Akeso's Phase II ADC+IO Combination Enters Uncharted First-Line Breast Cancer Territory With No Validating Precedent

Akeso Doses First Patient in Phase II Breast Cancer Trial

Akeso has initiated a Phase II clinical trial, dosing the first patient with a combination of AK146D1, a TROP2/Nectin-4 bispecific antibody-drug conjugate, and ivonescimab, a PD-1/VEGF bispecific antibody. This study targets advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer and triple-negative breast cancer as a first-line treatment. The trial is part of Akeso's "IO2.0 + ADC2.0" strategy, aiming to enhance efficacy and tolerability by combining immuno-oncology agents with next-generation ADCs.

• Akeso's "IO2.0 + ADC2.0" strategy combines immuno-oncology agents and next-generation antibody-drug conjugates to address major cancers. This innovative approach aims to overcome the therapeutic limitations of earlier ADCs and improve treatment outcomes by leveraging synergistic mechanisms.
• The Phase II trial evaluates AK146D1, a TROP2/Nectin-4 bispecific ADC, which has previously demonstrated favorable anti-tumor activity and a manageable safety profile in earlier clinical investigations. It is combined with ivonescimab, a first-in-class PD-1/VEGF bispecific antibody, which has shown superior clinical performance compared to PD-1 inhibitor-based therapies in several Phase III studies.
• The study specifically targets advanced breast cancer, focusing on its use as a first-line treatment for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer and triple-negative breast cancer. The trial's primary objective is to assess whether this combination can increase efficacy while maintaining manageable tolerability for patients.

Assessing the Safety Profile of AK146D1 and Ivonescimab

Published safety and tolerability data for ivonescimab (AK112) derive primarily from phase 1 dose-escalation studies conducted in patients with advanced solid tumors. In a phase 1a study conducted in Chinese patients, treatment-related adverse events (TRAEs) were reported in 89.8% of participants. The most frequently observed TRAEs included proteinuria (33.9%), aspartate aminotransferase (AST) elevation (27.1%), white blood cell count decrease (22.0%), alanine aminotransferase (ALT) elevation (20.3%), and anemia (20.3%). Grade ≥3 TRAEs occurred in 23.7% of patients, with serious TRAEs in 11.9%. Notably, only one dose-limiting toxicity (DLT) was identified in the 10 mg/kg Q2W cohort, no treatment-related deaths were reported, and no dose-dependent escalation in adverse event frequency was observed — a reassuring tolerability signal at this stage of development.

A separate phase 1a dose-escalation study established a maximum tolerated dose (MTD) of 20 mg/kg every two weeks, with two DLTs reported at the 30 mg/kg dose level. Grade ≥3 TRAEs occurred in 27.5% of patients in this cohort. The most common TRAEs across all grades included rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%), and pruritus (11.8%) — a profile broadly consistent with the combined mechanism of PD-1 and VEGF pathway inhibition. The most frequently reported grade ≥3 TRAEs were hypertension (13.7%), ALT increase (5.2%), AST increase (3.9%), and colitis (3.9%), reflecting toxicities attributable to both the anti-angiogenic and immune checkpoint components of the molecule.

No published safety or tolerability data for AK146D1 were identified in the available literature at this time. The current evidence base is therefore limited to ivonescimab's phase 1 findings, which collectively suggest a manageable safety profile at recommended doses, with adverse event patterns that align with the known class effects of anti-PD-1 and anti-VEGF agents. Further data from ongoing and later-phase studies will be critical to fully characterising the long-term tolerability of ivonescimab across its investigated indications.

Targeting Unmet Needs in Advanced Breast Cancer Subtypes

Advanced breast cancer remains a therapeutic frontier defined by biologically heterogeneous patient populations, many of whom continue to face inadequate treatment options despite recent advances. Over the past three years, clinical and translational research has increasingly converged on several high-priority unmet needs, spanning disease subtype, resistance mechanisms, and metastatic patterns.

• Brain and leptomeningeal metastases in HER2-positive disease: Approximately 31% of patients with HER2-positive metastatic breast cancer develop brain metastases, representing a historically underserved population. Trastuzumab deruxtecan (T-DXd) has demonstrated a 64.9% objective response rate in patients with active brain metastases, while tucatinib (HER2CLIMB trial) reduced intracranial progression by 68% and improved overall survival (24.7 vs. 19.2 months). Leptomeningeal metastases present an even more acute unmet need, with T-DXd achieving clinical benefit rates of 71.4–100%, median OS of 10.4–13.3 months, and median PFS of 8.9–17.5 months across studies.

• HER2-low and HER2-ultralow breast cancer: Approximately 80% of invasive breast cancers are classified as HER2-negative, yet many harbor detectable HER2 surface expression. Roughly 50% of primary or metastatic breast cancers qualify as HER2-low (IHC 1+ or IHC 2+/ISH−). DESTINY-Breast04 established T-DXd's clinical benefit in HER2-low disease after prior chemotherapy, while DESTINY-Breast06 extended this benefit to HER2-ultralow tumors (IHC 0 with membrane staining) in HR-positive patients who had not received prior chemotherapy in the advanced setting.

• Post-CDK4/6 inhibitor progression: Patients progressing after CDK4/6 inhibitor therapy represent a large and growing population with limited viable options. In the EMERALD trial control arm — where all patients had received prior CDK4/6 inhibition — median PFS on endocrine monotherapy was only 1.9 months. ESR1 mutation-mediated resistance defines a biologically distinct endocrine-resistant phenotype, for which next-generation oral selective estrogen receptor degraders (SERDs) are favored. For tumors with PIK3CA–AKT–PTEN pathway alterations, fulvestrant combined with capivasertib is preferred given its activity across PIK3CA, AKT1, and PTEN alterations with a manageable safety profile.

• Refractory triple-negative breast cancer (TNBC): Advanced TNBC carries poor prognosis due to its aggressive biology and limited post-first-line therapeutic options. The phase III ASCENT trial established sacituzumab govitecan's superiority over chemotherapy in relapsed/refractory TNBC, improving both median PFS and OS. Additionally, early-stage TNBC patients with residual invasive disease after neoadjuvant therapy remain at high recurrence risk; the OptimICE-RD trial is evaluating sacituzumab govitecan plus pembrolizumab versus physician's choice in this setting.

• Endocrine-independent and viscerally aggressive disease: Patients exhibiting rapid progression, visceral crisis, or endocrine-independent biology represent a clinically distinct population requiring early escalation of therapy. Current guidance recommends early transition to antibody-drug conjugates — including T-DXd or sacituzumab govitecan — in this context, given demonstrated superiority over conventional chemotherapy in appropriately selected patients. Short duration of response to CDK4/6 inhibitors, as a proxy for endocrine resistance, similarly supports earlier consideration of chemotherapy or ADC-based regimens.

Akeso's Broader Strategy for AK146D1 and Ivonescimab

Ivonescimab (AK112) is being evaluated across a broad range of oncology indications beyond advanced breast cancer, reflecting Akeso's ambition to position the asset as a platform bispecific. The trials span both early-phase dose-finding studies and pivotal Phase 3 registrational efforts, with intervention models ranging from single-arm designs to randomised controlled trials. No clinical trial data for AK146D1 in indications outside advanced breast cancer was identified in the available literature.

Akeso's Dual-Target Strategy: A New Frontier in Breast Cancer

The initiation of Akeso's Phase II trial, combining their novel AK146D1 (a TROP2/Nectin-4 bispecific antibody-drug conjugate) with ivonescimab (a PD-1/VEGF bispecific antibody), signals a significant strategic move in the oncology landscape. This 'IO2.0 + ADC2.0' approach is a bold attempt to redefine first-line treatment for advanced HR+/HER2- and triple-negative breast cancer, two indications notoriously difficult to treat and with substantial unmet needs. The rationale is compelling:

• Ivonescimab's dual blockade of PD-1 and VEGF aims to simultaneously relieve immunosuppression and inhibit tumor angiogenesis, pathways critical for tumor growth and immune evasion. Studies indicate that this bispecific approach can enhance antitumor immunity and potentially offer a more favorable toxicity profile than combining two separate agents.

• AK146D1 targets Nectin-4, a protein increasingly recognized as a promising ADC target in solid tumors, with existing evidence supporting its efficacy in other cancers like urothelial carcinoma. The bispecific nature of AK146D1 (TROP2/Nectin-4) suggests a multi-pronged attack on tumor cells.

This combination strategy seeks to leverage the synergistic effects of immunotherapy and targeted ADCs to overcome resistance mechanisms that often limit the effectiveness of monotherapies or simpler combinations. For Akeso, success in this trial would not only validate their innovative platform but also establish a strong foothold in a highly competitive and clinically challenging therapeutic area.

However, the path forward is not without its complexities. The combination of multiple potent agents, while promising for efficacy, necessitates careful evaluation of potential cumulative toxicities. Furthermore, the literature highlights the heterogeneity of Nectin-4 expression across different tumor subtypes, which could impact the broad applicability of AK146D1 and underscore the need for robust biomarker identification to select patients most likely to benefit. The emergence of resistance mechanisms, such as P-gp upregulation, also remains a consideration for long-term efficacy. Defining the optimal patient population and thoroughly characterizing the safety profile will be crucial for this novel combination to realize its full potential and unlock new horizons in breast cancer treatment.