Gao Bo, Carlino Matteo S, Michael Michael, Underhill Craig, Marshall Henry, Gunjur Ashray, So Jane, Kee Damien, Antill Yoland, Lam Wei-Sen, Chan Howard, Harrup Rosemary, Hamilton Anne, Grady John, Ballinger Mandy, Tavancheh Elnaz, Yoon Won-Hee, Palmer Jodie, Thomas David, Wilkie Kylie, Cebon Jonathan, Klein Oliver
Department of Medical Oncology, Blacktown and Westmead Hospitals, Sydney, Australia.
Melanoma Institute of Australia, University of Sydney, Sydney, Australia.
JAMA Oncol. 2025 Jul 3. doi: 10.1001/jamaoncol.2025.1916.
Gynecological clear cell cancers (CCCs) are aggressive malignant neoplasms with low response rate to chemotherapy. The treatment of patients with metastatic disease remains an area of significant unmet need.
To evaluate the efficacy of combined anti-programmed cell death 1 protein (PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade using nivolumab and ipilimumab in advanced gynecological CCCs.
DESIGN, SETTING, AND PARTICIPANTS: The MoST-CIRCUIT prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced selected rare cancers. Patients with advanced clear cell ovarian cancer (CCOC)/clear cell endometrial cancer (CCEC) with a maximum of 1 course of prior systemic therapy were enrolled from August 2021 to February 2024 across 17 Australian and New Zealand sites.
Patients received nivolumab, 3 mg/kg, and ipilimumab, 1 mg/kg, every 3 weeks for 4 doses followed by nivolumab, 480 mg, every 4 weeks for 96 weeks until disease progression or the development of unacceptable toxic effects.
Coprimary end points were objective response rate (ORR) and 6-month progression-free survival (PFS) as assessed by RECIST version 1.1 criteria, with the secondary end points being median overall survival, PFS, and treatment-related toxic effects.
Of 28 included patients, the median (range) age was 55 (34-77) years. A total of 24 had CCOC and 4 had CCEC; 19 (68%) had a previous course of therapy. Overall ORR was 54% (95% CI, 35-71), with 3 (12%) with complete response and 12 (42%) with partial response; the ORR was 55% (95% CI, 35-73) in the CCOC group and 50% (95% CI, 9-91) in the CCEC group. The median duration of response has not been reached, with all responses ongoing. The 6-month PFS was 58% (95% CI, 39-74), and the median overall survival has not been reached. A total of 9 patients (35%) experienced a grade 3 or 4 immune-related adverse event, and a grade 5 myocarditis occurred in 1 patient.
In this nonrandomized clinical trial, immunotherapy using combined anti-PD-1/CTLA-4 blockade demonstrated encouraging activity with a high rate of durable responses in patients with advanced gynecological CCCs. This regimen should be further investigated in this patient population with unmet medical need.
ClinicalTrials.gov Identifier: NCT04969887.
妇科透明细胞癌（CCC）是侵袭性恶性肿瘤，对化疗反应率低。转移性疾病患者的治疗仍是一个存在重大未满足需求的领域。
评估纳武利尤单抗和伊匹木单抗联合阻断程序性细胞死亡1蛋白（PD-1）/细胞毒性T淋巴细胞相关蛋白4（CTLA-4）在晚期妇科CCC中的疗效。
设计、设置和参与者：MoST-CIRCUIT前瞻性多中心2期非随机临床试验纳入了晚期特定罕见癌症患者。2021年8月至2024年2月，在澳大利亚和新西兰的17个地点招募了最多接受过1个疗程先前全身治疗的晚期透明细胞卵巢癌（CCOC）/透明细胞子宫内膜癌（CCEC）患者。
患者每3周接受一次纳武利尤单抗3mg/kg和伊匹木单抗1mg/kg，共4剂，随后每4周接受一次纳武利尤单抗480mg，共96周，直至疾病进展或出现不可接受的毒性作用。
共同主要终点是根据实体瘤疗效评价标准（RECIST）1.1版标准评估的客观缓解率（ORR）和6个月无进展生存期（PFS），次要终点是中位总生存期、PFS和治疗相关毒性作用。
在纳入的28例患者中，中位（范围）年龄为55（34-77）岁。共有24例患有CCOC，4例患有CCEC；19例（68%）曾接受过一个疗程的治疗。总体ORR为54%（95%CI，35-71），3例（12%）完全缓解，12例（42%）部分缓解；CCOC组的ORR为55%（95%CI，35-73），CCEC组为50%（95%CI，9-91）。缓解持续时间中位数尚未达到，所有缓解仍在持续。6个月PFS为58%（95%CI，39-74），中位总生存期尚未达到。共有9例患者（35%）发生3级或4级免疫相关不良事件，1例患者发生5级心肌炎。
在这项非随机临床试验中，联合抗PD-1/CTLA-4阻断的免疫疗法在晚期妇科CCC患者中显示出令人鼓舞的活性和高持久缓解率。对于这一有未满足医疗需求的患者群体，该方案应进一步研究。
ClinicalTrials.gov标识符：NCT04969887。
