Challenging the status quo: ivonescimab’s bid to displace anti-PD-(L)1 inhibitors

Introduction

The treatment landscape of advanced non-small cell lung cancer (NSCLC) underwent a dramatic transformation over a decade ago with the advent of immune checkpoint inhibitors (ICIs). Initially evaluated and approved in the second-line setting, where they demonstrated a survival benefit over docetaxel in phase 3 randomised trials (1-7), ICIs quickly moved into the first-line arena. Today, both ICI monotherapy, particularly in patients with high programmed cell death 1 ligand 1 (PD-L1) expression, and ICI combined with chemotherapy for unselected PD-L1 populations have become the standard of care (8). Nevertheless, a substantial proportion of patients, especially those with PD-L1 expression below 50%, derive limited benefit from ICI monotherapy (9). Although the addition of chemotherapy improves objective response rates (ORRs) and overall efficacy, it also increases toxicity (10,11).

To address these limitations, several strategies have been explored to enhance ICI efficacy, including the incorporation of antiangiogenic agents. Angiogenesis in NSCLC is primarily driven by the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway. Prior to the immunotherapy era, combining chemotherapy with bevacizumab (an anti-VEGF antibody) proved superior to chemotherapy alone (12). More recently, the IMpower150 trial demonstrated that chemotherapy plus bevacizumab and atezolizumab outperformed chemotherapy alone (13). However, direct comparisons between ICI monotherapy and ICI plus antiangiogenic combinations are lacking, and the incidence of treatment-related severe adverse events tends to be higher with antiangiogenic regimens, particularly in patients with squamous histology, leading to their frequent exclusion from such trials (13).

Given these challenges, new strategies are needed to harness the antiangiogenic effects of VEGF inhibition without a dramatic increase in toxicity. Ivonescimab, a first-in-class bispecific antibody that targets both programmed cell death 1 (PD-1) and VEGF, offers a novel approach (14). The simultaneous binding of both targets is theorized to enhance antitumor activity while improving the safety profile, potentially resulting in a more potent drug than current ICI monotherapy (15). Importantly, this dual-action agent may provide a chemotherapy-free alternative, especially for patients with PD-L1 expression below 50%. In the following sections, we explore the design and outcomes of the phase 1b trial of ivonescimab in immunotherapy-naïve NSCLC patients and discuss its potential to redefine the therapeutic landscape.

Study design

Following a successful phase 1a dose-expansion study, several doses and administration schedules were selected for further exploration in this phase 1b trial: 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W, and 30 mg/kg Q3W. The primary aim was to determine the optimal dose for future studies, and the primary endpoints were the ORR and safety profile of ivonescimab (16).

Patients with advanced NSCLC who were unsuitable for chemoradiotherapy, lacked EGFR, ALK, or ROS1 alterations, and had not previously been treated with an ICI (with most being treatment-naïve), were enrolled exclusively in China. Although the study included both squamous and non-squamous histology, it excluded patients at a higher risk of bleeding (for example, those with tumours involving critical organs or major blood vessels). This exclusion criterion, while prudent for safety, must be considered when generalizing the findings.

Given the trial’s early-phase nature, safety was a key endpoint. Adverse events (AEs) were monitored until 30 days after the last dose (or 90 days for serious AEs) or until the initiation of subsequent antitumor therapy, whichever occurred first. It is important to note that immune-related adverse events (irAEs) can emerge later in the treatment course, even after discontinuation, and some may persist chronically. Therefore, while the safety data from this trial are promising, they should be interpreted with caution. Extended follow-up and further studies will be necessary to fully delineate the long-term safety profile of ivonescimab.

Results

In this phase 1b trial, 108 patients received at least one dose of ivonescimab. The majority (86.1%) were treatment-naïve, and roughly half of the patients had squamous NSCLC. The PD-L1 expression distribution was as expected, with approximately one-third of patients in each subgroup (<1%, 1–49%, and ≥50%).

Safety

AEs were monitored until 30 days (90 days for serious AEs) after the last dose of the study drug or the initiation of other antitumor treatment, whichever occurred first. Overall, ivonescimab demonstrated a favourable safety profile with no new safety signals detected. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 22.2% of patients, while treatment-emergent adverse events (TEAEs) were reported in 38.0% of patients, rates comparable to those observed with single-agent ICIs, such as KEYNOTE-024, which reported a 31.2% incidence of TRAEs. As anticipated, both irAEs and VEGF-related AEs were observed. The overall rate of irAEs was 22.2%, with only 3.7% being grade ≥3. Most VEGF-related adverse events were mild to moderate (grade 1–2), with events such as proteinuria, hypertension, and haematuria. Bleeding-related adverse events occurred in 20.0% of squamous patients and 30.2% of non-squamous patients; notably, grade ≥3 bleeding events were infrequent, observed in 0.0% of squamous and 1.9% of non-squamous patients. These findings may hint at a differential class effect compared to traditional combinations of ICIs with VEGF(R) inhibitors (Table 1). It is important to interpret these safety data with caution, given the relatively short median follow-up of 10.4 months and the lack of long-term surveillance in patients who discontinued treatment.

Efficacy

Along with safety, the co-primary endpoint was ORR. In patients receiving at least one dose of ivonescimab (n=108), the ORR was 39.8%, with similar results in squamous (41.8%) and non-squamous NSCLC patients (37.7%). Ivonescimab showed higher efficacy in those with increased PD-L1 levels. In fact, ORRs were notably higher in patients with tumour proportion score (TPS) greater than or equal to 1% (51.4%) and TPS ≥50% (57.1%), compared with only 14.7% in patients with TPS less than 1%. In first-line treatment, the ORR was 60.9%, with 51.9% (14 of 27) in the TPS 1–49% subgroup and 73.7% (14 of 19) in the TPS ≥50% subgroup. As expected, the benefit from second-line therapy was shorter, with an ORR of 42.9% in patients with TPS greater than or equal to 1% and 25.0% in those with TPS less than 1%.

The median PFS (mPFS) was 11.4 months overall [95% CI: 6.8–not estimable (NE)], highlighting a difference based on PD-L1 status, not reached (NR) (95% CI: 6.2–NE) in PD-L1-positive patients versus 7.2 months (95% CI: 4.8–11.5) in PD-L1-negative ones. Furthermore, mPFS was longer in non-squamous NSCLC [13.9 months (95% CI: 7.2–NE)] compared to squamous NSCLC [6.9 months (95% CI: 5.5–11.6)]. Among the 67 treatment-naive patients with PD-L1 positivity, the 6- and 9-month PFS rates were 64.1% and 52.2%, respectively.

Discussion

The HARMONi-5 trial demonstrates that ivonescimab monotherapy has an acceptable safety profile in patients with advanced NSCLC. Considering the efficacy and safety data, the dose of 20 mg/kg Q3W was selected for subsequent studies. Because PD-1 and VEGF are co-expressed in the tumour microenvironment, the dual-target design of ivonescimab promotes enhanced, tumour-specific biodistribution and retention, thereby reducing its systemic distribution and lowering off-target toxicity (14). This bispecific antibody may offer a more controllable safety profile than the concurrent administration of separate PD-1 and VEGF inhibitors.

In recent years, multiple studies have evaluated chemotherapy-free regimens in combination with antiangiogenic therapy for first-line NSCLC patients, such as pembrolizumab plus lenvatinib (17), the anti-T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) antibody tiragolumab with atezolizumab (18,19), and pembrolizumab plus ramucirumab (20). Overall, these combinations did not yield improvements in survival outcomes, clinical benefit, or tolerability when compared to the standard of care treatments.

Ivonescimab was further evaluated in the phase III Harmoni-2 trial, where it was compared in first line to pembrolizumab in the Chinese population (21). Ivonescimab reduced the risk of disease progression or death by 49%, resulting in a mPFS improvement of 5.3 months. Interestingly, ORR appeared similar between subgroups. A clinically meaningful benefit was observed across various patient populations, including those with low PD-L1 expression [TPS 1–49%, mPFS hazard ratio (HR) =0.54], high PD-L1 expression (TPS ≥50%, mPFS HR =0.46), squamous (mPFS HR =0.48) and non-squamous histology (mPFS HR =0.54). Notably, only 1.5% of patients discontinued ivonescimab due to TRAEs compared with 3.0% for pembrolizumab. The most common TRAEs associated with ivonescimab were proteinuria (grade 3 or higher in 3.0% vs. 0.0% for pembrolizumab) and hypertension (grade ≥3 in 5.1% vs. 0.5%). Interestingly, the safety profile of patients with squamous and non-squamous histology was similar, including grade 3 or worse haemorrhage events, which were observed in only two non-squamous NSCLC patients. These findings are encouraging, particularly when compared to bevacizumab, which is not recommended for squamous NSCLC due to its high risk of severe haemorrhagic events. Overall, the findings suggest a promising and well-tolerated alternative to chemotherapy-based treatments, especially for patients with squamous histology and PD-L1 expression below 50%.

Notably, in KEYNOTE-042, which represents the current chemo-free standard of care, pembrolizumab achieved an ORR of 27% and a mPFS of 5.4 months in patients with PD-L1 TPS ≥1%, with grade ≥3 TRAEs occurring in 18% of cases (9).

Furthermore, regimens that included a chemotherapy backbone, such as KEYNOTE-189 and KEYNOTE-407, reported ORRs of 48.3% and 57.9% with mPFS of 9.0 and 6.4 months, respectively, for patients treated with pembrolizumab plus chemotherapy (10,11). However, the toxicity burden of this regimen is significant, as grade ≥3 TRAEs were observed in 72.1% and 69.8% of patients in these trials, thereby limiting the clinical applicability for many individuals who cannot tolerate such adverse events.

Several limitations must be considered for this trial, including its nonrandomized design, the relatively short follow-up period of 1 year and heterogeneity in histology and PD-L1 status. However, it could be considered a promising agent and ongoing studies, such as Harmoni-3 (NCT05899608) and Hamoni-7 (NCT06767514), will further elucidate the agent’s efficacy and safety in broader settings and ethnicity, as well as provide long-term safety data. Furthermore, ivonescimab is also being investigated in other clinical contexts, such as in patients with NSCLC harboring EGFR mutations who have progressed on osimertinib (22). In parallel, other compounds with a similar bispecific design are undergoing clinical development, underscoring the growing interest and potential of this therapeutic class (23).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-60/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-60/coif). I.G.R. reports receiving consulting fees and support for attending meetings from Janssen. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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