Summit Therapeutics' Ivonescimab Shows "Positive Trend" in Overall Survival, but Misses Statistical Significance in Key Global Lung Cancer Trial

NEW YORK, NY – May 30, 2025 – Summit Therapeutics (NASDAQ: SMMT) today announced top-line results from its pivotal Phase III HARMONi clinical trial, evaluating its investigational bispecific antibody, ivonescimab, in combination with chemotherapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed after EGFR TKI therapy. While the trial met its primary endpoint of progression-free survival (PFS) with a statistically significant and clinically meaningful improvement, the other co-primary endpoint, overall survival (OS), did not achieve statistical significance, although it showed a positive trend.

The HARMONi trial demonstrated that ivonescimab plus chemotherapy significantly reduced the risk of disease progression or death, with a hazard ratio of 0.52 (95% CI: 0.41 – 0.66; p<0.00001). This robust PFS benefit was consistent across both Asian and Western patient populations, highlighting the potential global impact of ivonescimab.

After previously showing PFS that bested the stalwart Keytruda, it was with great anticipation that Summit Therapeutics reported overall survival for their HARMONi trial for EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed after EGFR TKI therapy. 

While the trial successfully met its primary endpoint of progression-free survival (PFS), the other co-primary endpoint, overall survival (OS), showed a positive trend but did not achieve statistical significance, with a hazard ratio of 0.79 (95% CI: 0.62 – 1.01; p=0.057). This did not cross the predefined threshold for statistical significance.

The FDA has previously indicated that a statistically significant overall survival benefit is a necessary factor to support marketing authorization for ivonescimab in this indication, which will be a key consideration for Summit's future regulatory filing plans.

Despite the miss on statistical significance for overall survival in this initial analysis, the clinically meaningful progression-free survival benefit and the positive trend in overall survival still represent a significant development for patients with this challenging form of lung cancer.

Currently, there are no FDA-approved regimens that have demonstrated a statistically significant overall survival benefit in this specific patient setting.

The safety profile of ivonescimab in combination with chemotherapy was reported as acceptable and manageable, with no new safety signals identified. Grade 3 or higher treatment-emergent adverse events were observed in 56.9% of patients in the ivonescimab arm versus 50.0% in the chemotherapy alone arm.

Summit Therapeutics plans to continue following patients for long-term outcomes to further mature the overall survival data. The full data set for HARMONi is expected to be presented at an upcoming major medical conference later this year, which will provide further insights into the potential of ivonescimab in this patient population.

This announcement comes after Summit Therapeutics' partner, Akeso, previously reported positive interim overall survival data for ivonescimab from the HARMONi-2 study in China, demonstrating a clinically meaningful trend favoring ivonescimab monotherapy over pembrolizumab in PD-L1 positive advanced NSCLC. The HARMONi-2 analysis showed a hazard ratio of 0.777 at 39% data maturity.

Investors will be closely watching for further updates from Summit Therapeutics as they navigate the regulatory path forward, particularly concerning the overall survival data which remains a critical component for potential marketing authorization in key global markets.

Implications for other bispecifics with PDL1/VEGF

Summit Therapeutics' ivonescimab miss on overall survival (OS) in the HARMONi trial has important implications for other PD-L1/VEGF bispecific antibodies and the broader oncology landscape.

1. OS Remains the Gold Standard for Regulatory Approval and Clinical Practice:

• FDA Scrutiny: The FDA's stance, reiterated by Summit, that a statistically significant OS benefit is generally required for approval in this indication.

• Physician Acceptance: Oncologists often prioritize therapies that demonstrate a clear OS advantage, especially in advanced disease settings. The lack of statistical significance for OS might temper enthusiasm and uptake, at least until further, more mature OS data becomes available.

• Competitive Landscape: The current standard of care in NSCLC, particularly for PD-L1 positive or negative disease in combination with chemotherapy, often involves regimens that have shown OS benefits New agents need to demonstrate competitive OS to displace these established treatments.

2. Challenges in Translating PFS to OS with Bispecifics:

• Subsequent Therapies: One of the most significant challenges in demonstrating an OS benefit in later-line settings (like EGFR TKI-resistant NSCLC) is the impact of subsequent therapies. Patients who progress on the control arm often receive other effective treatments, which can "dilute" or mask the OS benefit of the investigational drug in the earlier line. This is a common issue in oncology trials, especially with the increasing availability of effective subsequent lines of therapy.

• Toxicity and Treatment Duration: While ivonescimab’s safety profile was reported as manageable, any drug, especially a bispecific with dual mechanisms, carries potential for adverse events. If toxicities, even manageable ones, lead to treatment discontinuations, it can impact the ability to deliver sustained anti-tumor effect, which is crucial for OS. The balance between efficacy and tolerability for long-term treatment is key.

3. Implications for Other PD-L1/VEGF Bispecific Antibodies in Development:

• Higher Bar for OS: The ivonescimab results raises the bar for other PD-L1/VEGF bispecifics. These programs will likely face increased scrutiny regarding their OS data and will need to demonstrate clear and statistically significant OS benefits to gain regulatory approval and market traction.

• Focus on Patient Selection and Early Lines: Developers might increasingly focus on patient populations where the unmet need is higher or where the impact of subsequent therapies is less confounding (e.g., first-line settings, or specific biomarker-driven subgroups).

• Different Formats and Fc Regions: The design of bispecific antibodies, including the presence or absence of an Fc region (which impacts half-life and effector functions), could become a more prominent discussion point. Ivonescimab has Fc-silencing mutations, in order to reduce certain immune-related adverse events. Other bispecific formats might have different safety and efficacy profiles that could influence OS.

4. Continued Promise Despite the OS Miss (for now):

• Strong PFS is Still Valuable: It's important to remember that a statistically significant and clinically meaningful PFS benefit is still a strong positive. For patients who have progressed on EGFR TKIs, delaying disease progression is a significant outcome, even if OS isn't yet statistically improved. This could still lead to conditional approvals or specific indications where PFS is deemed sufficient.

• Longer Follow-up: As Summit noted, the OS data is not yet fully mature, especially for Western patients. Longer follow-up could eventually reveal a statistically significant OS benefit.

• Different Settings: Ivonescimab has shown positive results in other NSCLC settings (e.g., first-line squamous NSCLC head-to-head against a PD-1 inhibitor), suggesting its potential is broad. The implications of this specific OS miss might be limited to this particular patient population (EGFR-mutant, post-TKI).

In summary, Summit's HARMONi OS data highlights the inherent challenges of translating strong PFS benefits into statistically significant OS improvements in certain oncology settings, particularly with the confounder of subsequent therapies. While the strong PFS for ivonescimab is encouraging, the OS miss places a greater burden on the company to provide more mature data or explore alternative regulatory pathways. For the broader class of PD-L1/VEGF bispecifics, it reinforces the need for robust OS data to achieve widespread adoption and regulatory success.

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