Ivonescimab Beats Durvalumab Head-to-Head in BTC: Magnitude Gap Remains the Critical Unknown

Akeso's Ivonescimab Achieves Significant OS in First-Line BTC

Akeso, Inc. announced that its Phase III HARMONi-GI1 study, evaluating ivonescimab combined with chemotherapy for first-line advanced biliary tract cancer (BTC), met its primary endpoint of overall survival (OS). An interim analysis by the Independent Data Monitoring Committee (IDMC) showed a clinically meaningful and statistically significant positive OS result compared to durvalumab plus chemotherapy, the current standard of care. The study also achieved all key secondary endpoints, including progression-free survival (PFS) and objective response rate (ORR). This marks the first Phase III study in BTC to demonstrate a statistically significant positive OS against the global gold standard, representing a major breakthrough for this difficult disease.

• The HARMONi-GI1 Phase III study, assessing ivonescimab in combination with chemotherapy for first-line advanced biliary tract cancer, successfully met its primary endpoint of overall survival (OS). An independent data monitoring committee's interim analysis confirmed a clinically meaningful and statistically significant positive OS benefit, positioning ivonescimab as a potential new standard of care against the current global gold standard of durvalumab plus chemotherapy.
• Beyond the primary OS endpoint, the study also achieved all key secondary endpoints, including progression-free survival (PFS) and objective response rate (ORR). This outcome is particularly significant as HARMONi-GI1 is the first Phase III study in biliary tract cancer to demonstrate a statistically significant positive OS result when compared directly to the established PD-L1 monoclonal antibody plus chemotherapy regimen, marking a major milestone in treating this aggressive disease.
• This positive result for HARMONi-GI1 represents ivonescimab's first successful Phase III study in gastrointestinal tumors, building upon four previous positive Phase III outcomes in lung cancer. This expansion of clinical value from lung cancer to a broader range of solid tumors underscores the drug's potential and Akeso's commitment to making this innovative therapy available to patients worldwide, with detailed results anticipated at an upcoming international conference.

Ivonescimab's OS Advantage Over SOC in Advanced BTC

The treatment landscape for advanced biliary tract cancer (BTC) has evolved substantially over the past several years. Gemcitabine plus cisplatin (GemCis) served as the long-standing first-line standard of care until the landmark TOPAZ-1 and KEYNOTE-966 trials established immunotherapy-chemotherapy combinations as the new benchmark. In TOPAZ-1, the addition of durvalumab to GemCis yielded a median OS of 12.8 months versus 11.5 months with placebo (HR 0.80; 95% CI 0.66–0.97), while KEYNOTE-966 demonstrated a median OS of 12.7 months with pembrolizumab versus 10.9 months with placebo (HR 0.83; 95% CI 0.72–0.95). A subsequent meta-analysis confirmed the OS superiority of both GemCis plus pembrolizumab (HR 0.99; p <0.001; RMST gain +1.1 months) and GemCis plus durvalumab (HR 0.98; p = 0.015; RMST gain +2.5 months) over GemCis alone. Other first-line combinations have also demonstrated OS benefit over GemCis alone, including GemCis plus S-1 (HR 0.97; RMST gain +2.8 months) and GemCis plus nab-paclitaxel (HR 0.98; RMST gain +2.1 months).

In the second-line setting, therapeutic options remain limited but have expanded incrementally through targeted and cytotoxic strategies. The phase 3 ABC-06 trial established FOLFOX plus active symptom control (ASC) as a standard second-line option, with a median OS of 6.2 months versus 5.3 months for ASC alone (adjusted HR 0.69; 95% CI 0.50–0.97; p = 0.031), and improved 12-month OS rates of 25.9% versus 11.4%, respectively. For biomarker-selected populations, pemigatinib — a selective FGFR1–3 inhibitor — received FDA approval in April 2020 for previously treated advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements, while ivosidenib, an IDH1 inhibitor, demonstrated improved progression-free survival versus placebo in the phase 3 ClarIDHy trial.

Emerging combination strategies in later lines of therapy have also shown preliminary clinical activity. In HER2-positive BTC, a phase 2 trial of trastuzumab plus FOLFOX as second- or third-line treatment yielded an ORR of 29.4% (95% CI 16.7–46.3), median PFS of 5.1 months, and a median OS of 10.7 months. A separate phase 2 trial evaluating nab-paclitaxel plus sintilimab in the second-line setting reported an ORR of 26.9%, median PFS of approximately 5.6 months (169 days; 95% CI 60–278 days), and a notably prolonged median OS of approximately 14.7 months (442 days; 95% CI 298–586 days). Collectively, these data underscore the incremental but meaningful advances being made across lines of therapy, while also highlighting the unmet need for more efficacious regimens in this difficult-to-treat malignancy.

HARMONi-GI1: Design and Endpoints in First-Line BTC

The first-line treatment landscape for advanced biliary tract cancer (BTC) has been shaped by several landmark randomized and single-arm trials evaluating chemotherapy backbones with or without targeted or immunotherapeutic agents. The table below summarizes the design parameters, patient populations, and key efficacy endpoints across these pivotal studies.

Ivonescimab's Growing Pipeline Beyond Biliary Tract Cancer

Ivonescimab is being investigated across a broad range of solid tumour indications beyond advanced biliary tract cancer, reflecting its dual mechanism targeting both PD-1 and VEGF pathways. Its most advanced approval to date is in EGFR-mutated locally advanced or metastatic non-squamous NSCLC, where it received first regulatory approval in China in May 2024. Phase 1a first-in-human data have further revealed preliminary efficacy signals across several additional tumour types.

Note: Specific intervention models (e.g., single-arm, randomised, combination backbone) for the investigational trials beyond the approved NSCLC indication are not available in the current literature base.

Ivonescimab's Breakthrough: A New Standard for First-Line BTC

The announcement of Akeso's ivonescimab achieving its primary endpoint of overall survival in first-line advanced biliary tract cancer (BTC) is a landmark event, signaling a potential paradigm shift in the treatment of this aggressive and often fatal disease. For years, patients with advanced BTC have faced a grim prognosis, with limited therapeutic options offering only modest benefits. The current standard of care, typically involving immune checkpoint inhibitors like durvalumab combined with chemotherapy, has provided some improvement, but the need for more impactful treatments has remained high.

Ivonescimab, a bispecific antibody designed to simultaneously target PD-1 and VEGF, represents an innovative approach. This dual mechanism aims to both unleash the immune system against cancer cells and starve tumors by inhibiting angiogenesis. The success of the HARMONi-GI1 study, particularly its ability to demonstrate superior overall survival against the established durvalumab-plus-chemotherapy regimen, underscores the potent synergistic potential of this bispecific strategy. This outcome not only validates the scientific premise behind dual-targeting antibodies but also positions ivonescimab to potentially become the new benchmark for first-line BTC therapy.

However, as with any significant advancement, certain considerations are paramount. The complete safety profile of ivonescimab in this combination will be crucial, especially given the known vascular-related adverse events associated with VEGF inhibition. Furthermore, while the initial data is compelling, understanding the long-term durability of response and identifying specific biomarkers that predict optimal patient selection will be key to maximizing its clinical utility and ensuring sustained benefit. The broader pharmaceutical landscape for BTC is also dynamic, with ongoing research into various immune-oncology combinations. Ivonescimab's entry will undoubtedly intensify competition, but its demonstrated superiority in overall survival against the current standard provides a strong foundation for market leadership and offers renewed hope for patients battling this challenging cancer.