG1 anti-PD-1 (programmed cell death protein 1) monoclonal antibody containing the Fc-silencing 'LALA' mutation. We assessed the efficacy and safety of two dosing regimens of prolgolimab in patients with advanced melanoma in a multicenter open-label parallel-arm phase II trial (MIRACULUM). We present the final analysis after 1 year of follow-up and additional efficacy results from 2 years of follow-up.
Patients with advanced cutaneous or non-cutaneous melanoma, including stable brain metastasis, without autoimmune disease and who underwent no prior targeted therapy, anti-PD-(L)1 or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) therapy were randomly assigned (1:1) to receive prolgolimab in 2 dosing regimens, 1 mg/kg every 2 weeks (arm 1) or 3 mg/kg every 3 weeks (arm 2), until disease progression or intolerable toxicity. Randomisation was stratified based on performance status (Eastern Cooperative Oncology Group 0 or 1), lactate dehydrogenase levels (elevated or normal) and prior systemic therapy (naive or previously treated). The primary outcome was the objective response rate, assessed as per immune-related Response Evaluation Criteria in Solid Tumours by independent central review. The hypothesis that each dosing regimen of prolgolimab has an overall response rate >28% was tested independently for each study arm comprising all patients who received at least one dose of prolgolimab. Exploratory assessment of efficacy, including subgroup analysis, at 2 years of follow-up was not specified in the protocol. This study is registered withClinicalTrials.gov(NCT03269565).
Between August 2017 and March 2018, 126 patients with advanced melanoma were enrolled. At main 1-year data cut-off, the median follow-up was 13.8 and 14.5 months in arm 1 and 2, respectively. An objective response was observed in 38.1% of patients (arm 1) and in 28.6% (arm 2). Grade III-IV treatment-related adverse events occurred in 12.7% and 3.2% of patients in arm 1 and 2, respectively. For exploratory efficacy analysis, the median follow-up was 25.4 and 25.7 months in arm 1 and 2, respectively. The 2-year progression-free survival was 33.3% in arm 1 and 30.2% in arm 2, and the 2-year overall survival was 57.1% and 46.0%, respectively.
The MIRACULUM study met its primary end-point in both the study arms. Prolgolimab showed significant antitumour activity and a manageable safety profile in patients with advanced melanoma.
普罗戈利单抗是一种IgG1抗程序性细胞死亡蛋白1（PD-1）单克隆抗体，含有Fc沉默的“LALA”突变。在一项多中心开放标签平行臂II期试验（MIRACULUM）中，我们评估了普罗戈利单抗两种给药方案在晚期黑色素瘤患者中的疗效和安全性。我们呈现了1年随访后的最终分析结果以及2年随访后的额外疗效结果。
患有晚期皮肤或非皮肤黑色素瘤（包括稳定的脑转移）、无自身免疫性疾病且未接受过先前靶向治疗、抗PD-（L）1或抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）治疗的患者被随机分配（1:1）接受普罗戈利单抗的两种给药方案，每2周1mg/kg（第1组）或每3周3mg/kg（第2组），直至疾病进展或出现无法耐受的毒性。随机分组根据体能状态（东部肿瘤协作组0或1）、乳酸脱氢酶水平（升高或正常）和先前的全身治疗（初治或曾接受治疗）进行分层。主要结局是客观缓解率，由独立中央审查按照实体瘤免疫相关疗效评价标准进行评估。对于每个研究组中所有接受至少一剂普罗戈利单抗的患者，分别独立检验普罗戈利单抗各给药方案的总体缓解率>28%这一假设。方案中未指定对2年随访时的疗效进行探索性评估，包括亚组分析。本研究已在ClinicalTrials.gov注册（NCT03269565）。
2017年8月至2018年3月，126例晚期黑色素瘤患者入组。在主要的1年数据截止时，第1组和第2组的中位随访时间分别为13.8个月和14.5个月。第1组38.1%的患者和第2组28.6%的患者观察到客观缓解。第1组和第2组分别有12.7%和3.2%的患者发生3 - 4级治疗相关不良事件。对于探索性疗效分析，第1组和第2组的中位随访时间分别为25.4个月和25.7个月。第1组的2年无进展生存率为33.3%，第2组为30.2%，2年总生存率分别为57.1%和46.0%。
MIRACULUM研究在两个研究组中均达到了主要终点。普罗戈利单抗在晚期黑色素瘤患者中显示出显著的抗肿瘤活性和可控的安全性。
