ASCO 2026: ADCs Are Redefining What Targeted Therapy Can Do

Antibody-drug conjugates — or ADCs — are not new. The concept of a "magic bullet" that delivers a cytotoxic payload directly to a tumour cell was articulated by Paul Ehrlich over a century ago. Gemtuzumab ozogamicin, the first modern ADC, received its initial FDA approval in 2000. But for most of the two decades that followed, ADC development was limited by narrow therapeutic windows, linker instability, and payload toxicity. The field fell short of its early promise. ASCO 2026 confirmed that antibody-drug conjugates have become one of the defining therapeutic platforms in modern oncology. Many now consider the field to have entered the “ADC 2.0” era, and it is a particularly important clinical and commercial story in oncology. 

What Changed: The Engineering Behind ADC 2.0 

The transformation of the ADC field came from advances in three components: the antibody, the linker, and the payload. First-generation ADCs used heterogeneous conjugation, cleavable linkers with poor stability, and conventional cytotoxic payloads. Modern ADCs use site-specific conjugation for defined drug-to-antibody ratios, stable cleavable linkers designed to preferentially release payload after internalisation within tumour cells and novel topoisomerase I inhibitors — most notably the DXd payload used in trastuzumab deruxtecan and related molecules — that are highly potent but have a shorter half-life in circulation, potentially reducing some forms of systemic toxicity. 

Critically, DXd-based payloads also produce a "bystander effect" — killing adjacent tumour cells that may not express the target antigen. This matters enormously in tumours with heterogeneous target expression. 

The ASCO 2026 ADC Landscape: Three Pivotal Results 
Three datasets at ASCO 2026 illustrate where the field now stands. 

First: izalontamab brengitecan (iza-bren), developed by SystImmune in collaboration with Bristol Myers Squibb, is a first-in-class bispecific ADC targeting both EGFR and HER3 simultaneously. In the Phase 3 PANKU-Breast02 trial in previously treated unresectable locally advanced or metastatic TNBC, iza-bren met both co-primary endpoints of PFS and OS — the first Phase 3 bispecific ADC to achieve this in TNBC. The confirmed ORR was 51.7% versus 20.5% with chemotherapy. Median PFS was 8.5 versus 3.1 months (HR 0.29; p<0.0001) and median OS was 15.9 versus 12.5 months (HR 0.60; p=0.0019). The bispecific design is intentional: targeting two receptors simultaneously reduces escape via single-receptor downregulation, a known mechanism of ADC resistance. 

Second: trastuzumab deruxtecan (T-DXd, ENHERTU) arrived at ASCO 2026 already transformed in its clinical identity — the result of a series of landmark trials over the preceding four years. DESTINY-Breast04, presented at ASCO 2022 and the recipient of a Plenary standing ovation, first demonstrated that T-DXd could produce meaningful PFS and OS benefit in patients with HER2-low metastatic breast cancer — a population previously classified as HER2-negative and excluded from HER2-directed therapy. DESTINY-Breast06 at ASCO 2024 extended that finding further still, into HER2-ultralow disease and into the HR-positive earlier-line setting, establishing T-DXd as standard of care across the full low-expression spectrum. By the time ASCO 2026 convened, T-DXd plus pertuzumab had already received FDA approval in December 2025 as a new first-line standard in HER2-positive metastatic breast cancer, based on DESTINY-Breast09 data presented at ASCO 2025. ASCO 2026 presentations focused on durability analyses and emerging questions around sequencing, maintenance strategy, and combination approaches — the natural evolution of a platform that has now demonstrated activity across the full HER2 expression spectrum. 

Third: JSKN016, a first-in-class TROP2/HER3 bispecific ADC developed by Alphamab Oncology, presented Phase 1 data at ASCO 2026 that generated considerable attention. In heavily pre-treated HER2-negative breast cancer patients — including both TNBC and hormone receptor-positive populations — the molecule demonstrated striking early antitumour activity and a manageable safety profile. The maximum tolerated dose was not reached. A Phase 3 TNBC trial has already opened, with the first patient dosed in March 2026. 

Why TROP2/HER3 Dual Targeting Matters 

JSKN016's design reflects a sophisticated understanding of the resistance biology that has begun to emerge with single-target ADCs. Sacituzumab govitecan, the approved TROP2-targeting ADC, has demonstrated that TROP2 expression can be downregulated over time, limiting durable responses. HER3 upregulation is also a well-characterised resistance mechanism to multiple targeted therapies across breast and lung cancer. By engaging both receptors simultaneously, JSKN016 aims to address both potential escape pathways. 

This is ADC 2.0 thinking applied not just to the engineering of the molecule, but to the biology of resistance. It also underscores how ADC innovation is becoming increasingly global, with important contributions emerging from biotechnology companies across multiple regions. 

The Science of Target Selection: Beyond HER2 

The success of T-DXd has validated the ADC platform so thoroughly that the question is no longer whether ADCs work — it is which targets, in which tumour contexts, with which payloads. At ASCO 2026, programmes targeting TROP-2 (datopotamab deruxtecan), HER3 (iza-bren, as a bispecific EGFR/HER3 ADC, and JSKN016, as a bispecific TROP2/HER3 ADC), DLL3 (in SCLC), CEACAM5 (in CRC and NSCLC), and FOLR1 (in ovarian cancer) all presented data. The pipeline of hundreds of ADC molecules in active clinical development represents the broadest wave of targeted oncology development since the PD-1 era began. 

The Remaining Challenge: Toxicity and Resistance 

ADCs are not without challenges. Interstitial lung disease (ILD) remains the most clinically significant safety concern for DXd-based conjugates, with Grade ≥3 ILD occurring in approximately 3–5% of patients across trials. Ocular toxicity, peripheral neuropathy, and haematological effects vary by payload class. As more patients receive sequential ADC therapies, the field is also confronting cross-resistance — particularly between agents that share the same payload or the same tumour target. 

Rational sequencing, combination strategies, and companion diagnostics for target expression will define the next phase of ADC development. The science is moving faster than the clinical infrastructure in many respects — and that is precisely where rigorous protocol design and medical expertise become essential. 

The Broader Implications 

ASCO 2026 confirmed that ADCs are no longer a niche category. They have become one of the most important therapeutic platforms in oncology, with activity now extending across tumour types and biomarker-defined populations that would have seemed implausible only a few years ago. 

ADCs are no longer defined by the question of whether they can deliver chemotherapy selectively. That question has largely been answered. The challenge now is determining which targets, payloads, and combinations will produce the next generation of transformative outcomes for patients. 

The remarkable progress of the past few years suggests that we are only at the beginning of that story. 

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