FDA Receives BLA for Ivonescimab in EGFR+ NSCLC

A biologics license application (BLA) has been submitted to the FDA for ivonescimab (AK112) for use in combination with chemotherapy. The proposed indication targets the treatment of patients with EGFR-mutated, locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) who have experienced disease progression following treatment with an EGFR tyrosine kinase inhibitor (TKI).

"This BLA submission, the first for ivonescimab, marks a critical milestone for Summit, our global clinical development plan, and the many patients with EGFR[-mutated] NSCLC in need of better therapeutics options," stated Robert W. Duggan and Maky Zanganeh, MD, co-CEOs of Summit Therapeutics, the sponsor, in a news release. "As we continue to support and expand ivonescimab’s rapid development via our growing set of global phase [3] trials and clinical collaborations, we look forward to the potential first US approval for ivonescimab in this difficult-to-treat setting."

BLA Submission and Regulatory Context

The submission marks a significant milestone for ivonescimab, a first-in-class bispecific antibody. The FDA previously granted breakthrough therapy designation for this indication, a status intended to expedite the development and review of drugs that demonstrate the potential for substantial improvement over existing therapies in serious conditions.

The BLA is primarily supported by data from the HARMONi/AK112-301 trial (NCT05184712).² This multicenter, double-blind, randomized phase 3 study evaluated the efficacy of ivonescimab combined with pemetrexed and carboplatin compared with a placebo plus the same chemotherapy regimen. The study population included patients who had progressed on a third-generation TKI, such as osimertinib (Tagrisso), which is currently the standard of care in the first-line setting for EGFR-mutated NSCLC.

Clinical Efficacy and Safety Profile

In the HARMONi trial, ivonescimab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with the chemotherapy-only cohort. Data published in 2024 in JAMA showed that, among 322 enrolled patients in the ivonescimab and placebo groups, the median PFS was 7.1 (95% CI, 5.9–8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2–5.6) months for placebo (difference, 2.3 months; HR, 0.46; 95% CI, 0.34–0.62; P <.001).³ The prespecified subgroup analysis showed PFS benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48; 95% CI 0.35–0.66) and those with brain metastases (HR, 0.40; 95% CI, 0.22–0.73).

The objective response rate was 50.6% (95% CI, 42.6%–58.6%) with ivonescimab and 35.4% (95% CI, 28.0%–43.3%) with placebo (difference, 15.6%; 95% CI, 5.3%–26.0%; P =.006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related AEsoccurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher VEGF-related AEs occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group.

Mechanism of Action: Dual Pathway Inhibition

Ivonescimab represents a novel therapeutic approach in oncology. As a bispecific antibody, it is designed to simultaneously block the PD-1 and VEGF pathways.^1,3

The rationale for this dual inhibition is based on the synergistic relationship between angiogenesis and immune evasion within the tumor microenvironment. VEGF inhibition not only limits tumor blood supply but also promotes the maturation of dendritic cells and increases the infiltration of T-cells into the tumor. By combining this with PD-1 blockade, ivonescimab aims to reverse immune suppression more effectively than monotherapy or separate combination regimens. This is particularly relevant in EGFR-mutated NSCLC, which has historically shown limited response to single-agent immune checkpoint inhibitors.

Future Outlook

Should the FDA approve the BLA, ivonescimab would become the first PD-1/VEGF bispecific antibody available in the United States.¹

Summit Therapeutics, in collaboration with Akeso Inc, continues to expand its clinical development program for ivonescimab, exploring its utility across various solid tumors where the dual inhibition of PD-1 and VEGF may provide therapeutic advantages over current standards of care.

REFERENCES

1. Summit Therapeutics announces submission of biologics license application (BLA) to U.S. FDA seeking approval for ivonescimab in combination with chemotherapy in 2l+ treatment of patients with EGFRm NSCLC. News release. Summit Therapeutics. January 12, 2026. Accessed January 13, 2026. https://tinyurl.com/yc6994hj

2. Phase 3 clinical study of AK112 for NSCLC patients. ClinicalTrials.gov. Updated June 28, 2024. Accessed January 13, 2026. https://clinicaltrials.gov/study/NCT05184712

3. Fang W, Zhao Y, Luo Y, et al. ivonescimab plus chemotherapy in non-small cell lung cancer with egfr variant: a Randomized Clinical Trial. JAMA. 2024 Aug 20;332(7):561-570. doi: 10.1001/jama.2024.10613. PMID: 38820549; PMCID: PMC11337070.