The clinical stakes are enormous. Digestive system cancers are among the most common malignancies in China and worldwide, and HER2-positive subtypes account for a meaningful share of them: roughly 12 to 13 percent of gastric cancers test positive for HER2, along with about 7 percent of colorectal cancers and between 5 and 20 percent of biliary tract cancers. Two HER2-targeted ADCs, trastuzumab deruxtecan and disitamab vedotin, have already been approved by China’s National Medical Products Administration for later-line treatment of advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, while trastuzumab deruxtecan has gained approvals in more than 65 countries since its first United States authorization in December 2019. As these drugs move into routine practice across primary and secondary care settings, the experts argue, standardized safety management becomes as important as the drugs’ celebrated efficacy.

At the heart of the consensus is a clear-eyed explanation of why ADCs cause harm at all. These drugs couple a HER2-directed monoclonal antibody to a cytotoxic payload through a chemical linker, and toxicity arises from both on-target and off-target mechanisms. On-target toxicity occurs when normal cells that also express HER2 internalize the conjugate and release the payload, an unavoidable consequence of imperfect antigen specificity. Off-target toxicity follows at least four distinct routes: Fc receptor-mediated nonspecific binding by immune cells; macropinocytosis-driven uptake driven by the drug’s surface charge or hydrophobic properties; premature payload release when linkers hydrolyze in the bloodstream or are cleaved by extracellular proteases; and the so-called bystander effect, in which released payloads diffuse out of tumor cells and are taken up by neighboring healthy tissue. Understanding these pathways, the authors contend, is the foundation for rational monitoring and intervention.

Hematologic toxicity dominates the safety profile. Neutropenia, driven by the direct suppressive effect of free payload on bone marrow myeloid progenitors and by Fc-mediated immune activation, occurs in 63 percent of gastric cancer patients treated with trastuzumab deruxtecan, with more than half of those cases reaching grade 3 or worse, and febrile neutropenia arising in 4.8 percent. With disitamab vedotin, neutrophil counts fall in 50.6 percent of patients. The consensus recommends primary prophylaxis with granulocyte colony-stimulating factor for high-risk patients—those over 65, with prior chemotherapy, bone marrow involvement, liver or renal impairment, or a history of febrile neutropenia—and advises patients to check their temperature, practice rigorous hand and oral hygiene, and avoid crowds. Thrombocytopenia, linked to off-target uptake of the drugs by megakaryocytes, affects 39 percent of gastric cancer patients on trastuzumab deruxtecan and prompts strong recommendations for thrombopoietic agents when platelets fall below 50 × 10⁹ per liter, along with practical precautions such as soft toothbrushes and electric razors.

Anemia is equally pervasive, reaching incidences of 58 percent with trastuzumab deruxtecan, 49.6 percent with disitamab vedotin, and as high as 68.8 percent in biliary tract cancer, where more than half of cases are grade 3. The consensus attributes this to direct damage of erythroid progenitors and nonspecific injury to the bone marrow microenvironment, and it calls for a multidisciplinary approach combining red cell transfusion, iron supplementation, erythropoiesis-stimulating therapy, and nutritional support. Notably, the experts emphasize patient education: monitoring hemoglobin, recognizing warning signs such as resting heart rates above 100 beats per minute and exertional breathlessness, eating heme iron–rich foods paired with vitamin C while avoiding coffee and tea with supplements, and restricting vigorous activity when hemoglobin drops below 80 grams per liter.

Gastrointestinal side effects receive equally granular attention. Nausea strikes 63 percent of gastric cancer patients on trastuzumab deruxtecan and vomiting 26 percent, driven by the topoisomerase I inhibitor payload damaging GI epithelium and triggering serotonin release from enterochromaffin cells. Real-world evidence proved dual antiemetic prophylaxis insufficient for some patients, prompting the NCCN to reclassify trastuzumab deruxtecan as highly emetogenic in January 2023, though ESMO retains the moderate label. The Chinese consensus recommends prophylactic antiemetics 30 minutes before infusion, continued for two to four days afterward, using dexamethasone plus a 5-HT3 receptor antagonist for standard-risk patients and adding an NK1 antagonist for high-risk ones, with olanzapine or mirtazapine reserved for refractory cases. Diarrhea, affecting 32 percent of gastric cancer patients on trastuzumab deruxtecan, is managed by a graded scheme: oral rehydration and loperamide for mild cases, hospitalization with fluid resuscitation and octreotide for severe or complicated presentations.

The most feared toxicity is interstitial lung disease, whose mechanisms include uptake by alveolar macrophages, bystander payload release, and possibly the amino-methylene spacer in the linker itself. Incidence ranges from 3.2 percent in Chinese gastric cancer patients in the DESTINY-Gastric06 trial to 20 percent with ARX788, with median onset around 84.5 days for trastuzumab deruxtecan. Because ILD is a diagnosis of exclusion, the consensus mandates ruling out infection, metastasis, and radiation pneumonitis, classifying subtypes on chest CT—organizing pneumonia is most common at 63.1 percent, while diffuse alveolar damage carries the gravest prognosis with roughly 42 percent mortality—and recommends high-resolution chest CT every 8 to 12 weeks, serum KL-6 monitoring, and pulse oximetry at each visit. Treatment is strictly graded: brief corticosteroids and a treatment pause for grade 1 disease, permanent drug discontinuation with at least 1 milligram per kilogram daily of prednisolone for grade 2 or higher, and immunosuppressants, antifibrotics, or biologics for refractory cases.

Liver injury, neurotoxicity, and ocular toxicity round out the organ-specific guidance. Hepatotoxicity, an on-target effect demonstrated in studies of trastuzumab emtansine binding HER2 on hepatocytes, manifests as AST and ALT elevations in up to 58 percent of patients, yet the consensus explicitly advises against routine prophylactic hepatoprotective drugs, reserving close monitoring for high-risk patients such as those with viral hepatitis, who should receive antiviral therapy before starting an ADC. Peripheral neuropathy, driven by free monomethyl auristatin E disrupting the neuronal microtubule network, affects nearly a third of patients on disitamab vedotin and is managed with B vitamins, neuroprotective agents, and gabapentinoids. Ocular toxicity is essentially confined to ARX788, which caused dry eye in 63.3 percent of treated patients, prompting recommendations for baseline eye screening and prompt ophthalmology referral. The document also flags the uncertain but potentially synergistic pulmonary risk when ADCs are combined with immune checkpoint inhibitors.

Dosing philosophy and team structure complete the framework. The consensus endorses 6.4 milligrams per kilogram every three weeks as the standard starting dose of trastuzumab deruxtecan in HER2-positive gastric cancer, based on superior efficacy over 5.4 milligrams per kilogram in phase I expansion and confirmation in DESTINY-Gastric01 and 06, with stepwise reductions to 5.4 and then 4.4 milligrams per kilogram and no re-escalation once reduced; disitamab vedotin starts at 2.5 milligrams per kilogram every two weeks, reducible to 2.0 or 1.5. Complex or severe adverse events should be routed through a structured multidisciplinary team led by an oncologist and including pulmonology, hepatology, ophthalmology, neurology, radiology, and clinical pharmacy. Perhaps most distinctively, the guideline champions a physician-led, patient-engaged model of education, arguing that informed patients who recognize early symptoms of infection, bleeding, breathlessness, or numbness are the first line of defense—experience the authors believe will transfer directly to the next generation of ADCs targeting other oncogenic pathways.

Subject of Research: Safety management of adverse events from HER2-targeted antibody–drug conjugates in digestive system cancers

Article Title: Chinese expert consensus on the management of adverse events to HER2-targeted antibody–drug conjugates in digestive system cancers (2025 edition)

Article References: Yu, Y., Wu, J., Lv, M., Cui, Y., Dai, G., Deng, T., Gong, L., Li, J., Li, H., Lin, R., Liu, Y., Peng, Z., Rao, S., Wang, F., Wang, F., Wei, J., Wu, S., Xue, J., Yang, W., … Liu, T. (2026). Chinese expert consensus on the management of adverse events to HER2-targeted antibody–drug conjugates in digestive system cancers (2025 edition). Clinical Cancer Bulletin, 5(1), Article 1. https://doi.org/10.1007/s44272-025-00053-z

Image Credits: AI Generated

DOI: 10.1007/s44272-025-00053-z

Keywords: HER2, antibody-drug conjugates, trastuzumab deruxtecan, disitamab vedotin, gastric cancer, biliary tract cancer, interstitial lung disease, adverse event management, expert consensus, drug safety, oncology, multidisciplinary team