Akeso, Inc. has dosed the first patient in a Phase Ib/II clinical study evaluating its investigational HER3-directed antibody-drug conjugate AK138D1, both as a monotherapy and in combination with the PD-1 and VEGF bispecific antibody ivonescimab, in advanced non-small cell lung cancer. The study, designated AK138D1-201, is intended to examine the regimen in several treatment settings, including first-line disease, progression after an epidermal growth factor receptor tyrosine kinase inhibitor and resistance following immunotherapy plus chemotherapy.
The July 28 Hong Kong-time dosing announcement represents an expansion of Akeso’s clinical combination strategy rather than evidence that the regimen improves patient outcomes. No response rate, progression-free survival result, dose-specific safety dataset or patient-level analysis from the new study is yet available, leaving the therapeutic value of the combination dependent on future clinical readouts.
The programme nevertheless deserves attention because it brings together two increasingly important oncology approaches. AK138D1 is designed to deliver a cytotoxic payload to HER3-expressing tumour cells, while ivonescimab combines immune-checkpoint inhibition and vascular endothelial growth factor blockade in a single molecule. Akeso is effectively testing whether a targeted drug-delivery platform can be combined with its most commercially and clinically advanced immunotherapy asset without narrowing the usable treatment window.
What does first-patient dosing reveal about Akeso’s IO 2.0 and ADC 2.0 strategy?
Akeso is developing AK138D1-201 as part of what it calls its IO 2.0 and ADC 2.0 strategy, an effort to use ivonescimab and cadonilimab as combination backbones for a growing portfolio of internally developed antibody-drug conjugates. The latest lung cancer study follows the June 2026 enrolment of the first patient in a separate Phase Ib/II trial evaluating AK138D1 alone and with ivonescimab in advanced breast cancer.
The strategy is commercially logical. A successful combination could extend the relevance of ivonescimab beyond its existing monotherapy and chemotherapy-based programmes, while giving Akeso a differentiated route for advancing its younger ADC pipeline. The company is also developing AK146D1, a Trop2 and Nectin-4 bispecific ADC, alongside additional candidates expected to enter clinical development. Chinese regulators cleared Phase II studies involving AK138D1 and AK146D1 combinations in March 2026.
However, a broad combination matrix can create as many development questions as it answers. Each regimen requires an appropriate dose, a defensible target population, manageable overlapping toxicities and evidence that the combination adds more than either component alone. Expanding several programmes simultaneously may generate optionality, but it also increases the number of clinical decisions Akeso must make before identifying which combinations warrant registrational investment.
The first-patient milestone therefore shows that the platform strategy is moving from concept into broader clinical execution. It does not yet demonstrate that the proposed IO and ADC pairing is biologically or commercially superior to simpler treatment regimens.
How is AK138D1-201 designed to test the HER3 ADC and ivonescimab combination?
The ClinicalTrials.gov record describes AK138D1-201 as a multicentre, open-label Phase Ib/II study with estimated enrolment of 265 patients with advanced non-small cell lung cancer. Listed treatment groups include AK138D1 monotherapy, AK138D1 with ivonescimab and a three-drug regimen combining AK138D1, ivonescimab and carboplatin. The study uses a randomized, parallel-assignment structure for at least part of its development programme, with adverse-event incidence and severity identified as a primary outcome measure.
The Phase Ib portion is intended to evaluate safety, tolerability and preliminary antitumour activity for the combination. The Phase II portion is expected to examine safety and efficacy for AK138D1 alone and in combination with ivonescimab. Primary completion is estimated for June 2028, while full study completion is currently projected for July 2030.
This structure allows Akeso to investigate several clinical hypotheses within one programme. The first-line setting could test whether the combination is sufficiently active and tolerable to compete with established immunotherapy and chemotherapy regimens. The post-EGFR-TKI setting addresses a population in which resistance mechanisms are heterogeneous and effective treatment options become progressively limited. The post-immunochemotherapy setting creates another opportunity, although prior checkpoint exposure could affect the incremental contribution of ivonescimab.
Patient selection will be especially important. HER3 is expressed across multiple solid tumours, but expression alone may not reliably identify patients who derive meaningful benefit from a HER3-directed ADC. The study will need to determine whether activity varies according to EGFR mutation status, previous therapies, HER3 expression, resistance mechanism, tumour histology or other molecular characteristics.
Why is HER3 an attractive target after treatment resistance in non-small cell lung cancer?
HER3 is a member of the human epidermal growth factor receptor family and can contribute to signalling pathways involved in tumour growth, survival and resistance. In EGFR-mutated non-small cell lung cancer, HER3 has attracted particular interest as a delivery target because it can remain present on tumour cells after resistance to EGFR-targeted therapies develops.
An antibody-drug conjugate does not necessarily need HER3 to function as the dominant cancer-driving alteration. Instead, the antibody can use HER3 as an entry point for delivering a cytotoxic payload into the tumour cell. This distinction is important because the biological rationale for an ADC can depend on target expression, internalisation, payload release and bystander activity rather than direct inhibition of the target’s signalling function.
Akeso describes AK138D1 as a fully humanized anti-HER3 immunoglobulin G1 antibody attached to a DXd topoisomerase I inhibitor payload through a cleavable linker. Following internalisation, the linker is intended to release the membrane-permeable payload, causing DNA damage and tumour-cell death. The company has said the candidate was engineered to reduce uptake in normal tissue and improve tumour penetration, although these design claims require clinical confirmation.
The broader HER3 ADC field has already provided evidence that the target can support antitumour activity. In the Phase II HERTHENA-Lung01 study, the investigational HER3-directed ADC patritumab deruxtecan produced a confirmed objective response rate of 29.8%, a median response duration of 6.4 months and median progression-free survival of 5.5 months in previously treated EGFR-mutated non-small cell lung cancer. Differences in molecules, patient populations, dosing and trial design prevent those results from being used as a direct benchmark for AK138D1.
No HER3-directed ADC had obtained regulatory approval when Akeso announced the new study. Patritumab deruxtecan previously received a Complete Response Letter from the United States Food and Drug Administration related to inspection findings at a third-party manufacturing facility, illustrating how manufacturing readiness can become as important as clinical efficacy for complex ADC programmes.
What must Akeso prove about AK138D1 safety and its proposed therapeutic window?
Safety may be the most consequential early question for AK138D1. Topoisomerase I inhibitor ADCs can produce clinically significant toxicities, including haematological adverse events, gastrointestinal effects and interstitial lung disease or pneumonitis. The frequency and severity of these events can vary substantially between molecules, doses, treatment schedules and patient populations.
Akeso reported that early AK138D1 monotherapy studies in China and Australia had shown antitumour activity, low haematological toxicity and no cases of interstitial lung disease. The July announcement did not provide the number of evaluable patients, dose levels, follow-up duration, response rate, grade 3 or higher adverse-event frequency, discontinuation rate or independent assessment of tumour responses. Those omissions make it impossible to determine the maturity or reliability of the reported signal from the announcement alone.
The absence of reported interstitial lung disease in an early dataset should not be interpreted as evidence that the risk has been eliminated. Rare but serious toxicities may emerge only after more patients are treated, higher cumulative exposure is reached or the therapy is combined with other agents.
The combination with ivonescimab adds another layer of complexity. Ivonescimab carries potential risks associated with immune-checkpoint inhibition and VEGF blockade. Depending on the population and regimen, investigators may need to evaluate immune-mediated adverse events, hypertension, proteinuria, bleeding, thrombotic events and treatment-related pulmonary toxicity alongside the ADC’s effects.
Phase Ib dose optimisation will therefore be central to the programme. Akeso must identify a dose that preserves adequate ADC exposure without causing unacceptable toxicity when combined with ivonescimab. A dose selected primarily from monotherapy experience may not automatically remain appropriate in a multi-agent regimen.
Can ivonescimab provide a credible immunotherapy backbone for an ADC combination?
Ivonescimab gives the programme a more advanced clinical foundation than AK138D1 alone. The bispecific antibody is designed to block PD-1 while also inhibiting VEGF, combining immune activation and anti-angiogenic activity. It is approved in China for specified non-small cell lung cancer indications and has been included in the country’s reimbursement system for eligible uses.
The drug has generated Phase III evidence across several lung cancer populations. Akeso’s HARMONi-6 study reported an overall survival benefit for ivonescimab plus chemotherapy over tislelizumab plus chemotherapy in first-line squamous non-small cell lung cancer in China. Summit Therapeutics, which holds development and commercial rights to ivonescimab across several major markets outside China, has also reported updated results from the global HARMONi programme in EGFR-mutated disease.
The United States Food and Drug Administration has accepted Summit Therapeutics’ biologics licence application seeking approval for ivonescimab with chemotherapy in EGFR-mutated non-squamous non-small cell lung cancer following EGFR-TKI treatment. The current Prescription Drug User Fee Act target date is November 14, 2026. Ivonescimab remains investigational in the United States pending the agency’s decision.
There is a plausible rationale for combining an ADC with a checkpoint-based therapy. ADC-mediated tumour-cell death may release tumour antigens and modify the local immune environment, while VEGF inhibition may affect tumour vasculature and immune suppression. Yet proposed synergy is not equivalent to demonstrated clinical benefit.
The study must show whether ivonescimab meaningfully improves response depth, response durability or disease control compared with AK138D1 alone. It must also establish that any improvement is large enough to justify added toxicity, treatment complexity and cost.
How does the AK138D1 trial fit Akeso’s commercial and investor narrative?
Akeso enters the programme with an established commercial business in China rather than operating solely as an early-stage biotechnology developer. The company reported 2025 commercial sales revenue of RMB3.03 billion, an increase of 51.48% from the previous year, supported by products including ivonescimab and cadonilimab.
That commercial base can help finance a broad clinical pipeline, but it also raises investor expectations. AK138D1 is likely to be viewed as a long-term pipeline signal rather than an immediate revenue catalyst. The first patient has only just entered the Phase Ib/II study, and the programme remains several clinical and regulatory steps away from a potential marketing application.
Akeso shares traded around HK$96 during the late morning Hong Kong session on July 28, down approximately 2.6% for the day. The shares were about 1.5% above their July 21 close and roughly 4.7% above the June 29 level, but remained around 38.5% lower over the preceding year. The reported 52-week range was HK$80.20 to HK$179.00, reflecting substantial volatility around expectations for ivonescimab, pipeline execution and the company’s valuation.
The intraday decline should not automatically be attributed to the trial announcement. The more defensible interpretation is that first-patient dosing provides limited near-term de-risking because it does not resolve questions about AK138D1’s dose, efficacy, safety or competitive position.
Which milestones will determine whether AK138D1 becomes more than a platform story?
The first meaningful readout will be the Phase Ib safety and dose-escalation experience. Investors and clinicians will need to see the frequency of dose-limiting toxicities, grade 3 or higher adverse events, treatment interruptions, dose reductions, discontinuations and interstitial lung disease across both monotherapy and combination cohorts.
Preliminary antitumour activity will also require context. Objective response rates should be accompanied by sample size, confidence intervals, prior-treatment history, response duration and progression-free survival follow-up. Early responses in a small, selected cohort would support continued development, but would not establish superiority over existing therapies or other investigational ADCs.
The Phase II portion must clarify which population offers the strongest benefit-risk profile. A regimen intended for first-line treatment faces a higher evidentiary threshold than one developed for heavily pretreated disease because effective immunotherapy, chemotherapy and targeted treatment options are already available in earlier settings.
Akeso will also need to establish whether HER3 expression or another biomarker can guide treatment selection. A broadly expressed target may enlarge the theoretical market, but an imprecise selection strategy could make later trials larger, more expensive and harder to interpret.
AK138D1-201 strengthens Akeso’s position in the rapidly expanding intersection of immunotherapy and antibody-drug conjugates. The programme’s importance, however, will not be determined by the number of combinations Akeso can initiate. It will be determined by whether AK138D1 can produce durable activity at a tolerable dose and whether ivonescimab contributes enough additional benefit to justify a more complex regimen.
