Ivonescimab Beats Active Immunotherapy Standard in BTC: Magnitude Gap Remains the Decisive Unknown

Akeso's Ivonescimab Phase III OS Data Selected as ESMO Late-Breaking Abstract

Akeso, Inc. announced that nearly 30 clinical studies, primarily featuring its bispecific antibodies ivonescimab and cadonilimab, will be presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, from October 23–27. A key highlight is the selection of positive overall survival results from the Phase III HARMONi-GI1 trial for ivonescimab plus chemotherapy as a Late-Breaking Abstract for the Presidential Symposium. This trial evaluated ivonescimab against durvalumab plus chemotherapy as first-line treatment for advanced biliary tract cancer. Additionally, breakthrough data for ivonescimab in advanced renal cell carcinoma and recurrent/metastatic thymic carcinoma will be presented, alongside extensive data for cadonilimab across multiple tumor types.

• Akeso's ivonescimab, a PD-1/VEGF bispecific antibody, will be featured in a Late-Breaking Abstract at the ESMO 2026 Presidential Symposium. This presentation will detail positive overall survival results from the randomized, controlled, double-blind Phase III HARMONi-GI1 trial, which compared ivonescimab plus chemotherapy to durvalumab plus chemotherapy as a first-line treatment for advanced biliary tract cancer. This selection underscores the significance of the data in a difficult-to-treat malignancy.
• Beyond biliary tract cancer, ivonescimab's broad development will be highlighted in 12 presentations at ESMO 2026. This includes breakthrough data from rapid oral presentations on ivonescimab-based regimens as first-line treatment for advanced renal cell carcinoma and recurrent/metastatic thymic carcinoma. Further progress will be showcased in lung cancer (including brain metastases), gastrointestinal cancers (esophageal and gastric), pancreatic cancer, glioblastoma, endometrial cancer, and head and neck squamous cell carcinoma, demonstrating its versatility.
• Cadonilimab, the world's first PD-1/CTLA-4 bispecific antibody, will be featured in 15 presentations covering more than ten tumor types. These include gastric cancer, renal cell carcinoma, lung cancer, esophageal squamous cell carcinoma, colorectal cancer, nasopharyngeal carcinoma, ovarian cancer, soft tissue sarcoma, pleural mesothelioma, and rectal cancer. The studies span various treatment settings, such as neoadjuvant, first-line, and second-line for advanced disease, emphasizing the extensive anti-tumor potential of this dual checkpoint inhibitor.

HARMONi-GI1: Design and Impact on First-Line Advanced BTC

Several pivotal randomized trials have defined the evolving first-line and targeted therapy landscape for advanced biliary tract cancer (BTC), spanning chemo-immunotherapy combinations, FGFR-directed agents, and novel triplet regimens. The studies below represent the key trials with available design parameters and endpoint data.

The Persistent Challenges in Treating Advanced Biliary Tract Cancer

Advanced biliary tract cancer (BTC) remains one of oncology's most formidable therapeutic challenges, characterized by aggressive biology, late-stage presentation, and a historically narrow treatment arsenal. While recent advances in chemoimmunotherapy and precision oncology have begun to reshape the landscape, significant barriers to durable disease control persist.

• Limited efficacy of the established first-line standard of care. Gemcitabine plus cisplatin has long been the reference regimen for unresectable BTC, yet it is associated with early recurrence, high resistance rates, and a median overall survival of approximately 1 year. Molecular heterogeneity across and within BTC subtypes further constrains the uniform applicability of this regimen.

• Absence of a validated second-line regimen. Despite the clinical need, a universally accepted second-line treatment does not exist for patients who progress on gemcitabine-based therapy. Investigational options — including capecitabine plus nab-paclitaxel, PD-1/PD-L1 inhibitors combined with nab-paclitaxel and fluorouracil-based agents, and nanoliposomal irinotecan — have demonstrated modest or preliminary activity, but none has been established through large randomized controlled trials.

• Molecular heterogeneity and the complexity of biomarker-guided therapy. Actionable alterations — including FGFR2 fusions, IDH1/2 mutations, HER2 amplification, BRAF V600E, and MSI-H — are frequent in intrahepatic disease but vary in prevalence across geographic regions and etiologic backgrounds. Comprehensive genomic profiling is essential to enable matched targeted therapy, yet access and implementation remain inconsistent at a population level.

• Acquired resistance to targeted agents. FGFR inhibitors, while achieving objective response rates of 35%–42% in FGFR2-rearranged intrahepatic cholangiocarcinoma, are subject to acquired resistance driven by secondary kinase-domain gatekeeper mutations that bypass inhibitory effects or cause steric hindrance. This temporal heterogeneity under selective pressure limits the durability of responses and necessitates next-generation inhibitor strategies and combination approaches.

• Infectious and biliary complications that interrupt oncologic treatment. Approximately 70% of BTC patients present with advanced disease, and obstructive jaundice requiring biliary drainage is common. Cholangitis frequently develops following stenting or bilio-intestinal bypass, leading to rapid deterioration of general condition and necessitating interruption of systemic therapy — a dynamic that complicates treatment continuity and limits the interpretability of chemotherapy benefit in this population.

• Scarcity of validated predictive biomarkers. Few models with robust predictive value exist for BTC. Emerging translational markers such as lymphocyte-to-monocyte ratio (LMR) have suggested prognostic relevance — with median overall survival of 32.4 months versus 8.6 months in high versus low LMR groups — but evidence remains limited by single-center designs and small sample sizes, underscoring the need for prospective validation.

Ivonescimab's Expanding Development Across Multiple Tumor Types

Ivonescimab (AK112) is under active clinical investigation across a broad range of solid tumour indications beyond biliary tract cancer, reflecting its dual mechanism of simultaneously blocking PD-1/PD-L1-mediated immunosuppression and VEGF-A-driven tumour angiogenesis. Developed by Akeso Biopharma, the agent has generated regulatory approvals and late-phase trial data in lung cancer, with an expanding pipeline spanning multiple tumour types.

• EGFR-mutated locally advanced or metastatic non-squamous NSCLC (post-TKI): In May 2024, ivonescimab in combination with pemetrexed and carboplatin received its first approval in China for patients who progressed after TKI therapy. Network meta-analysis data place ivonescimab plus chemotherapy (SUCRA = 0.779) among the leading regimens for PFS in this setting, and a pooled analysis across 5 studies (1,365 patients) demonstrated a significant PFS benefit (HR = 0.53, 95% CI: 0.45–0.62) and improved ORR (OR = 1.65, 95% CI: 1.31–2.09) and DCR (OR = 2.29, 95% CI: 1.18–4.44) versus control treatments.

• Advanced squamous NSCLC (first-line): The randomised, double-blind, phase 3 HARMONi-6 trial evaluated ivonescimab (20 mg/kg IV) plus paclitaxel (175 mg/m²) and carboplatin (AUC 5 mg/mL per min) every 3 weeks for four cycles, followed by ivonescimab monotherapy maintenance for up to 24 months, versus tislelizumab plus the same chemotherapy backbone. Median PFS was 11·1 months (95% CI 9·9–not evaluable) with ivonescimab versus 6·9 months (5·8–8·6) with tislelizumab (HR 0·60 [95% CI 0·46–0·78]; one-sided p<0·0001), with benefit consistent regardless of PD-L1 status. A prespecified interim OS analysis (data cutoff Feb 27, 2026) reported median OS of 27·9 months (95% CI 27·89–NE) versus 23·7 months (20·11–NE) with tislelizumab (HR 0·66 [95% CI 0·50–0·87]; p=0·0017).

• Locally advanced pancreatic ductal adenocarcinoma: A case report documents ivonescimab combined with AG chemotherapy (nab-paclitaxel and gemcitabine) in a patient enrolled in a clinical trial. After 13 administrations of AG chemotherapy and 9 infusions of AK112, imaging demonstrated partial tumour regression sufficient for a multidisciplinary team to deem the lesion potentially resectable, and a total pancreatectomy was subsequently performed. The intervention model is combination therapy (ivonescimab plus AG chemotherapy), with broader efficacy across the pancreatic cancer population awaiting validation through large-scale clinical trials.

• Multiple additional solid tumours (phase 1a dose escalation): A first-in-human phase 1a study enrolled 51 patients with advanced solid tumours, administering ivonescimab at doses of 0.3, 1, 3, 10, 20, or 30 mg/kg IV every 2 weeks using a 3+3+3 escalation design, with dose expansion at 10 and 20 mg/kg. Efficacy signals were observed in platinum-resistant ovarian cancer (5/19 patients [26.3%] achieving partial response), mismatch repair proficient colorectal cancer, NSCLC, and both MMR-deficient and MMR-proficient endometrial cancer. The confirmed ORR across 47 evaluable patients was 25.5% (12/47) and DCR was 63.8% (30/47).

• Broader solid tumour pipeline (PD-1/VEGF bispecific class): Ivonescimab is one of 3 bispecific antibodies within the PD-1/VEGF target class, which accounts for 56 registered clinical trials (8.2% of the BsAb solid tumour pipeline). Akeso Biopharma is identified as a primary driver of this development, with ivonescimab featuring in 51 trials (7.5% of all BsAb solid tumour trials), spanning breast cancer, liver cancer, and gastric cancer, among other tumour types. Clinical studies are underway in multiple countries worldwide.

Akeso's Bispecifics: Redefining Standards in Challenging Cancers

The upcoming ESMO Congress is poised to be a pivotal event for Akeso, Inc., particularly with the late-breaking overall survival data from the Phase III HARMONi-GI1 trial for ivonescimab in first-line advanced biliary tract cancer (BTC). This is a disease area where current immune checkpoint inhibitor (ICI) plus chemotherapy regimens offer only marginal survival benefits, leaving a significant unmet need. The potential for ivonescimab, a PD-1/VEGF bispecific antibody, to demonstrate superior OS could redefine the standard of care, building on promising Phase II data that showed a 66.7% objective response rate and a median overall survival of 16.8 months.

This success would not only establish ivonescimab as a leading therapy in BTC but also validate Akeso's innovative bispecific antibody platform. The extensive data presentations for both ivonescimab and cadonilimab (a PD-1/CTLA-4 bispecific) across various solid tumors, including breakthrough data in advanced renal cell carcinoma and recurrent/metastatic thymic carcinoma, highlight a robust and diversified pipeline. This strategic focus on both prevalent and rare cancers, where treatment options are often limited, positions the company for significant market penetration.

However, the path forward is not without considerations:

• The safety profile of bispecific antibodies, while generally manageable, requires careful attention. For instance, cadonilimab has shown a notable incidence of immune-related adverse events (43.3% any grade, 11.3% grade ≥3), with increased treatment-related adverse events when combined with other agents. This underscores the importance of patient selection and proactive adverse event management.

• The identification of resistance biomarkers, such as MAP2K7 for ivonescimab in BTC, suggests that not all patients may benefit equally. This could necessitate the development of companion diagnostics or tailored combination strategies to optimize treatment outcomes.

• In rare indications like recurrent/metastatic thymic carcinoma, while the unmet need is high, emerging therapies like palbociclib and combinations of pembrolizumab and lenvatinib are already demonstrating activity, indicating a competitive environment for novel agents.

Ultimately, the strong showing at ESMO could solidify Akeso's position as a key innovator in oncology, leveraging its bispecific antibody technology to address challenging cancers and potentially reshape treatment paradigms.