Dr Riess on the Investigation of Ivonescimab in Advanced NSCLC

"In particular, [there was] a PFS benefit in the 1% to 49% PD-L1 expression subgroup, as well as the 50% or above expression subgroup…This was particularly noteworthy because the phase 3 KEYNOTE-042 trial [NCT02220894] looked at PD-L1 expression [of] 1% or more with pembrolizumab, and the benefit was really driven by the 50% or more subgroup.”

Jonathan Wesley Riess, MD, MS, director, Thoracic Oncology, associate professor, medicine, Division of Hematology and Oncology, University of California, Davis Comprehensive Cancer Center, discusses initial data from the phase 3 HARMONi-2 trial (NCT05499390) evaluating ivonescimab (AK112; SMT112) vs pembrolizumab (Keytruda) in patients with advanced non–small cell lung cancer (NSCLC).

Results from the HARMONi-2 trial were presented during the 2024 IASLC World Conference on Lung Cancer. At the planned interim analysis, first-line treatment with ivonescimab led to a clinically significant improvement in independent radiology review committee (IRRC)–assessed progression-free survival (PFS) vs pembrolizumab in patients with advanced NSCLC and a PD-L1 tumor proportion score (TPS) of at least 1%, Riess reports.

At a median follow-up of 8.67 months, the median PFS was 11.14 months (95% CI, 7.33-not estimable) for patients treated with ivonescimab (n = 198) compared with 5.82 months (95% CI, 5.03-8.21) for those who received pembrolizumab (n = 200; HR, 0.51; 95% CI, 0.38-0.69; P < .0001).

The PFS benefit with ivonescimab was consistent across key subgroups, including patients with PD-L1 expression of 1% to 49% (HR, 0.54; 95% CI, 0.37-0.78) and those with a PD-L1 expression of at least 50% (HR, 0.48; 95% CI, 0.29-0.79). PFS benefits ivonescimab were also observed in those with both squamous (HR, 0.50; 95% CI, 0.33-0.76) and nonsquamous (HR, 0.55; 95% CI, 0.36-0.88) histologies. The PD-L1 subgroup findings were particularly noteworthy because prior data, such as those from the phase 3 KEYNOTE-042 trial (NCT02220894), showed that pembrolizumab’s benefit was primarily driven by patients with PD-L1 expression of at least 50%, Riess notes. However, overall survival data from HARMONi-2 were not mature at the time of the primary analysis, Riess adds.

Since HARMONi-2 was conducted in a Chinese-specific population, these results will need validation in more diverse global populations, Riess concludes.

Notably, the FDA granted fast track designation to ivonescimab plus platinum-based chemotherapy for adults with EGFR-mutant locally advanced or metastatic NSCLC who experience disease progression following EGFR tyrosine kinase inhibitor therapy, based data from the phase 3 HARMONi-A trial (NCT05184712). The agent is also under priority review in China for the frontline treatment of patients with PD-L1–positive, locally advanced or metastatic NSCLC.