The simplest description of an antibody-drug conjugate is a precision delivery vehicle: an antibody that homes to a tumor antigen, carrying a cytotoxic payload attached by a linker. The conceptually elegant design, which went through decades of failures to get the chemistry right, has now produced 13 FDA-approved products and become the most active area of oncology drug development outside immunotherapy. The DESTINY-Breast04 data published in NEJM in 2022 didn't just validate an ADC โ it redefined how breast cancer is classified, splitting HER2-low (IHC 1+ or 2+/ISH-) into a separate treatable population that had previously had no targeted options. That's what a successful ADC does: it creates a new category of treatable patient.
This article is for informational purposes only and does not constitute medical advice. ADC therapy eligibility depends on tumor biomarker status, prior treatment history, and organ function. Consult your oncologist for guidance specific to your diagnosis.
Summary
FDA has approved 13 ADCs across breast, bladder, lung, cervical, endometrial, gastric, and hematologic cancers. DESTINY-Breast04 established T-DXd for HER2-low breast cancer (PFS 9.9 vs 5.1 months, HR 0.50). EV-302 established enfortumab vedotin + pembrolizumab as 1st-line urothelial cancer standard of care (PFS HR 0.45, OS HR 0.47). The bystander effect โ where released payload kills adjacent antigen-negative cells โ explains some efficacy in heterogeneous tumors. The 2026 pipeline focuses on novel targets (TROP2, FRฮฑ, NaPi2b, ROR1), combination with checkpoint inhibitors, and reducing key toxicities (ILD for T-DXd, peripheral neuropathy for enfortumab). Over 900 ADC trials are currently registered globally.
ClinicalMetric Analysis
- The HER2-low designation from DESTINY-Breast04 is clinically significant but analytically messy. IHC 1+ and IHC 2+/ISH- are defined by pathology scoring that carries meaningful inter-rater variability. Studies have shown concordance rates between central and local labs for HER2-low scoring of approximately 70โ80%. This means that some patients labeled HER2-low at local testing would be reclassified at central review โ and vice versa. When ordering T-DXd based on a HER2-low diagnosis, the quality of the HER2 testing matters more than in HER2-amplified disease, where the signal is larger and the classification is more robust. This testing quality issue is underappreciated in clinical practice.
- The interstitial lung disease signal with T-DXd requires ongoing vigilance even as it is manageable in most cases. Grade 1โ2 ILD occurred in approximately 10โ15% of patients in the DESTINY trials. Most cases respond to corticosteroids and treatment interruption. But grade 3+ ILD, though infrequent (1โ2%), is potentially fatal and has driven several trial withdrawals. The ILD risk is not fully predicted by baseline lung function, prior radiation, or other conventional risk factors. Clinicians using T-DXd should have a low threshold for imaging when respiratory symptoms emerge, even mild ones.
- The bystander effect is a feature, not just a property โ and it has implications for which tumors ADCs can treat. Cleavable linkers release payload inside the cell, but also allow membrane-permeable payload to diffuse into neighboring cells. This enables ADCs to kill antigen-negative tumor cells in the vicinity โ critical for solid tumors with antigen heterogeneity. T-DXd's deruxtecan payload is membrane-permeable; its bystander effect is one reason it works in tumors with low or heterogeneous HER2 expression. ADCs with non-cleavable linkers have no bystander effect and are better suited to homogeneous target expression. Understanding which linker/payload combination a given ADC uses matters for predicting which tumors it will work against.
The Three ADCs Defining the 2026 Standard
Trastuzumab deruxtecan (T-DXd, Enhertu, AstraZeneca/Daiichi Sankyo) is the most discussed ADC in clinical practice. It targets HER2 and carries a topoisomerase I inhibitor (deruxtecan) at a drug-antibody ratio of 8:1 โ higher than older ADCs, contributing to its potency. DESTINY-Breast04: 498 patients with HER2-low metastatic breast cancer, T-DXd vs physician's choice chemotherapy. Median PFS 9.9 vs 5.1 months (HR 0.50, 95% CI 0.40โ0.63, p<0.001). Median OS 23.4 vs 16.8 months (HR 0.64). T-DXd also has approvals in HER2+ gastric cancer (DESTINY-Gastric01), HER2-mutant NSCLC (DESTINY-Lung02: ORR 49.0%), and HER2-ultralow breast cancer. DESTINY-Breast06 extended the benefit to HER2-ultralow (IHC >0 but <1+).
Sacituzumab govitecan (Trodelvy, Gilead) targets TROP2, expressed broadly in epithelial cancers. In triple-negative breast cancer (ASCENT trial), it achieved PFS 4.8 vs 1.7 months and OS 12.1 vs 6.7 months vs single-agent chemo. Approved for TNBC, HR+ HER2-negative mBC after endocrine therapy and โฅ2 lines of chemo, and urothelial carcinoma. Key toxicity: grade 3+ neutropenia (~50%) and diarrhea (~10%). Now moving into earlier lines and combinations.
Enfortumab vedotin (Padcev, Seagen/Pfizer) targets Nectin-4, expressed in 97% of urothelial carcinomas. EV-302/KEYNOTE-A39: enfortumab vedotin + pembrolizumab as 1st-line urothelial cancer vs platinum-based chemo. PFS HR 0.45 (median 12.5 vs 6.3 months), OS HR 0.47 (median 31.5 vs 16.1 months). These are among the largest improvements in overall survival ever demonstrated in urothelial cancer. Peripheral neuropathy (~50% any grade, ~4% grade 3+) is the key management challenge; dose modifications are common.
The ADC Target Landscape: What's Being Pursued
Beyond HER2, TROP2, and Nectin-4, the 2026 pipeline spans: FRฮฑ (folate receptor alpha) โ expressed in ovarian and endometrial cancers; mirvetuximab soravtansine (Elahere) is FDA-approved for FRฮฑ-high platinum-resistant ovarian cancer, with OS HR 0.67 in MIRASOL. NaPi2b โ upifitamab rilsedotin in platinum-resistant ovarian and NSCLC. ROR1 โ expressed on multiple solid tumors and some leukemias; VLS-101 and NBF-006 in Phase 1/2. Mesothelin โ expressed in mesothelioma, ovarian, and pancreatic cancers; anetumab ravtansine and ZL-1211 in Phase 2. B7-H3 โ ifinatamab deruxtecan Phase 1/2 in SCLC and solid tumors; early data showing ORR 35โ40% in SCLC second-line.
Target competition has become a real issue: multiple companies are pursuing TROP2 ADCs with different linkers and payloads, and distinguishing their clinical profiles from Trodelvy will require head-to-head comparisons that sponsors are not incentivized to conduct.
Combinations and Moving into Earlier Lines
The field's focus has shifted from single-agent efficacy in late-line settings toward combinations (particularly with checkpoint inhibitors) and earlier line deployment. The rationale is clear: if an ADC's mechanism involves releasing immunogenic cell death signals (which many topoisomerase I inhibitor payloads do), combination with PD-1/PD-L1 inhibitors should amplify the immune response. DESTINY-Breast09 (T-DXd + pertuzumab vs docetaxel + HP as 1st line HER2+ mBC) and BEGONIA (sacituzumab govitecan + durvalumab in TNBC 1st line) are two trials testing this logic. Early BEGONIA data showed 44% ORR โ a promising signal in a population where durvalumab alone achieves ~10%.
Eligibility for ADC Trials
Most ADC trials require confirmed tumor expression of the target antigen โ requiring fresh or archival biopsy with IHC or ISH testing. The specific expression threshold (e.g., HER2-low definition for T-DXd) varies by trial and should be verified against the specific protocol. Standard exclusions include prior allergy to the specific antibody component, active interstitial lung disease (for T-DXd trials), active neuropathy grade โฅ2 (for enfortumab vedotin trials), and standard organ function requirements. Prior exposure to the same ADC or same-target ADC may be excluded depending on the trial. Biomarker testing at qualified labs using companion diagnostics is typically required before enrollment rather than at the time of screening.