Hong Kong-listed Akeso, Inc. (HKEX: 9926) announced on June 15, 2026 that the first patient has been enrolled in the Phase Ib/II clinical study AK138D1-202, evaluating its internally-developed next-generation HER3 antibody-drug conjugate (ADC), AK138D1, as monotherapy and in combination with ivonescimab (the PD-1/VEGF bispecific antibody already approved in China for non-small cell lung cancer) for the treatment of advanced breast cancer. The trial enrolls patients with the two breast cancer subtypes that account for the bulk of unmet medical need: hormone receptor-positive, HER2-negative (HR+/HER2-) disease — roughly 65% of all breast cancers — and triple-negative breast cancer (TNBC), which represents 10 to 20% of cases. Early-phase data already show meaningful single-agent activity in breast cancer with a favorable safety profile, particularly low hematologic toxicity and the absence of interstitial lung disease (ILD) — the dose-limiting adverse event that has constrained earlier HER3 ADCs. Akeso is positioning AK138D1 plus ivonescimab as its flagship "IO2.0 + ADC2.0" combination, joining a broader company pipeline that now includes more than 50 innovative assets, with 27 in clinical trials and 15 bispecific or multispecific antibodies.
For international patients with refractory breast cancer — particularly those whose disease has progressed on multiple lines of chemotherapy, CDK4/6 inhibitors, PARP inhibitors, or earlier-generation ADCs like trastuzumab deruxtecan (T-DXd) — the AK138D1 story is one to watch. The combination arm pairs a Chinese-discovered, next-generation HER3 ADC with a Chinese-discovered PD-1/VEGF bispecific, both from the same company, both currently in clinical development in China and Australia. Patients in countries where these combinations are not yet accessible may find the clinical-trial enrollment route through major Chinese academic cancer centers a realistic near-term option.
Breast cancer is the most common malignancy in women worldwide, with an estimated 2.3 million new cases diagnosed annually by the World Health Organization. The disease is heterogeneous, and treatment selection depends on three biomarkers: the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). HR+/HER2- breast cancer — driven by estrogen signaling, lacking HER2 overexpression — accounts for roughly 65% of all cases and is treated in the first line with endocrine therapy plus a CDK4/6 inhibitor (palbociclib, ribociclib, abemaciclib), with sequential lines of endocrine therapy, targeted therapy (PI3K inhibitors, PARP inhibitors for BRCA-mutated disease, mTOR inhibitors), and chemotherapy as the disease progresses. TNBC, defined by the absence of ER, PR, and HER2, accounts for 10 to 20% of cases and is more aggressive, with a younger age distribution, a higher prevalence in women of African and Hispanic ancestry, and a 5-year overall survival rate roughly 10 percentage points lower than HR+ disease. Until the advent of immune checkpoint inhibitors and TROP2-directed ADCs, TNBC had limited targeted-therapy options and was managed primarily with cytotoxic chemotherapy.
Therapy for both subtypes has shifted meaningfully in the last 5 years. For HR+/HER2- disease, the addition of CDK4/6 inhibitors to first-line endocrine therapy extended median progression-free survival from around 14 months to 24 to 28 months, and the oral SERD and PROTAC estrogen-receptor degrader classes are now in late-stage development for ESR1-mutated resistant disease. For TNBC, pembrolizumab (Keytruda) plus chemotherapy became the standard of care in the first-line metastatic setting on the strength of the KEYNOTE-355 trial, and sacituzumab govitecan (Trodelvy, a TROP2-directed ADC) and fam-trastuzumab deruxtecan-nxki (Enhertu, a HER2-directed ADC) both demonstrated activity in pretreated TNBC. Despite these advances, metastatic HR+/HER2- and TNBC remain lethal: 5-year survival for metastatic breast cancer in the United States is around 30%, and substantially lower in low- and middle-income countries where access to newer biologics is constrained.
Against this backdrop, the AK138D1-202 trial is targeting the second-line-plus metastatic population — patients whose disease has progressed on at least one prior line of endocrine-based therapy (for HR+/HER2-) or chemotherapy plus immunotherapy (for TNBC) — and the preclinical and early clinical data suggest AK138D1 has activity in this setting. Whether the activity translates into clinically meaningful survival benefit is the question the trial is designed to answer.
AK138D1 is a next-generation, differentiated HER3-targeting ADC developed in-house at Akeso. The architecture follows the standard ADC pattern — a monoclonal antibody linked to a cytotoxic payload via a chemical linker — but with several design choices that distinguish it from earlier HER3 ADCs and from the broader ADC class.
The antibody component of AK138D1 is patritumab, a fully humanized IgG1 monoclonal antibody that binds the extracellular domain of HER3 (human epidermal growth factor receptor 3, also known as ERBB3). HER3 is a member of the EGFR / HER family of receptor tyrosine kinases and is broadly expressed across many solid tumors, including breast, ovarian, colon, gastric, lung, skin, and pancreatic cancers. Unlike HER2, which has the cleanest druggable biology in the family, HER3 has historically been a difficult target: it has weak intrinsic kinase activity on its own, it depends on heterodimerization with HER2 or EGFR for potent signaling, and its expression is heterogeneous within a single tumor. The previous generation of HER3 ADCs — patritumab deruxtecan (HER3-DXd, U3-1402), developed by Daiichi Sankyo — demonstrated activity in HER3-mutated non-small cell lung cancer and in breast cancer, but dose-limiting toxicities (chiefly hematologic and gastrointestinal) and the binding site barrier limited clinical development.
AK138D1 is conjugated to the cytotoxic payload via a cleavable linker named MC-AAA (maleimide-alanine-alanine-alanine). The MC-AAA linker is designed to be stable in circulation (to limit off-target payload release and bystander toxicity) and to be cleaved preferentially by intracellular enzymes — specifically cathepsins — once the ADC is internalized into the tumor cell. The cleavable design is in contrast to the cleavable but more payload-leaky linkers used in some earlier ADCs, and to the non-cleavable linkers (which require complete antibody catabolism for payload release). The cleavable design gives AK138D1 both intracellular payload release (killing the bound tumor cell) and a bystander effect (the membrane-permeable DXd payload can diffuse to neighboring tumor cells that may not express HER3 as highly).
The payload is DXd (exatecan derivative, an inhibitor of topoisomerase I — the same payload used in trastuzumab deruxtecan / Enhertu and datopotamab deruxtecan / Datroway). Topoisomerase I inhibitors work by trapping the enzyme-DNA complex during DNA replication, generating double-strand DNA breaks and triggering apoptosis. The DXd payload has a higher drug-to-antibody ratio (DAR) potential than many earlier ADC payloads (typical DAR of 8 for the deruxtecan platform) and is membrane-permeable, which enables the bystander effect. The trade-off is that DXd is associated with interstitial lung disease (ILD) in some patients — a class effect that has been a serious safety concern with T-DXd, particularly in lung cancer patients with pre-existing pulmonary compromise.
One of the most interesting design features of AK138D1, and the one Akeso highlights most prominently in its corporate communications, is the engineering to reduce uptake in normal tissues and to prevent the clustering of ADC molecules on the tumor surface — addressing what biologists call the binding site barrier. The binding site barrier is a well-documented phenomenon in antibody therapeutics: high-affinity antibodies bind tightly to the first antigens they encounter on the surface of a tumor, which can block their penetration deeper into the tumor mass and leave the interior cells undertreated. The result is heterogeneous drug distribution, with high concentrations at the tumor rim and low concentrations at the tumor core. AK138D1's design — by Akeso's description — moderates the on-rate / off-rate of the antibody-antigen interaction to allow more uniform distribution through the tumor mass, and it prevents the cross-linking / clustering of adjacent HER3-bound ADCs that contributes to off-target normal-tissue uptake.
The practical result, per Akeso's preclinical and early clinical reports, is an ADC that achieves deeper tumor penetration, more uniform intratumoral distribution, and lower off-target toxicity than conventional HER3 ADCs — including low hematologic toxicity and the absence of interstitial lung disease in the early clinical experience. The data are early (Phase I in China and Australia), but the safety profile is the headline number that justifies the next-phase development.
The AK138D1-202 study is a Phase Ib/II trial — a combined dose-finding / dose-expansion design that allows the company to identify the recommended Phase II dose in the dose-finding phase and then expand into the relevant patient populations. The trial enrolls patients with the two breast cancer subtypes where HER3 is expressed and where the unmet need is highest:
The trial enrolls patients across multiple treatment lines — from treatment-naïve to heavily pretreated — and includes patients with diverse PD-L1 expression levels. The inclusion of treatment-naïve patients is unusual for a Phase Ib/II and suggests Akeso is exploring earlier-line use of AK138D1 in parallel with the later-line expansion. The trial includes both monotherapy and combination arms — AK138D1 alone, and AK138D1 in combination with ivonescimab.
Ivonescimab is Akeso's PD-1/VEGF bispecific antibody, approved in China for EGFR-mutated non-small cell lung cancer (HARMONi-2) and in development for multiple other indications including squamous lung cancer (HARMONi-6, covered in our prior piece on the ivonescimab ASCO plenary data) and TNBC. The biological rationale for combining an ADC with a PD-1/VEGF bispecific in breast cancer is layered:
Whether this rationale translates into clinical synergy is the central hypothesis of AK138D1-202. The same hypothesis is being tested across the industry — combinations of HER2 ADCs with checkpoint inhibitors (e.g., T-DXd plus pembrolizumab in DESTINY-Breast09), combinations of TROP2 ADCs with checkpoint inhibitors (e.g., sacituzumab govitecan plus pembrolizumab in ASCENT-04), and the IO+ADC wave more broadly.
The breast cancer ADC space is no longer empty. Two ADCs are established in clinical practice, a third is in late-stage development, and a fourth generation of bispecific ADCs is moving through preclinical and Phase I development.
| ADC | Target | Payload | Approved Indications (2026) | Key Limitations |
|---|---|---|---|---|
| Trastuzumab deruxtecan (T-DXd, Enhertu) | HER2 | DXd (topo I) | HER2+ metastatic breast cancer (DESTINY-Breast03), HER2-low (DESTINY-Breast04), HER2-ultralow (DESTINY-Breast06) | ILD risk (~10 to 15% all grades), limited activity in HER2-zero disease |
| Sacituzumab govitecan (Trodelvy) | TROP2 | SN-38 (topo I) | TNBC (ASCENT), HR+/HER2- (TROPiCS-02), urothelial | Modest PFS benefit in HR+/HER2-, UGT1A1 polymorphism dosing |
| Datopotamab deruxtecan (Datroway) | TROP2 | DXd (topo I) | HR+/HER2- metastatic breast cancer (TROPION-Breast01) | Modest PFS benefit, ILD risk, ocular toxicity (keratitis) |
| AK138D1 (Akeso) | HER3 | DXd (topo I) | Phase Ib/II in HR+/HER2- and TNBC; not yet approved | Early clinical data, no peer-reviewed Phase III, China-and-Australia only |
The strategic positioning of AK138D1 within this field is interesting. T-DXd has set a high bar in HER2-expressing breast cancer — DESTINY-Breast03 showed median PFS of approximately 29 months for T-DXd versus 7 months for the previous standard in HER2+ metastatic disease. Sacituzumab govitecan and datopotamab deruxtecan have carved out niches in TNBC and HR+/HER2- disease, respectively, but with more modest efficacy gains than T-DXd in HER2+ disease. A HER3-directed ADC enters a competitive space but with a different target biology: HER3 is expressed independently of HER2 and is enriched in some HR+/HER2- and TNBC tumors that are HER2-low or HER2-zero, where neither T-DXd nor the TROP2 ADCs have demonstrated strong activity.
AK138D1's positioning — particularly the combination with ivonescimab — also positions it to compete with the next wave of breast cancer IO+ADC combinations. If the AK138D1-202 trial shows meaningful activity with a tolerable safety profile, the next step would be a randomized Phase III against an active comparator (most likely sacituzumab govitecan or T-DXd, depending on the patient population). That Phase III, if it happens, will be 2 to 3 years away at minimum.
Akeso's framing of AK138D1 plus ivonescimab as the company's flagship "IO2.0 + ADC2.0" combination is a deliberate positioning move. The "IO2.0" label refers to the second generation of immuno-oncology therapeutics — bispecific antibodies like ivonescimab that combine two synergistic immune / anti-angiogenic targets in a single molecule, rather than combining two separate antibodies. The "ADC2.0" label refers to the second generation of antibody-drug conjugates — molecules engineered for better tumor penetration, lower off-target toxicity, and more uniform intratumoral distribution than the first-generation ADCs that started with trastuzumab emtansine (T-DM1, Kadcyla) and T-DXd.
The IO+ADC combination strategy is the dominant theme in oncology drug development in 2026, with multiple combinations either approved or in late-stage development. The major combinations in clinical development or in early clinical use include:
The Akeso pipeline is particularly interesting because the company is one of the few — possibly the only — oncology biotech globally with multiple internally-developed bispecific antibodies (the IO2.0 side) and multiple internally-developed ADCs and bispecific ADCs (the ADC2.0 side). The strategic question is whether the IO2.0 + ADC2.0 combinations are synergistic, additive, or merely additive with manageable toxicity. The next 2 to 3 years of clinical readouts will determine whether the strategy is the right bet.
AK138D1 is one of two lead ADCs in Akeso's pipeline. The other is AK146D1, a TROP2/Nectin4 bispecific ADC in Phase I development. TROP2 and Nectin4 are both expressed in epithelial cancers (TROP2 in breast, lung, gastric, urothelial; Nectin4 in urothelial, breast, lung), and a bispecific ADC targeting both antigens could address intra-tumor heterogeneity and prevent antigen-loss resistance. Akeso also lists additional earlier-stage ADC programs in its corporate disclosures. The Dual-Shield ADC technology platform that anchors the ADC work is in-house, which gives Akeso manufacturing control and the ability to iterate on linker and payload chemistry without depending on external collaborators — a meaningful competitive advantage.
Akeso started the decade as a Chinese biotech specializing in bispecific antibodies, with a particular focus on immuno-oncology bispecifics that combined two immune targets in a single molecule. The company's lead asset, cadonilimab (PD-1/CTLA-4 bispecific), was approved in China for cervical cancer in 2022, and ivonescimab (PD-1/VEGF bispecific) has since become the company's flagship oncology asset, with approvals in EGFR-mutated NSCLC (HARMONi-2) and other indications under regulatory review. The pivot in 2026 has been twofold: (1) extending the bispecific franchise into autoimmune and inflammatory disease (the gumokimab anti-IL-17 approval on June 12, the manfidokimab dual IL-4Rα/IL-31 program, the AK139 IL-4Rα/ST2 first-in-class bispecific), and (2) building a parallel ADC franchise anchored by AK138D1 (HER3 ADC), AK146D1 (TROP2/Nectin4 bispecific ADC), and earlier-stage programs.
Akeso now describes itself with five technology platforms: Tetrabody (bispecific antibody engineering), AI-powered drug R&D, Dual-Shield ADC, Dual-Lock T-cell engager (TCE), and Tissue-Smart siRNA/mRNA. The pipeline counts more than 50 innovative assets, with 27 in clinical trials, 15 bispecific or multispecific antibodies or bispecific ADCs, and 8 commercially approved drugs. That scale — combined with wholly-owned GMP manufacturing and an integrated commercialization system in China — makes Akeso one of the few Chinese biotechs operating at the scale of a global top-tier specialty biopharma.
The first-patient-enrolled announcement is, by itself, a routine clinical-trial milestone. Most Phase I trials enroll their first patient within weeks of site activation, and Phase Ib/II trials typically enroll their first patient within 1 to 3 months of study initiation. The announcement is not a clinical-data milestone — no efficacy or safety data are presented. What it does signal is:
For international patients with HR+/HER2- or TNBC whose disease has progressed on multiple lines of standard therapy, the AK138D1-202 trial is a potential pathway to access a next-generation ADC + immunotherapy combination before it is commercially available anywhere in the world. The practical reality is that the trial is in its very early stages — the first patient was just enrolled — and the dose-expansion phase will likely run through 2026 and into 2027 before initial efficacy data are available. Patients who enter the trial now are enrolling into the dose-expansion cohorts, with the understanding that early-phase trial enrollment carries the usual risks of unknown efficacy, unknown optimal dose, and unknown long-term safety.
For international patients considering this route, the practical workflow is similar to other Chinese clinical-trial enrollment pathways:
The receiving hospital's clinical trial team will review your diagnostic workup (pathology, biomarker status, prior treatment history, imaging) against the AK138D1-202 inclusion / exclusion criteria. The relevant criteria include confirmation of HR+/HER2- or TNBC histology, prior treatment lines, measurable disease per RECIST 1.1, adequate organ function, and exclusion of patients with active autoimmune disease, active interstitial lung disease, prior treatment with HER3-directed therapy, or other contraindications to ADC or immunotherapy.
Trial enrollment typically requires an initial 2 to 4 week stay in the destination city for screening, baseline imaging, first dose administration, and safety monitoring. Subsequent follow-up visits are typically every 3 weeks (the standard ADC dosing interval). For patients enrolling in the dose-expansion cohort, the schedule is typically more intensive during the first 3 months and then tapers to every-6-week or every-12-week visits.
The investigational drug (AK138D1) is provided free under the trial protocol. The cost to the patient is the hospital fees for the infusion visits, the laboratory monitoring, the imaging (CT / MRI every 6 to 9 weeks), and the travel and accommodation in China. For self-pay international patients, the all-in cost of trial participation is typically US$15,000 to US$40,000 per year depending on the trial site, the number of on-site visits required, and the duration of treatment. Health insurance typically does not cover the cost of clinical-trial participation in a foreign country, but some international insurers and specialty medical-loyalty programs have begun to reimburse portions of the cost.
Patients who respond to AK138D1 (with or without ivonescimab) and remain on therapy will need to coordinate with a home oncologist willing to manage the maintenance phase. For patients in countries where AK138D1 is not yet approved, this means finding an oncologist who is willing to continue prescribing a Chinese-trial drug under a named-patient or compassionate-use framework — a non-trivial undertaking that requires the home oncologist to engage with the Chinese trial site's clinical team and with the local regulatory authority.
For patients interested in AK138D1-202 enrollment, the practical first step is to identify whether the trial is being conducted at a site accessible to international patients. Akeso has not published the full list of trial sites as of June 2026, but the company's standard practice for breast cancer trials is to enroll at top Chinese academic cancer centers — most likely Fudan University Shanghai Cancer Center, Sun Yat-sen University Cancer Center, Peking University Cancer Hospital, National Cancer Center / Cancer Hospital, Chinese Academy of Medical Sciences (CICAMS), and possibly West China Hospital Sichuan University and Tongji Hospital. For international patients, the most common entry point is through one of these hospitals' international patient offices, which can coordinate trial-site referrals, medical-records review, and initial consultation appointments.
The trial is also expected to enroll at Australian sites (Akeso has an Australian clinical-trial subsidiary) — though the Australian sites may have different enrollment priorities and may be more accessible to patients from Southeast Asia and the Pacific.
Considering AK138D1-202 trial enrollment or another Chinese oncology clinical trial?
Our team can help with medical-records review, eligibility pre-screening, hospital and trial-site coordination, and travel logistics for breast cancer and other oncology trials at Fudan Shanghai Cancer Center, Sun Yat-sen Cancer Center, PKU Cancer Hospital, and other top Chinese academic cancer centers.
Get a Free Pre-Screening AssessmentFor the breast cancer ADC field, the AK138D1-202 trial is one of several IO+ADC combinations moving through development. The next 18 months will be telling. Watch for:
For international patients with refractory HR+/HER2- or TNBC, the bottom line is that the IO+ADC combination wave is real and that AK138D1 plus ivonescimab is one of several promising combinations in clinical development. The realistic timeline for commercial access in any major market is 3 to 5 years away at minimum, and clinical-trial enrollment through a Chinese academic cancer center is the most accessible near-term path. As the AK138D1-202 data mature and the broader IO+ADC field becomes clearer, we will update this site with the most relevant developments for international patients considering their options.