Ivonescimab Shows Significant PFS Improvement Over Pembrolizumab in PD-L1+ NSCLC

Xiuning Le, MD, PhD

Ivonescimab was safe and demonstrated improved efficacy compared with pembrolizumab (Keytruda) in patients with PD-L1–positive non–small cell lung cancer (NSCLC), stirring excitement among investigators about the agent’s future potential in the space, according to Xiuning Le, MD, PhD.

At a median follow-up of 8.7 months (IQR, 7.1-10.3), data from the preplanned interim analysis of the phase 3 HARMONi-2 study (NCT05499390) published in Lancet showed that patients who received ivonescimab (n = 198) achieved a median progression-free survival (PFS) of 11.1 months (95% CI, 7.3-not estimable) vs 5.8 months (95% CI, 5.0-8.2) with pembrolizumab (n = 200; HR, 0.51; 95% CI, 0.38-0.69; 1-sided P < .0001).1 Additionally, the objective response rates were 50% (95% CI, 43%-57%) and 39% (95% CI, 32%-46%), respectively. Overall survival (OS) data were immature at the time of the analysis.

“Ivonescimab is a bispecific antibody [with] 1 arm targeting PD-1 [and] the other targeting VEGF-A,” Le explained in an interview with OncLive®. “Those are 2 important players in the solid tumor arena; [the] PD-1/PD-L1 axis is the key immune checkpoint, and VEGF plays a major role in the tumor microenvironment. We know that hypoxia is associated with tumor growth, and VEGF up-regulation helps tumors grow, so inhibiting the VEGF component, either at VEGF-A or at the receptor, has shown some efficacy in multiple solid tumor subtypes. [Developing] a bispecific antibody to [target] both makes biological sense, and it makes sense to test it in solid tumors.”

In the interview, Le discussed the rationale for the study, key safety data from HARMONi-2, and future research plans for ivonescimab. Le is an associate professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What was the rationale for comparing ivonescimab with pembrolizumab in PD-L1–positive NSCLC?

Le: HARMONi-2 was designed to test whether ivonescimab was superior in terms of efficacy to a simple immune checkpoint inhibitor [such as] the PD-1 inhibitor pembrolizumab. In [patients with] NSCLC, because of the VEGF component, VEGF inhibition can potentiate [a] checkpoint inhibitor’s efficacy, and [we hoped] that would translate into prolonged PFS and OS. [In the] lung cancer space, especially in NSCLC, there’s unmet need in the frontline [setting] to continue to improve the activity of immune therapies for patients who are diagnosed with metastatic [disease].

What were the key design characteristics of the study?

This was a China-only study, [and] the total patient population was 398. At this stage, the [investigators] are still trying to identify signals [showing] which types of patients can benefit [the most from ivonescimab]. [The study enrolled] treatment-naive patients with unresectable advanced/metastatic NSCLC with no EGFR mutations or ALK alterations. Patients’ tumors needed to have a PD-L1 [tumor proportion score (TPS)] of at least 1%. That’s consistent with the population of patients who can derive benefit from PD-1/PD-L1 blockade.

Patients were [randomly assigned 1:1] to receive ivonescimab or pembrolizumab. The study was double-blinded. The primary end point was PFS. We feel this is a fair enrollment. I don’t [believe] any of the characteristics between the 2 arms were not balanced. Each arm contained [approximately] 200 patients [and] the proportion of patients with a high vs a low PD-L1 [TPS] were very similar. Age, gender, and performance status [were also] similar. Overall, I [believe] the study was reasonably balanced.

Were there any new safety signals reported with ivonescimab?

[In terms of] safety data, there were no surprises. The bispecific antibody has the potential to target PD-1 and VEGF, so in the safety aggregation we saw common toxicities [of these targets]. We saw VEGF inhibition on-target toxicities, including high blood and proteinuria in some patients. But overall, the treatments in both arms were well tolerated, and there was nothing new or unexpected.

In light of these findings, how does ivonescimab fit into the NSCLC treatment paradigm?

As a field we are very excited about these data, but we have to be careful interpreting them. This [study included] less than 400 patients and we enrolled patients from only 1 country. [Although] we are happy [with these results], we want to roll out global, even larger, confirmatory studies. The study team is now enrolling [patients] in the frontline setting with PD-L1–high [disease], as well as a PD-L1–medium to –low population, and patients with an EGFR mutation after initial TKI [therapy]. We look forward to seeing the results of those large studies, with the hope of confirming this fantastic efficacy.

One area that is very important in lung cancer specifically is moving the needle [in terms of] OS. We can always have something [that is superior] in the frontline setting, but does that mean that we are using up a downstream option just to make the frontline [results] better and not changing the totality of OS? [Other] trials also have OS as a coprimary end point and I believe more rigorous, bigger testing is going to be important for us to truly celebrate that we have [achieved] another major step forward in the immunotherapy space for lung cancer.

What are the next steps for this research?

Moving forward, ivonescimab could serve as a good combination drug, just like we’ve seen with pembrolizumab [in combination with] chemotherapy and antibody-drug conjugates. Ivonescimab showed a good safety profile and good tolerability. It’s not beyond the imagination that, when we truly know this drug is superior to PD-1 monotherapy, we can start to [examine] combinations and bring novel treatment ideas to the field to benefit different types of patients at different stages [of disease]. That’s why the data from HARMONi-2 are so exciting; we see an immediate plan. We see a big field potentially opening in the future.

Reference

Xiong A, Wang L, Chen J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet. 2025;405(10481):839-849. doi:10.1016/S0140-6736(24)02722-3