Esophageal cancer remains a highly lethal malignancy worldwide with poor outcomes after progression on standard first-line therapies. The current standard for many patients with advanced disease includes combination chemoimmunotherapy, but survival after progression is limited. The review positions antibody-drug conjugates (ADCs) as a transformative therapeutic class with potential to address the substantial unmet need in later lines of therapy for both esophageal adenocarcinoma and esophageal squamous cell carcinoma.
ADCs link a monoclonal antibody directed at a tumor-associated antigen to a potent cytotoxic payload. This design aims to concentrate cytotoxic activity within tumor cells while reducing systemic exposure and off-target toxicity. The review highlights that ADCs can exert direct tumor cell killing and, for some constructs, a bystander killing effect that may extend activity to tumors with heterogeneous or lower antigen expression.
The authors advocate integrating ADCs into the therapeutic algorithm for patients who progress after first-line chemoimmunotherapy. Selection of an appropriate ADC should be guided by tumor histology (adenocarcinoma versus squamous cell carcinoma) and validated predictive biomarkers for target expression. Distinct toxicity profiles of individual ADCs must be weighed when making treatment decisions.
For patients with HER2-positive gastroesophageal junction adenocarcinoma, the review endorses trastuzumab deruxtecan as the preferred ADC option. The endorsement is based on reported overall survival benefit and the agent’s robust bystander killing effect, which may also confer activity in HER2-low tumors. The review emphasizes that trastuzumab deruxtecan’s efficacy and unique mechanism justify its selection in this molecular subgroup, while also noting the importance of monitoring for known organ-specific toxicities associated with the agent (see toxicity section).
In tumors that are HER2-negative, the review identifies TROP2 (trophoblast cell-surface antigen 2) as a promising target because moderate-to-strong expression has been observed in nearly 80% of gastroesophageal adenocarcinomas. The ADC sacituzumab tirumotecan is described as being under phase III investigation in this setting. The authors highlight TROP2-directed ADCs as a rational strategy for later-line therapy in HER2-negative patients, pending phase III results and regulatory decisions.
For esophageal squamous cell carcinoma (ESCC), the review advocates for biomarker-guided ADC selection:
B7-H3: Overexpression in more than 90% of ESCC supports the development and use of B7-H3–targeted ADCs in this subtype.
Nectin-4: Enfortumab vedotin, which targets Nectin-4, is offered as a possible later-line alternative for Nectin-4–expressing tumors, although the review characterizes its activity as modest in this context.
Bispecific targeting EGFR and HER3: The bispecific ADC BL-B01D1, which targets both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), is reported to have shown compelling efficacy in immunotherapy-refractory ESCC. The authors describe BL-B01D1 as a potential breakthrough option for this difficult-to-treat subgroup.
These observations underscore that histology-specific antigen prevalence should inform ADC choice in ESCC, and that biomarker testing is essential for optimal selection.
The review notes CLDN18.2 (claudin-18.2) as another actionable target in gastroesophageal junction adenocarcinoma. Several ADCs directed at CLDN18.2—CMG901, IBI343, and tecotabart vedotin—are identified as promising later-line options. The authors recommend assessing CLDN18.2 expression where available to identify patients who might benefit from these investigational ADCs.
The authors emphasize that ADCs have distinctive toxicity profiles that must be carefully managed. A specific safety concern highlighted is interstitial lung disease (ILD) associated with trastuzumab deruxtecan; clinicians should be vigilant for pulmonary symptoms and apply appropriate monitoring and management strategies. Overall, the review stresses that validated predictive biomarkers should guide patient selection to maximize benefit and limit harm.
Beyond later-line use, the review strongly supports advancing ADCs into earlier lines of therapy and perioperative settings through rigorously designed clinical trials. The authors argue that moving ADCs earlier in the treatment course may improve long-term outcomes for patients with both adenocarcinoma and squamous cell carcinoma of the esophagus. They call for continued biomarker development, prospective validation of predictive assays, and evaluation of ADC combinations and sequencing with existing therapies.
Summary
Antibody-drug conjugates are presented as a clinically important and biologically distinct class of therapeutics for esophageal cancer after progression on first-line chemoimmunotherapy. The review recommends trastuzumab deruxtecan for HER2-positive gastroesophageal junction adenocarcinoma, highlights TROP2- and CLDN18.2-targeted ADCs for HER2-negative disease, and supports biomarker-driven ADC selection in esophageal squamous cell carcinoma (notably B7-H3, Nectin-4, and EGFR/HER3 bispecific strategies). Careful attention to toxicity, particularly ILD, and prospective trials to test ADCs earlier in disease course are emphasized as priorities.
Note: Specific trial identifiers, detailed efficacy metrics, and regulatory statuses beyond what is summarized in the source abstract were not reported in the source document and therefore are not provided here.