Ivonescimab Secures Pivotal OS Win in NSCLC: Redefining the PD-1/VEGF Bispecific Landscape

Ivonescimab (AK112), developed by Akeso Biopharma and licensed to Summit Therapeutics, is redefining the PD-1/VEGF bispecific antibody landscape. The drug has demonstrated a 50% objective response rate (ORR) and 11.14-month progression-free survival (PFS) in first-line PD-L1–positive NSCLC (HARMONi-2, outperforming Keytruda), a statistically significant overall survival (OS) benefit in EGFR-mutant NSCLC (HARMONi-A, August 2025), and a PFS win in first-line squamous NSCLC (HARMONi-6). Together, these results highlight ivonescimab’s potential to reshape treatment standards across multiple NSCLC settings.

With two approvals in China, a third supplemental New Drug Application (sNDA) under review, and a $5 billion licensing deal with Summit, ivonescimab is emerging as a global oncology frontrunner. Commercial traction is strong: H1 2025 sales reached RMB 1,401.6 million, up 49.2% year-over-year, reflecting expanded NRDL access and growing physician adoption. A recent collaboration with Revolution Medicines further expands its reach.

Mechanism and Strategic Advantage

Ivonescimab is the first PD-1/VEGF bispecific antibody built on Akeso’s TETRABODY platform (IgG1 tetravalent). By simultaneously blocking PD-1 to restore immune response and VEGF to inhibit angiogenesis, the drug delivers synergistic anti-tumor activity in the tumor microenvironment.

Unlike pembrolizumab (Keytruda) or bevacizumab, ivonescimab offers both a chemo-free option in some settings and enhanced efficacy when paired with chemotherapy.

Regulatory Milestones in China

• First Indication (May 2024): Combination with chemotherapy for EGFR-mutated non-squamous NSCLC after EGFR-TKI progression. Listed in the NRDL (2025) and awarded a Class I recommendation in CSCO Guidelines.
• Second Indication (April 2025): Monotherapy in first-line PD-L1-positive NSCLC (TPS ≥1%), marking a novel chemo-free regimen; also included in the 2025 CSCO Guidelines.
• Third Indication (sNDA accepted, July 2025): Combination with chemotherapy for first-line squamous NSCLC (HARMONi-6), addressing the key limitation of bevacizumab, which is contraindicated in squamous disease.

Together with inclusion in eight clinical guidelines, these approvals secure ivonescimab’s place as a cornerstone of lung cancer treatment in China.

Clinical Data: Redefining NSCLC Standards

HARMONi-2 (Phase III, First-Line PD-L1 ≥1% NSCLC)

• Design: Ivonescimab monotherapy vs. pembrolizumab.
• Results: ORR 50% vs. 38.5% (Keytruda), DCR 89.9% vs. 70.5%, and median PFS 11.14 vs. 5.82 months. HR for PFS = 0.51.
• Significance: First bispecific to outperform Keytruda head-to-head in NSCLC. Full OS data expected at upcoming 2025 conferences.

HARMONi-A (Phase III, EGFR-Mutant NSCLC Post-TKI)

• Design: Ivonescimab + chemotherapy vs. chemotherapy alone.
• Results: Final analysis (Aug 2025): confirmed a statistically significant and clinically meaningful OS benefit, resolving earlier interim doubts (HRs shifted from ~0.72 to 0.80 with longer follow-up). PFS also improved (HR ≈0.46; 7.1 vs. 4.8 months).
• Significance: First PD-1/VEGF bispecific to show an OS win in EGFR-mutated NSCLC, a post-TKI setting with limited options. Chinese approval is now backed by robust long-term survival data.

HARMONi-6 (AK112-306, Phase III, First-Line Squamous NSCLC)

• Design: Ivonescimab + chemotherapy vs. tislelizumab + chemotherapy in 532 patients.
• Results: Met primary PFS endpoint (April 2025), with benefits in PD-L1–positive and –negative subgroups. Safety profile favorable, grade ≥3 bleeding events comparable to control.
• Significance: Offers the first PD-1/VEGF approach viable in squamous NSCLC, where bevacizumab is contraindicated.

Other Key Trials

• Phase II NSCLC data: ORR 53.5% (treatment-naïve), 68.4% (EGFR-mutant post-TKI), and 40% (post-PD-1/PD-L1 + chemotherapy).
• Ongoing Phase III trials:
  • Harmoni-8A: IO-resistant NSCLC (docetaxel combo)
  • AK112-311: SCLC consolidation post-chemoradiotherapy
  • AK112-312: First-line metastatic CRC vs. bevacizumab
  • AK112-310: First-line pancreatic cancer ± AK117 (CD47)
  • AK112-309: Biliary tract cancer vs. durvalumab combo (enrollment complete)
  • AK117-302: R/M HNSCC (PD-L1+) vs. pembrolizumab
  • AK112-308: First-line TNBC (PD-L1–negative) vs. chemotherapy
  • Global trials: Harmoni-3 (NSCLC chemo combo vs. Keytruda) and Harmoni-7 (PD-L1 high NSCLC vs. Keytruda monotherapy).

Safety Profile

Manageable profile with 29.4% grade ≥3 TRAEs. Most common: proteinuria (31.5%), AST increase (19.8%), hypercholesterolemia (16.2%).
No new safety signals in HARMONi-A final OS analysis or HARMONi-6, with bleeding events similar to controls — supporting broad utility, including in squamous NSCLC.

Strategic Partnerships

• Summit Therapeutics (2022): $500M upfront, up to $5B in milestones for ex-China rights. Summit’s market cap surged to ~$18B on ivonescimab momentum.
• Revolution Medicines (June 2025): Collaboration on RAS(ON) inhibitors.
• Pfizer (Feb 2025): Testing combinations with vedotin ADCs.

Expanding into Cold Tumors

Ivonescimab is being tested in colorectal, pancreatic, and biliary tract cancers, with five first-line Phase III trials targeting historically immune-cold tumors.

Market Impact and Future Outlook

Ivonescimab’s dual approvals, OS-confirming HARMONi-A results, and multiple Phase III wins make it a disruptive force in lung cancer therapy. The OS confirmation directly addresses earlier skepticism, solidifying its standard-of-care role in China and setting a precedent for PD-1/VEGF bispecifics globally.

Following its clinical success, ivonescimab is showing strong commercial traction. In H1 2025, Akeso reported commercial sales of RMB 1,401.6 million, a 49.2% year-over-year increase, reflecting expanded NRDL access and growing physician adoption.

Global momentum remains under watch:

• HARMONi-2: PFS superiority over Keytruda, but interim OS (22% death-risk reduction) not statistically significant.
• HARMONi (multinational): PFS benefit, OS trend positive but not yet significant; Summit expects follow-up may shift outcomes, especially in Western cohorts.

Ivonescimab will be presented for the second consecutive year in the WCLC 2025 Presidential Symposium (Sept 7, 2025), underscoring its global recognition. The HARMONi program is a multiregional, double-blind, placebo-controlled Phase III study evaluating ivonescimab plus platinum-doublet chemotherapy in EGFR-mutant NSCLC post-3rd generation TKI failure. Over 2,800 patients have been treated globally across HARMONi, HARMONi-3, and HARMONi-7, further validating its clinical breadth. Its tetravalent PD-1/VEGF bispecific design allows cooperative binding in the tumor microenvironment, potentially enhancing efficacy and selectivity. FDA Fast Track designation supports potential U.S. filings once mature OS data are available.

With the global bispecific antibody market worth $12B in 2024, ivonescimab is a high-stakes player. Data expected at WCLC and ESMO 2025, along with potential U.S. regulatory filings once mature OS data are available, will determine whether it can replicate its China success on the world stage.

Next: Explore the broader China PD-1/VEGF bispecific landscape and upcoming licensing opportunities in our follow-up analysis: Beyond Ivonescimab: China’s Next Billion PD-1/VEGF Bispecific Licensing Opportunities.

References

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