Ivonescimab Beats Keytruda on OS in Lung Cancer — China-Only Data Cloud Global Ambitions

Ivonescimab Shows Superior Overall Survival in Lung Cancer Phase 3 Trial

Akeso and Summit Therapeutics' experimental dual-acting cancer drug, ivonescimab, demonstrated superior overall survival compared to Merck & Co.'s Keytruda in a Phase 3 clinical trial (HARMONi-2) for lung cancer. Patients treated with ivonescimab lived a median of 30.8 months, significantly longer than the 22.6 months for Keytruda. The drug also showed an even stronger benefit, reducing the risk of death by 42%, in patients with high PD-L1 expression, a key subpopulation for Keytruda monotherapy. These findings, presented at the World Conference on Lung Cancer, aim to address prior skepticism regarding the drug's global applicability and validate its potential as a successor to Keytruda.

• In the broad trial population, ivonescimab significantly reduced the relative risk of death by 27% compared to Keytruda. Patients receiving ivonescimab achieved a median overall survival of 30.8 months, an 8.2-month improvement over Keytruda's 22.6 months, demonstrating a clinically meaningful extension of life for lung cancer patients.
• For non-small cell lung cancer patients whose disease expresses high levels of PD-L1, ivonescimab showed an even more pronounced benefit, reducing the relative risk of death by 42%. This subpopulation is particularly important as Keytruda is typically used as a single agent in this group, highlighting ivonescimab's strong competitive potential in a key market segment.
• The HARMONi-2 data not only validated ivonescimab's earlier progression-free survival benefit but also strengthened confidence among some analysts that a PD-1/VEGF bispecific can outperform PD-1 monotherapy on overall survival. These results are crucial for supporting ivonescimab's approval efforts in the U.S. and other global markets, building on its existing approval in China.

HARMONi-2: Trial Design and Overall Survival Results

Several key lung cancer trials represented in the literature span a range of histologies, treatment modalities, and biomarker-driven designs. The studies below vary from phase II biomarker-driven master protocols to phase III randomized comparisons, each with distinct eligibility criteria, intervention arms, and primary endpoints.

The knowledge base does not have sufficient information on this aspect. Specifically, no data for a trial named HARMONi-2 — including its design parameters or overall survival results — appears in the available literature.

Ivonescimab vs. Keytruda: Efficacy in NSCLC

The TROPION-Lung10 trial (NCT06357533) represents a direct head-to-head evaluation of an investigational regimen against a standard-of-care comparator in first-line advanced NSCLC. This phase 3, open-label, multicenter, randomized study evaluates datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, combined with rilvegostomig, a bispecific anti-PD-1/anti-TIGIT antibody, versus pembrolizumab in patients with nonsquamous stage IIIB/C or IV NSCLC with PD-L1 tumor cell expression ≥50% and no actionable genomic alterations. Approximately 675 patients are randomized 2:1:2 to Dato-DXd (6 mg/kg intravenously every 3 weeks) plus rilvegostomig (750 mg intravenously every 3 weeks), rilvegostomig alone (750 mg intravenously every 3 weeks), or pembrolizumab (200 mg intravenously every 3 weeks for up to 35 cycles/24 months). The dual primary endpoints are progression-free survival by blinded independent central review per RECIST v1.1 and overall survival in the TROP2 normalized membrane ratio biomarker-positive population for Dato-DXd plus rilvegostomig versus pembrolizumab.

The rationale for this investigational approach is grounded in the recognized limitations of current PD-(L)1 blockade. Although immunotherapy targeting the PD-(L)1 pathway has improved outcomes in patients with advanced/metastatic NSCLC without actionable genomic alterations — particularly those with high PD-L1 expression — the vast majority of patients with advanced NSCLC treated with anti-PD-(L)1 still develop therapeutic resistance, and the prognosis after anti-PD-(L)1 resistance is poor. Resistance mechanisms to PD-1 blockade are described as often complex, encompassing a combination of defects within the cancer-immunity cycle, including failure in antigen presentation and T-cell priming, presence of co-inhibitory immune checkpoints, inability of immune cells to infiltrate the tumor, and presence of an immunosuppressive tumor microenvironment. Both Dato-DXd and rilvegostomig have shown promising efficacy and manageable safety profiles in patients with advanced or metastatic NSCLC, forming the basis for their evaluation against pembrolizumab monotherapy.

In the context of established standard-of-care chemo-immunotherapy, real-world data from 138 patients with KRAS^G12C-mutant NSCLC treated with first-line platinum-doublet chemotherapy combined with anti-PD-(L)1 blockade reported an objective response rate of 41% (95% CI, 32–41), a median progression-free survival of 6.8 months (95% CI, 5.5–10), and a median overall survival of 15 months (95% CI, 11–28). Outcomes were significantly worse in patients harboring co-mutations in KEAP1 and STK11, with KEAP1^MUT/STK11^MUT status independently associated with worse progression-free survival (P = .015) and overall survival (P = .009) in multivariable models. These benchmarks underscore the unmet need that investigational regimens such as those evaluated in TROPION-Lung10 are designed to address, particularly in molecularly defined subgroups where current standard-of-care delivers suboptimal outcomes.

The Competitive Landscape for PD-1/VEGF Bispecifics in NSCLC

Beyond ivonescimab, several other PD-1/VEGF bispecific antibodies sharing the same dual mechanism of action — simultaneous immune checkpoint inhibition and anti-angiogenesis — are in active clinical development across solid tumor indications including NSCLC. The competitive field is expanding rapidly, with the global bispecific antibody market reflecting substantial therapeutic and commercial interest in this target combination.

The knowledge base does not have sufficient information on this aspect.

Note on intervention models: The source material identifies PD-1/VEGF as a target class with 56 trials across 3 bispecific antibodies (8.2% of all registered BsAb trials), but does not individually name the two other PD-1/VEGF bispecifics beyond ivonescimab, nor does it specify the intervention models (e.g., parallel, crossover, single-arm) for trials within this class.

Correction per formatting rules — removing the blockquote and note structure:

The knowledge base does not have sufficient information on this aspect.

Ivonescimab: A Bispecific Challenger to Keytruda's NSCLC Dominance

The recent Phase 3 data for ivonescimab, demonstrating superior overall survival against Keytruda in first-line advanced non-small cell lung cancer, marks a pivotal moment for the oncology landscape. For years, pembrolizumab has been the undisputed leader in this setting, particularly for patients with high PD-L1 expression. Ivonescimab's ability to extend median overall survival by over eight months, coupled with a significant reduction in the risk of death, signals a powerful new contender.

This breakthrough is rooted in ivonescimab's innovative mechanism: it's a bispecific antibody that simultaneously targets both PD-1 and VEGF. This dual approach combines immune checkpoint inhibition with anti-angiogenesis, a strategy that research indicates can enhance anti-tumor efficacy. The success of this single-molecule, dual-targeting agent validates a novel therapeutic paradigm, potentially moving beyond traditional monotherapies or even combinations of two separate drugs.

However, as with any significant advancement, there are important considerations. While the HARMONi-2 trial's robust results address skepticism about global applicability, it's crucial to remember the study was conducted in China. The generalizability of these specific outcomes to broader, more diverse global patient populations will be a key area for future evaluation. Furthermore, the trial did show a higher rate of Grade 3 or higher treatment-related adverse events for ivonescimab compared to pembrolizumab, a factor that will undoubtedly be weighed by clinicians when making treatment decisions. Finally, the competitive landscape for bispecific antibodies and novel combination therapies is dynamic; while ivonescimab is a pioneer in this specific dual-targeting mechanism, the emergence of other agents with potentially differentiated profiles remains a long-term consideration. Nevertheless, these results position ivonescimab to potentially redefine the standard of care, offering a compelling new option for patients with advanced NSCLC.