Ivonescimab Plus Chemotherapy Phase III HARMONi Results Published in The Lancet Oncology
Summit Therapeutics Inc. has announced the publication of primary analysis results from its global Phase III HARMONi clinical trial in The Lancet Oncology, providing peer-reviewed evidence supporting the potential of ivonescimab as a treatment option for patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).
The HARMONi study evaluated ivonescimab in combination with platinum-doublet chemotherapy in patients with locally advanced or metastatic non-squamous NSCLC whose tumors harbor EGFR mutations and whose disease had progressed following treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI).
According to the published results, the combination of ivonescimab and chemotherapy produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with placebo plus platinum-doublet chemotherapy. The findings address an important area of unmet medical need because treatment options can become limited after patients with EGFR-mutated lung cancer progress following targeted EGFR therapy.
The HARMONi study was conducted across 114 cancer centers and hospitals in Asia, Europe and North America, making it a geographically diverse clinical program. The randomized, double-blind, multicenter Phase III trial was designed to determine whether adding ivonescimab to chemotherapy could improve outcomes for patients whose disease had progressed after treatment with a third-generation EGFR TKI.
Significant Progression-Free Survival Benefit
At the primary analysis, patients who received ivonescimab plus chemotherapy experienced a median PFS of 6.8 months, compared with 4.4 months for patients receiving placebo plus chemotherapy.
The resulting hazard ratio was 0.52, with a 95% confidence interval of 0.41 to 0.66 and a p-value of less than 0.0001. These results demonstrate a statistically significant reduction in the risk of disease progression or death in the ivonescimab-containing treatment group.
Importantly, the PFS benefit was observed consistently across the study’s preplanned patient subgroups. Consistency across subgroups can be an important consideration when evaluating whether a treatment effect may extend across different characteristics within the overall study population.
For patients whose disease has progressed following targeted EGFR therapy, an improvement in PFS could represent an important therapeutic benefit, particularly in a setting where subsequent treatment options may be less effective or limited.
While the primary overall survival (OS) analysis showed a positive trend favoring ivonescimab plus chemotherapy, the difference had not reached statistical significance at the time of that analysis. Summit continues to monitor longer-term outcomes as the HARMONi dataset matures.
Addressing an Unmet Need in EGFR-Mutated Lung Cancer
EGFR mutations represent an important molecular driver in a subset of NSCLC patients. Third-generation EGFR TKIs have become an important component of treatment for eligible patients, but tumors can eventually develop resistance and progress.
Once progression occurs after targeted EGFR treatment, the treatment landscape can become more challenging. Physicians may need to rely on chemotherapy-based approaches, combinations or clinical trials depending on the patient’s disease characteristics and available options.
The HARMONi study was specifically designed to address this treatment gap.
Xiuning Le, M.D., Ph.D., Associate Professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center and lead author of the HARMONi manuscript, highlighted the limited treatment options available after progression on third-generation EGFR TKIs.
Le also pointed to the potential significance of ivonescimab’s mechanism of action, which is designed to simultaneously target PD-1 and VEGF within a single molecule.
According to the investigators, this dual-targeting strategy could offer a differentiated approach to immunotherapy in EGFR-mutated NSCLC.
Dual Targeting of PD-1 and VEGF
Ivonescimab is designed to combine two biological activities within a single therapeutic construct. It targets programmed cell death protein 1 (PD-1), an immune checkpoint involved in regulating T-cell activity, while also targeting vascular endothelial growth factor (VEGF), a signaling pathway associated with tumor blood vessel formation and the tumor microenvironment.
The rationale behind simultaneously targeting these pathways is to potentially address complementary mechanisms involved in cancer progression and immune response.
Traditional immune checkpoint inhibitors that target the PD-1 or PD-L1 pathway have had varying levels of effectiveness across different lung cancer populations. In particular, previous Phase III studies have not established a clear benefit for traditional anti-PD-(L)1 therapies in the specific setting represented by patients with EGFR-mutated NSCLC following progression on EGFR-directed therapy.
The HARMONi results therefore provide clinical evidence supporting further investigation of a dual PD-1 and VEGF targeting strategy in this patient population.
The publication in The Lancet Oncology adds an additional layer of scientific validation because the primary findings have undergone peer review and are now available to the broader oncology community.
Manageable Safety Profile
In addition to evaluating efficacy, the HARMONi trial assessed the safety of ivonescimab in combination with chemotherapy.
Summit reported that the safety profile observed with the combination was manageable and generally consistent with previous clinical experience with ivonescimab.
Of particular note, treatment-related Grade 3–5 hemorrhage events occurred in less than 1% of patients receiving ivonescimab plus chemotherapy.
Safety is an important consideration when combining immunotherapy and anti-angiogenic mechanisms with chemotherapy, particularly because therapies that influence tumor blood vessels can potentially be associated with bleeding-related risks.
The reported low incidence of severe treatment-related hemorrhage provides additional information regarding the tolerability of the treatment combination in the HARMONi population.
The company continues to evaluate longer-term safety and efficacy data as follow-up continues.
Peer-Reviewed Publication Marks an Important Milestone
Maky Zanganeh, Ph.D., President and Co-Chief Executive Officer of Summit Therapeutics, described the publication in The Lancet Oncology as important peer-reviewed support for the scientific rationale behind ivonescimab.
The publication comes as Summit continues to advance the development program for the investigational therapy and prepares for additional data disclosures.
Zanganeh emphasized the challenges faced by patients following progression on EGFR TKIs and said the HARMONi findings support continued development of ivonescimab for patients with significant unmet medical needs.
Robert W. Duggan, Chairman and Co-Chief Executive Officer of Summit Therapeutics, also recognized the contribution of patients, caregivers, investigators and clinical teams involved in the global HARMONi program.
The trial’s international scope required collaboration across numerous clinical centers and healthcare professionals, allowing the company to evaluate ivonescimab in a broad patient population.
Updated Overall Survival Data to Be Presented at WCLC 2026
Although the primary HARMONi analysis demonstrated a statistically significant PFS benefit, overall survival data remain an important area of continued evaluation.
Summit previously announced an updated OS analysis based on a June 2026 data cutoff. The updated analysis continued to show a positive OS trend for patients receiving ivonescimab plus chemotherapy compared with chemotherapy alone.
The company also reported that efficacy and safety findings were consistent between Asian and Western patient populations.
In the Western population specifically, the OS hazard ratio was 0.76, which Summit said was consistent with the global study population.
Additional details from the updated HARMONi analysis are scheduled to be presented at the International Association for the Study of Lung Cancer’s 2026 World Conference on Lung Cancer (WCLC 2026).
The presentation is scheduled for September 15, 2026, during the session titled “OA14 The Breakthrough Immunotherapy for Advanced NSCLC.” The presentation will provide the oncology community with further information regarding the longer-term survival outcomes observed in the study.
The additional data could help provide a clearer understanding of whether the early positive survival trend ultimately translates into a statistically significant overall survival advantage as follow-up continues.
Potential Role in the Treatment Landscape
The HARMONi findings could have implications for the treatment of patients with EGFR-mutated advanced NSCLC who have exhausted or progressed beyond third-generation EGFR-targeted therapy.
The treatment landscape for EGFR-mutated NSCLC has evolved considerably as targeted therapies have improved. However, resistance remains a major challenge, and patients eventually require alternative treatment strategies.
Chemotherapy remains an important component of treatment after progression, but there remains considerable interest in developing combinations that can improve outcomes without creating unacceptable toxicity.
Ivonescimab’s dual-targeting mechanism is being investigated as one potential approach.
By combining PD-1 and VEGF targeting in one molecule and administering the therapy alongside platinum-doublet chemotherapy, the HARMONi regimen is intended to address multiple components of tumor biology and immune regulation.
The Phase III results provide evidence that this strategy can extend the period before disease progression in the studied population.
Regulatory Review Underway
The HARMONi data also support Summit’s ongoing regulatory efforts in the United States.
The U.S. Food and Drug Administration (FDA) has assigned a Prescription Drug User Fee Act (PDUFA) goal action date of November 14, 2026, for Summit’s Biologics License Application (BLA) for ivonescimab in combination with platinum-doublet chemotherapy.
The proposed indication covers patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC whose disease has progressed following treatment with a third-generation EGFR TKI.
The PDUFA date represents an important upcoming regulatory milestone for Summit. The FDA’s review will consider the available clinical and manufacturing information submitted as part of the application before determining whether the therapy meets the requirements for approval.
If approved, ivonescimab could potentially become a new treatment option for patients facing progression after third-generation EGFR-targeted therapy.
Continued Development of Ivonescimab
The HARMONi program is part of Summit Therapeutics’ broader effort to develop ivonescimab as a potential treatment across multiple cancer settings.
The therapy’s dual-targeting mechanism is intended to distinguish it from conventional checkpoint inhibitors and other immunotherapies that act primarily through a single pathway.
The positive HARMONi PFS results provide important clinical evidence supporting this development strategy. At the same time, continued follow-up will be necessary to better understand overall survival, durability of response and long-term safety.
The upcoming WCLC 2026 presentation is expected to provide additional information as the data mature.
For clinicians and researchers, these findings may also contribute to ongoing discussions about the role of immunotherapy in EGFR-mutated NSCLC. The historically challenging response to conventional immune checkpoint inhibition in this molecularly defined population makes the development of alternative immunotherapy strategies particularly important.
The publication of the HARMONi primary analysis in The Lancet Oncology represents a significant milestone for Summit Therapeutics and the broader development program for ivonescimab.
The Phase III study demonstrated that ivonescimab combined with platinum-doublet chemotherapy significantly improved progression-free survival compared with chemotherapy alone. Median PFS increased from 4.4 months to 6.8 months, while the hazard ratio of 0.52 indicated a substantial reduction in the risk of disease progression or death.
The PFS benefit was consistent across preplanned subgroups, while the treatment’s safety profile remained manageable. Although the primary OS analysis did not yet demonstrate a statistically significant difference, the positive survival trend has continued in subsequent follow-up analyses.
With additional OS data scheduled for presentation at WCLC 2026 and an FDA PDUFA action date of November 14, 2026, the coming months could represent an important period for the ivonescimab program.
For patients with EGFR-mutated advanced NSCLC whose disease has progressed after third-generation EGFR TKI therapy, new treatment approaches remain urgently needed. The HARMONi results suggest that targeting PD-1 and VEGF simultaneously with ivonescimab, in combination with chemotherapy, may offer a meaningful new strategy for this difficult-to-treat population.
As Summit continues to evaluate longer-term data and advance its regulatory activities, the company remains focused on determining whether ivonescimab can translate its promising clinical results into a new treatment option for patients with advanced lung cancer and significant unmet medical needs.
About EGFR-Mutated NSCLC
Lung cancer is the second most commonly diagnosed cancer worldwide and remains the leading cause of cancer-related death globally, with an estimated 2.6 million new cases and 1.9 million deaths in 2024.1 In the United States, the American Cancer Society estimates that approximately 230,000 new lung cancer cases will be diagnosed and nearly 125,000 deaths from lung cancer will occur in 2026.2 Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, representing approximately 80% to 85% of all cases.1,3
EGFR mutations are among the most common actionable oncogenic drivers in non-squamous NSCLC, occurring in approximately 10-15% of patients in western populations and 40-50% of patients in Asia.4,5 Activating EGFR mutations can drive tumor growth through aberrant EGFR signaling.6 EGFR tyrosine kinase inhibitors (TKIs), including third-generation EGFR TKIs, are an important treatment approach for patients with advanced EGFR-mutated NSCLC.4
Despite advances with EGFR-targeted therapy, most patients with locally advanced or metastatic EGFR-mutated NSCLC eventually experience disease progression after treatment with a third-generation EGFR TKI.7 In patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC previously treated with a third-generation EGFR TKI, treatment options remain limited, underscoring the need for new therapeutic approaches after progression on EGFR-targeted therapy.7
About Ivonescimab
Ivonescimab, known as SMT112 in Summit’s license territories, North America, South America, Europe, the Middle East, Africa, and Japan, and as AK112 outside of Summit’s license territories, is a novel, potential first-in-class investigational bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. By design, ivonescimab displays unique cooperative binding to each of its intended targets with multifold higher affinity to PD-1 when in the presence of VEGF.
This design is intended to differentiate ivonescimab as there is potentially higher expression (presence) of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) as compared to normal tissue in the body. Summit believes ivonescimab’s specifically engineered tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the TME (Zhong, et al, iScience, 2025).
This tetravalent structure, the intentional novel design of the molecule, and bringing these two targets into a single bispecific antibody with cooperative binding qualities have the potential to direct ivonescimab to the tumor tissue versus healthy tissue. The intent of this design, together with a half-life of 6 to 7 days after the first dose (Zhong, et al, iScience, 2025) increasing to approximately 10 days at steady state dosing, is to improve upon previously established efficacy thresholds, side effects, and safety profiles associated with prior approved drugs to these targets.
Ivonescimab was engineered by Akeso Inc. (HKEX Code: 9926.HK) and is currently utilized in multiple Phase III clinical trials. Over 4,000 patients have been treated with ivonescimab in clinical studies globally, and over 70,000 patients when considering those treated in a commercial setting in China, as noted by Akeso.
There are currently 16 Phase III clinical studies that are either announced, ongoing, or have been completed studying ivonescimab, five of which are Summit-sponsored global studies, one of which is a multiregional study sponsored by a cooperative group, and 10 of which are being or have been conducted in China by Akeso. Summit began its clinical development of ivonescimab in NSCLC, commencing enrollment in 2023 in two multiregional Phase III clinical trials, HARMONi and HARMONi-3.
In 2025, Summit began enrolling patients in HARMONi-7. Summit expanded its Phase III clinical development program into colorectal cancer (CRC) in the fourth quarter of 2025 by initiating enrollment in HARMONi-GI3. In 2026, Summit announced initiation of HARMONi-GU1, a Phase II/III study in urothelial carcinoma (bladder cancer) with global clinical trial site activations planned to begin by the fourth quarter of 2026.
HARMONi is a Phase III clinical trial evaluating ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who were previously treated with a third-generation EGFR TKI (e.g., osimertinib). Detailed results of the study were provided in September 2025, and a Biologics License Application (BLA) was submitted to the United States Food and Drug Administration (FDA) for marketing authorization, which the FDA accepted for filing in January 2026; the goal Prescription Drug User Fee Act (PDUFA) date is November 14, 2026.
HARMONi-3 is a Phase III clinical trial evaluating ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic, squamous or non-squamous NSCLC, irrespective of PD-L1 expression. The clinical trial is evaluating the two histologies as individual, separately powered cohorts with independent statistical powering.
HARMONi-7 is a Phase III clinical trial evaluating ivonescimab monotherapy compared to pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression.
HARMONi-GI3 is a Phase III clinical trial evaluating ivonescimab in combination with chemotherapy compared with bevacizumab plus chemotherapy in patients with first-line unresectable metastatic CRC.
HARMONi-GU1 is a Phase II/III clinical trial evaluating ivonescimab plus the antibody drug conjugate (ADC) enfortumab vedotin (EV) compared to pembrolizumab plus EV as first-line therapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).
ILLUMINE is a Phase III study being conducted by GORTEC, a cooperative group dedicated to Head and Neck Oncology, in recurrent / metastatic head and neck squamous cell carcinoma (r/m HNSCC). ILLUMINE is a three-arm Phase III clinical trial designed to evaluate ivonescimab monotherapy, as well as ivonescimab in combination with ligufalimab, Akeso’s proprietary anti-CD47 monoclonal antibody, compared to monotherapy pembrolizumab in patients with PD-L1 positive r/m HNSCC.
Four Phase III ivonescimab clinical trials have read out to date, all four with positive data, in NSCLC. In addition to Summit’s positive HARMONi study, Akeso has had positive read-outs in three single-region (China), randomized Phase III clinical trials, HARMONi-A, HARMONi-2, and HARMONi-6, for ivonescimab in NSCLC, including a statistically significant overall survival benefit in both the HARMONi-A and HARMONi-6 studies. A manageable, consistent safety profile was achieved in each of these studies.
HARMONi-A was a Phase III clinical trial which evaluated ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with an EGFR TKI.
HARMONi-2 is a Phase III clinical trial evaluating monotherapy ivonescimab against monotherapy pembrolizumab in patients with locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression.
HARMONi-6 is a Phase III clinical trial evaluating ivonescimab in combination with platinum-based chemotherapy compared with tislelizumab, an anti-PD-1 antibody, in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous NSCLC, irrespective of PD-L1 expression.
Akeso is actively conducting multiple Phase III clinical studies in settings outside of NSCLC, including biliary-tract cancer, triple-negative breast cancer, head and neck squamous cell carcinoma, small cell lung cancer, colorectal cancer, and pancreatic cancer.
Ivonescimab is an investigational therapy that is not approved by any regulatory authority in Summit’s license territories, including the United States and Europe. Ivonescimab was initially approved for marketing authorization in China in May 2024.
About Summit Therapeutics Inc.
Summit Therapeutics Inc. is a biopharmaceutical oncology company focused on the discovery, development, and commercialization of patient-, physician-, caregiver- and societal-friendly medicinal therapies intended to improve quality of life, increase potential duration of life, and resolve serious unmet medical needs.
Summit was founded in 2003 and the company’s shares are listed on the Nasdaq Global Market (symbol “SMMT”). Summit is headquartered in Miami, Florida, with additional offices in Palo Alto, California, Princeton, New Jersey, Dublin, Ireland, and Oxford, UK.