Summit Therapeutics has announced the completion of enrollment in its Phase III HARMONi clinical trial, a multi-regional study evaluating ivonescimab in patients with EGFR-mutated non-small cell lung cancer (NSCLC). The trial, sponsored by Summit, assesses ivonescimab plus platinum-doublet chemotherapy versus placebo plus platinum-doublet chemotherapy in patients with locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI). The company anticipates topline data from the HARMONi trial in mid-2025.
In addition, the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to ivonescimab for use in combination with platinum-based chemotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR mutations who have experienced disease progression following EGFR-TKI therapy. The FDA's Fast Track designation is designed to expedite the development and review of drugs that treat serious conditions and fill unmet medical needs.
HARMONi Trial Design and Objectives
The HARMONi trial is designed with dual primary endpoints of progression-free survival (PFS) and overall survival (OS). It includes patients from North America, Europe, and China with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed following third-generation EGFR TKI therapy. This patient population has previously shown unsuccessful results with PD-1 monoclonal antibodies in Phase III global clinical trials.
Dr. Maky Zanganeh, Chief Executive Officer and President of Summit, expressed gratitude to the investigators, site coordinators, the Summit team, and the participating patients. Robert W. Duggan, Chairman & Chief Executive Officer of Summit, stated that completing enrollment in the HARMONi study represents a step towards bringing a drug to patients that is intended to improve the quality and potential duration of life for those facing serious unmet medical needs.
Ivonescimab: A Novel Bispecific Antibody
Ivonescimab, also known as SMT112 in Summit’s licensed territories and AK112 in China and Australia, is a novel, potential first-in-class investigational bispecific antibody. It combines immunotherapy effects via PD-1 blockade with anti-angiogenesis effects by blocking VEGF into a single molecule. Ivonescimab displays unique cooperative binding to each of its intended targets with multifold higher affinity when in the presence of both PD-1 and VEGF.
This bispecific design potentially differentiates ivonescimab due to the higher expression of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) compared to normal tissue. The tetravalent structure of ivonescimab enables higher avidity in the TME, with over 18-fold increased binding affinity to PD-1 in the presence of VEGF in vitro, and over 4-times increased binding affinity to VEGF in the presence of PD-1 in vitro. The intent of this design, together with a half-life of 6 to 7 days, is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets.
Prior Clinical Data and Ongoing Trials
Ivonescimab was engineered by Akeso Inc. and is currently engaged in multiple Phase III clinical trials. Over 1,800 patients have been treated with ivonescimab in clinical studies globally. Summit has initiated clinical development of ivonescimab in NSCLC, commencing enrollment in 2023 in two multi-regional Phase III clinical trials, HARMONi and HARMONi-3, with plans to initiate HARMONi-7 in early 2025.
HARMONi-3 is a Phase III clinical trial designed to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic squamous NSCLC. HARMONi-7 is a planned Phase III clinical trial intended to evaluate ivonescimab monotherapy compared to pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 TPS > 50%).
Akeso has also reported positive readouts in two single-region (China), randomized Phase III clinical trials for ivonescimab in NSCLC, HARMONi-A and HARMONi-2. 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 (PD-L1 TPS >1%). In the HARMONi-2 trial, ivonescimab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to pembrolizumab, with a median PFS of 11.14 months versus 5.82 months (HR, 0.51; p<0.0001).
Perioperative NSCLC Data
Data from a Phase II study of perioperative ivonescimab, either as monotherapy or combined with chemotherapy, for resectable NSCLC were presented at the 25th World Conference on Lung Cancer (WCLC). The study results demonstrated high rates of pathological complete response (pCR) and major pathological response (MPR). In the ivonescimab + chemotherapy cohort, the pCR rate was 43.6%, and the MPR rate was 71.8%.
Future Directions
Summit plans to initiate HARMONi-7 in early 2025, a multi-regional Phase III clinical trial comparing ivonescimab monotherapy to pembrolizumab monotherapy in metastatic NSCLC patients with high PD-L1 expression (PD-L1 TPS≥50%).
