LEAP-006: limits and potential of integrating anti-angiogenic agents into first-line multimodal therapy for non-squamous non-small cell lung cancer

Introduction

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of advanced non-small cell lung cancer (NSCLC) (1-4). ICIs with or without platinum-based chemotherapy are the standard of care for the first line treatment in patients with non-squamous (non-SQ) histology who are not eligible for targeted therapies (3,5). However, despite these advances, a meaningful subset of patients continues to derive suboptimal outcomes (6), underscoring an urgent need for novel therapeutic strategies to further improve survival. This unmet need is particularly evident in specific subgroups, such as patients with programmed death-ligand 1 (PD-L1) <1% tumors or those without a history of tobacco use.

Among the approaches under investigation, the addition of anti-angiogenic therapy to immunotherapy has gained particular interest. The rationale for this combination is grounded in the potential synergistic interactions between anti-angiogenic agents and immunotherapy, supported by evidence suggesting that vascular endothelial growth factor (VEGF) inhibition can reshape the tumor microenvironment (TME), enhance T-cell infiltration, and thereby increase the efficacy of ICIs (7-9).

The phase 3 LEAP-006 trial (10) aimed to address this question, evaluating pembrolizumab plus pemetrexed and platinum chemotherapy with or without lenvatinib as first-line therapy for metastatic non-SQ NSCLC without actionable genomic alterations (AGAs). Lenvatinib is an oral inhibitor of multiple tyrosine kinases, including VEGF receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs). This was the first randomized study directly testing whether the addition of an anti-angiogenic multi-kinase inhibitor to the established ICIs plus chemotherapy backbone could extend clinical benefit.

Although LEAP-006 trial failed to meet its primary endpoints, with notable safety concerns, it provided critical insights into the feasibility and limitations of this multimodal approach.

In this editorial, we will discuss the results of LEAP-006, highlighting both its strengths and limitations, and we will explore the future perspectives and open questions for the integration of anti-angiogenic agents in the first-line treatment of NSCLC.

LEAP-006 study: design, efficacy, and safety findings

The phase 3 LEAP-006 trial (10) was a two-part, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of adding lenvatinib to chemo-immunotherapy in patients with previously untreated stage IV non-SQ NSCLC without EGFR, ALK, or ROS1 actionable alterations.

Part 1 of the study consisted of an open-label safety run-in, during which 13 patients received lenvatinib in combination with pembrolizumab plus pemetrexed and either carboplatin or cisplatin. The primary endpoints were to assess dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuation due to AEs. Notably, 2 DLTs (grade 3 hyponatremia), both in the cisplatin group, were reported. Twelve participants experienced treatment-related AEs, including 10 with grade ≥3 events. Two patients died and 9 discontinued any study treatment due to treatment-related AEs.

Part 2, initiated after review of the safety profile from part 1, was the randomized, double-blind, placebo-controlled efficacy phase. The primary endpoints were progression-free survival (PFS) and overall survival (OS), while secondary endpoints included objective response rate (ORR), duration of response (DOR), safety, patient reported outcomes (PROs), and time to true deterioration (TTD). A total of 748 patients were randomized: 375 to the lenvatinib arm and 373 to the placebo arm.

The protocol included 3 interim analyses and one final analysis (FA). At the FA data cutoff (median follow-up 36.6 months, range, 28.4–46.4 months), 519 patients (69.4%) had experienced disease progression or death, and 488 (65.2%) had died. Neither primary endpoint was met: median PFS was 12.1 months with lenvatinib versus 9.5 months with placebo [hazard ratio (HR) 0.88; 95% confidence interval (CI): 0.74–1.04], and median OS was 21.8 versus 22.1 months (HR 1.05; 95% CI: 0.88–1.26). The 36-month PFS rates were 21.9% in the lenvatinib arm and 21.5% in the placebo arm, while the 36-month OS rates were 33.0% and 36.5%, respectively.

Regarding secondary endpoints, no statistically or clinically meaningful differences were observed between treatment arms for ORR, PROs, or TTD. Notably, grade 3–5 treatment-related AEs occurred in 69.7% of patients in the lenvatinib arm versus 55.6% in the placebo arm, with 21 and 10 treatment-related deaths, respectively. AEs of special interest for pembrolizumab were also more frequent in the lenvatinib arm (42.4%) than in the placebo arm (32.8%).

VEGF(R) inhibition: promises and challenges

The negative outcome of LEAP-006 is consistent with findings from related studies. In LEAP-007 (11), lenvatinib combined with pembrolizumab did not improve OS compared with pembrolizumab alone in patients with PD-L1 ≥1% NSCLC. Similarly, both the LEAP-008 (12) and the SAPPHIRE trial (13), conducted in the post-immunotherapy setting and combining an anti-programmed cell death protein 1 (PD-1) agent with lenvatinib and sitravatinib, respectively, failed to demonstrate survival benefits over docetaxel (Table 1). Overall, these results suggest that the simple addition of anti-angiogenic multi-kinase inhibitors to established immunotherapy-based regimens may not be sufficient to extend survival.

Interestingly, the LEAP-006 subgroup analysis did not demonstrate a statistically significant benefit from the addition of lenvatinib to the standard of care in any patient subgroup, including those traditionally considered less responsive to ICI-based regimens. In particular, no PFS or OS improvement was observed among patients with PD-L1 <1% tumors or in those without a history of tobacco use.

By contrast, the IMpower150 trial (14) reported improved PFS and OS with atezolizumab plus bevacizumab and chemotherapy compared with bevacizumab plus chemotherapy. However, important differences in study design and control arms limit direct comparisons. IMpower150 evaluated the addition of immunotherapy to an anti-VEGF backbone, whereas LEAP-006 (10) tested the reverse strategy, adding an anti-angiogenic agent to a chemo-immunotherapy regimen. The signal in IMpower150 was driven by the atezolizumab plus bevacizumab plus chemotherapy arm, while the atezolizumab plus chemotherapy arm did not significantly improve OS compared with bevacizumab plus chemotherapy, highlighting that benefit arose from ICI in the context of VEGF inhibition (Table 1). This synergy was particularly evident in subgroups with EGFR mutations or liver metastases, settings where VEGF-mediated immunosuppression is prominent. Thus, IMpower150 does not establish anti-VEGF agents as broadly beneficial in all-comers, but rather points to a more nuanced, biology-driven therapeutic niche.

Within this framework, multiple studies have attempted to refine clinicopathologic and translational features predictive of benefit from anti-angiogenic therapies in NSCLC. The prospective ANGIOMET study suggested a potential prognostic role of genetic variants in VEGFR-1 and VEGF-A, as well as pre-treatment plasma levels of VEGF-A, in patients with NSCLC treated with chemotherapy plus bevacizumab (15). Other approaches—such as PET-CT assessment of tumor neoangiogenesis and detection of activated circulating vascular endothelial cells through liquid biopsy—have also been explored as potential predictors of response to anti-angiogenic therapy; however, none of these methods are currently applicable in routine clinical practice and all remain confined to the research setting (16).

The addition of anti-angiogenic antibodies to established immunotherapy-based regimens also raises important safety concerns. In the experimental arm of LEAP-006 (10), toxicities consistent with the lenvatinib profile were observed, along with a higher incidence of pembrolizumab-related AEs. Rates of grade ≥3 treatment-related AEs and treatment-related deaths were higher with lenvatinib versus placebo. This was consistent with the safety results of LEAP-007 (11), where grade ≥3 treatment-related AEs occurred in 57.9% of patients treated with pembrolizumab plus lenvatinib compared with 24.4% receiving pembrolizumab plus placebo. The magnitude of this difference prompted unblinding of the study and discontinuation of both lenvatinib and placebo.

However, the rationale for combining anti-VEGF(R) and immunotherapy remains biologically compelling. VEGF-driven angiogenesis promotes immunosuppression by impairing dendritic cell maturation, enhancing regulatory T-cell recruitment, and reducing T-cell trafficking into tumors (Figure 1A). Anti-angiogenic agents may help restore normal tumor vasculature, improving immune cell infiltration and anti-tumor activity (7-9) (Figure 1B). Within this framework, bispecific antibodies capable of simultaneously targeting PD-1/PD-L1 and VEGF/VEGFR offer a rational strategy and may replace traditional PD-1/PD-L1 blockade (17). Importantly, these are engineered with reduced Fc functionality, in order to minimize Fc-mediated antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, thus improving the immunosafety profile.

Figure 1 Overview of VEGF-mediated immunosuppression and the rationale for combined VEGF(R) and PD-1/PD-L1 inhibition. (A) Immunosuppressive effects of VEGF on the TME. (B) Synergistic effects of PD-1/PD-L1 and VEGF(R) inhibitors on the TME. DC, dendritic cell; HIF-1, hypoxia-inducible factor 1; MHC II, major histocompatibility complex class II; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1; T-reg, regulatory T cell; TAM, tumor-associated macrophage; TCR, T cell receptor; TME, tumor microenvironment; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Interestingly, the bispecific antibody ivonescimab, which targets both PD-1 and VEGF via cooperative binding (17), has already shown promising results in the HARMONi-2 randomised trial (18), where it was compared to pembrolizumab in untreated patients with locally advanced or metastatic PD-L1-positive NSCLC. In fact, ivonescimab improved PFS versus pembrolizumab (HR 0.51, P<0.0001) while maintaining a manageable safety profile. Similarly, at the prespecified interim analysis of the ongoing phase 3 HARMONi-6 trial (NCT05840016), ivonescimab plus chemotherapy provided a statistically and clinically significant PFS benefit over tislelizumab plus chemotherapy in the first-line treatment of squamous NSCLC, irrespective of PD-L1 status (19). The ongoing HARMONi-3 (NCT05899608) study is comparing ivonescimab plus chemotherapy versus the current standard of care (pembrolizumab plus chemotherapy) in patients with locally advanced or metastatic NSCLC, without neither histology nor PD-L1 restrictions.

Notably, ivonescimab has also been investigated in EGFR-mutant non-SQ NSCLC, a setting where VEGF-mediated resistance mechanisms play a central role. In the HARMONi-A study (20), patients progressing on osimertinib were randomized to receive platinum-based chemotherapy plus either ivonescimab or placebo (Table 1). At the first interim analysis, ivonescimab demonstrated a PFS improvement of 2.3 months compared with placebo (HR 0.46, P<0.001). These findings reinforce the hypothesis that there are subgroups of patients who may derive greater benefit from anti-angiogenic agents due to their tumor biology.

Conclusions

In recent years, significant efforts have been made to enhance ICIs efficacy in NSCLC. Within this framework, TME modulation has gained a central role, with VEGF(R) inhibition emerging as a particularly attractive strategy. However, many trials aimed at enhancing ICI efficacy by adding anti-VEGF(R) agents have shown disappointing results.

The negative findings of LEAP-006 reinforce the robustness of pembrolizumab plus chemotherapy as the standard of care for first-line non-SQ NSCLC. A major limitation of this study has been the lack of appropriate patient selection. While VEGF inhibition offers compelling preclinical rationale and has demonstrated clinical benefit in other tumor types when combined with ICIs, its unselected application in NSCLC failed to improve outcomes and was associated with increased toxicity.

Future progress will likely depend on biomarker-oriented approaches. Identifying angiogenic, immunologic, or composite signatures that define patient subgroups most likely to benefit from anti-VEGF/ICI combinations will be critical. Incorporating these markers into prospective trial designs will help move toward a more precise, personalized treatment strategy for AGA-negative NSCLC.

Meanwhile, the development of novel agents—including bispecific antibodies capable of simultaneously targeting VEGF(R) and PD-(L)1 with high affinity—remains an appealing avenue, as these could enhance efficacy while reducing overlapping toxicities.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2034/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2034/coif). V.S. was supported by an American-Italian Cancer Foundation Post-Doctoral Fellowship, year 2025–2026. F.P. declares personal fees from EMD SeronoEMD Serono, Inc. and is supported by Fondazione Gianni Bonadonna Fellowship 2024, in collaboration with the European School of Oncology. M.A. declares research funding from AstraZeneca, Amgen, Owkin, Lifen, and Sandoz. B.R. declares advisory board/consultant: Amgen, Regeneron, AstraZeneca, AbbVie, Bristol-Mayer Squibb, Bayer, Caris Life, and Lilly; honoraria: AstraZeneca, Society for ImmunoTherapy of Cancer, and Targeted Oncology; speakers bureau: AstraZeneca, and Regeneron; travel support: Regeneron, AstraZeneca, Bristol-Mayer Squibb, and Genentech; and research funding to institution: AstraZeneca. The other authors have 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
2. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378:2288-301. [Crossref] [PubMed]
3. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:198-211. [Crossref] [PubMed]
4. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol 2023;41:1999-2006. [Crossref] [PubMed]
5. Rodríguez-Abreu D, Powell SF, Hochmair MJ, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol 2021;32:881-95. [Crossref] [PubMed]
6. Mariniello A, Borgeaud M, Weiner M, et al. Primary and Acquired Resistance to Immunotherapy with Checkpoint Inhibitors in NSCLC: From Bedside to Bench and Back. BioDrugs 2025;39:215-35. [Crossref] [PubMed]
7. Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to Modulate Antitumor Immunity. Front Immunol 2018;9:978. [Crossref] [PubMed]
8. Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 2020;52:1475-85. [Crossref] [PubMed]
9. Ren S, Xiong X, You H, et al. The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer. Front. Immunol 2021;12:689132. [Crossref] [PubMed]
10. Herbst RS, Cho BC, Zhou C, et al. Lenvatinib Plus Pembrolizumab, Pemetrexed, and a Platinum as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 LEAP-006 Study. J Thorac Oncol 2025;20:1302-14. [Crossref] [PubMed]
11. Yang JC, Han B, De La Mora Jiménez E, et al. Pembrolizumab With or Without Lenvatinib for First-Line Metastatic NSCLC With Programmed Cell Death-Ligand 1 Tumor Proportion Score of at least 1% (LEAP-007): A Randomized, Double-Blind, Phase 3 Trial. J Thorac Oncol 2024;19:941-53. [Crossref] [PubMed]
12. Leighl NB, Paz-Ares L, Abreu DR, et al. LEAP-008: Lenvatinib Plus Pembrolizumab for Metastatic NSCLC That Has Progressed After an Anti-Programmed Cell Death Protein 1 or Anti-Programmed Cell Death Ligand 1 Plus Platinum Chemotherapy. J Thorac Oncol 2025;20:1489-504. [Crossref] [PubMed]
13. Borghaei H, de Marinis F, Dumoulin D, et al. SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Ann Oncol 2024;35:66-76. [Crossref] [PubMed]
14. Socinski MA, Nishio M, Jotte RM, et al. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol 2021;16:1909-24. [Crossref] [PubMed]
15. Jantus-Lewintre E, Massutí Sureda B, González Larriba JL, et al. Prospective Exploratory Analysis of Angiogenic Biomarkers in Peripheral Blood in Advanced NSCLC Patients Treated With Bevacizumab Plus Chemotherapy: The ANGIOMET Study. Front Oncol 2021;11:695038. [Crossref] [PubMed]
16. Zhao W, Jiang J. Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer. Cancer Control 2024;31:10732748241270589. [Crossref] [PubMed]
17. Zhong T, Huang Z, Pang X, et al. 1194 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. J Immunother Cancer 2023;11:A1-A1731.
18. 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]
19. HARMONi-6, Featuring Ivonescimab Combined with Chemotherapy vs. Tislelizumab Plus Chemotherapy in 1L Treatment of Patients with Squamous NSCLC in China, to be Showcased in Presidential Symposium at ESMO 2025 [Internet]. 2025. Available online: https://smmttx.com/news/press-releases/news-details/2025/HARMONi-6-Featuring-Ivonescimab-Combined-with-Chemotherapy-vs--Tislelizumab-Plus-Chemotherapy-in-1L-Treatment-of-Patients-with-Squamous-NSCLC-in-China-to-be-Showcased-in-Presidential-Symposium-at-ESMO-2025/default.aspx
20. 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]