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Observational Study
. 2025 Jan;28(1):63-73.
doi: 10.1007/s10120-024-01560-z. Epub 2024 Nov 2.

Prognostic and predictive factors for the efficacy and safety of trastuzumab deruxtecan in HER2-positive gastric or gastroesophageal junction cancer

Amane Jubashi  1   2 , Izuma Nakayama  3 , Shigehiro Koganemaru  4 , Naoya Sakamoto  5   6 , Shioto Oda  7 , Yuki Matsubara  1 , Yu Miyashita  1 , Seiya Sato  1 , Shinpei Ushiyama  1 , Akinori Kobayashi  1 , Ukyo Okazaki  1 , Dai Okemoto  1 , Kazumasa Yamamoto  1 , Saori Mishima  1 , Daisuke Kotani  1 , Akihito Kawazoe  1 , Tadayoshi Hashimoto  1   8 , Yoshiaki Nakamura  1   8 , Yasutoshi Kuboki  1   4 , Hideaki Bando  1 , Takashi Kojima  1 , Takayuki Yoshino  1 , Hisamitsu Miyaaki  2 , Kazuhiko Nakao  2 , Kohei Shitara  1
Affiliations
Observational Study

Prognostic and predictive factors for the efficacy and safety of trastuzumab deruxtecan in HER2-positive gastric or gastroesophageal junction cancer

Amane Jubashi et al. Gastric Cancer. 2025 Jan.

Abstract

Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC.

Methods: A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen.

Results: Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD.

Conclusions: Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.

Keywords: Gastric cancer; Interstitial lung disease; Optimize dosing; Trastuzumab deruxtecan; Tumor burden.

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Conflict of interest statement

Declarations. Conflict of interest: A. Jubashi have no conflict of interest. I. Nakayama has received research funding from Ono, MSD, and CHUGAI PHARMACEUTICAL CO., LTD. outside the submitted work. S. Koganemaru has received research funding from Eisai Inc., Amgen, Bristol-Myers Squibb, MSD, Daiichi Sankyo, AbbVie and Incyte outside the submitted work. Y. Matsubara has received honoraria from Taiho, Takeda, Elli Lilly Japan, MSD, and Bristol-Myers Squibb outside the submitted work. S. Mishima has received honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Eli Lilly Co., Ltd. outside the submitted work. D. Kotani has received honoraria from Takeda, Chugai, Lilly, MSD, Ono, Taiho, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Eisai, and Merck biopharma and research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneos Health, Cimic, and Cimicshiftzero outside the submitted work. A. Kawazoe has received honoraria from Daiichi Sankyo, Lilly, Ono, Taiho, Bristol-Myers Squibb, and Merck Serono biopharma and research funding from Ono, MSD, Taiho, Bayer, Sumitomo Dainippon and AstraZeneca outside the submitted work. T. Hashimoto has received honoraria from CytoGen, Inc. and Takata Pharmaceutical outside the submitted work. Y. Nakamura plays an advisory role at Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation, and Gilead Sciences, Inc.; is included in the speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company, and Guardant Health Japan Corp; and has received research funding from Seagen, Inc., Genomedia Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd., and Chugai Pharmaceutical Co., Ltd. outside the submitted work. Y. Kuboki has received personal fees for advisory roles from Taiho, Takeda, and Boehringer Ingelheim; honoraria from Taiho, Ono, Bayer, and Sanofi; and institutional grants or contracts with Taiho, Takeda, Ono, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GlaxoSmithKline, Genmab, Astellas, and Daiichi Sankyo outside the submitted work. H. Bando has received research fund from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly Japan outside the submitted work. T. Kojima has received honoraria as an invited speaker and for manuscript writing from Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd., Covidien Japan, Inc., MSD K.K., TAIHO PHARMACEUTICAL CO., LTD., and Oncolys BioPharma Inc.; research funding from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, BeiGene Ltd., EPS Corporation., MSD K.K., Amgen Inc., SHIONOGI & Co., Ltd., and CHUGAI PHARMACEUTICAL CO., LTD. outside the submitted work. T. Yoshino has received honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD K.K; consulting fee from Sumitomo Corp.; and research funding from Amgen, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO biosystems, Genomedia, Medical & Biological Laboratories, Merus N.V., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, Taiho Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. K. Nakao has received honoraria from AstraZeneca outside the submitted work. K. Shitara has received personal fees for advisory roles from Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Merck Pharmaceutical, Taiho Pharmaceutical, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim, and Janssen; honoraria (lecture fee) from Takeda and Bristol-Myers Squibb; and research funding from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck Pharmaceutical, Medi Science, Eisai, and Amgen outside the submitted work. All remaining authors have no competing interest. Informed consent: All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later versions. Informed consent to be included in the study or the equivalent was obtained from all patients.

Figures

Fig. 1
Fig. 1
Best % change from baseline in the cumulative diameter of the target lesions. The waterfall plot displays each patient’s best response to T-DXd treatment compared with baseline, as measured by the maximum % reduction or minimum % increase in the cumulative of diameter of the target lesions. Among the 91 patients with at least one postbaseline tumor assessment, the best overall responses are indicated by the following colors: blue for CR, green for PR, gray for SD, and red for PD
Fig. 2
Fig. 2
Maximum % change in target lesion size from baseline among patients who developed ILD. The waterfall plot shows the best response to treatment for the subset of 14 patients who developed ILD, as assessed by the greatest % decrease or smallest % increase in the cumulative diameter of the target lesions relative to baseline measurements. Each bar corresponds to an individual patient, with colors denoting their best overall response, as follows: blue for CR, green for PR, gray for SD, and red for PD
Fig. 3
Fig. 3
Relationship between ILD presence and tumor burden in patients who received 6.4 mg/kg T-DXd. Of the 72 patients who were treated with 6.4 mg/kg T-DXd and had one or more measurable lesions, 13 developed ILD. Tumor burden was assessed by the (a) total tumor diameter of the target lesions using the RECIST criteria (maximum of five lesions, up to two per organ); (b) total tumor diameter of all measurable lesions; and (c) number of measurable lesions
See this image and copyright information in PMC

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