胃癌领域抗肿瘤药物相关间质性肺病/肺炎的研究进展及展望

doi:10.19401/j.cnki.1007-3639.2025.09.008

摘要/Abstract

摘要：

胃癌发病率高，疾病负担沉重，且治疗困难。近年来，免疫检查点抑制剂（immune checkpoint inhibitor，ICI）、人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）和紧密连接蛋白18.2（Claudin 18.2，CLDN18.2）抑制剂等多种新型抗肿瘤药物为胃癌患者带来获益，单药治疗和不同联合治疗方案均在胃癌临床治疗中展现出巨大潜力。然而，由抗肿瘤药物诱发的间质性肺病/肺炎（interstitial lung disease/pneumonia，ILD/p），尤其是免疫抑制剂类药物和抗体药物偶联物（antibody-drug conjugate，ADC）药物相关ILD的发生风险，已然成为影响患者获益的关键安全性问题。由于不同抗肿瘤药物诱发ILD的风险和机制各不相同，且ILD多数起病隐匿，较难察觉。因此，深入理解不同抗肿瘤药物相关ILD的发生风险及其独特机制、合理且个体化的用药监测及患者管理至关重要。有鉴于此，本文系统性回顾分析近年来胃癌领域抗肿瘤药物相关临床研究中ILD/p的发生率、临床特征及ILD/p相关危险因素，旨在阐明不同抗肿瘤药物之间的风险分层、机制差异，以提升临床认知，从而使更多胃癌患者临床获益。

关键词: 胃癌, 抗肿瘤药物, 间质性肺病, 肺炎, 进展

Abstract:

Gastric cancer presents a high incidence rate and substantial disease burden, posing significant therapeutic challenges. Recent advances have yielded significant benefits for gastric cancer patients through novel anti-tumor agents, including immune checkpoint inhibitor (ICI), human epidermal growth factor receptor 2 (HER2)-targeted therapies, and claudin 18.2 (CLDN18.2)-directed agents. Both monotherapy and various combination regimens demonstrate considerable promise in gastric cancer treatment. However, a critical safety concern potentially limiting patient benefit is drug-induced interstitial lung disease (ILD)/pneumonitis, particularly associated with ICI and antibody-drug conjugate (ADC). The risk and underlying mechanisms of ILD vary considerably across different anti-tumor drug classes, and its often insidious onset makes early detection difficult. Therefore, a deep understanding of the distinct ILD risks and mechanisms associated with different agents, coupled with rational, individualized drug monitoring and patient management, is paramount. This review systematically analyzes the incidence rates, clinical characteristics, and risk factors associated with ILD/pneumonitis reported in recent clinical trials of anti-tumor therapies for gastric cancer. It aimed to elucidate the risk stratification and mechanistic differences between drug classes, thereby enhancing clinical awareness and ultimately helping to maximize clinical outcomes for gastric cancer patients.

Key words: Gastric cancer, Anticancer drug, Interstitial lung disease, Pneumonitis, Progress

中图分类号:

R735.2

郭晓玉, 曲秀娟. 胃癌领域抗肿瘤药物相关间质性肺病/肺炎的研究进展及展望[J]. 中国癌症杂志, 2025, 35(9): 874-883.

GUO Xiaoyu, QU Xiujuan. Research progress and future perspectives of anticancer drug-induced interstitial lung disease/pneumonia in gastric cancer[J]. China Oncology, 2025, 35(9): 874-883.

图/表 3

表1

表2

表3

参考文献 75

[1]	BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2]	ZHENG R S, CHEN R, HAN B F, et al. Cancer incidence and mortality in China, 2022[J]. Zhonghua Zhong Liu Za Zhi, 2024, 46(3): 221-231.
[3]	CONTE P, ASCIERTO P A, PATELLI G, et al. Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment[J]. ESMO Open, 2022, 7(2): 100404.
[4]	DAI H P, MA F, REN Y H, et al. Expert consensus on the diagnosis and treatment of anticancer drug-induced interstitial lung disease[J]. Curr Med Sci, 2023, 43(1): 1-12.
[5]	SPAGNOLO P, BONNIAUD P, ROSSI G, et al. Drug-induced interstitial lung disease[J]. Eur Respir J, 2022, 60(4): 2102776.
[6]	中国抗癌协会胃癌专业委员会. 基于PD-L1蛋白表达水平的胃癌免疫治疗专家共识(2023年版)[J]. 中国肿瘤临床, 2024, 51(2): 55-63.
	China Anti-Cancer Association Committee of Gastric Cancer. Expert consensus on immunotherapy of gastric cancer based on the expression level of PD-L1 protein (2023 edition)[J]. Chin J Clin Oncol, 2024, 51(2): 55-63.
[7]	KIM S T, SHESHADRI A, SHANNON V, et al. Distinct immunophenotypes of T cells in bronchoalveolar lavage fluid from leukemia patients with immune checkpoint inhibitors-related pulmonary complications[J]. Front Immunol, 2021, 11: 590494.
[8]	SATAKE H, LEE K W, CHUNG H C, et al. Pembrolizumab or pembrolizumab plus chemotherapy versus standard of care chemotherapy in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Asian subgroup analysis of KEYNOTE-062[J]. Jpn J Clin Oncol, 2023, 53(3): 221-229.
[9]	CHUNG H C, KANG Y K, CHEN Z D, et al. Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): a randomized, open-label, phase 3 trial in Asian patients[J]. Cancer, 2022, 128(5): 995-1003.
[10]	HUANG J, MO H N, ZHANG W L, et al. Promising efficacy of SHR-1210, a novel anti-programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China[J]. Cancer, 2019, 125(5): 742-749. doi: 10.1002/cncr.31855 pmid: 30508306
[11]	KANG Y K, CHEN L T, RYU M H, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2022, 23(2): 234-247.
[12]	SHITARA K, AJANI J A, MOEHLER M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer[J]. Nature, 2022, 603(7903): 942-948.
[13]	DING X W, WANG X J, LI B, et al. PERSIST: a multicenter, randomized phase Ⅱ trial of perioperative oxaliplatin and S-1 (SOX) with or without sintilimab in resectable locally advanced gastric/gastroesophageal junction cancer (GC/GEJC)[J]. J Clin Oncol, 2023, 41(4_suppl): 364.
[14]	DU R, MING J, GENG J, et al. 1215P Neoadjuvant concurrent chemoradiotherapy combined with immunotherapy in the treatment of adenocarcinoma of the oesophagogastric junction: a phase Ⅱ study[J]. Ann Oncol, 2022, 33: S1104.
[15]	CHEN S X, ZHANG Z B, ZHENG X, et al. Response efficacy of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis[J]. Front Oncol, 2021, 11: 562315.
[16]	MOEHLER M, DVORKIN M, BOKU N, et al. Phase Ⅲ trial of avelumab maintenance after first-line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: results from JAVELIN gastric 100[J]. J Clin Oncol, 2021, 39(9): 966-977.
[17]	VERSCHOOR Y L, KODACH L, VAN DEN BERG J, et al. Neoadjuvant atezolizumab plus docetaxel/oxaliplatin/capecitabine in non-metastatic gastric and gastroesophageal junction adenocarcinoma: the PANDA trial[J]. J Clin Oncol, 2022, 40(16_suppl): 4059.
[18]	KIM H D, RYU M H, PARK Y S, et al. A phase 2 study of durvalumab plus DOS (docetaxel, oxaliplatin, S-1) neoadjuvant chemotherapy followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable locally advanced gastric cancer: an interim efficacy report[J]. J Clin Oncol, 2023, 41(4_suppl): 408.
[19]	王静远, 刘天舒. 双免治疗及抗体药物偶联物在晚期胃癌治疗中应用进展[J]. 中国实用外科杂志, 2024, 44(10): 1179-1185.
	WANG J Y, LIU T S. Application progress of dual immunotherapy and antibody drug conjugates in the treatment of advanced gastric cancer[J]. Chin J Pract Surg, 2024, 44(10): 1179-1185.
[20]	PIETRANTONIO F, RAIMONDI A, LONARDI S, et al. INFINITY: a multicentre, single-arm, multi-cohort, phase Ⅱ trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC)[J]. J Clin Oncol, 2023, 41(4_suppl): 358.
[21]	KIM W H, GOMEZ-IZQUIERDO L, VILARDELL F, et al. HER2 status in gastric and gastroesophageal junction cancer: results of the large, multinational HER-EAGLE study[J]. Appl Immunohistochem Mol Morphol, 2018, 26(4): 239-245.
[22]	VAN CUTSEM E, BANG Y J, FENG F Y, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer[J]. Gastric Cancer, 2015, 18(3): 476-484. doi: 10.1007/s10120-014-0402-y pmid: 25038874
[23]	SHENG W Q, HUANG D, YING J M, et al. HER2 status in gastric cancers: a retrospective analysis from four Chinese representative clinical centers and assessment of its prognostic significance[J]. Ann Oncol, 2013, 24(9): 2360-2364. doi: 10.1093/annonc/mdt232 pmid: 23788757
[24]	HUANG D, LU N, FAN Q H, et al. HER2 status in gastric and gastroesophageal junction cancer assessed by local and central laboratories: Chinese results of the HER-EAGLE study[J]. PLoS One, 2013, 8(11): e80290.
[25]	PRESS M F, CORDON-CARDO C, SLAMON D J. Expression of the HER2/neu proto-oncogene in normal adult and fetal tissues[J]. Oncogene, 1990, 5(7): 953-962.
[26]	JANJIGIAN Y Y, KAWAZOE A, YAÑEZ P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer[J]. Nature, 2021, 600(7890): 727-730.
[27]	CATENACCI D V T, KANG Y K, YOON H H, et al. Margetuximab with retifanlimab as first-line therapy in HER2⁺/PD-L1⁺ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A[J]. ESMO Open, 2022, 7(5): 100563.
[28]	RIVERA F, IZQUIERDO-MANUEL M, GARCÍA-ALFONSO P, et al. Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase Ⅱ trial[J]. Eur J Cancer, 2021, 145: 158-167.
[29]	WAGNER A D, GRABSCH H I, MAUER M, et al. Integration of trastuzumab (T), with or without pertuzumab (P), into perioperative chemotherapy (CT) of HER2 positive gastric (GC) and esophagogastric junction cancer (EGJC): first results of the EORTC 1203 INNOVATION study, in collaboration with the Korean Cancer Study Group, and the Dutch Upper GI Cancer Group[J]. J Clin Oncol, 2023, 41(16_suppl): 4057.
[30]	YU S N, LIU Q, HAN X W, et al. Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment[J]. Exp Hematol Oncol, 2017, 6: 31. doi: 10.1186/s40164-017-0091-4 pmid: 29209558
[31]	TABERNERO J, SHEN L, ELIMOVA E, et al. HERIZON-GEA-01: zanidatamab+chemo±tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma[J]. Future Oncol, 2022, 18(29): 3255-3266.
[32]	ZHANG J, JI D M, CAI L, et al. First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: results from a phase Ⅰ study[J]. Clin Cancer Res, 2022, 28(4): 618-628.
[33]	FU Z W, LI S J, HAN S F, et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy[J]. Signal Transduct Target Ther, 2022, 7: 93.
[34]	TARANTINO P, MODI S N, TOLANEY S M, et al. Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: a review[J]. JAMA Oncol, 2021, 7(12): 1873-1881. doi: 10.1001/jamaoncol.2021.3595 pmid: 34647966
[35]	TARANTINO P, RICCIUTI B, PRADHAN S M, et al. Optimizing the safety of antibody-drug conjugates for patients with solid tumours[J]. Nat Rev Clin Oncol, 2023, 20(8): 558-576. doi: 10.1038/s41571-023-00783-w pmid: 37296177
[36]	KUMAGAI K, AIDA T, TSUCHIYA Y, et al. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys[J]. Cancer Sci, 2020, 111(12): 4636-4645.
[37]	WEI Q, YANG T, ZHANG Z W, et al. Perivascular niche-resident alveolar macrophages promote interstitial pneumonitis related to trastuzumab deruxtecan treatment[J]. Cancer Res, 2025, 85(11): 2081-2099.
[38]	SHITARA K, BANG Y J, IWASA S, et al. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial[J]. Nat Med, 2024, 30(7): 1933-1942. doi: 10.1038/s41591-024-02992-x pmid: 38745009
[39]	VAN CUTSEM E, DI BARTOLOMEO M, SMYTH E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study[J]. Lancet Oncol, 2023, 24(7): 744-756. doi: 10.1016/S1470-2045(23)00215-2 pmid: 37329891
[40]	JANJIGIAN Y Y, VAN LAARHOVEN H W M, RHA S Y, et al. Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03)[J]. Ann Oncol, 2024, 35: S878.
[41]	CRYSTAL R G, GADEK J E, FERRANS V J, et al. Interstitial lung disease: current concepts of pathogenesis, staging and therapy[J]. Am J Med, 1981, 70(3): 542-568. pmid: 7011012
[42]	YAO X J, JIANG J, WANG X, et al. A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity[J]. Breast Cancer Res Treat, 2015, 153(1): 123-133.
[43]	SHI F, LIU Y L, ZHOU X X, et al. Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy[J]. Drug Deliv, 2022, 29(1): 1335-1344. doi: 10.1080/10717544.2022.2069883 pmid: 35506447
[44]	PENG Z, LIU T S, WEI J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase Ⅱ study[J]. Cancer Commun (Lond), 2021, 41(11): 1173-1182.
[45]	KAWAKAMI H, UCHINO K, HASHIMOTO W, et al. Real-world safety of trastuzumab deruxtecan with gastric cancer: all-patient post-marketing surveillance study in Japan[J]. J Clin Oncol, 2025, 43(4_suppl): 399.
[46]	SHEN L, CHEN P, LU J, et al. 129MO Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2-positive (HER2⁺) advanced gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric06 (DG-06) final analysis[J]. Ann Oncol, 2024, 35: S1454-S1455.
[47]	德曲妥珠单抗临床管理路径及不良反应处理共识专家组. 德曲妥珠单抗临床管理路径及不良反应处理中国专家共识(2024版)[J]. 中华肿瘤杂志, 2024, 46(4): 304-318.
	Trastuzumab Deruxtecan Clinical Management Pathway and Adverse Reaction Management Consensus Expert Group. Chinese expert consensus on the management of clinical pathway and adverse events of trastuzumab deruxtecan (2024 edition)[J]. Chin J Oncol, 2024, 46(4): 304-318.
[48]	KOGANEMARU S, SHITARA K. Antibody-drug conjugates to treat gastric cancer[J]. Expert Opin Biol Ther, 2021, 21(7): 923-930.
[49]	THUSS-PATIENCE P C, SHAH M A, OHTSU A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study[J]. Lancet Oncol, 2017, 18(5): 640-653.
[50]	ZHANG Y, QIU M Z, WANG J F, et al. Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma[J]. Cell Rep Med, 2022, 3(11): 100814.
[51]	JHAVERI K, HAN H, DOTAN E, et al. 460MO Preliminary results from a phase Ⅰ study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers[J]. Ann Oncol, 2022, 33: S749-S750.
[52]	SHAH R R. Tyrosine kinase inhibitor-induced interstitial lung disease: clinical features, diagnostic challenges, and therapeutic dilemmas[J]. Drug Saf, 2016, 39(11): 1073-1091.
[53]	SATOH T, XU R H, CHUNG H C, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN: a randomized, phase Ⅲ study[J]. J Clin Oncol, 2014, 32(19): 2039-2049.
[54]	RANDOLPH HECHT J, BANG Y J, QIN S K, et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC: a randomized phase Ⅲ trial[J]. J Clin Oncol, 2016, 34(5): 443-451.
[55]	ZHU L J, LI S, BAO J, et al. First-line of camrelizumab plus pyrotinib and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: a dose escalation and expansion phase Ⅰ study[J]. J Clin Oncol, 2023, 41(4_suppl): 356.
[56]	LIU D, KOU F R, GONG J F, et al. Pyrotinib alone or in combination with docetaxel in refractory HER2-positive gastric cancer: a dose-escalation phase Ⅰ study[J]. Cancer Med, 2023, 12(9): 10704-10714.
[57]	SINGH P, TOOM S, HUANG Y W. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer[J]. J Hematol Oncol, 2017, 10(1): 105.
[58]	SHITARA K, LORDICK F, BANG Y J, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial[J]. Lancet, 2023, 401(10389): 1655-1668. doi: 10.1016/S0140-6736(23)00620-7 pmid: 37068504
[59]	SHAH M A, SHITARA K, AJANI J A, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial[J]. Nat Med, 2023, 29(8): 2133-2141. doi: 10.1038/s41591-023-02465-7 pmid: 37524953
[60]	SAHIN U, TÜRECI Ö, MANIKHAS G, et al. FAST: a randomised phase Ⅱ study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma[J]. Ann Oncol, 2021, 32(5): 609-619.
[61]	NAKAYAMA I, QI C S, CHEN Y, et al. Claudin 18.2 as a novel therapeutic target[J]. Nat Rev Clin Oncol, 2024, 21(5): 354-369. doi: 10.1038/s41571-024-00874-2 pmid: 38503878
[62]	QU J L, HE X, LUO Y, et al. Evaluation of second-line apatinib plus irinotecan as a treatment for advanced gastric adenocarcinoma or gastroesophageal conjunction adenocarcinoma: a prospective, multicenter phase Ⅱ trial[J]. Front Oncol, 2023, 13: 1072943.
[63]	JING C, WANG J Y, ZHU M Y, et al. Camrelizumab combined with apatinib and S-1 as second-line treatment for patients with advanced gastric or gastroesophageal junction adenocarcinoma: a phase 2, single-arm, prospective study[J]. Cancer Immunol Immunother, 2022, 71(11): 2597-2608. doi: 10.1007/s00262-022-03174-9 pmid: 35304622
[64]	LI S, YU W B, XIE F, et al. Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer[J]. Nat Commun, 2023, 14(1): 8.
[65]	FUKUOKA S, HARA H, TAKAHASHI N, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase ib trial (REGONIVO, EPOC1603)[J]. J Clin Oncol, 2020, 38(18): 2053-2061. doi: 10.1200/JCO.19.03296 pmid: 32343640
[66]	XU R H, WANG F, SHEN L, et al. Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): a randomized, multicenter, double-blind, placebo-controlled, phase 3 study[J]. J Clin Oncol, 2024, 42(36_suppl): 438780.
[67]	WAINBERG Z A, ENZINGER P C, KANG Y K, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study[J]. Lancet Oncol, 2022, 23(11): 1430-1440. doi: 10.1016/S1470-2045(22)00603-9 pmid: 36244398
[68]	TURKES F S, CRUX R, TRAN A, et al. 1253P Safety and efficacy of Wnt inhibition with a DKK1 inhibitor, DKN-01, in combination with atezolizumab in patients with advanced oesophagogastric adenocarcinoma: phase Ⅱa results of the WAKING trial[J]. Ann Oncol, 2022, 33: S1120-S1121.
[69]	WAINBERG Z A, VAN CUTSEM E, MOEHLER M H, et al. Trial in progress: Phase 1b/3 study of bemarituzumab+mFOLFOX6+nivolumab versus mFOLFOX6+nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102)[J]. J Clin Oncol, 2022, 40(16_suppl): TPS4165.
[70]	OHTSU A, AJANI J A, BAI Y X, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase Ⅲ GRANITE-1 study[J]. J Clin Oncol, 2013, 31(31): 3935-3943.
[71]	KLEMPNER S J, SONBOL B B, WAINBERG Z A, et al. A phase 2 study (DisTinGuish) of DKN-01 in combination with tislelizumab+chemotherapy as first-line (1L) therapy in patients with advanced gastric or GEJ adenocarcinoma (GEA)[J]. J Clin Oncol, 2023, 41(16_suppl): 4027.
[72]	VAN HERPE F, VAN CUTSEM E. The role of cMET in gastric cancer-a review of the literature[J]. Cancers (Basel), 2023, 15(7): 1976.
[73]	SHAH M A, BANG Y J, LORDICK F, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial[J]. JAMA Oncol, 2017, 3(5): 620-627. doi: 10.1001/jamaoncol.2016.5580 pmid: 27918764
[74]	YU P F, DU Y A, XU Z Y, et al. Adjuvant nab-paclitaxel plus S-1 versus capecitabine plus oxaliplatin for patients with stage Ⅲ gastric adenocarcinoma after D2 dissection: a multicenter, open-label, randomized phase 3 study[J]. J Clin Oncol, 2023, 41(16_suppl): 4054.
[75]	MORGAN E, ARNOLD M, CONSTANZA CAMARGO M, et al. The current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: a population-based modelling study[J]. EClinicalMedicine, 2022, 47: 101404.

Target	Clinical trial	Clinical phase	Intervention	Treatment setting	Incidence of ILD/pneumonia all grade	Incidence of ILD/pneumonia grade 3+
PD-1	KEYNOTE-062^[8]	Ⅲ	Pembrolizumab+Cis+Fu/Cap	1L	0.78%	NA
	KEYNOTE-063^[9]	Ⅲ	Pembrolizumab	2L	2.10%	NA
	NCT02742935^[10]	Ⅰ	Camrelizumab	2L+	3.30%	3.30%
	ATTRACTION-4^[11]	Ⅱ/Ⅲ	Nivolumab+SOX/CAPOX	1L	4.20%	1.90%
	CheckMate-649^[12]	Ⅲ	Nivolumab+FOLFOX/CAPOX	1L	<1.00%	<1.00%
	PERSIST^[13]	Ⅱ	Sintilimab+SOX	perioperative	1.00%	1.00%
	NCT04061928^[14]	Ⅱ	Toripalimab+chemoradiotherapy	neoadjuvant	35.00%	NA
PD-L1	JAVELIN Gastric 100^[16]	Ⅲ	Avelumab	1L	2.50%	0.80%
PD-L1+CTLA-4	INFINITY^[20]	Ⅱ	Tremelimumab+durvalumab	neoadjuvant	5.60%	5.60%

Target	Clinical trial	Clinical phase	Intervention	Treatment setting	Incidence of ILD/pneumonia all grade	Incidence of ILD/pneumonia grade 3+
HER2 monoclonal antibody	KEYNOTE-811^[26]	Ⅲ	Trastuzumab+pembrolizumab+ FP/CAPOX	1L	5.10%	1.40%
	MAHOGANY^[27]	Ⅱ/Ⅲ	Margetuximab+retifanlimab	1L	4.70%	0.00%
	NEOHX^[28]	Ⅱ	Trastuzumab+capecitabine/oxaliplatin	Perioperative	6.00%	6.00%
HER2 ADC	DESTINY-Gastric01^[38]	Ⅱ	T-DXd	3L	9.60%	2.40%
	DESTINY-Gastric02^[39]	Ⅱ	T-DXd	2L	10.10%	3.50%
	DESTINY-Gastric03^[40]	Ⅱ	T-DXd (6.4 mg/kg)+5-fluorouracil/Cap+pembrolizumab	1L	19.00%	7.00%
	DESTINY-Gastric06^[46]	Ⅱ	T-DXd	3L	3.20%	0.00%
	GATSBY^[49]	Ⅱ/Ⅲ	T-DM1	2L	7.10%	4.00%
	CTR20190639^[50]	Ⅰ	ARX788	2L	20.00%	3.30%
HER2 TKI	TyTAN^[53]	Ⅲ	Lapatinib+paclitaxel	2L	2.29%	0.76%

Target	Clinical trial	Clinical phase	Intervention	Treatment setting	Incidence of ILD/pneumonia all grade	Incidence of ILD/pneumonia grade 3+
CLDN18.2	SPOTLIGHT^[58]	Ⅲ	Zolbetuximab+mFOLFOX6	1L	2.15%	NA
	GLOW^[59]	Ⅲ	Zolbetuximab+CAPOX	1L	2.36%	NA
	FAST^[60]	Ⅱ	Zolbetuximab+EOX	2L	2.60%	NA
Antiangiogenic drugs	NCT03878472^[64]	Ⅱ	Apatinib+camrelizumab+ S-1±oxaliplatin	neoadjuvant	4.00%	NA
	REGONIVO^[65]	Ⅰb	Regorafenib (160 mg)+ nivolumab	3L+	33.00%	33.00%
FGFR2	FIGHT^[67]	Ⅱ	Bemarituzumab+mFOLFOX6	1L	1.30%	1.30%
mTOR	GRANITE-1^[70]	Ⅲ	Everolimus	2L+	3.00%	0.70%
DKK1	WAKING^[68]	Ⅱa/b	DKN01+atezolizumab	2/3L	8.30%	0.00%