Summit Therapeutics’ Ivonescimab Shows Promise in Phase III Lung Cancer Trial Despite Mixed Results

May 30, 2025

Summit Therapeutics’ Ivonescimab Shows Promise in Phase III Lung Cancer Trial Despite Mixed Results

Key Takeaways:

Ivonescimab met progression-free survival endpoint with 48% risk reduction
Overall survival missed statistical significance (p=0.057)
FDA approval pathway complicated by mixed primary endpoints
PD-1/VEGF bispecific market remains highly competitive

Phase III HARMONi Trial Results: A Detailed Analysis

Summit Therapeutics Inc. (NASDAQ: SMMT) announced results from its pivotal HARMONi Phase III trial, testing ivonescimab in EGFR-mutated non-small cell lung cancer (NSCLC). The bispecific antibody demonstrated a statistically significant improvement in progression-free survival (PFS) but failed to reach significance for overall survival (OS).

Primary Endpoint Performance

The trial evaluated ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with EGFR-mutated NSCLC who progressed after EGFR tyrosine kinase inhibitor therapy. Key results include:

Progression-Free Survival: Hazard ratio 0.52 (48% risk reduction) – Met primary endpoint
Overall Survival: Hazard ratio 0.79 (p=0.057) – Missed statistical significance
Patient Population: Global trial with 38% Western enrollment

Regulatory Challenges for Ivonescimab Approval

The FDA has indicated that statistically significant overall survival benefit would be necessary for marketing authorization in this indication. This regulatory stance reflects the agency’s cautious approach in populations where PD-1 monoclonal antibodies have previously failed to demonstrate benefits in global Phase III trials.

Historical Context: PFS vs OS in NSCLC Approvals

Analysis of FDA-approved solid tumor therapies reveals evolving endpoint acceptance:

1995-2006: Overall survival primary focus
2007-2009: Shift toward PFS acceptance begins
Current landscape: PFS-OS correlation remains contentious (R² = 0.69)

Among 19 randomized NSCLC trials supporting FDA approvals since 1990:

9 trials showed improvements in both OS and PFS
6 trials showed PFS improvement only
3 trials showed OS improvement only

Ivonescimab: Next-Generation Bispecific Technology

Mechanism of Action

Ivonescimab represents a novel PD-1/VEGF bispecific antibody designed to:

Block PD-1 for immunotherapy effects
Inhibit VEGF for anti-angiogenic effects
Utilize tetravalent structure for “cooperative binding”
Achieve multifold higher PD-1 affinity when VEGF is present

Previous Clinical Success

The China-only HARMONi-2 study demonstrated ivonescimab’s potential:

49% risk reduction vs. pembrolizumab (Keytruda) in first-line PD-L1+ NSCLC
Median PFS: 11.14 months vs. 5.82 months for pembrolizumab
Consistent benefit across squamous and non-squamous histologies

Competitive Landscape: PD-1/VEGF Bispecific Market

Major Players and Pipeline

The PD-1/VEGF bispecific space has intensified with at least eight major programs:

BioNTech: BNT327 in global Phase III trials
Pfizer/3SBio: $1.3 billion licensing deal for SSGJ-707
OncoC4/Ottimo Pharma: Next-generation VEGFR2-targeting approaches
Multiple Chinese biotechs: Dominating early innovation

Partnership Dynamics

Summit’s licensing agreement with Akeso represents one of biotech’s largest recent partnerships:

Total value: Up to $5 billion
Geographic scope: North America, South America, Europe, Middle East, Africa, Japan
Strategic significance: Access to breakthrough Chinese innovation

Market Impact and Investment Implications

Immediate Market Response

The mixed Phase III results impacted Summit’s $2.8 billion market capitalization and raised broader questions about bispecific antibody valuations. The results highlight both the promise and challenges of next-generation immunotherapies.

Geographic Innovation Centers

Nearly all PD-1/VEGF bispecific candidates originate from Chinese biotechnology companies, creating:

Opportunities: Western partnerships for global development
Challenges: Dependence on international licensing
Strategic implications: Need for early-stage collaboration

Strategic Considerations for Biotech Executives

Regulatory Strategy Lessons

Endpoint Selection: PFS acceptance creates accelerated pathways, but OS remains gold standard
Trial Design: Multiregional studies essential for global approval
Competitive Timing: First-mover advantage may be limited in rapidly advancing fields

Development Priorities

Careful endpoint strategy aligned with regulatory expectations
International partnership development for breakthrough technologies
Differentiated positioning in crowded competitive landscapes

Looking Forward: Regulatory Path and Market Dynamics

Summit plans to proceed with regulatory filing despite the OS miss, though timing remains under consideration. The decision reflects calculated risk-taking in an increasingly stringent regulatory environment.

Key Questions for the Industry

Will FDA accept totality of evidence across multiple ivonescimab trials?
How will competitive dynamics evolve as Chinese innovations reach global markets?
What role will overall survival continue to play in accelerated approval pathways?

What We Should Take Away From This

The HARMONi Phase III results demonstrate both the clinical potential and regulatory complexity of next-generation bispecific antibodies. While the 48% PFS improvement validates the PD-1/VEGF approach, the OS miss underscores challenges in translating surrogate endpoints to definitive patient outcomes.

For biotech professionals, these results highlight the critical importance of regulatory strategy in competitive oncology markets. As the bispecific antibody field matures, success will require not just breakthrough science, but sophisticated understanding of regulatory pathways and competitive positioning in a rapidly evolving landscape.

The ultimate test for ivonescimab—and the broader PD-1/VEGF bispecific class—will determine whether regulatory agencies embrace the totality of evidence or maintain strict adherence to overall survival standards in this high-stakes therapeutic arena.

About Summit Therapeutics: Summit Therapeutics (NASDAQ: SMMT) is a biopharmaceutical company focused on developing innovative cancer treatments through partnerships with leading global biotechnology companies.

Investment Disclosure: This article is for informational purposes only and does not constitute investment advice. Readers should conduct their own research before making investment decisions.