Roughly one year after AK146D1 cleared its first Phase Ia patient dose in July 2025, Akeso has already pushed the bispecific ADC into a Phase II combination study, a pace that reflects both the asset’s preclinical profile and the company’s calculated bet on stacking two novel mechanisms rather than pairing a new ADC with a proven checkpoint inhibitor. The AK146D1-201 trial combines AK146D1, which targets both TROP2 and Nectin-4 on a single conjugate, with ivonescimab, the company’s PD-1/VEGF bispecific antibody, in patients with advanced NSCLC, with first-line disease as the primary focus.
The design carries real logic. TROP2 and Nectin-4 are independently validated ADC targets in solid tumors, and building both into one molecule is an attempt to broaden tumor coverage while managing payload toxicity within a tighter therapeutic window than conventional single-target ADCs allow. Ivonescimab adds a second layer of complexity: by blocking both PD-1 and VEGF simultaneously, it addresses immunosuppression and tumor angiogenesis in one agent. Akeso’s rationale for the pairing is that each drug’s mechanism should amplify the other’s effect, and the Phase III HARMONi-6 data presented at ASCO 2026 gave ivonescimab credibility as a combination backbone, showing an overall survival benefit over tislelizumab plus chemotherapy in 532 patients with squamous NSCLC. That result, reported in The Lancet, matters here because it demonstrates ivonescimab can function as an anchor agent rather than just an experimental add-on.
The competitive context for TROP2 targeting in NSCLC is intensifying. Datopotamab deruxtecan received FDA approval in May 2026 for triple-negative breast cancer, and single-target TROP2 ADCs are advancing across multiple tumor types. Akeso’s bispecific ADC strategy is a direct response to that crowded field: differentiate by dual antigen engagement rather than by competing on payload chemistry alone. Preclinical data for AK146D1 showed anti-tumor activity in models expressing either target, and regulatory clearance from the FDA, Australia’s TGA, and China’s NMPA for the Phase I study suggests the safety package was sufficient across multiple review standards.
Phase II in NSCLC is a long road from a registration-enabling readout, but the endpoint that will define whether this combination has a future is objective response rate in biomarker-unselected or broadly selected first-line patients. If AK146D1 plus ivonescimab produces responses in tumors with low or absent TROP2 expression, that would validate the Nectin-4 arm of the bispecific and separate this asset from the single-target TROP2 class entirely.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
