一项针对罕见肿瘤的双抗CTLA-4和抗PD-1阻断的II期篮子试验（DART）SWOG S1609：高钙血症型卵巢小细胞癌队列中的持久反应和延迟假性进展

A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: durable responses and delayed pseudoprogression in small cell carcinoma of the ovary, hypercalcemic type cohort.

作者信息

Chae Young Kwang, Othus Megan, Patel Sandip Pravin, Aljumaily Raid, Win Khine Z, Pejovic Tanya, Thomas Sajeve S, Robinson William R, Kim Hye Sung, Chung Liam Il-Young, McLeod Christine M, Chen Helen X, Sharon Elad, Streicher Howard, Ryan Christopher W, Blanke Charles D, Kurzrock Razelle

机构信息

Department of Medical Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

SWOG Statistics and Data Management Center, Seattle, Washington, USA.

出版信息

Cancer Commun (Lond). 2025 May 22. doi: 10.1002/cac2.70020.

DOI:10.1002/cac2.70020

PMID:40402690

Abstract

BACKGROUND

The combined use of anti-programmed cell death protein 1 (PD-1)/anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint inhibitors has been effective in various cancer types. The Southwest Oncology Group (SWOG) Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The purpose of the study was to evaluate the potential clinical benefit of ipilimumab and nivolumab in patients with SCCOHT.

METHODS

DART was a prospective, open-labeled, multicenter (>1,000 US sites), multi-cohort phase II clinical trial of intravenous administration of ipilimumab (1 mg/kg, every 6 weeks) plus nivolumab (240 mg, every 2 weeks). The primary endpoint was overall response rate [ORR, confirmed complete response (CR) and partial response (PR)] per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease ≥6 months), and toxicity. Immune responses were also evaluated.

RESULTS

Six patients (median age, 30.5 years; median, 2 prior therapies; no prior immunotherapy exposure) with advanced/metastatic SCCOHT were evaluable. ORR and CBR were both 16.7% (1/6) with one patient having a confirmed CR lasting 46.2+ months. However, another patient had a confirmed immune CR (iCR) with immune PFS (iPFS) of 53+ months [ORR/iORR, 33.3% (2/6)]. Notably, the latter patient had a progressing lesion at 24 weeks after initial response, but with renewed regression with ongoing therapy, suggesting delayed pseudo-progression. At 12-months, 3 patients remained alive. Median PFS was 1.4 months (range, 0.9 months-not reached); median OS was 14.2 months (2 months-not reached). No adverse events caused treatment discontinuation.

CONCLUSION

Two of 6 patients (33.3%) with SCCOHT achieved durable CR/iCR and long-term survival with ipilimumab plus nivolumab. Correlative studies to determine response and resistance markers are ongoing.

GOV REGISTRY

NCT02834013.

摘要

背景

抗程序性细胞死亡蛋白1（PD-1）/抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）检查点抑制剂的联合使用在多种癌症类型中均有效。西南肿瘤协作组（SWOG）开展的罕见肿瘤双重抗CTLA-4和抗PD-1阻断（DART）S1609研究，对伊匹单抗和纳武单抗在超罕见癌症中的应用进行了研究，其中包括高钙血症型卵巢小细胞癌（SCCOHT）。本研究的目的是评估伊匹单抗和纳武单抗对SCCOHT患者的潜在临床获益。

方法

DART是一项前瞻性、开放标签、多中心（超过1000个美国研究点）、多队列的II期临床试验，静脉给予伊匹单抗（1mg/kg，每6周一次）加纳武单抗（240mg，每2周一次）。主要终点是根据实体瘤疗效评价标准（RECIST）得出的总缓解率[ORR，确认的完全缓解（CR）和部分缓解（PR）]。次要终点包括无进展生存期（PFS）、总生存期（OS）、临床获益率（CBR；总缓解加疾病稳定≥6个月）和毒性。同时也评估了免疫反应。

结果

6例晚期/转移性SCCOHT患者（中位年龄30.5岁；中位，既往接受过2次治疗；未接受过免疫治疗）可进行评估。ORR和CBR均为16.7%（1/6），1例患者确认CR持续46.2 +个月。然而，另1例患者确认有免疫完全缓解（iCR），免疫无进展生存期（iPFS）为53 +个月[ORR/iORR，33.3%（2/6）]。值得注意的是，后1例患者在初始缓解后24周出现疾病进展，但随着持续治疗再次出现缓解，提示延迟性假进展。12个月时，3例患者仍存活。中位PFS为1.4个月（范围0.9个月-未达到）；中位OS为14.2个月（2个月-未达到）。无不良事件导致治疗中断。