Next-generation ADCs and emerging conjugate platforms in breast cancer: a ClinicalTrials.gov landscape analysis.

Abstract

e15026 Background: Antibody–drug conjugates (ADCs) are reshaping breast cancer management, yet their rapid proliferation raises concerns regarding therapeutic redundancy. We investigated the 2025 development pipeline to test the hypothesis that current strategies, heavily skewed toward shared targets and payloads, may be creating cross-resistance bottlenecks, thereby underscoring a critical need for novel antigens and alternative cytotoxic mechanisms to ensure viable future sequencing. Methods: We queried ClinicalTrials.gov on December 31, 2025, for interventional “Breast Cancer/Breast Neoplasms” studies with statuses recruiting, not-yet-recruiting, or active-not-recruiting using keywords enriching for next-generation platforms (ADCs, radiopharmaceuticals, PROTACs, immune-conjugates, oncolytic viruses). Terms corresponding to commonly used payloads were excluded. Manual review removed non-breast, diagnostic-only, radiotherapy-only, and ineligible interventions. Basket trials that included the breast cancer cohort were retained. ADCs were classified by payload class (tubulin vs non-tubulin vs novel) and construct architecture (bispecific, biparatopic). Phases were listed as early (phase 1 and 2) and late (phase 3). Results: Of 154 screened trials, 119 met inclusion criteria. ADCs dominated the landscape (62/119, 52.1%), followed by radiopharmaceuticals (16.0%), oncolytic viruses (9.2%), non-ADC antibodies (4.2%), and other modalities (18.5%). Most trials were early-stage (Phase 1 or 2 at 42.0% and 51.3%) and actively recruiting (62.2%). Mean planned enrollment was highest for ADCs (236) compared with radiopharmaceuticals (109) and oncolytic viruses (32). Within ADCs (n = 62), targets were concentrated in HER2 (25) and TROP2 (11), with expansion into HER3 (7), EGFR (6), and Nectin-4 (6). Payloads included Topoisomerase-I (42/62, 67.7%), microtubule inhibitors (17.7%) and structurally novel architectures (14.5%). Latter included bispecific ADCs (EGFR×HER3; n = 2) and biparatopic HER2 ADCs (n = 6). Overall, ADCs comprised 87.5% (7/8) of late phase, with one single non-ADC trial using an endocrine PROTAC degrader. Among non-ADC antibodies (n = 5), bispecifics were prominent (n = 4), targeting PD-(L)1×VEGF (n = 3) and CD28×Nectin-4 (n = 1). Radiopharmaceutical trials (n = 19) frequently utilized 177Lu and explored theranostic 68Ga/177Lu pairing. Conclusions: In a ClinicalTrials.gov landscape enriched for next-generation conjugate constructs, ADCs had predominance of topoisomerase-I payloads (68%) with emerging presence of structurally novel architectures (15%), including bispecific and biparatopic constructs. These data highlight an urgent strategic imperative to diversify payload mechanisms and validate novel surface antigens to prevent therapeutic bottlenecks and secure effective sequencing pathways for future patients.