Clinical Trials of New Drugs · asia
HER3 ADC Teams Up With Bispecific Antibody: First Patient Dosed in Lung Cancer Combination Trial
Akeso has advanced its HER3 antibody-drug conjugate AK138D1 into a trial evaluating it as monotherapy and in combination with ivonescimab, enrolling patients with advanced non-small cell lung cancer in both the first-line setting and after treatment failure. This 265-patient study has only just begun and is currently designed to answer questions about safety and preliminary response, rather than superiority in efficacy.
The combination of antibody-drug conjugates (ADCs) and immunotherapy is gradually moving from later-line exploration into earlier lung cancer treatment settings. Akeso announced that the first patient has been dosed in a Phase Ib/II trial evaluating the HER3-directed ADC AK138D1. The study will assess both the drug as monotherapy and in combination with the PD-1/VEGF bispecific antibody ivonescimab.
The study, registered as NCT07623356 and designated AK138D1-201, is sponsored by Akeso and uses a multicenter, open-label design. It is expected to enroll 265 patients with advanced non-small cell lung cancer. Publicly available information lists three experimental regimens: AK138D1 monotherapy, AK138D1 plus ivonescimab, and the two agents combined with the platinum-based chemotherapy drug carboplatin.
AK138D1 is designed to use an HER3-recognizing antibody to deliver a cytotoxic drug to tumor cells. Ivonescimab acts simultaneously on the PD-1 and VEGF pathways in an attempt to combine immune activation with regulation of tumor vasculature. The hypothesis behind combining the two agents is that, alongside the ADC’s direct killing of tumor cells, the treatment may reshape the tumor environment in a way that favors an immune response. However, this potential synergy still awaits validation in human data.
Akeso said the study includes first-line patients who have not received systemic treatment for advanced disease, as well as populations that have developed resistance to EGFR inhibitors or immunochemotherapy. This means the trial is exploring more than a single later-line option and also addresses the competition to determine whether first-line lung cancer treatment can reduce reliance on conventional chemotherapy. However, prognosis varies substantially among patients with different treatment histories, and subsequent results will need to be interpreted by population and treatment group.
Background
In recent years, lung cancer drug development has frequently explored combinations of ADCs and PD-1-class immunotherapies, with some large trials directly challenging first-line standard regimens that include chemotherapy. AK138D1-201 also retains a three-drug regimen incorporating carboplatin, indicating that the development strategy is not simply to eliminate chemotherapy, but to compare whether combinations of different intensities can achieve a better balance between efficacy and tolerability.
The most important limitation at this stage is that no efficacy or safety results are yet available for interpretation. The trial’s primary endpoints include the incidence and severity of adverse events, as well as investigator-assessed objective response rate according to RECIST 1.1. The open-label design also means that early tumor responses must be viewed cautiously. In addition, some clinical trial information platforms still show the study as not yet recruiting, creating a timing discrepancy with the company’s statement that the first patient has been dosed. The study’s progress remains subject to subsequent registry updates and formal results.