Summit's PD-1xVEGF Drug Shows Mixed Results in Global Trial, Raising Questions About Regional Consistency

Summit Therapeutics' closely watched PD-1xVEGF antibody, ivonescimab, has yielded mixed results in its first global phase 3 trial, challenging claims of regional consistency while still offering a glimmer of hope for potential approval. The detailed data, presented at the 2025 World Conference on Lung Cancer, paint a complex picture of the drug's performance across different patient populations.

Progression-Free Survival Data Reveals Regional Disparities

The HARMONi trial, which evaluated ivonescimab in combination with chemotherapy for second-line EGFR-mutated non-small cell lung cancer (NSCLC), initially reported a 48% reduction in the risk of disease progression or death. However, longer-term follow-up data revealed significant differences between Chinese and Western patient populations.

In European and North American patients, ivonescimab's progression-free survival (PFS) improvement was 33% (hazard ratio 95% CI: 0.45-1.00), notably lower than the 45% recorded in Chinese patients. This 12-percentage-point difference exceeded the 10-percentage-point threshold that some analysts considered the limit for claiming similarity between populations.

Summit's chief business and strategy officer, Dave Gancarz, defended the results, stating, "I think the reality is that the Chinese patients are not completely identical to the North American patients." He noted that about 14% of patients in the China-only HARMONi-A trial had only received earlier-generation EGFR inhibitors, unlike the Western cohort in HARMONi.

Overall Survival Data Offers New Hope

While the trial missed its overall survival (OS) endpoint in the primary analysis, newly updated data presented at WCLC suggest that ivonescimab may still have a chance at approval. A fresh analysis with a September data cut showed an expanded death risk reduction of 22% (HR 95% CI: 0.62-0.98) with an improved nominal p value of 0.0332 for the overall population.

The subgroup analysis revealed:

• 16% risk reduction (HR 95% CI: 0.53-1.32) for North American and EU patients
• 30% risk reduction (HR 95% CI: 0.38-1.30) for North American patients specifically
• 24% risk reduction (HR 95% CI: 0.58-0.99) for Chinese patients

Although these results are not statistically significant, they provide a more consistent picture across regions compared to the PFS data. The median overall survival was 17 months for Western patients, not reached for North American patients, and 16.7 months for Chinese patients.

Implications for Approval and Future Development

The FDA has previously indicated that a statistically significant OS benefit is necessary to support an approval in second-line EGFR-mutated NSCLC. While the current data do not meet this threshold, analysts suggest that meaningful OS benefit in the Western subgroup, combined with robust PFS, could still persuade regulators.

Summit intends to seek FDA approval but has not yet decided on the exact timing or dataset to be submitted. "We're very encouraged by this data," Gancarz said, adding that the company is still evaluating next steps.

The results from HARMONi raise important questions about the global applicability of clinical trial data, particularly when comparing outcomes between Chinese and Western populations. As the pharmaceutical industry continues to grapple with these issues, the case of ivonescimab serves as a crucial example of the challenges and opportunities in global drug development.