度伐利尤单抗联合曲美木单抗治疗不可切除肝细胞癌的抗肿瘤作用及免疫介导的不良事件

Antitumor effects and immune-mediated adverse events of durvalumab plus tremelimumab treatment for unresectable hepatocellular carcinoma.

作者信息

Ito Takanori, Shimose Shigeo, Tani Joji, Tomonari Tetsu, Saeki Issei, Takeuchi Yasuto, Hatanaka Takeshi, Sasaki Kyo, Kakizaki Satoru, Kanayama Yuki, Yoshioka Naoki, Naito Takehito, Takeuchi Mamiko, Yasunaka Tetsuya, Sakata Masahiro, Iwamoto Hideki, Itano Satoshi, Shirono Tomotake, Tanabe Norikazu, Yamamoto Takafumi, Naganuma Atsushi, Nishina Sohji, Otsuka Motoyuki, Takami Taro, Takayama Tetsuji, Kawaguchi Takumi, Kawashima Hiroki

机构信息

Department of Gastroenterology and Hepatology, Nagoya University Hospital, Nagoya, Japan.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

出版信息

Hepatol Res. 2025 Apr;55(4):577-587. doi: 10.1111/hepr.14151. Epub 2024 Dec 15.

DOI:10.1111/hepr.14151

PMID:40318087

Abstract

AIM

Durvalumab plus tremelimumab (Dur/Tre) is a first-line systemic treatment option for unresectable hepatocellular carcinoma (uHCC). However, the management of severe immune-mediated adverse events (imAEs) is challenging. Therefore, we investigated the relationship between severe imAEs and antitumor responses in patients with uHCC treated with Dur/Tre.

METHODS

We included 157 patients with uHCC treated with Dur/Tre in this multicenter, retrospective study and analyzed the relationship between progression-free survival (PFS)/antitumor response and severe imAEs requiring high-dose corticosteroid treatment.

RESULTS

Thirty-two patients (20.4%) developed severe imAEs, including enterocolitis/diarrhea (n = 10), liver injury (n = 9), interstitial lung disease (n = 5), rashes (n = 4), cytokine-release syndrome/fever (n = 2), pancreatitis (n = 2), and others (n = 4) (median follow-up period, 6.8 months). Infliximab was administered in six patients with steroid-refractory enterocolitis. Although the objective response rate (ORR) and disease control rate (DCR) were significantly higher with first-line therapy than with later-line therapy (p = 0.026), the frequency of severe imAEs was not significantly different (p = 0.221). The ORR and DCR in patients with and without severe imAEs were 15.6% and 17.6% and 65.6% and 47.2%, respectively, with no significant differences. Five patients with severe imAEs, including rashes and liver injury, showed objective responses (partial response + complete response). Among patients who achieved an objective response, the PFS at 10 months was good (100% and 70.3% with and without high-dose corticosteroids, respectively).

CONCLUSIONS

Severe imAEs of Dur/Tre treatment requiring high-dose corticosteroid treatment did not affect antitumor efficacy, which differed depending on the type of imAEs. Therefore, appropriately managing imAEs is essential to guide sequential treatment.

摘要

目的

度伐利尤单抗联合曲美木单抗（Dur/Tre）是不可切除肝细胞癌（uHCC）的一线全身治疗方案。然而，严重免疫介导的不良事件（imAEs）的管理具有挑战性。因此，我们研究了接受Dur/Tre治疗的uHCC患者中严重imAEs与抗肿瘤反应之间的关系。

方法

在这项多中心回顾性研究中，我们纳入了157例接受Dur/Tre治疗的uHCC患者，并分析了无进展生存期（PFS）/抗肿瘤反应与需要高剂量皮质类固醇治疗的严重imAEs之间的关系。

结果

32例患者（20.4%）发生了严重imAEs，包括小肠结肠炎/腹泻（n = 10）、肝损伤（n = 9）、间质性肺疾病（n = 5）、皮疹（n = 4）、细胞因子释放综合征/发热（n = 2）、胰腺炎（n = 2）及其他（n = 4）（中位随访期6.8个月）。6例类固醇难治性小肠结肠炎患者接受了英夫利昔单抗治疗。虽然一线治疗的客观缓解率（ORR）和疾病控制率（DCR）显著高于二线及后续治疗（p = 0.026），但严重imAEs的发生率无显著差异（p = 0.221）。发生和未发生严重imAEs患者的ORR和DCR分别为15.6%和17.6%以及65.6%和47.2%，无显著差异。5例发生严重imAEs（包括皮疹和肝损伤）的患者出现了客观反应（部分缓解+完全缓解）。在达到客观反应的患者中，10个月时的PFS良好（使用和未使用高剂量皮质类固醇的患者分别为100%和70.3%）。