Bispecific immune-angiogenic blockade in extensive-stage small-cell lung cancer—positioning ivonescimab

Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases and is characterized by rapid proliferation, early dissemination, and dismal prognosis. Despite its high initial sensitivity to platinum-etoposide chemotherapy, most patients relapse within months, and the 5-year survival rate remains below 8% (1).

The addition of immune checkpoint inhibitors (ICIs) to chemotherapy has modestly prolonged survival. In the IMpower133 trial, the combination of atezolizumab plus carboplatin-etoposide (CE) improved median overall survival (OS) compared with chemotherapy alone [12.3 vs. 10.3 months, hazard ratio (HR) for death, 0.70; 95% confidence interval (CI): 0.54–0.91; P=0.007] (2). Similarly, the CASPIAN trial demonstrated a survival benefit with durvalumab plus chemotherapy (12.9 vs. 10.5 months; HR, 0.73; 95% CI: 0.59–0.91; P=0.0047) (3). However, nearly all patients eventually develop resistance, highlighting the urgent need for novel therapeutic strategies.

Ivonescimab (AK112) is a humanized IgG1 bispecific antibody that targets both programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF)-A (4). This dual mechanism is supported by preclinical evidence that VEGF signaling not only promotes angiogenesis but also fosters an immunosuppressive microenvironment through PD-1 upregulation on CD8-positive cytotoxic T cells. Dual blockade of PD-1 and VEGF can therefore act synergistically to restore antitumor immunity and inhibit tumor vascularization (5).

Ivonescimab has shown encouraging activity in early-phase trials across multiple solid tumors and was recently approved in China for non-small cell lung cancer (NSCLC). In the HARMONi-2 phase 3 trial conducted in China, ivonescimab significantly prolonged median progression-free survival (PFS) compared with pembrolizumab (11.1 vs. 5.8 months; HR, 0.51; 95% CI: 0.38–0.69; one-sided P<0.0001) (4). Several ongoing clinical studies are evaluating ivonescimab in thoracic malignancies. Table 1 summarizes the main clinical trials.

Recently, Chen et al. reported the results of a phase 1b study in patients with extensive-stage SCLC (ES-SCLC) (10). The study enrolled 35 previously untreated patients who received ivonescimab at doses of 3, 10, or 20 mg/kg plus CE. The confirmed objective response rate was 80%, with a disease control rate of 91.4%, while median PFS was 6.9 months, and median OS reached 14.5 months. The 1-year OS rate was 72%. Previously published phase 3 trials, including IMpower133 and CASPIAN, reported 1-year OS rates of 51.7% and 53.7%, respectively. These figures are provided for context only; differences in trial phase, methodology, and cohort composition preclude any formal comparisons. Regarding safety, grade ≥3 treatment-related adverse events occurred in 60% of patients, mainly hematologic toxicities consistent with chemotherapy. Immune-related adverse events were reported in 40% of patients, mostly grade 1–2, and overall toxicity was considered manageable. While recognizing the limitations of early-phase data and cross-study comparisons, these findings suggest that ivonescimab may induce deeper and more durable responses than programmed death-ligand 1 (PD-L1) inhibitors combined with chemotherapy.

The integration of angiogenesis inhibitors into SCLC therapy has long been pursued. In the GOIRC-AIFA FARM6PMFJM trial, bevacizumab combined with chemotherapy improved PFS (5.7 vs. 6.7 months, P=0.030) but not OS (8.9 vs. 9.8 months, HR, 0.78; 95% CI: 0.58–1.06; P=0.113) (11). More recently, the BEAT-SC phase 3 study reported that adding bevacizumab to atezolizumab-chemotherapy significantly improved PFS compared to atezolizumab-chemotherapy alone (5.7 vs. 4.4 months; HR, 0.70; 95% CI: 0.54–0.90; P=0.0060), though OS data remain immature (13.0 vs. 16.6 months; HR, 1.22; 95% CI: 0.89–1.67; P=0.2212) (12).

The ETER-701 phase 3 trial further explored this concept, assessing benmelstobart (a novel PD-L1 inhibitor) in combination with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. Median OS was significantly prolonged with benmelstobart and anlotinib plus CE (19.3 vs. 11.9 months; HR 0.61; P=0.0002), whereas the addition of anlotinib alone to CE did not improve OS (13.3 vs. 11.9 months; HR 0.86; P=0.1723) (13).

Ongoing studies continue to investigate the synergy between ICIs and antiangiogenic drugs. For instance, the PEERS trial (phase 2, multicenter, open-label) (NCT05384015) is evaluating lenvatinib (a multi-kinase inhibitor with anti-VEGF receptor activity) combined with pembrolizumab plus chemotherapy in treatment-naïve ES-SCLC. Collectively, these data reinforce the biologic rationale for dual immune-angiogenic targeting. By simultaneously addressing immune evasion and tumor vascular support, bispecific antibodies may offer a more streamlined and potentially superior therapeutic strategy. Ivonescimab’s bispecific structure supports this concept by targeting PD-1 and VEGF-A within a single molecule. Through the formation of soluble complexes with VEGF dimers, ivonescimab increases its affinity for PD-1 more than 10-fold, resulting in stronger and more sustained PD-1 blockade and enhanced T-cell activation. Reciprocally, PD-1 engagement improves VEGF signaling pathway inhibition, creating a cooperative dual-target effect that cannot be achieved by combining two separate monoclonal antibodies. This mechanism also promotes vascular normalization, reduces T-cell exhaustion, and mitigates immunosuppressive signaling within the tumor microenvironment. In addition, Fc-silencing mutations minimize Fc-mediated effector functions, which may reduce off-target toxicity and improve tolerability relative to an ICI plus bevacizumab regimen. Overall, these mechanistic features highlight the potential for ivonescimab to deliver more integrated and effective modulation of both pathways than two independent therapeutic drugs (5,14).

An important limitation when integrating anti-angiogenic therapy into the treatment of SCLC relates to the typical disease presentation. SCLC tumors are often large, centrally located, and may encase or infiltrate major thoracic vessels. In this context, anti-VEGF therapies carry a theoretical and clinically documented risk of severe pulmonary hemorrhage and fatal hemoptysis, as observed in NSCLC with central lesions invading large vessels (15). Consequently, most anti-angiogenic clinical trials exclude patients with central cavitating tumors or vascular invasion, potentially limiting the generalizability of results to the real-world SCLC population, where such features are common.

Another limitation that warrants careful consideration in the clinical application of ivonescimab for ES-SCLC is the background risk of thromboembolic complications. Patients with SCLC have a documented incidence of venous thromboembolism, ranging from approximately 4% to 11% across different cohorts (16,17). Because ivonescimab incorporates VEGF blockade, these overlapping vulnerabilities—thrombotic and bleeding risks—could be magnified, especially in real-world populations that are often underrepresented in clinical trials due to strict exclusion criteria. Thus, while dual PD-1/VEGF inhibition holds promise, its applicability in SCLC may be constrained by the delicate balance between efficacy and vascular safety. Therefore, these considerations underscore the need for careful patient selection, vigilant safety monitoring, and exploration of biomarkers that could help optimize the balance between efficacy and risk in this challenging lung cancer subtype.

Phase 1b data of ivonescimab plus CE in ES-SCLC are encouraging, demonstrating efficacy outcomes that compare favorably with existing standards and a manageable toxicity profile. The bispecific design of ivonescimab addresses two critical pathways in SCLC—immune evasion and angiogenesis—providing a compelling biologic rationale. Pending results from larger randomized trials, ivonescimab may represent a next-generation frontline option for ES-SCLC and, depending from ongoing phase 3 trials (i.e., HARMONi-3 and HARMONi-7), could also have a role in first-line NSCLC, either in combination with chemotherapy or as monotherapy.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-127/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-127/coif). E.S.G. reports having received honoraria for lectures from Roche, BMS, Astra Zeneca, Pfizer Takeda, and AMGEN; support for attending meetings from Roche, BMS, Johnson and Johnson, MSD, and Takeda; and fees for participation on advisory boards for BMS, outside the submitted work. J.B.B. reports having received honoraria for lectures from Regeneron, AstraZeneca, Bristol Myers Squibb (BMS), Takeda, Roche, Merck, and Pfizer; support for attending meetings from MSD (Merck), Roche, and AstraZeneca; and fees for participation on advisory boards for MSD (Merck), Roche, Pierre Fabre, and AstraZeneca, outside the submitted work. The authors have no other 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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References

1. Franco F, Carcereny E, Guirado M, et al. Epidemiology, treatment, and survival in small cell lung cancer in Spain: Data from the Thoracic Tumor Registry. PLoS One 2021;16:e0251761. [Crossref] [PubMed]
2. Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9. [Crossref] [PubMed]
3. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-39. [Crossref] [PubMed]
4. 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;405:839-49. [Crossref] [PubMed]
5. Zhong T, Huang Z, Pang X, et al. Abstract B123: Mechanism of action of ivonescimab (AK112/SMT112): a first-in-class tetravalent Fc-silent bispecific antibody with dual blockade of PD-1 and VEGF that promotes cooperative biological effects. Mol Cancer Ther 2023; [Crossref]
6. Frentzas S, Austria Mislang AR, Lemech C, et al. Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors. J Immunother Cancer 2024;12:e008037. [Crossref] [PubMed]
7. Wang L, Luo Y, Ren S, et al. A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC. J Thorac Oncol 2024;19:465-75. [Crossref] [PubMed]
8. HARMONi-A Study Investigators. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA 2024;332:561-70. [Crossref] [PubMed]
9. Goldman JW, Passaro A, Laskin J, et al. Ivonescimab vs placebo plus chemo, phase 3 in patients with EGFR+ NSCLC progressed with 3rd gen EGFR-TKI treatment: HARMONi. International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain.
10. Chen Z, Wu L, Wang Q, et al. Brief Report: Ivonescimab Combined With Etoposide Plus Carboplatin as First-Line Treatment for Extensive-Stage SCLC: Results of a Phase 1b Clinical Trial. J Thorac Oncol 2025;20:233-9. [Crossref] [PubMed]
11. Tiseo M, Boni L, Ambrosio F, et al. Italian, Multicenter, Phase III, Randomized Study of Cisplatin Plus Etoposide With or Without Bevacizumab as First-Line Treatment in Extensive-Disease Small-Cell Lung Cancer: The GOIRC-AIFA FARM6PMFJM Trial. J Clin Oncol 2017;35:1281-7. [Crossref] [PubMed]
12. Ohe Y, Han B, Nishio M, et al. BEAT-SC: A randomized phase III study of bevacizumab or placebo in combination with atezolizumab and platinum-based chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). J Clin Oncol 2024;42:8001. [Crossref]
13. Cheng Y, Chen J, Zhang W, et al. Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial. Nat Med 2024;30:2967-76. [Crossref] [PubMed]
14. Shi F, Yang L, Gao Y, et al. Unlocking new horizons in oncology: ivonescimab's dual-target approach to anti-VEGF/PD-1(L1) therapy. Front Immunol 2025;16:1599181. [Crossref] [PubMed]
15. Hu H, Fu Z, Liu J, et al. Pulmonary haemorrhage and haemoptysis associated with bevacizumab-related treatment regimens: a retrospective, pharmacovigilance study using the FAERS database. Front Pharmacol 2024;15:1339505. [Crossref] [PubMed]
16. Dimakakos E, Livanios K, Vathiotis I, et al. Risk Factors for Venous Thromboembolism in Patients With Small Cell Lung Cancer. Anticancer Res 2021;41:1523-8. [Crossref] [PubMed]
17. Dimakakos E, Livanios K, Gkiozos I, et al. New data for venous thromboembolism in patients with small cell lung cancer: A review. Phlebology 2018;33:517-22. [Crossref] [PubMed]