Ivonescimab Significantly Extends OS Over Pembrolizumab in PD-L1-Positive Advanced NSCLC

A prespecified interim analysis of the phase 3 HARMONi-2 trial (NCT05499390) found that ivonescimab (AK112; Summit Therapeutics) significantly prolonged overall survival (OS) compared with pembrolizumab (Keytruda; Merck) as first-line treatment for patients with PD-L1-positive advanced non–small cell lung cancer (NSCLC).^1,2

The data were presented at the International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer.¹

What Is Ivonescimab and Why Does This Trial Matter?

Ivonescimab is a first-in-class PD-1/VEGF bispecific antibody that previously demonstrated a statistically significant progression-free survival (PFS) benefit over pembrolizumab in treatment-naive patients with PD-L1-positive advanced NSCLC—a median of 11.1 months versus 5.8 months (HR, 0.51; 95% CI, 0.38-0.69; P < .0001).¹ Those findings supported ivonescimab’s regulatory approval in China for this population in April 2025.²

The new analysis reports overall survival, the trial's key secondary end point—the data pharmacists and oncology teams need to gauge whether a PFS signal is translating into a survival benefit patients will actually feel.

How Was the Trial Designed?

HARMONi-2 randomly assigned 398 treatment-naive patients with locally advanced or metastatic NSCLC (PD-L1 tumor proportion score (TPS) of at least 1%, no EGFR or ALK alterations) 1:1 to ivonescimab 20 mg/kg (n = 198) or pembrolizumab 200 mg (n = 200) every 3 weeks, at centers in China between November 2022 and August 2023.¹

What Did the Overall Survival Data Show?

At the August 20, 2026, data cutoff, 234 OS events had occurred. Median OS was about 30.8 months with ivonescimab versus 22.6 months with pembrolizumab (HR, 0.73; 95% CI, 0.57-0.95; P = 0.009)—a statistically significant survival benefit. The benefit was held up across prespecified subgroups: HR 0.65 (95% CI, 0.45-0.95) in squamous histology and 0.79 (95% CI, 0.55-1.14) in nonsquamous histology; HR 0.85 (95% CI, 0.61-1.18) in PD-L1 TPS 1%-49% and 0.58 (95% CI, 0.38-0.89) in TPS greater than or equal to 50%.¹

Does the Safety Profile Change With Longer Follow-Up?

Safety remained broadly comparable between arms with extended follow-up. Any-grade treatment-related adverse events (TEAEs) occurred in 93.4% of ivonescimab-treated patients versus 84.9% with pembrolizumab, with serious TEAEs occurring in 29.9% versus 21.6%, respectively. Discontinuations due to TEAEs were similar (4.1% vs 5.0%), as were immune-related AEs (34.0% vs 33.7%).¹

“Ivonescimab significantly prolonged OS versus pembrolizumab in this patient population and retained a comparable safety profile with extended follow-up,” said Caicun Zhou, MD, PhD, of Shanghai East Hospital, Tongji University School of Medicine.¹

What Should Pharmacists Take Away?

For pharmacy teams that are counseling on first-line NSCLC regimens, the slightly higher rate of TEAEs with ivonescimab—without a corresponding rise in discontinuations or immune-related AEs—suggests tolerability remains manageable even as the survival data mature. As Zhou noted, the results “consolidate its status as a standard of care therapy in this setting” in China, where ivonescimab is already approved.¹ It remains investigational in the US and other markets, so US-based pharmacists should treat this as an important signal to watch rather than a current formulary consideration.

REFERENCES

1. Zhou C, et al. Overall survival with ivonescimab versus pembrolizumab as first-line treatment for PD-L1-positive advanced non-small cell lung cancer: interim analysis of the phase 3 HARMONi-2 trial. Presented at: IASLC 2026 World Conference on Lung Cancer; September 13, 2026; Seoul, Republic of Korea.

2. A study of AK112 monotherapy compared to pembrolizumab monotherapy in subjects with PD-L1 positive locally advanced or metastatic non-small cell lung cancer (HARMONi-2). ClinicalTrials.gov identifier: NCT05499390. Updated March 9, 2026. Accessed September 10, 2026. https://clinicaltrials.gov/study/NCT05499390