Less is more: lessons from adding antiangiogenesis to 1L chemo-immunotherapy in non-small cell lung cancer (LEAP-006)

Introduction

Anti-programmed cell death 1/programmed death-ligand 1 [PD-(L)1] monoclonal antibodies, such as pembrolizumab, combined with chemotherapy are a standard of care for patients with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC) without targetable alterations (1). Despite a significant survival improvement versus chemotherapy alone, most patients eventually develop resistance. in the pivotal trial KEYNOTE-189, median overall survival (OS) was 22 months and only 19.5% of patients were alive at 5 years, highlighting the need for more effective strategies to prevent and overcome resistance (1).

In the last year, interest has grown around the vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor (VEGFR) axis as a potential therapeutic co-target. Beyond its role in angiogenesis, vascular endothelial growth factor (VEGF) signalling shapes an immunosuppressive tumour microenvironment by impairing dendritic-cell maturation and antigen presentation, expanding T-regulatory cells and upregulating inhibitory checkpoints on CD8⁺ T cells (2,3). These immune effects coexist with structurally and functionally abnormal vasculature that sustains hypoxia and impairs effector-cell trafficking. Transient “vascular normalization”, achieved with anti-angiogenic therapy, can improve perfusion and leukocyte infiltration and, in preclinical studies, has been shown to enhance responses to immune-checkpoint blockade (4).

With this rationale, lenvatinib, a small multikinase inhibitor with activity against VEGFR1–3 among other targets, has been explored with pembrolizumab across solid tumours, demonstrating antitumour activity with a manageable safety profile in selected, previously treated patients (5,6). In metastatic NSCLC specifically, phase 1/2 trials reported objective response rates (ORRs) in around one-third of patients, meeting prespecified activity thresholds despite several lines of prior therapy. As an example, In the phase 1b/2 study KEYNOTE-146, lenvatinib plus pembrolizumab demonstrated an ORR of 33% in 21 participants with metastatic NSCLC, 52% of whom had received at least two previous systemic therapies (6).

These preliminary, encouraging results prompted investigators to test this combination in the first line setting. LEAP-006, a large, global, double-blind phase 3 trial, randomised patients with untreated metastatic non-squamous NSCLC to pembrolizumab-platinum-pemetrexed with or without lenvatinib, with progression-free survival (PFS) and OS as co-primary endpoints (7).

Study design and results

LEAP-006 was a two-part, phase 3, randomised, double-blind first-line study. Part 1 was an open-label safety run-in of lenvatinib plus pembrolizumab and platinum-based chemotherapy. Part 2 randomised 748 participants (1:1) to receive pembrolizumab-pemetrexed-platinum with lenvatinib (n=375) or placebo (n=373) for four induction cycles, followed by maintenance pembrolizumab (up to 35 cycles) and pemetrexed with continued lenvatinib or placebo. The co-primary endpoints were PFS and OS.

At the final analysis, median time from randomization to data cutoff was 36.8 (range, 28.4–46.4) months. PFS was numerically longer in the lenvatinib arm [12.1 vs. 9.5 months; hazard ratio (HR) =0.88; P=0.0798] but did not meet the pre-specified threshold for statistical significance. OS was similar between arms [21.8 vs. 22.1 months; HR =1.05; 95% confidence interval (CI): 0.88–1.26; P=0.708]. Thus, the addition of lenvatinib did not improve either co-primary endpoint over pembrolizumab-chemotherapy alone. The ORR was higher (60.0% vs. 53.6%) and duration of response slightly longer with lenvatinib. Patient-reported outcomes showed no clinically meaningful differences between arms and time-to-true deterioration in key lung symptoms was comparable, indicating no quality-of-life advantage with the triplet. Moreover, the incidence of grade ≥3 treatment-related adverse events (TRAEs) was higher in the lenvatinib arm (69.7% of patients in the versus 55.6%), and incidence of treatment-related deaths was 5.6% versus 2.7%, respectively. TRAEs were consistent with the lenvatinib profile, such as hypertension and proteinuria, and contributed to more dose modifications and discontinuations across study components.

Discussion

The phase 3 LEAP-006 results provide important insights on the clinical value of adding anti-angiogenic therapy to first-line chemo-immunotherapy. Although biologically plausible and associated with a numerically higher response rate and longer duration of response, the combination did not translate early tumour control into better survival outcomes. Patient-reported outcomes echoed these results, and the safety profile of the combination was clinically meaningful, with more grade ≥3 TRAEs, more discontinuations, and more treatment-related deaths in the lenvatinib arm.

This evidence is aligned with other trials summarized in Table 1. LEAP-007 tested the same hypothesis in the chemotherapy-free setting [PD-L1 tumour proportion score (TPS) ≥1%], randomising pembrolizumab monotherapy versus pembrolizumab + lenvatinib (8). The combination achieved a nominal PFS gain but did not improve OS and carried a higher toxicity burden, with increased rates of grade ≥3 TRAEs as well as more dose interruptions and discontinuations versus pembrolizumab alone. Notably, the lenvatinib dose selected for this study was 20 mg od compared to 8 mg od in the LEAP-006 trial.

Beyond LEAP-006, the broader immunotherapy (IO)-anti-angiogenic landscape in advanced NSCLC is heterogeneous, and the choice of angiogenic partner may meaningfully influence both efficacy and tolerability. VEGF-pathway inhibition can be delivered through bevacizumab-based chemo-IO regimens, VEGFR-directed multi-kinase inhibitors, or emerging dual-target compounds such as PD-(L)1/VEGF bispecifics. Differences in potency, off-target effects, and scheduling can translate into distinct toxicity patterns and may ultimately determine whether incremental benefit is achievable on top of established chemo-immunotherapy backbones. Collectively, the trials below provide empirical insight into how these pharmacologic differences translate into clinical benefit-risk profiles.

The SAPPHIRE trial evaluated sitravatinib, a VEGFR/tumour-associated macrophages (TAM)-axis multikinase inhibitor, in combination with nivolumab versus docetaxel in the second-line setting (9). Despite a solid mechanistic rationale for overcoming IO resistance via vascular and myeloid reprogramming, the combination regimen did not achieve better outcomes compared to docetaxel (median OS 12.2 vs. 10.6 months; HR =0.86). Toxicity was substantial with about half of patients in the investigational arm experienced grade ≥3 adverse events (AEs).

In contrast, the HARMONi-2 trial suggests that a strategy integrating immune and angiogenic blockade within a single compound may be more effective. Ivonescimab, a bispecific antibody anti PD-1/VEGF, achieved a statistically and clinically meaningful PFS benefit versus pembrolizumab in previously untreated PD-L1-positive NSCLC (median 11.1 vs. 5.8 months; HR =0.51), with OS data not yet mature (10). Notably, the discontinuation rate due to TRAEs was low, and the safety profile was characterized by manageable VEGF-class events, such as proteinuria and hypertension. While the study was conducted in a single country (China) and global confirmatory trials are ongoing, these data suggest that synchronous, single-molecule engagement of PD-1 and VEGF may capture the intended immune-vascular synergy without the toxicity profile seen when using two different agents.

Several factors could have potentially contributed to the negative results of VEGFR-PD-1 combinations in LEAP-006 and related clinical trials. First, the incidence of adverse events was higher with lenvatinib (grade ≥3 TRAEs 69.7% vs. 55.6%; grade-5 TRAEs 5.6% vs. 2.7%), and discontinuations are more frequent (37.3%), possibly blunting any marginal efficacy. Second, broad kinase inhibition can suppress multiple signalling pathways beyond angiogenesis, increasing off-target toxicity without necessarily delivering proportionate anti-tumour benefit (11). Third, the treatment paradigm in non-oncogene-addicted NSCLC is rapidly evolving toward biomarker-driven selection. It is likely that multi-kinase inhibitors with VEGF/VEGFR activity confer benefit only in biologically defined subsets, like angiogenic or myeloid-inflamed microenvironments, rather than across all-comers (12). The absence of biomarker enrichment likely contributed to the failure of lenvatinib-based regimens, despite a strong biological rationale for synergy with PD-(L)1 blockade.

Several biomarkers have been analysed and correlated with efficacy in anti-angiogenic based strategies. For example, data from the IMpower 151 have suggested that tumours harbouring immune-response gene signatures may derive particular benefit from the combination of atezolizumab, bevacizumab, carboplatin and paclitaxel (ABCP) (13). Furthermore, the APPLE study reported that adding bevacizumab to chemo-immunotherapy improved PFS in patients with low baseline serum VEGF-A (14). These signals are hypothesis-generating only as none has yet been prospectively validated as a predictive biomarker to select patients for anti-angiogenic plus IO strategies.

Moving forward, prospective biomarker-driven studies alongside engineered compounds, like bispecific anti-PD-1 and anti-VEGF antibodies, may be necessary to realise the long-theorised immune-vascular synergy in NSCLC.

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-25-120/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-120/coif). I.G.R. reports consulting fees from Pfizer, Boehringer Ingelheim, and Johnson & Johnson; payment or honoraria from Pfizer, Boehringer Ingelheim, Johnson & Johnson, MSD, and Immedica; support from Johnson & Johnson and Pfizer; and participation on advisory boards for Johnson & Johnson and AstraZeneca. R.C. reports grants or contracts from Roche, PharmaMar, GSK, Janssen, AstraZeneca, Taiho, ArriVent, BioNTech, Bristol-Myers Squibb, Gilead, MSD, Nuvalent, and OSE Immunotherapeutics; consulting fees from Janssen, Pfizer, Merck Sharp & Dohme, PharmaMar, ArriVent, Roche, Bristol Myers Squibb, AstraZeneca, Biontech, GSK, and Takeda; payment or honoraria from Janssen, Beigene, Regeneron, AstraZeneca, GSK, and Takeda; support for attending meetings and/or travel from Takeda and Janssen; participation on advisory boards for PharmaMar, Janssen, Astrazeneca, and Arrivent; and stock or stock options in Supportive Care UK and LOC. The other author has no conflicts of interest to declare.

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