FDA Accepts BLA for Ivonescimab in Pretreated EGFR-Mutated NSCLC

The FDA has accepted for filing a biologics license application (BLA) for ivonescimab (AK112) in combination with chemotherapy for the treatment of patients with EGFR-mutated, locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC).¹ The application specifically targets patients whose disease has progressed following treatment with a third-generation tyrosine kinase inhibitor (TKI), such as osimertinib (Tagrisso).

The FDA has assigned a Prescription Drug User Fee Act goal action date of November 14, 2026. This regulatory milestone marks the first BLA acceptance for a PD-1/VEGF bispecific antibody in the United States. If approved, ivonescimab could redefine the second-line therapeutic landscape for the approximately 14,000 US patients annually who face limited options after TKI failure.

Clinical Efficacy: Results from the HARMONi Trial

The BLA submission is supported by data from the multi-regional, phase 3 HARMONi trial (NCT06396065). The study evaluated the efficacy and safety of ivonescimab combined with platinum-doublet chemotherapy (pemetrexed and carboplatin) compared to placebo plus the same chemotherapy regimen.²

According to the data cited in the application, the ivonescimab-based regimen demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS).¹ Independent radiographic review committee assessment identified a median PFS of 6.8 months in the ivonescimab arm vs 4.4 months in the placebo arm. This corresponds to a hazard ratio (HR) of 0.52 (95% CI, 0.41-0.66; P <.0001), representing a 48% reduction in the risk of disease progression or death.

Secondary end points also favored the investigational arm, including a 6-month PFS rate of 54.0% for ivonescimab vs 34.7% for the control. Notably, subgroup analyses indicated a consistent benefit across various patient demographics, including those with brain metastases (HR, 0.40; 95% CI, 0.22-0.73), a population that typically presents significant management challenges in thoracic oncology.

Mechanism of Action: PD-1 and VEGF Synergy

Ivonescimab is a first-in-class bispecific antibody designed with a tetravalent structure that simultaneously binds to PD-1 and VEGF. This dual-target approach aims to exploit the physiological synergy between immune checkpoint inhibition and antiangiogenesis.

From a clinical standpoint, the simultaneous inhibition of these pathways is intended to reverse the immunosuppressive tumor microenvironment (TME). VEGF is a known mediator of immunosuppression, contributing to the recruitment of myeloid-derived suppressor cells (MDSCs) and regulatory T cells while inhibiting the maturation of dendritic cells. By neutralizing VEGF locally within the TME, ivonescimab may enhance the infiltration and activation of cytotoxic T cells, thereby potentiating the anti-tumor immune response mediated by PD-1 blockade.

Furthermore, the cooperative binding property of ivonescimab allows it to preferentially accumulate in tissues where both PD-1 and VEGF are highly expressed—typically the tumor site—potentially narrowing the therapeutic window and reducing systemic toxicities compared to combinations of separate agents.

Trial Design and Safety Profile

The HARMONi trial enrolled patients with histologically or cytologically confirmed unresectable locally advanced or metastatic nonsquamous NSCLC harboring EGFR-sensitizing mutations (exon 19del or L858R).² All patients had progressed on or following a third-generation EGFR TKI.

The safety profile of ivonescimab remained consistent with previous studies.¹ Grade 3 or higher treatment-emergent adverse events (TEAEs) were primarily chemotherapy-related, including neutropenia and anemia. Immune-related AEs and VEGF-related toxicities (such as hypertension or proteinuria) were reported but generally manageable within the clinical setting. The incidence of grade 3 or higher VEGF-related AEs was approximately 3.1% in early datasets, supporting a favorable benefit-risk profile in this pretreated population.

Future Outlook and Ongoing Investigations

Ivonescimab was originally developed by Akeso Inc and is already approved in China, where over 60,000 patients have been treated commercially. Summit Therapeutics holds the rights for development and commercialization in North America, South America, Europe, and other global regions.

Beyond the EGFR-mutated setting, ivonescimab is being investigated in other phase 3 trials, including HARMONi-3 (NCT05899608), which compares ivonescimab plus chemotherapy with pembrolizumab (Keytruda) plus chemotherapy in first-line squamous NSCLC, and HARMONi-7 (NCT06767514), a head-to-head monotherapy trial against pembrolizumab in patients with high PD-L1 expression.

REFERENCES

1. Summit Therapeutics announces U.S. FDA acceptance of biologics license application (BLA) seeking approval for ivonescimab in combination with chemotherapy in treatment of patients with EGFRm NSCLC post-TKI therapy. News release. Summith Therapeutics. January 29, 2026. Accessed January 29, 2026. https://tinyurl.com/yetu55nn

2. Phase III study of AK112 for NSCLC patients. ClinicalTrials.gov. Updated October 8, 2024. Accessed January 29, 2026. https://clinicaltrials.gov/study/NCT06396065