Ivonescimab (AK112; SMT112), a novel bispecific antibody targeting PD-1 and VEGF, has demonstrated a clinically significant improvement in efficacy compared to pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC). The phase 3 HARMONi-2 trial revealed that frontline treatment with ivonescimab significantly improved progression-free survival (PFS) compared to pembrolizumab in patients with advanced disease and a PD-L1 tumor proportion score (TPS) of at least 1%. This finding suggests ivonescimab may become a new standard of care for this patient population. The trial was presented at the 2024 IASLC World Conference on Lung Cancer.
Encouraging data from the HARMONi-2 trial led to China’s National Center for Drug Evaluation granting priority review to the supplemental new drug application seeking approval of ivonescimab for the frontline treatment of patients with PD-L1–positive locally advanced or metastatic NSCLC. Furthermore, based on data from the phase 3 HARMONi-A trial, the FDA granted fast track designation to ivonescimab plus platinum-based chemotherapy for treating adult patients with locally advanced or metastatic EGFR-mutant NSCLC who experience disease progression following EGFR-TKI therapy.
HARMONi-2 Trial Results
The HARMONi-2 trial, a phase 3 study, compared ivonescimab to pembrolizumab as a first-line treatment for PD-L1-positive advanced NSCLC. At a median follow-up of 8.67 months, patients who received ivonescimab (n = 198) achieved a median PFS of 11.14 months (95% CI, 7.33-not estimable) compared with 5.82 months (95% CI, 5.03-8.21) among those treated with pembrolizumab (n = 200). The hazard ratio was 0.51 (95% CI, 0.38-0.69; P < .0001).
The PFS benefit observed with ivonescimab compared to pembrolizumab was consistent across major clinical subgroups, including those with PD-L1 TPS of 1% to 49% (stratified HR, 0.54; 95% CI, 0.37-0.79) and those with PD-L1 TPS of at least 50% (stratified HR, 0.46; 95% CI, 0.28-0.75). Benefits were also seen in both squamous (stratified HR, 0.48; 95% CI, 0.31-0.74) and nonsquamous (stratified HR, 0.54; 95% CI, 0.36-0.82) histology populations. Overall survival (OS) data were not mature at the time of the primary analysis.
Mechanism of Action and Cooperative Binding
Ivonescimab is a bispecific antibody that targets both PD-1 and VEGF. VEGF is a key cytokine involved in the development of blood vessels, including those in tumors. By blocking VEGF, ivonescimab can modify the tumor microenvironment and inhibit angiogenesis. The PD-1 targeting component acts as an immune checkpoint inhibitor.
Notably, ivonescimab exhibits cooperative binding properties, where binding to one target increases the affinity for binding to the other. This unique functional property may contribute to its favorable efficacy profile compared to combining a VEGF antibody like bevacizumab with a PD-1 antibody like pembrolizumab.
HARMONi-A Trial in EGFR-Mutant NSCLC
In the phase 3 HARMONi-A trial, ivonescimab plus chemotherapy (n = 161) elicited a median PFS per IRRC assessment of 7.1 months (95% CI, 5.9-8.7) in patients with EGFR-mutant nonsquamous NSCLC who progressed on prior EGFR TKIs vs 4.8 months (95% CI, 4.2-5.6) in those who received placebo plus chemotherapy (n = 161; HR, 0.46; 95% CI, 0.34-0.62; P < .001). At 52% data maturity, there was also a favorable trend seen regarding OS (HR, 0.80; 95% CI, 0.59-1.08).
Safety Profile
Ivonescimab has a shorter half-life, which may contribute to a more tolerable safety profile. In the HARMONi-2 trial, patients treated with ivonescimab (n = 197) vs pembrolizumab (n = 199) experienced grade 3 or higher treatment-related adverse effects (TRAEs; 29.4% vs 15.6%), serious TRAEs (20.8% vs 16.1%), and TRAEs leading to discontinuation (1.5% vs 3.0%). TRAEs led to death in 1 patient who received ivonescimab and 2 patients who received pembrolizumab. The most common AEs observed with ivonescimab were proteinuria (any-grade, 31.5% vs 10.1%) and hypertension (15.7% vs 2.5%).
