Impact of claudin 18.2 expression on treatment outcomes of first-line immunochemotherapy in patients with HER2-negative, proficient MMR, PD-L1 CPS ⩾1 metastatic gastric/gastroesophageal junction cancer

Fei Zhang; Izuma Nakayama; Naoya Sakamoto; Dai Okemoto; Amane Jubashi; Yuki Matsubara; Yu Miyashita; Seiya Sato; Shinpei Ushiyama; Akinori Kobayashi; Ukyo Okazaki; Kazumasa Yamamoto; Saori Mishima; Daisuke Kotani; Akihito Kawazoe; Tadayoshi Hashimoto; Yoshiaki Nakamura; Yasutoshi Kuboki; Hideaki Bando; Takashi Kojima; Takayuki Yoshino; Takeshi Kuwata; Kohei Shitara

doi:10.1177/17588359251369042

Impact of claudin 18.2 expression on treatment outcomes of first-line immunochemotherapy in patients with HER2-negative, proficient MMR, PD-L1 CPS ⩾1 metastatic gastric/gastroesophageal junction cancer

Ther Adv Med Oncol. 2025 Sep 20:17:17588359251369042. doi: 10.1177/17588359251369042. eCollection 2025.

Authors

Fei Zhang¹, Izuma Nakayama², Naoya Sakamoto^{3

4}, Dai Okemoto¹, Amane Jubashi¹, Yuki Matsubara¹, Yu Miyashita¹, Seiya Sato¹, Shinpei Ushiyama¹, Akinori Kobayashi¹, Ukyo Okazaki, Kazumasa Yamamoto¹, Saori Mishima¹, Daisuke Kotani¹, Akihito Kawazoe¹, Tadayoshi Hashimoto^{1

5}, Yoshiaki Nakamura^{1

5}, Yasutoshi Kuboki¹, Hideaki Bando¹, Takashi Kojima¹, Takayuki Yoshino¹, Takeshi Kuwata^{3

6}, Kohei Shitara¹

Affiliations

¹ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
² Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
³ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
⁴ Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
⁵ Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
⁶ Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Abstract

Background: The effect of claudin 18.2 (CLDN18.2) expression on the outcomes of a first-line immune checkpoint inhibitor (ICI)-containing chemotherapy (ICI-chemo) in patients with human epidermal growth factor receptor 2 (HER2)-negative, proficient mismatch repair (pMMR), and programmed death-ligand 1 (PD-L1)-expressing metastatic or recurrent gastric or gastroesophageal junction cancers (mGC/GEJC) remains unclear.

Objectives: We assessed the effects of CLDN18.2 expression on the outcomes of first-line ICI-containing chemotherapy in patients with HER2-negative, pMMR, and PD-L1-expressing mGC/GEJC.

Patients and methods: Medical records of patients with HER2-negative, pMMR, and PD-L1 combined positive score (CPS) ⩾1 unresectable/metastatic or recurrent GC/GEJC who received first-line ICI-chemo or chemotherapy alone (chemo-alone) between January 2016 and August 2024 were retrospectively analyzed. The impact of CLDN18.2 status on the clinical outcomes was evaluated in patients receiving ICI-chemo and chemo-alone to assess the prognostic significance of CLDN18.2 in the absence of ICI.

Results: A total of 150 patients were treated with ICI-chemo, whereas 313 patients received chemo-alone. CLDN18.2 positivity (⩾2+ in ⩾75% tumor cells) was identified in 42 patients (28.0%) in the ICI-chemo group and 94 patients (30.0%) in the chemo-alone group. There were no significant differences in the objective response rate (ORR; 68.3% vs 70.3%, p = 0.842), disease control rate (DCR; 92.7% vs 94.1%, p = 0.718), progression-free survival (PFS; hazard ratio (HR) 1.01, p = 0.955), or overall survival (OS; HR 1.12, p = 0.615) between CLDN18.2-positive and CLDN18.2-negative patients in the ICI-chemo group. Similarly, the DCR, ORR, PFS, and OS outcomes were comparable between the CLDN18.2-positive and -negative patients in the chemo-alone group.

Conclusion: CLDN18.2 expression exerted no impact on outcomes of first-line ICI-chemo and chemo-alone in patients with HER2-negative, pMMR, and PD-L1 CPS ⩾1 mGC/GEJC.

Keywords: claudin 18.2; gastric cancer; immunochemotherapy; proficient mismatch repair; programmed death-ligand 1.