Summit Therapeutics Inc. has announced a significant milestone in its oncology development efforts, completing patient enrollment for the HARMONi Phase III clinical trial. This pivotal study seeks to evaluate the efficacy of Ivonescimab, a novel bispecific antibody, in combination with platinum-doublet chemotherapy as a second-line treatment for patients with epidermal growth factor receptor-mutated (EGFRm) non-squamous non-small cell lung cancer (NSCLC) who have progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. Patients from North America, Europe, and China are participating in this trial, underscoring the global relevance and reach of this research.

The HARMONi Phase III clinical trial represents a significant advancement in addressing treatment challenges for EGFR-mutant NSCLC, a patient group that often displays resistance to current immunotherapy options. Ivonescimab’s unique bispecific combination targets both programmed death-1 (PD-1) and vascular endothelial growth factor (VEGF), offering a dual mechanism of action that has the potential to provide superior clinical outcomes. Dr. Maky Zanganeh, Chief Executive Officer of Summit Therapeutics Inc., expressed appreciation for the investigators, site coordinators, and, most importantly, the patients whose participation made this milestone possible. Dr. Zanganeh emphasized that reaching this point is an essential step toward demonstrating Ivonescimab’s potential to revolutionize treatment approaches for advanced NSCLC, which remains one of the most challenging cancers worldwide.

FDA Fast Track Designation to Accelerate Patient Access

The U.S. Food and Drug Administration (FDA) granted Fast Track designation to Ivonescimab when used in combination with platinum-based chemotherapy for advanced EGFR-mutant NSCLC. The Fast Track program is specifically designed to facilitate the expedited development and regulatory review of drugs that target serious conditions and fill unmet medical needs. With this designation, Ivonescimab is eligible for more frequent communication with the FDA, rolling review opportunities, and an accelerated pathway toward approval. These measures are particularly significant for NSCLC patients who urgently require effective alternatives after standard therapies have failed.

Robert W. Duggan, Executive Chairman of Summit Therapeutics Inc., indicated that the completion of patient enrollment in the HARMONi Phase III trial aligns with the company’s mission to enhance and extend the lives of patients facing critical medical challenges. Duggan stated that Ivonescimab’s dual-targeting approach—simultaneously addressing the PD-1 and VEGF pathways—positions the drug as a potentially transformative treatment for patients with EGFR-mutant NSCLC. He also highlighted that the FDA’s Fast Track designation is not only an acknowledgment of Ivonescimab’s promise but also a reinforcement of Summit Therapeutics Inc.’s leadership in advancing innovative oncology treatments.

How Ivonescimab Works: Targeting Tumor Growth and Immune Evasion

Ivonescimab, known as SMT112 in regions outside of China and Australia, represents an innovative approach to cancer therapy by integrating immune checkpoint inhibition with anti-angiogenesis effects. By blocking PD-1, Ivonescimab enables the immune system to better recognize and attack malignant cells. Concurrently, VEGF inhibition impedes the development of new blood vessels that supply nutrients to tumors, effectively starving the cancer and preventing its progression. This dual-action mechanism is designed to concentrate treatment effects on tumor tissue while minimizing adverse effects on healthy cells. Phase II clinical data have suggested a favorable efficacy profile for Ivonescimab, particularly in patients with limited treatment options.

The tetravalent structure of Ivonescimab enhances its ability to bind simultaneously to both PD-1 and VEGF, significantly improving its targeting efficacy within the tumor microenvironment. Cooperative binding facilitates a higher affinity for both targets in tumor tissues compared to normal tissues, potentially leading to enhanced therapeutic effects. This unique binding characteristic helps overcome immune evasion strategies that tumors often employ and restricts their ability to form new blood vessels, a key factor in preventing metastasis and improving patient outcomes.

Summit Therapeutics Inc.’s strategic partner, Akeso Inc., initially developed Ivonescimab. In May 2024, Akeso received marketing approval for Ivonescimab in China, following positive results from the HARMONi-A Phase III study, which involved patients with EGFR-mutant NSCLC who had progressed after EGFR-TKI treatment. The approval from China’s National Medical Products Administration (NMPA) marked a substantial milestone, validating Ivonescimab’s therapeutic potential in the oncology field. Summit Therapeutics Inc. is concurrently pursuing additional global clinical trials, positioning the HARMONi trial as its first major multi-regional Phase III effort. The partnership between Summit Therapeutics Inc. and Akeso reflects a broader trend of cross-border collaborations to accelerate the development of innovative cancer therapies.

Future Directions for HARMONi Clinical Trials and Ivonescimab

Summit Therapeutics Inc. is poised to announce topline results from the HARMONi Phase III clinical trial by mid-2025. The dual primary endpoints—progression-free survival (PFS) and overall survival (OS)—are key measures of Ivonescimab’s effectiveness in prolonging life and delaying disease progression in patients with EGFR-mutant NSCLC. In addition to the HARMONi trial, Summit Therapeutics Inc. is actively pursuing other clinical trials to broaden the application of Ivonescimab across a variety of NSCLC patient groups.

The HARMONi-3 study aims to evaluate Ivonescimab combined with chemotherapy versus pembrolizumab, another PD-1 inhibitor, in patients with first-line metastatic squamous NSCLC. Meanwhile, the HARMONi-7 trial is investigating Ivonescimab monotherapy compared to pembrolizumab in patients with high PD-L1 expression, focusing on whether the bispecific targeting approach is superior in a highly immunogenic environment. These trials are anticipated to provide a more comprehensive understanding of Ivonescimab’s potential across different patient profiles and treatment contexts.

With over 1,800 patients treated globally, Ivonescimab shows considerable promise as a first-in-class therapy for NSCLC patients who have exhausted other options. Summit Therapeutics Inc. remains steadfast in its commitment to expanding its clinical development program and securing regulatory approvals across key regions, including the United States and Europe. The company’s goal is to establish Ivonescimab as a cornerstone of lung cancer treatment, offering new hope for patients facing limited therapeutic options.

Expert Perspective: Bridging the Gap in NSCLC Treatment

Experts in oncology have consistently noted that one of the primary challenges in treating NSCLC, particularly EGFR-mutant cases, is the high rate of resistance to existing targeted therapies. Combining immunotherapy with anti-angiogenic strategies—such as with Ivonescimab—could be a major advancement for patients who have exhausted conventional treatments. Ivonescimab’s ability to simultaneously engage multiple therapeutic pathways may reduce the likelihood of tumors evading treatment, ultimately improving clinical outcomes.

Also, the completion of patient enrollment for the HARMONi Phase III clinical trial is a critical milestone that could shift the treatment paradigm for EGFR-mutant NSCLC. If Ivonescimab demonstrates meaningful improvements in delaying disease progression and extending survival, it could set a new standard of care for this challenging and lethal form of lung cancer.

  Akeso Inc., Europe, FDA, HARMONi Phase III, Ivonescimab, Jonathan Smith, Maky Zanganeh, National Medical Products Administration, North America, Robert W. Duggan, Summit Therapeutics