Antibody-Drug Conjugate (ADC) Clinical Trials — 2026 Pipeline Tracker

Q: What is an antibody-drug conjugate (ADC)?

An antibody-drug conjugate (ADC) is a targeted cancer therapy that combines three components: a monoclonal antibody that binds to a specific tumor antigen, a cytotoxic payload (usually a chemotherapy agent), and a chemical linker that connects them. The antibody delivers the payload directly to tumor cells expressing the target antigen, releasing the cytotoxin upon internalization. This targeted delivery concentrates the drug at the tumor while sparing normal tissue — in theory achieving the efficacy of chemotherapy with greater selectivity. Modern ADCs are defined by their linker-payload chemistry: cleavable linkers allow payload release in the tumor microenvironment even for cells that don't internalize the ADC (bystander effect), while stable linkers limit cytotoxicity to antigen-positive cells only.

Q: What are the most important ADCs in clinical trials in 2026?

The most clinically important ADCs in active 2026 trials include: Enhertu (trastuzumab deruxtecan, T-DXd) — HER2-targeting, developed by Daiichi Sankyo/AstraZeneca, approved in breast, gastric, and NSCLC; Dato-DXd (datopotamab deruxtecan) — TROP2-targeting, pivotal Phase 3 trials in breast cancer and NSCLC; Trodelvy (sacituzumab govitecan) — TROP2-targeting by Gilead, approved in TNBC and urothelial cancer; Padcev (enfortumab vedotin) — Nectin-4 targeting by Pfizer/Seagen, approved in urothelial cancer; Polivy (polatuzumab vedotin) — CD79b targeting by Roche, approved in DLBCL; patritumab deruxtecan — HER3-targeting by Daiichi Sankyo, NSCLC; ifinatamab deruxtecan (I-DXd) — B7-H3 targeting, small cell lung cancer.

Q: How does the DXd payload differ from other ADC payloads?

DXd (deruxtecan) is a topoisomerase I inhibitor payload developed by Daiichi Sankyo that has become the dominant ADC payload in the industry. Key advantages: very high drug-to-antibody ratio (DAR ~8, higher than many competitors), membrane-permeable payload enabling strong bystander effect (killing neighboring antigen-negative cells), and cleavable linker that releases payload in the tumor microenvironment. Compared to MMAE (used in vedotin ADCs like Padcev, Polivy, Brentuximab) and DM1 (emtansine, used in Kadcyla), DXd produces deeper responses at lower antigen expression thresholds — validated by Enhertu's landmark activity in HER2-low breast cancer, a population that would not benefit from trastuzumab-based therapies.

Q: What is HER2-low breast cancer and why does it matter for ADCs?

HER2-low breast cancer is defined as IHC 1+ or IHC 2+/ISH-negative HER2 expression — a level previously considered insufficient for HER2-targeted therapy. The DESTINY-Breast04 trial demonstrated that Enhertu (trastuzumab deruxtecan) produced a 49% reduction in progression risk versus chemotherapy in HER2-low metastatic breast cancer patients, transforming this patient population from 'HER2-negative' to 'HER2-targetable.' This expanded the HER2-treatable breast cancer population by an estimated 60% — turning what was a niche category into one of the largest breast cancer subgroups. DESTINY-Breast06 further extended this by showing activity in HER2-ultralow (IHC 0 with incomplete staining) disease, potentially expanding the targetable population even further.

108+

Active industry ADC trials (2026)

20+

Phase 3 pivotal ADC studies

15+

Approved ADCs worldwide

DXd-platform ADCs in late-stage trials

Phase 3 ADC Trials — Active 2026

The following pivotal trials represent the registration-intent programs that will define ADC standard of care across breast cancer, NSCLC, hematology, and urothelial cancer through 2028.

NCT ID	ADC / Regimen	Sponsor	Indication	Phase
NCT04784715	Enhertu (T-DXd) ± pertuzumab vs taxane + trastuzumab	AstraZeneca	HER2+ metastatic breast cancer (1L)	Phase 3
NCT05113251	Enhertu (T-DXd) vs standard treatment (DESTINY-Breast09)	AstraZeneca	HER2+ early breast cancer (adjuvant)	Phase 3
NCT04494425	Enhertu (T-DXd) vs chemotherapy (DESTINY-Breast06)	AstraZeneca	HER2-low / HER2-ultralow metastatic breast cancer	Phase 3
NCT05629585	Dato-DXd ± durvalumab vs chemotherapy	AstraZeneca	HR+/HER2- metastatic breast cancer (TROPION-Breast02)	Phase 3
NCT05104866	Dato-DXd vs docetaxel (TROPION-Lung08)	AstraZeneca	Non-squamous NSCLC 2L+	Phase 3
NCT05687266	Dato-DXd + durvalumab vs chemo + pembrolizumab (1L NSCLC)	AstraZeneca	NSCLC 1st line (TROPION-Lung08)	Phase 3
NCT05555732	Dato-DXd + pembrolizumab ± chemo	Daiichi Sankyo	NSCLC 1st line (TROPION-Lung04)	Phase 3
NCT04704934	Enhertu (T-DXd) vs ramucirumab + paclitaxel	Daiichi Sankyo	HER2+ gastric/GEJ cancer 2L+ (DESTINY-Gastric04)	Phase 3
NCT06486441	Trodelvy (sacituzumab govitecan) vs physician's choice	Gilead Sciences	HR+/HER2- metastatic breast cancer (TROPiCS-02 Asia)	Phase 3
NCT05911295	Disitamab vedotin + pembrolizumab vs chemotherapy	Pfizer / Seagen	Urothelial cancer 1L (EV-302 extension)	Phase 3
NCT05374512	Dato-DXd vs investigator's choice chemotherapy	AstraZeneca	Triple-negative breast cancer (TROPION-Breast01)	Phase 3
NCT04873362	Adjuvant atezolizumab ± bevacizumab + Kadcyla	Roche	HER2+ early breast cancer (adjuvant)	Phase 3
NCT03274492	Polivy (polatuzumab vedotin) + R-CHOP vs R-CHOP	Roche	Previously untreated DLBCL	Phase 3

Source: ClinicalTrials.gov, Q1 2026. For a live, continuously updated list, set up a DataLookout alert.

How ADCs Work: The Guided Missile Model

Antibody-drug conjugates combine three engineering components into a single therapeutic molecule. The antibody is selected for high-affinity, selective binding to a tumor-associated antigen — a protein expressed at higher levels on cancer cells than on normal tissue. The payload is typically an extremely potent cytotoxic agent: topoisomerase inhibitors (irinotecan derivatives like DXd, SN-38), microtubule disruptors (maytansines like DM1, DM4; auristatins like MMAE, MMAF), or DNA alkylators (PBDs, calicheamicin). The linker holds the two together in circulation and releases the payload under specific tumor-microenvironment conditions — low pH in lysosomes (cleavable linkers) or intracellular enzymes (lysosomal proteases).

The key parameters that determine ADC activity are: antigen expression and internalization rate (the antibody must engage and be taken up by tumor cells); drug-to-antibody ratio (DAR) (more payload per antibody typically means greater potency but worse tolerability); linker stability (too unstable = premature payload release in circulation, toxicity; too stable = no payload release in tumor); and bystander effect (membrane-permeable payloads can diffuse from killed antigen-positive cells into neighboring antigen-negative tumor cells — critical for heterogeneous tumors with variable antigen expression).

DXd (Daiichi Sankyo's deruxtecan payload) achieves best-in-class bystander effect through its membrane permeability, enabling activity in HER2-low and even HER2-ultralow breast cancer populations — a paradigm shift validated by the DESTINY-Breast04 and DESTINY-Breast06 trials. This bystander mechanism has redefined minimum antigen thresholds for ADC utility and triggered a wave of competitive TROP2- and HER3-targeting programs attempting to replicate this low-antigen-expression activity.

ADC Targets: The Competitive Landscape

HER2 (ERBB2)

Enhertu (T-DXd) · Kadcyla (T-DM1) · Disitamab vedotin (RC48) · ZW49 · ARX788

TROP2 (TACSTD2)

Dato-DXd · Trodelvy (sacituzumab govitecan) · SKB264 · MK-2870

HER3 (ERBB3)

Patritumab deruxtecan (HER3-DXd) · HLX22

Nectin-4

Padcev (enfortumab vedotin) · Disitamab vedotin (dual HER2/Nectin-4)

CD79b

Polivy (polatuzumab vedotin) · loncastuximab tesirine

B7-H3 (CD276)

Ifinatamab deruxtecan (I-DXd) · Vobramitamab duocarmazine · DS-7300

CEACAM5 (CEA)

Tusamitamab ravtansine · BI 907828 combination

CDH6 (Cadherin-6)

Raludotatug deruxtecan (R-DXd) · DS-6000

FRα (Folate Receptor α)

Elahere (mirvetuximab soravtansine) · STRO-002

CD33

Mylotarg (gemtuzumab ozogamicin) · pivekimab sunirine

BCMA

Blenrep (belantamab mafodotin) — re-evaluation in combination trials

CD30

Adcetris (brentuximab vedotin) — Hodgkin lymphoma, ALCL

The DXd Platform: Daiichi Sankyo's ADC Engine

Daiichi Sankyo's DXd payload platform has become the most clinically validated ADC technology in oncology. The five primary DXd ADCs in late-stage development represent a systematic attack on the major oncology targets:

Enhertu (trastuzumab deruxtecan, T-DXd): HER2-targeting. FDA-approved in HER2+ metastatic breast cancer (all lines), HER2-low metastatic breast cancer (DESTINY-Breast04), HER2+ gastric/GEJ cancer, and HER2-mutant NSCLC. Expanding into adjuvant breast cancer (DESTINY-Breast05/09) and other HER2-expressing solid tumors.
Dato-DXd (datopotamab deruxtecan): TROP2-targeting. Phase 3 trials in 1L and 2L NSCLC (TROPION-Lung series), HR+/HER2- metastatic breast cancer (TROPION-Breast02), and TNBC (TROPION-Breast01). Direct competitor to Trodelvy in TROP2 space.
Patritumab deruxtecan (HER3-DXd): HER3-targeting. Phase 2 HERTHENA-Lung01 trial showed 29.8% ORR in heavily pre-treated NSCLC including post-EGFR inhibitor settings. Phase 3 HERTHENA-Lung02 randomized trial underway.
Ifinatamab deruxtecan (I-DXd): B7-H3-targeting. Phase 2 IDeate-Lung01 trial in extensive-stage SCLC (NCT05280470). B7-H3 is broadly expressed in SCLC and other difficult-to-treat solid tumors — this program represents a potential breakthrough for a disease with very limited targeted therapy options.
Raludotatug deruxtecan (R-DXd): CDH6-targeting. Phase 1/2 data in ovarian cancer and renal cell carcinoma, with Phase 3 planning underway. CDH6 is expressed in multiple solid tumors where HER2 and TROP2 have limited expression.

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Trodelvy (Sacituzumab Govitecan): Gilead's TROP2 Play

Trodelvy (sacituzumab govitecan), developed by Immunomedics and acquired by Gilead in 2020, is the first approved TROP2-targeting ADC. It uses an anti-TROP2 antibody conjugated to SN-38 (the active metabolite of irinotecan) via a cleavable linker with a DAR of approximately 7.6. FDA approvals span triple-negative breast cancer (2L+), HR+/HER2- metastatic breast cancer (2L+, ASCENT and TROPiCS-02 trials), and urothelial cancer (2L+).

Trodelvy faces direct competition from Dato-DXd (AstraZeneca/Daiichi Sankyo) in both TNBC and HR+/HER2- breast cancer — arguably the highest-stakes ADC rivalry in the industry. The key competitive differentiator is the payload: SN-38 (Trodelvy) vs DXd (Dato-DXd). Dato-DXd's Phase 3 TROPION-Breast01 trial in TNBC failed its primary PFS endpoint versus chemotherapy, a setback for the DXd platform in this specific setting. Trodelvy's ASCENT demonstrated a significant PFS and OS benefit in TNBC, reinforcing its position. However, in HR+ breast cancer, TROPION-Breast02 continues enrolling with positive momentum from Phase 2 signals. The outcome of these competing Phase 3 trials will determine market share in the largest ADC breast cancer setting.

Enhertu and the HER2-Low Revolution

The DESTINY-Breast04 trial (N Engl J Med 2022) delivered one of the most significant results in breast cancer oncology in a decade: Enhertu (trastuzumab deruxtecan) reduced risk of progression or death by 49% versus chemotherapy in patients with HER2-low (IHC 1+ or IHC 2+/ISH-) metastatic breast cancer. The median PFS was 9.9 months vs 5.1 months; overall survival favored T-DXd (23.4 vs 16.8 months).

The clinical impact: approximately 60% of all metastatic breast cancer patients previously classified as HER2-negative are now eligible for Enhertu. This single trial transformed HER2 from a binary (positive/negative) classification to a continuous spectrum — HER2-high (IHC 3+ / ISH+), HER2-low (IHC 1+, IHC 2+/ISH-), and HER2-ultralow (IHC 0 with incomplete staining). DESTINY-Breast06 subsequently showed activity in HER2-ultralow disease, further extending the targetable population.

For competitive intelligence professionals, the implication is significant: any company with a breast cancer pipeline must now account for Enhertu as the effective standard of care in a much larger patient population than previously. See our breast cancer clinical trials tracker for the full competitive landscape. For TROP2 competitive intelligence, see the TNBC clinical trials tracker.

ADC Safety: The Interstitial Lung Disease Signal

The most important class-level safety issue for DXd ADCs is drug-related interstitial lung disease (ILD) and pneumonitis. Enhertu carries a boxed warning for ILD in its prescribing information — rates of any-grade ILD in breast cancer trials have ranged from 10–15%, with Grade 3+ events in 1–3%. The mechanism is not fully elucidated but may relate to DXd payload release in lung tissue and/or macrophage-driven inflammatory response.

ILD is an active area of monitoring in Dato-DXd, HER3-DXd, and I-DXd trials as well. The FDA and investigators require protocol-specified ILD monitoring procedures, dose delays/reductions, and steroid-based management algorithms for all DXd ADC studies. Non-DXd ADCs (vedotin-based: MMAE/MMAF) have different toxicity profiles centered on peripheral neuropathy and neutropenia rather than ILD.

Related Clinical Trial Trackers

Breast Cancer Clinical Trials — Full Pipeline Tracker — all breast cancer trials including HER2+, HER2-low, TNBC, and HR+/HER2- programs
Triple-Negative Breast Cancer (TNBC) Clinical Trials — TROP2 ADCs, immune checkpoint, BRCA-targeted, and antibody combinations
NSCLC Clinical Trials Tracker — HER2-mutant NSCLC, HER3-DXd, Dato-DXd programs alongside EGFR/ALK/KRAS programs
Daiichi Sankyo Pipeline Monitor — all DXd ADC programs from Enhertu to R-DXd
AstraZeneca Pipeline Monitor — Enhertu and Dato-DXd co-development trials
Gilead Sciences Pipeline Monitor — Trodelvy and Yescarta/Tecartus programs

Frequently Asked Questions

What is an antibody-drug conjugate (ADC)?

An ADC is a targeted cancer therapy combining a monoclonal antibody, a cytotoxic payload, and a chemical linker. The antibody delivers the payload directly to tumor cells expressing the target antigen — concentrating the cytotoxin where it's needed while sparing normal tissue. ADCs have been described as "targeted chemotherapy" but the analogy is imprecise: modern ADCs like Enhertu achieve tumor cell killing at antigen expression levels far below those required for conventional HER2-targeted antibodies, and the bystander effect means they can kill neighboring antigen-negative tumor cells as well. The result is a much broader therapeutic window and activity in patient populations previously considered HER2-negative.

What are the most important ADCs in clinical trials in 2026?

The most clinically consequential ADC programs in 2026 active trials are: (1) Enhertu (trastuzumab deruxtecan, AstraZeneca/Daiichi Sankyo) — the gold standard HER2-targeting ADC, with multiple Phase 3 trials expanding into adjuvant and earlier-line settings; (2) Dato-DXd (datopotamab deruxtecan, AstraZeneca/Daiichi Sankyo) — TROP2-targeting, Phase 3 trials in breast cancer and NSCLC competing with Trodelvy; (3) Trodelvy (sacituzumab govitecan, Gilead) — TROP2-targeting, approved and generating Phase 3 data in Asian populations and new indications; (4) Padcev (enfortumab vedotin, Pfizer/Seagen) — Nectin-4 targeting, approved in urothelial cancer with expanding combination trials; (5) Patritumab deruxtecan (HER3-DXd, Daiichi Sankyo) — HER3-targeting in NSCLC with Phase 3 underway; (6) Ifinatamab deruxtecan (I-DXd) — B7-H3-targeting in SCLC.

How does the DXd payload differ from other ADC payloads?

DXd (exatecan derivative) is a topoisomerase I inhibitor with three distinguishing features: (1) very high drug-to-antibody ratio (~8), meaning more drug per antibody than most competitors; (2) membrane permeability enabling a strong bystander effect — DXd released inside one tumor cell can cross into neighboring cells, killing antigen-negative cells in a heterogeneous tumor; (3) cleavable linker that releases payload in lysosomes after ADC internalization. Compared to MMAE-based vedotin ADCs (Padcev, Polivy, Brentuximab), DXd produces activity at lower antigen expression levels. Compared to DM1/DM4-based emtansine ADCs (Kadcyla), DXd achieves higher potency and better bystander effect. The bystander mechanism is the primary reason Enhertu works in HER2-low and HER2-ultralow breast cancer — a paradigm shift that Kadcyla (which requires HER2 3+ or ISH+) cannot achieve.

What is HER2-low breast cancer and why does it matter for ADCs?

HER2-low is defined as IHC 1+ or IHC 2+/ISH-negative — a level previously considered insufficient for HER2-targeted therapy. DESTINY-Breast04 demonstrated Enhertu's activity in this population (49% PFS reduction vs chemotherapy), expanding the HER2-treatable breast cancer population by ~60%. This redefinition has cascading competitive implications: oncologists now assess HER2 expression on a continuous scale, patients previously excluded from HER2-targeted therapy are now eligible, and competitors must account for Enhertu in a much larger patient population. DESTINY-Breast06 further extended this into HER2-ultralow disease. For ADC competitive intelligence, this means the addressable market for HER2-targeting ADCs is dramatically larger than previously modeled.

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