A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair—Proficient Colorectal or Pancreatic Cancer

IF 3.3 3区医学 Q2 ONCOLOGY

Clinical colorectal cancer Pub Date : 2024-09-01 DOI:10.1016/j.clcc.2024.05.002

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引用次数: 0

Abstract

Background

The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib).

Methods

PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing.

Results

A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes.

Conclusions

In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

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一项针对错配修复功能良好的结直肠癌或胰腺癌患者的II期开放标签随机试验：durvalumab与奥拉帕利（olaparib）或塞地拉尼（cediranib）的联合疗法

背景在错配修复熟练的结直肠癌（pMMR-CRC）或胰腺腺癌（PDAC）中使用免疫疗法的疗效有限。DAPPER（NCT03851614）是一项2期篮子研究，将pMMR CRC或PDAC患者随机分配到durvalumab+olaparib（durvalumab+olaparib）或durvalumab+cediranib（durvalumab+cediranib）。共同主要终点包括肿瘤微环境（TME）的药效学免疫变化和安全性。客观反应率、无进展生存期（PFS）和总生存期（OS）均已确定。通过多重免疫组化和 RNA 序列分析配对肿瘤样本。结果共有 31 例转移性 pMMR-CRC 患者被随机分配到 A 组（16 例）或 B 组（15 例）。在28名可评估患者中，3名患者病情稳定（SD）（2名患者接受了durvalumab + olaparib治疗，1名患者接受了durvalumab + cediranib治疗），25名患者病情进展（PD）。在18名可评估的患者中，1名患者使用durvalumab + cediranib治疗后获得部分应答（未经证实），1名患者使用durvalumab + olaparib治疗后获得SD应答，16名患者获得PD应答。与基线相比，pMMR-CRC和PDAC的治疗活检中CD3+/CD8+免疫浸润未见明显变化，与治疗组无关。结论在pMMR-CRC或PDAC患者中，durvalumab + olaparib和durvalumab + cediranib显示出有限的抗肿瘤活性。TME的不同免疫成分与治疗结果相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical colorectal cancer 医学-肿瘤学

CiteScore

5.50

自引率

2.90%

发文量

审稿时长

27 days

期刊介绍： Clinical Colorectal Cancer is a peer-reviewed, quarterly journal that publishes original articles describing various aspects of clinical and translational research of gastrointestinal cancers. Clinical Colorectal Cancer is devoted to articles on detection, diagnosis, prevention, and treatment of colorectal, pancreatic, liver, and other gastrointestinal cancers. The main emphasis is on recent scientific developments in all areas related to gastrointestinal cancers. Specific areas of interest include clinical research and mechanistic approaches; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; and integration of various approaches.