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

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.

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

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.

MK-2870 (Sacituzumab Tirumotecan): Merck's Challenge to Dato-DXd and Trodelvy

Merck has launched a broad Phase 3 rollout for sacituzumab tirumotecan (MK-2870), a next-generation TROP2-targeting ADC designed to compete directly against Gilead's Trodelvy (sacituzumab govitecan) and Daiichi Sankyo/AstraZeneca's Dato-DXd. As of Q1 2026, MK-2870 has at least 6 concurrent Phase 3 trials across NSCLC, endometrial cancer, TNBC, and gastroesophageal adenocarcinoma — a remarkably broad simultaneous rollout reflecting Merck's conviction in the TROP2 target and MK-2870's differentiation from its predecessors.

Key MK-2870 Phase 3 programs by indication:

• NSCLC (EGFR-mutated, post-TKI, MK-2870-009): Testing MK-2870 vs. platinum chemotherapy after EGFR TKI failure — targeting the same post-osimertinib population that Daiichi Sankyo's HER3-DXd (patritumab deruxtecan) is pursuing, potentially with different TROP2 antigen biology
• NSCLC (squamous, MK-2870-023): Pembrolizumab maintenance ± MK-2870 in squamous NSCLC — an immunotherapy + ADC maintenance strategy
• TNBC (MK-2870-011, MK-2870-012): Multiple lines of TNBC being tested, both as monotherapy and in combination with pembrolizumab — directly overlapping with Trodelvy's approval in 2L TNBC
• Endometrial cancer (MK-2870-005): Post-platinum/post-IO endometrial — the same setting where sacituzumab govitecan (ASCENT-GYN-01) is running a Phase 3 trial
• Gastroesophageal (MK-2870-015): A highly competitive indication already involving Daiichi Sankyo's T-DXd (HER2+), zolbetuximab (CLDN18.2+), and now MK-2870 for TROP2-expressing GEA

The MK-2870 wave represents the most consequential competitive development in TROP2-targeted therapy since Trodelvy's approval. If multiple MK-2870 trials read out positively by 2027–2028, Merck would hold regulatory approvals across the same TROP2-expressing tumor types currently served by Gilead and AstraZeneca — redefining the commercial TROP2 landscape.

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

• ADC Clinical Trials by the Numbers — how many ADC trials are running, by phase, start year, and sponsor, counted daily from ClinicalTrials.gov
• 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

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