Phase 3 HARMONi-2 Trial: Ivonescimab Outperforms Pembrolizumab in PD-L1–Positive NSCLC

The investigational bispecific antibody ivonescimab showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to pembrolizumab in patients with PD-L1–positive non-small cell lung cancer (NSCLC), according to results from the phase 3 HARMONi-2 trial.

The results were presented by Caicun Zhou, PhD, MD, of the Shanghai Pulmonary Hospital during the first Presidential Symposium during the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.

“This is the first randomized phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel compound compared with pembrolizumab in non-small cell lung cancer,” Dr. Zhou said during an IASLC press conference on the study.

Ivonescimab, also known as AK112, is an investigational bispecific antibody directed against PD-1 and VEGF. The HARMONi-2 study compared ivonescimab monotherapy and pembrolizumab monotherapy as a first-line treatment for PD-L1 positive advanced NSCLC because the investigational bispecific antibody has shown promise as a first-line treatment in early phase studies.

HARMONi-2 Design and Patient Characteristics

The researchers randomized 398 patients from 55 centers in China to receive ivonescimab (n=198) or pembrolizumab (n=200). The study included patients with untreated locally advanced or metastatic NSCLC with an Eastern Cooperative Oncology Group performance status of 0-1. All patients were positive for PD-L1, but the researchers randomized patients with negative EGFR mutations or ALK rearrangements in a 1:1 ratio to receive either 20 mg/kg of ivonescimab or 200 mg of pembrolizumab every 3 weeks.

The primary endpoint was PFS, with secondary endpoints including overall survival (OS), investigator-assessed PFS, the objective response rate (ORR), the duration of response, the disease control rate, and safety.

HARMONi-2 Results Presented at IASLC 2024 World Conference on Lung Cancer

The pre-planned interim analysis presented at the Presidential Symposium showed that the median PFS was 11.14 months in patients receiving ivonescimab, significantly longer than the 5.82 months in patients receiving pembrolizumab (stratified hazard ratio [HR], 0.51; 95% CI, 0.38 to 0.69; P<.0001). The PFS benefit of the investigational bispecific antibody was “broadly consistent” within pre-specified subgroups, including populations with:

• Squamous NSCLC: HR, 0.50; 95% CI, 0.33 to 0.76
• Non-squamous NSCLC: HR, 0.55; 95% CI, 0.36 to 0.84
• TPS 1-49%: HR, 0.54; 95% CI, 0.37 to 0.78
• TPS ≥50%: HR, 0.48; 95% CI, 0.29 to 0.79
• Liver metastases: HR, 0.47; 95% CI 0.23 to 0.98
• Brain metastases: HR, 0.55; 95% CI, 0.28 to 1.05

Dr. Zhou reported that “no new safety signals were observed with ivonescimab,” with treatment-related serious adverse events (TRSAEs) observed in 20.8% of patients in the ivonescimab arm and 16.1% in the pembrolizumab arm.

“Particularly, ivonescimab also demonstrated a very manageable safety profile in squamous cell carcinoma patients,” Dr. Zhou and colleagues reported, noting that the TRSAE rates were 18.9% and 18.7% in the respective arms.

The rate of grade ≥3 immune-related AEs were 7.1% in the ivonescimab arm and 8.0% in the pembrolizumab arm.

Dr. Zhou and colleagues concluded by reflecting on the implications of the study and how it could change treatment for certain patients.

“Compared to pembrolizumab, ivonescimab demonstrated a statistically significant and clinically meaningful improvement in PFS in PD-L1 positive NSCLC,” Dr. Zhou and colleagues concluded. “The data support ivonescimab monotherapy as a new first-line treatment option for PD-L1 positive [advanced] NSCLC patients.”

Reference

Zhou C, Chen J, Wu L, et al. Phase 3 Study of Ivonescimab (AK112) vs. Pembrolizumab as First-line Treatment for PD-L1-positive Advanced NSCLC: Primary Analysis of HARMONi-2. PL02.04. Presented at the IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California.