局部晚期错配修复缺陷型结直肠癌的新辅助免疫治疗。

Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer.

机构信息

From the Departments of Gastrointestinal Oncology (M.C., Y.L.V., P.B.T., C.G., S.D., N.V.B., I.L.H., M.E.V.L.), Medical Oncology (M.C., C.G., N.V.B., E.E.V., J.B.H.), Biometrics (S.B.), Surgery (B.A.G., K.K., G.L.B.), Pathology (P.S., J.G.B.), Molecular Oncology and Immunology (E.E.V., T.N.S.), and Radiology (R.G.B.-T.), and the Division of Molecular Carcinogenesis (L.F.W.), Netherlands Cancer Institute, and the Department of Gastroenterology and Hepatology, OLVG Hospital (A.U.V.L.), Amsterdam, the Department of Surgery, Catharina Hospital Eindhoven, Eindhoven (J.W.B.), the Department of Surgery, Haga Hospital, the Hague (T.S.A.), the Department of Surgery, Tergooi MC, Hilversum (E.R.H.), the Department of Surgery, Spaarne Gasthuis, Haarlem (S.J.O.), Oncode Institute, Utrecht (E.E.V., L.F.W., T.N.S.), the Faculty of EEMCS, Delft University of Technology, Delft (L.F.W.), GROW School for Oncology and Reproduction, Maastricht University, Maastricht (R.G.B.-T., G.L.B.), and the Departments of Gastroenterology and Hepatology (M.E.V.L.), Hematology (T.N.S.), and Medical Oncology (J.B.H.), Leiden University Medical Center, Leiden - all in the Netherlands; the Faculty of Medicine, University of Iceland, Reykjavik (P.S.); and the Melanoma Clinic, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (J.B.H.).

出版信息

N Engl J Med. 2024 Jun 6;390(21):1949-1958. doi: 10.1056/NEJMoa2400634.

DOI:10.1056/NEJMoa2400634

PMID:38838311

Abstract

BACKGROUND

Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.

METHODS

We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses.

RESULTS

Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease.

CONCLUSIONS

In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.).

摘要

背景

在非转移性结直肠癌患者中，约有 10%至 15%存在错配修复缺陷（dMMR）肿瘤。在这些患者中，化疗的疗效有限。新辅助免疫治疗的应用已显示出良好的效果，但该方法的数据有限。

方法

我们进行了一项 2 期研究，入组了未经治疗的局部晚期、先前未转移的 dMMR 结直肠癌患者，给予新辅助纳武利尤单抗联合伊匹单抗治疗。主要终点为安全性，定义为及时手术（即由于治疗相关毒性事件导致计划手术推迟不超过 2 周）和 3 年无疾病生存率。次要终点包括病理缓解和基因组分析结果。

结果

在入组的 115 例患者中，113 例（98%；97.5%置信区间[CI]，93%至 100%）及时进行了手术；2 例手术推迟超过 2 周。5 例（4%）出现 3 级或 4 级免疫相关不良事件，无患者因不良事件停止治疗。在可进行疗效分析的 111 例患者中，109 例（98%；95%CI，94%至 100%）观察到病理缓解，包括 105 例（95%）达到主要病理缓解（定义为≤10%存活肿瘤残留）和 75 例（68%）达到病理完全缓解（0%存活肿瘤残留）。中位随访 26 个月（范围，9 至 65 个月），无患者疾病复发。