Summit's Ivonescimab Shows Mixed Results in Phase III NSCLC Trial, Raising Questions for FDA Approval

Summit Therapeutics' bispecific antibody ivonescimab has demonstrated varied efficacy across different patient populations in its Phase III HARMONi trial for non-small cell lung cancer (NSCLC), potentially complicating its path to FDA approval. The trial results, presented at the 2025 World Conference on Lung Cancer, reveal geographical inconsistencies in overall survival (OS) benefits, particularly between Asian and Western patient cohorts.

Overall Survival Data Highlights Regional Disparities

In the Phase III HARMONi trial, ivonescimab, when combined with chemotherapy, showed a median overall survival of 16.8 months in Western patients, compared to 14 months in the placebo plus chemotherapy arm. This 22% benefit narrowly missed statistical significance with a p-value of 0.0332, falling short of the FDA's requirement for a statistically significant OS benefit to support marketing authorization.

The drug's performance varied significantly across regions:

• Asian patients experienced a 24% overall survival benefit
• Western subgroup (North America and European countries) saw a 16% reduction in the risk of death
• North American patients specifically showed a 30% OS benefit in favor of ivonescimab, though median OS had not been reached at the time of data cutoff

Progression-Free Survival and Mechanism of Action

Despite the OS data complexities, ivonescimab demonstrated more consistent results in progression-free survival (PFS):

• The drug reduced the risk of disease progression or death by 43% compared to the placebo arm
• This analysis included both Western and Asian patients with at least six months of follow-up

Ivonescimab's mechanism of action targets both the PD-1 and VEGF pathways, aiming to prevent tumor immune evasion and inhibit new blood vessel formation. This dual approach has garnered attention, especially after the drug outperformed Merck's Keytruda in the Phase III HARMONi-2 trial, showing significantly better PFS in advanced NSCLC patients.

Regulatory Challenges and Future Prospects

The geographical inconsistencies in ivonescimab's efficacy pose significant challenges for its regulatory pathway in the United States. While Summit Therapeutics initially expressed intentions to file a Biologics License Application, the company's latest statements have been more measured. Co-CEO Robert Duggan emphasized the drug's potential benefits to patients globally, "including the United States," without explicitly confirming plans for an FDA submission.

Industry analysts, including Truist Securities, have noted that ivonescimab's regulatory path in EGFR-mutant lung cancer remains uncertain and may depend on "an act of leniency by the FDA." As Summit Therapeutics navigates these challenges, the pharmaceutical industry watches closely to see how regulators will address the complexities of geographically diverse clinical trial results in the era of precision medicine.