HER3-targeted therapy in lung cancer carries a specific cautionary data point that Akeso is betting against: in the Phase III trial that led Daiichi Sankyo and Merck to voluntarily withdraw their BLA for patritumab deruxtecan in May 2025, interstitial lung disease occurred in 5% of treated patients, including two fatal cases. That toxicity record, combined with a Phase III overall survival miss, effectively defines the ceiling the field has been unable to break through. Akeso’s first patient dosing in AK138D1-201, a Phase Ib/II study of its next-generation HER3 ADC combined with ivonescimab, is a direct claim that its engineering choices change that calculus.
The engineering distinction matters here. AK138D1 uses the same DXd payload and patritumab antibody backbone as the Daiichi Sankyo agent, but Akeso redesigned the construct specifically to minimize uptake in normal tissues and prevent surface aggregation on tumor cells. Early monotherapy studies conducted in China and Australia reported no cases of ILD and low hematologic toxicity, which is the safety profile the HER3 space urgently needs before combination regimens become credible. Study AK138D1-201 will evaluate the drug as monotherapy and in combination with ivonescimab, the PD-1/VEGF bispecific that beat pembrolizumab on progression-free survival in the HARMONi-2 Phase III trial, across three distinct NSCLC settings: first-line, post-EGFR-TKI resistance, and post-immuno-chemotherapy resistance. Covering all three in a single protocol is an ambitious design choice that acknowledges HER3 expression drives resistance across multiple treatment contexts, not just one.
The combination logic rests on complementary mechanisms. Ivonescimab’s VEGF arm normalizes the tumor vasculature and improves immune infiltration; the HER3 ADC delivers cytotoxic payload directly to tumor cells while releasing membrane-permeable DXd that can kill neighboring antigen-low cells through a bystander effect. Akeso argues these mechanisms amplify each other’s immune-activating activity. That thesis remains preclinical in nature for this specific pairing, and the Phase Ib dose-escalation portion of this study is where it will meet its first real test in humans outside China.
The single number to track from this trial’s early readouts is the ILD rate in the combination arm. If AK138D1 sustains a clean pulmonary safety profile when paired with ivonescimab, the ILD signal that grounded the prior generation of HER3 ADCs becomes a differentiating asset rather than a class-wide liability, and the combination’s path into registrational studies gains real momentum.
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.
