Akeso Inc. has announced positive overall survival (OS) results from the randomized, double-blind Phase III HARMONi-2 study, evaluating ivonescimab monotherapy versus pembrolizumab monotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors express positive PD-L1. In this preplanned secondary endpoint analysis, ivonescimab demonstrated a statistically significant improvement in OS compared to pembrolizumab, building on prior data that led to marketing authorization in China in April 2025. Full results are expected to be presented at the 2026 World Conference on Lung Cancer in Seoul, South Korea.

Clinical Takeaway

✔ Ivonescimab monotherapy achieved a statistically significant overall survival benefit over pembrolizumab monotherapy in PD-L1-positive advanced NSCLC, marking a notable outcome for a bispecific antibody in this setting.

✔ This OS result represents a preplanned secondary endpoint analysis in HARMONi-2, following a primary PFS analysis that already demonstrated a hazard ratio of 0.51, a result that supported Chinese regulatory approval.

✔ Ivonescimab remains investigational and unapproved in the United States, Europe, and other Summit Therapeutics license territories; however, global Phase III trials, including HARMONi-7 in PD-L1-high NSCLC, are actively enrolling.

Drug Profile & Mechanism

  • Drug name: Ivonescimab (AK112; known as SMT112 in Summit’s license territories including North America, South America, Europe, the Middle East, Africa, and Japan)
  • Drug class: Novel, potential first-in-class investigational bispecific antibody with a tetravalent structure (four binding sites)
  • Dual targets: Simultaneously blocks PD-1 (immune checkpoint; immunotherapy mechanism) and VEGF (anti-angiogenesis mechanism) within a single molecule
  • Cooperative binding: Engineered to display multifold higher affinity to PD-1 in the presence of VEGF, with avidity preferentially concentrated in the tumor microenvironment (TME) where both PD-1 and VEGF expression are elevated relative to normal tissue
  • Half-life: Approximately 6–7 days after first dose, increasing to approximately 10 days at steady-state dosing
  • Developer: Engineered by Akeso Inc. (HKEX: 9926.HK); licensed to Summit Therapeutics Inc. (NASDAQ: SMMT) for territories including the US and Europe

    • Target Population

    • Indication: Locally advanced or metastatic NSCLC
    • Biomarker requirement: Tumors with positive PD-L1 expression (encompasses both PD-L1 low and PD-L1 high subgroups)
    • Line of therapy: First-line setting
    • Histologies included: Both squamous and non-squamous NSCLC

    Study Design

    • Study name: HARMONi-2 (AK112-303)
    • Phase: Phase III
    • Design: Randomized, double-blind, active-controlled
    • Comparator: Pembrolizumab monotherapy
    • Geography: Single-region, multi-center study conducted entirely in China
    • Sponsor: Akeso Inc.; all data generated, managed, and analyzed exclusively by Akeso

    Endpoints

    • Primary endpoint: Progression-free survival (PFS) by Independent Radiologic Review Committee (IRRC)
    • Secondary endpoint (reported here): Overall survival (OS) — preplanned analysis

    Efficacy Outcomes

    • Overall Survival (secondary endpoint — current announcement):
      • Ivonescimab monotherapy demonstrated a statistically significant improvement in OS compared to pembrolizumab monotherapy in PD-L1-positive advanced NSCLC
      • Detailed OS data are scheduled for presentation at an upcoming medical conference
    • Progression-Free Survival (primary endpoint — prior analysis):
      • Hazard ratio (HR): 0.51 (95% CI: 0.38–0.69; p<0.0001) favoring ivonescimab over pembrolizumab
      • Clinically meaningful PFS benefit demonstrated across all evaluated subgroups:
      • — PD-L1 low expression
      • — PD-L1 high expression
      • — Squamous histology
      • — Non-squamous histology

    Regulatory Context

    • China (NMPA): Akeso received marketing authorization for ivonescimab from China’s National Medical Products Administration (NMPA) based on HARMONi-2 PFS data in April 2025; ivonescimab was initially approved in China in May 2024 and is commercially available for NSCLC indications
    • United States (FDA): Ivonescimab remains investigational and unapproved in Summit’s license territories; however, a Biologics License Application (BLA) for a separate indication (ivonescimab + chemotherapy in EGFR-mutated NSCLC post-third-generation EGFR TKI, based on the HARMONi study) was accepted for filing by the FDA in January 2026, with a PDUFA goal date of November 14, 2026
    • Europe: Ivonescimab is not approved by any regulatory authority in Europe

    Key Clinical Implications

    ✔ A statistically significant OS advantage over pembrolizumab monotherapy in PD-L1-positive NSCLC positions ivonescimab as a potentially practice-changing agent in this heavily contested first-line setting, where pembrolizumab has long been a standard of care.

    ✔ The combination of PFS HR of 0.51 and now a statistically significant OS benefit from HARMONi-2 reflects a clinically robust and consistent treatment effect, strengthening confidence in the biological rationale for dual PD-1/VEGF blockade.

    ✔ Subgroup consistency across PD-L1 low, PD-L1 high, squamous, and non-squamous histologies suggests broad applicability of ivonescimab’s mechanism beyond PD-L1 enriched populations, which may inform future biomarker strategies.

    ✔ HARMONi-7, the global Phase III trial directly comparing ivonescimab to pembrolizumab in PD-L1-high NSCLC, is now enrolling and will be critical for determining whether these survival benefits observed in China translate to Western patient populations and can support regulatory approval in the US and Europe.

    ✔ Clinicians should note that these data originate from a single-region China study; while robust, regulatory bodies in the US and Europe will require data from multiregional studies such as HARMONi-7 before any approvals in those territories can be considered.

    Bottom Line

    The HARMONi-2 OS data represent a significant milestone for ivonescimab, making it the first bispecific PD-1/VEGF inhibitor to demonstrate a statistically significant overall survival benefit over pembrolizumab monotherapy in a randomized Phase III trial in PD-L1-positive advanced NSCLC. Combined with consistent PFS superiority and cross-subgroup benefits, these results reinforce the clinical rationale for targeting both immune checkpoint and angiogenic pathways simultaneously.

    Sources

    Sources:

    • Summit Therapeutics Inc. (2025). Ivonescimab Monotherapy Demonstrates Statistically Significant Overall Survival Benefit Compared to Pembrolizumab Monotherapy in PD-L1-Positive Advanced NSCLC in HARMONi-2 Study Conducted by Akeso in China [Press Release]. Business Wire. https://www.businesswire.com
    • Zhong, et al. (2025). Ivonescimab cooperative binding and tetravalent structure. iScience. [Referenced in Summit Therapeutics press release as: Zhong, et al, iScience, 2025]