丹麦哥本哈根大学医院Mansoor R. Mirza团队研究了多塔利单抗治疗原发性晚期或复发子宫内膜癌的疗效与安全性。这一研究成果发表在2023年3月27日出版的《新英格兰医学杂志》上。

多塔利单抗是一种针对程序性细胞死亡1受体的免疫检查点抑制剂。化疗联合免疫疗法治疗子宫内膜癌可能具有协同作用。

研究组进行了一项临床3期、全球双盲、随机、安慰剂对照试验。招募符合条件的原发性晚期III或IV期或首次复发子宫内膜癌症患者，将其按1:1的比例随机分配，每3周（6个周期）接受多塔利单抗（500 mg）或安慰剂，加上卡铂（浓度-时间曲线下的面积，5 mg/ml/min）和紫杉醇（175 mg/m²体表面积），随后每6周注射一次多塔利单抗（1000mg）或安慰剂，持续3年。主要终点是研究者根据实体瘤缓解评估标准（RECIST）1.1版评估的无进展生存率和总生存率。还对安全性进行了评估。

在接受随机分组的494名患者中，118名（23.9%）患有错配修复缺陷型（dMMR）、微卫星不稳定性高型（MSI-H）肿瘤。在dMMR–MSI-H人群中，多塔利单抗组24个月时的无进展生存率估计为61.4%，安慰剂组为15.7%（进展或死亡的风险比为0.28）；在所有参与者中，多塔利单抗组24个月无进展生存率为36.1%，安慰剂组为18.1%（危险比为0.64），组间差异均显著。

24个月时，多塔利单抗组和安慰剂组的总生存率分别为71.3%和56.0%（死亡风险比为0.64）。治疗期间发生或恶化的最常见不良事件是恶心（多塔利单抗组53.9%和安慰剂组45.9%）、脱发（53.5%和50.0%）和疲劳（51.9%和54.5%）。多塔利单抗组的危重和严重不良事件比安慰剂组更频繁。

研究结果表明，多塔利单抗联合卡铂-紫杉醇显著提高了原发性晚期或复发性子宫内膜癌患者的无进展生存率，且对dMMR-MSI-H人群有显著益处。

附：英文原文

Title: Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer | NEJM

Author: Mansoor R. Mirza, M.D.,, Dana M. Chase, M.D.,, Brian M. Slomovitz, M.D.,, René dePont Christensen, Ph.D.,, Zoltán Novák, Ph.D.,, Destin Black, M.D.,, Lucy Gilbert, M.D.,, Sudarshan Sharma, M.D.,, Giorgio Valabrega, M.D.,, Lisa M. Landrum, M.D., Ph.D.,, Lars C. Hanker, M.D.,, Ashley Stuckey, M.D.,, Ingrid Boere, M.D., Ph.D.,, Michael A. Gold, M.D.,, Annika Auranen, M.D.,, Bhavana Pothuri, M.D.,, David Cibula, M.D.,, Carolyn McCourt, M.D.,, Francesco Raspagliesi, M.D.,, Mark S. Shahin, M.D.,, Sarah E. Gill, M.D.,, Bradley J. Monk, M.D.,, Joseph Buscema, M.D.,, Thomas J. Herzog, M.D.,, Larry J. Copeland, M.D.,, Min Tian, Ph.D.,, Zangdong He, Ph.D.,, Shadi Stevens, M.D.,, Eleftherios Zografos, M.D.,, Robert L. Coleman, M.D.,, and Matthew A. Powell, M.D.

Issue&Volume: 2023-03-27

Abstract:

Background

Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer.

Methods

We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration–time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed.

Results

Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair–deficient (dMMR), microsatellite instability–high (MSI-H) tumors. In the dMMR–MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group.

Conclusions

Dostarlimab plus carboplatin–paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR–MSI-H population.

DOI: 10.1056/NEJMoa2216334

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2216334