一线纳武利尤单抗联合低剂量伊匹木单抗治疗微卫星高度不稳定的晚期胃癌或食管胃交界癌的II期研究（NO LIMIT，WJOG13320G）

Phase II Study (NO LIMIT, WJOG13320G) of First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High Advanced Gastric or Esophagogastric Junction Cancer.

作者信息

Kawakami Hisato, Kadowaki Shigenori, Makiyama Akitaka, Tsuda Masahiro, Hirata Kenro, Sugimoto Naotoshi, Machida Nozomu, Hara Hiroki, Hirano Hidekazu, Esaki Taito, Komatsu Yoshito, Hironaka Shuichi, Kobayashi Yukari, Kakimi Kazuhiro, Chiba Yasutaka, Boku Narikazu, Hyodo Ichinosuke, Muro Kei

机构信息

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan.

Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.

出版信息

J Clin Oncol. 2025 Jul;43(19):2184-2195. doi: 10.1200/JCO-24-02463. Epub 2025 May 16.

DOI:10.1200/JCO-24-02463

PMID:40378356

Abstract

PURPOSE

Microsatellite instability-high (MSI-H) advanced gastric or esophagogastric junction cancer (AGC), accounting for 5%-6% of all AGC cases, has shown an enhanced responsiveness to immunotherapy. We performed a single-arm phase II study to evaluate the combination of nivolumab (NIVO) and low-dose (LD) ipilimumab (IPI) for first-line treatment of MSI-H AGC.

PATIENTS AND METHODS

Patients with MSI-H AGC received NIVO (240 mg once every 2 weeks) and IPI (1 mg/kg once every 6 weeks). The primary end point was overall response rate (ORR) assessed by blinded independent central review. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and biomarker analysis. MSI-H status was confirmed with an MSI-IVD Kit (Falco).

RESULTS

Twenty-nine patients were enrolled. The ORR was 62.1% (95% CI, 42.3 to 79.3), with a complete response rate of 10.3%. The DCR was 79.3% (95% CI, 60.3 to 92.0). Treatment-related adverse events (TRAEs) of any grade occurred in 93.1% of patients, with those of grade ≥3 manifesting in 37.9% of patients. At the data cutoff (median follow-up of 9.0 months), treatment had been discontinued in 21 patients, with such discontinuation being due to TRAEs in 12 (41.4%) patients. However, after exclusion of one patient with progressive disease, the remaining 11 patients showed long-term antitumor efficacy after treatment discontinuation (range of response duration, 0.9+ to 15.6+ months). The median PFS was 13.8 months (95% CI, 13.7 months to not reached [NR]) and the median OS was NR (95% CI, 13.7 months to NR), with a 12-month OS rate of 79.5%.

CONCLUSION

NIVO plus LD-IPI showed robust and durable antitumor efficacy as a first-line treatment for MSI-H AGC. Although TRAEs often led to treatment discontinuation, treatment efficacy was subsequently sustained in most patients.

摘要

目的

微卫星高度不稳定（MSI-H）的晚期胃癌或食管胃交界癌（AGC）占所有AGC病例的5%-6%，对免疫治疗表现出更高的反应性。我们开展了一项单臂II期研究，以评估纳武利尤单抗（NIVO）与低剂量（LD）伊匹木单抗（IPI）联合用于MSI-H AGC一线治疗的效果。

患者与方法

MSI-H AGC患者接受NIVO（每2周一次，每次240 mg）和IPI（每6周一次，每次1 mg/kg）治疗。主要终点为通过盲法独立中央审查评估的总缓解率（ORR）。次要终点包括疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）、安全性和生物标志物分析。使用MSI-IVD试剂盒（Falco）确认MSI-H状态。

结果

共入组29例患者。ORR为62.1%（95%CI，42.3至79.3），完全缓解率为10.3%。DCR为79.3%（95%CI，60.3至92.0）。93.1%的患者发生了任何级别的治疗相关不良事件（TRAEs），37.9%的患者发生了≥3级TRAEs。在数据截止时（中位随访9.0个月），21例患者停止了治疗，其中12例（41.4%）因TRAEs停药。然而，排除1例疾病进展患者后，其余11例患者在停药后显示出长期抗肿瘤疗效（缓解持续时间范围为0.9+至15.6+个月）。中位PFS为13.8个月（95%CI，13.7个月至未达到[NR]），中位OS为NR（95%CI，13.7个月至NR），12个月OS率为79.5%。