Immune checkpoint inhibitor resistance in non-small cell lung cancer: limits of vascular endothelial growth factor inhibition and new directions
Editorial Commentary

Immune checkpoint inhibitor resistance in non-small cell lung cancer: limits of vascular endothelial growth factor inhibition and new directions

Hiroyasu Kaneda ORCID logo

Department of Clinical Oncology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan

Correspondence to: Hiroyasu Kaneda, MD, PhD. Department of Clinical Oncology, Graduate School of Medicine, Osaka Metropolitan University, Asahimachi 1-4-3, Abeno-ku, Osaka 545-8585, Japan. Email: kaneda.hiroyasu@omu.ac.jp.

Comment on: 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.

Keywords: Non-small cell lung cancer (NSCLC); immune checkpoint inhibitors (ICIs); vascular endothelial growth factor inhibition (VEGF inhibition); tumor microenvironment (TME); resistance

Submitted Sep 12, 2025. Accepted for publication Nov 10, 2025. Published online Nov 26, 2025.

doi: 10.21037/jtd-2025-1882

Introduction

Over the past decade, the introduction of immune checkpoint inhibitors (ICIs) has transformed the management of non-small cell lung cancer (NSCLC) (1). Initially studied in previously treated metastatic disease, ICIs were soon adopted in the first-line setting for advanced disease and, more recently, incorporated into perioperative therapy. Multiple randomized trials have consistently demonstrated a survival benefit, establishing ICIs as the cornerstone of contemporary NSCLC treatment (2-7). Nevertheless, important limitations persist: approximately half of patients derive no benefit, and even among responders, disease progression is common. Long-term survival is achieved in only about 20% of patients, highlighting resistance as a central challenge in the ICI era.

Unlike targeted therapies, in which resistance mechanisms can often be categorized as primary or acquired based on relative prevalence, ICI resistance is more complex. It remains uncertain whether distinct mechanisms preferentially drive primary versus acquired resistance; rather, many contributors may underlie both. Mechanistic studies within the framework of the cancer-immunity cycle have identified multiple barriers to immune surveillance, including loss of tumor antigenicity, impaired antigen presentation, T-cell exclusion, and the accumulation of immunosuppressive cell populations in the tumor microenvironment (TME) (8). Among these, dysregulated vascular endothelial growth factor (VEGF) signaling is particularly significant. Beyond promoting angiogenesis, VEGF promotes immune dysfunction by impairing dendritic cell maturation, recruiting regulatory T cells, and restricting cytotoxic lymphocyte infiltration (9-12).

The integration of ICIs, either as monotherapy or in combination with chemotherapy, for patients without actionable oncogenic drivers has been a major therapeutic milestone. This shift, however, has created an urgent need for effective strategies after immunotherapy failure. Preclinical data suggest that VEGF blockade can reprogram the TME from an immune-excluded “cold” state into a more inflamed, permissive milieu, potentially restoring ICI responsiveness. Clinically, ICI-VEGF combinations improved survival in renal cell carcinoma (RCC) (13) and hepatocellular carcinoma (HCC) (14). RCC and HCC are biologically more angiogenesis-driven, whereas NSCLC is characterized by molecular heterogeneity, stromal fibrosis, and immune exclusion, which may partly explain the inconsistent efficacy of VEGF-ICI combinations. In NSCLC, evaluation of anti-angiogenic strategies with ICIs has produced mixed results. The phase II Lung-MAP S1800A trial (15) (ramucirumab plus pembrolizumab) demonstrated a survival benefit in the post-ICI setting, whereas several phase III programs, including lenvatinib (16) (LEAP-008) and sitravatinib (17) (SAPPHIRE), reported less favorable outcomes. Reflecting these inconsistencies, current development efforts are expanding beyond VEGF to include antibody-based strategies [bispecific antibodies, T-cell engagers, antibody-drug conjugates (ADCs)], targeted agents, adoptive cell therapies, therapeutic vaccines, and intratumoral immunotherapies. Although resistance mechanisms are diverse, they converge clinically on an immunosuppressive TME characterized by ineffective or dysfunctional cytotoxic T-cell activity (18). While potential biomarkers of resistance have been described, their clinical utility remains limited. Continued progress will require deeper molecular dissection of resistance biology, careful characterization of heterogeneous response-progression phenotypes, and dynamic monitoring of immunomodulation during treatment. Notably, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells continue to drive immune evasion after VEGF blockade, and targeting this myeloid axis [for example via colony-stimulating factor-1 receptor (CSF1R), AXL, or phosphoinositide 3-kinase-gamma (PI3Kγ) inhibition] is an emerging therapeutic direction (19).

LEAP-008 trial insights: challenges of VEGF-ICI combinations in NSCLC

The LEAP-008 study compared lenvatinib plus pembrolizumab with docetaxel in patients with metastatic NSCLC previously treated with anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) therapy and platinum-based chemotherapy. The trial did not demonstrate improvements in progression-free survival (PFS) or overall survival (OS) compared with docetaxel alone (16). Similar outcomes were reported in earlier phase III studies of lenvatinib combinations [LEAP-006 (20) and LEAP-007 (21)], despite preclinical data suggesting immunomodulatory effects. The rationale for combining pembrolizumab with lenvatinib rests on the antitumor and anti-angiogenic effects of VEGF inhibition and on its capacity to remodel the TME. Lenvatinib has been shown to shift macrophages from an immunosuppressive M2 phenotype toward an inflammatory M1 phenotype (22) and to suppress T-helper type 2 (Th2) cells while enhancing T helper type 1 (Th1)-driven immune responses, thereby promoting memory T-cell activation (23). Through these mechanisms, lenvatinib may convert a “cold” TME into an “immune-hot” state more responsive to ICIs. The negative clinical results may reflect several contributing factors. First, the TME after prior ICI exposure is often profoundly immunosuppressive, rendering VEGF inhibition alone unlikely to reverse resistance. Second, patient populations in these trials were heterogeneous, including both primary and acquired resistance, which may have diluted potential benefits in specific subgroups. Third, the toxicity of combination regimens can limit dose intensity and treatment continuity, thereby reducing efficacy. Treatment-related adverse events (AEs), including grade 3 or 4 events, occurred at comparable frequencies between groups; however, the incidence of grade 5 events was higher, and treatment discontinuation due to AEs was more frequent in the combination arm, indicating considerable toxicity associated with this regimen. Lenvatinib monotherapy demonstrated a modest objective response rate (ORR) of 12.5%, contributing to the higher ORR observed with the combination (22.7%) but without a corresponding survival benefit. Subgroup analyses suggested potential benefit in certain patient populations (such as those not receiving immediate prior ICI); however, the small numbers render these findings exploratory rather than definitive. Overall, the results suggest that overcoming ICI resistance cannot be achieved solely through VEGF inhibition, underscoring the involvement of additional mechanisms in the development and persistence of resistance. While VEGF-ICI combinations have demonstrated clinical utility in the first-line setting, their role after ICI resistance may still be clinically meaningful if applied in carefully selected patient populations, with appropriate agents, and in specific treatment contexts.

The concept of combining ICIs with VEGF-targeting therapies has attracted considerable attention as a potential strategy to overcome resistance (9). Several recent phase III trials have evaluated the efficacy of combining anti-PD-1/PD-L1 agents with VEGF inhibitors in previously treated NSCLC. However, most of these pivotal studies have yielded negative trial outcomes. In the post-immunotherapy setting, combinations of ICIs and VEGF-tyrosine kinase inhibitors (TKIs) have consistently failed to demonstrate superiority over standard chemotherapy (docetaxel with or without ramucirumab or nintedanib), thereby limiting their clinical utility. An exception was the phase II Lung-MAP S1800A trial, in which ramucirumab plus pembrolizumab improved overall survival (OS) compared with standard chemotherapy. This signal of efficacy, however, was not confirmed in the subsequent Pragmatica-Lung trial (NCT05633602), a pragmatic phase III study presented at American Society of Clinical Oncology (ASCO) 2025 (24), where ramucirumab plus pembrolizumab failed to improve OS over standard of care, resulting in a negative result. Given the limited success of VEGF inhibition in overcoming ICI resistance, attention has shifted toward alternative therapeutic approaches. Current strategies aim to restore antitumor immunity through antibody-based therapies, including bispecific antibodies, T-cell engagers, and ADCs, as well as targeted therapies, adoptive cell therapies, therapeutic vaccines, and intratumoral immunotherapies (18). Although several phase III trials of these novel strategies have already reported results, many have not demonstrated substantial clinical benefit to date. Nevertheless, these approaches remain under active investigation, and continued exploration may yield future breakthroughs in addressing the persistent challenge of ICI resistance in NSCLC.

Management of ICI-resistant NSCLC: current landscape and future directions

The management of ICI-resistant NSCLC remains a critical area of unmet medical need. Therapeutic strategies aimed at overcoming resistance have diversified, encompassing both direct tumor-targeting approaches and interventions designed to reprogram the TME and restore T-cell function. Despite extensive investigation, randomized phase III trials evaluating VEGF-targeted therapies, TAM kinase inhibitors (17,25), alternative checkpoint inhibitors such as T-cell immunoglobulin and mucin domain-3 (Tim-3) (26), and T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) (27), and multiple ADCs (28,29) have not demonstrated consistent improvements in OS (Table 1). Reversible epigenetic alterations—including chromatin remodeling and aberrant DNA methylation—can silence antigen-presentation machinery [e.g., beta2-microglobulin, human leukocyte antigen (HLA)] and attenuate interferon-γ signaling, thereby fostering immune ignorance and driving secondary resistance; consequently, evaluating DNA methyltransferase, histone deacetylase, or bromodomain and extra-terminal domain inhibitors in combination with ICIs represents a rational approach to restore tumor immunogenicity (38).

Table 1

Post-ICI NSCLC trials (docetaxel/pemetrexed comparator)

Trial Experimental arm n PFS (months) OS (months) Ref.
Lung-MAP S1800A Ramucirumab + pembrolizumab 136 4.5 vs. 5.2; HR 0.69, 80% CI: 0.66–1.14; P=0.25 14.5 vs. 11.6; HR 0.69, 80% CI: 0.51–0.92; P=0.05 (15)
SAPPHIRE Sitravatinib + nivolumab 577 4.4 vs. 5.4; HR 1.08, 95% CI: 0.89–1.32; P=0.45 12.2 vs. 10.6; HR 0.86, 95% CI: 0.70–1.05; P=0.14 (17)
CONTACT-01 Atezolizumab + cabozantinib 366 4.6 vs. 4.0; HR 0.74, 95% CI: 0.59–0.92 10.7 vs. 10.5; HR 0.91, 95% CI: 0.70–1.18 (25)
TROPION-Lung01 Datopotamab deruxtecan 604 4.4 vs. 3.7; HR 0.75, 95% CI: 0.62–0.91; P=0.004 12.9 vs. 11.8; HR 0.94, 95% CI: 0.78–1.14; P=0.53 (28)
CARMEN-LC03 Tusamitamab ravtansine 389 5.4 vs. 5.9; HR 1.14, 95% CI: 0.86–1.51 12.8 vs. 11.5; HR 0.85, 95% CI: 0.64–1.11 (30)
EVOKE-01 Sacituzumab govitecan 603 4.1 vs. 3.9; HR 0.92, 95% CI: 0.77–1.11 11.1 vs. 9.8; HR 0.84, 95% CI: 0.68–1.04; P=0.053 (29)
LEAP-008 Pembrolizumab +lenvatinib 422 5.6 vs. 4.2; HR 0.89, 95% CI: 0.70–1.12; P=0.16 11.3 vs. 12.0; HR 0.98, 95% CI: 0.78–1.23; P=0.44 (16)
KEYVIBE-002 Vibostolimab/pembrolizumab ± docetaxel 255 5.6 vs. 3.2; HR 0.77, 95% CI: 0.53–1.13; P=0.09 10.2 vs. 8.8; HR 0.76, 95% CI: 0.50–1.15 (31)
COSTAR Lung Cobolimab + dostarlimab ± docetaxel 500 OS not improved (26)
LATIFY Durvalumab +ceralasertib 580 Ongoing (phase 3) (32)
PRESERVE-003 Gotistobart 600 Ongoing (phase 2–3) (33)
TeliMET NSCLC-01 Telisotuzumab vedotin 698 Ongoing (phase 3) (34)
Be6A Lung-01 Sigvotatug vedotin 600 Ongoing (phase 3) (35)
HUDSON (umbrella) Durvalumab + targeted agents 268 5.8 vs. 2.7 17.4 vs. 9.4 (36)
ATALANTE-1 OSE2101 219 2.7 vs. 3.0; HR 1.28, 95% CI: 0.82–2.00 8.8 vs. 8.3; HR 0.86, 95% CI: 0.62–1.19 (37)

CI, confidential interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; Ref, reference.

The central focus in overcoming ICI resistance lies in transforming the TME from an immunologically “cold” state into an inflamed “hot” milieu capable of sustaining effective antitumor immunity. Ultimately, therapeutic efficacy depends on the activation and recruitment of cytotoxic T lymphocytes into the tumor bed. Experience with VEGF inhibition combined with ICIs demonstrates that resistance mechanisms are heterogeneous and complex, extending beyond the TME to include tumor-intrinsic factors such as serine/threonine kinase 11 (STK11)/Kelch-like ECH-associated protein 1 (KEAP1) co-mutations (39-42) or Janus kinase/signal transducer and activator of transcription (JAK/STAT) (43,44) pathway alterations. Clinically, resistance is categorized as either primary or secondary, reflecting fundamentally distinct biology (45,46) (Table 2). Primary resistance is typically associated with intrinsically low tumor immunogenicity or profoundly immunosuppressive microenvironments. In contrast, secondary resistance emerges after an initial response and reflects dynamic tumor evolution and adaptive escape mechanisms. Evaluating both categories within the same clinical trial risks obscuring therapeutic signals and underscores the need for tailored strategies that address the predominant mechanisms within each group. Over time, initially immune-inflamed tumors can transition towards immune-exhausted phenotypes through treatment-induced adaptive changes in the TME, highlighting the importance of longitudinal immune profiling and biomarker-based stratification in clinical trials to capture and respond to this dynamic evolution of resistance.

Table 2

Clinical definitions and biological features of primary and secondary resistance to immune checkpoint inhibitors

Items   Primary resistance   Secondary (acquired) resistance
Definition (SITC 2023 consensus & ESMO)   PD or SD <6 months after ≥2 cycles of ICI; progression ≤3 months after last dose if discontinued   Progression after initial CR/PR or durable SD ≥6 months; progression >3 months after last ICI dose if discontinued
Clinical features   Early progression without objective response   Recurrence/progression after initial benefit
Approximate incidence   5–20%   60–75%
Major resistance mechanisms   Low immunogenicity (low neoantigen load)   Antigen loss (clonal selection)
  Antigen-presentation loss (MHC loss, B2M mutation)   JAK/STAT pathway defects
  Immunosuppressive TME (Tregs, MDSCs, VEGF, adenosine pathway)   Compensatory checkpoints (TIM-3, LAG-3, TIGIT)
  Oncogenic drivers (EGFR, ALK, STK11, KEAP1)   Tumor heterogeneity
  Metabolic reprogramming (lactate, hypoxia, VEGF)

ALK, anaplastic lymphoma kinase; B2M, beta-2-microglobulin; CR, complete response; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; ICI, immune checkpoint inhibitor; JAK/STAT, Janus kinase/signal transducer and activator of transcription; KEAP1, Kelch-like ECH-associated protein 1; LAG-3, lymphocyte activation gene-3; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility class; PD, disease progression; PR, partial response; SD, stable disease; SITC, Society for Immunotherapy of Cancer; STK11, serine/threonine kinase 11; TIGIT, T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain; TIM-3, T-cell immunoglobulin and mucin domain-3; TME, tumor microenvironment; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.

At present, numerous molecular and immunological pathways of resistance have been identified at the preclinical and translational levels, yet clinical trials have not delivered meaningful advances clinically. This discrepancy may partly reflect the absence of resistance-based stratification in trial design, as well as the inherent complexity and heterogeneity of resistance biology. Future progress will require the integration of biomarker-driven patient selection, resistance-tailored treatment strategies, and pragmatic trial designs that enroll patients with poor prognostic features who most urgently need novel therapies. Reducing logistical barriers, including limited tissue availability and delays in molecular profiling, will also be essential to ensure that innovative therapies reach the patients most in need.

Conclusions

VEGF inhibition remains biologically compelling but has not fulfilled its promise as a strategy to overcome ICI resistance in NSCLC. Although the phase II Lung-MAP S1800A trial suggested a survival benefit with ramucirumab plus pembrolizumab, this finding was not confirmed in the phase III Pragmatica-Lung trial (NCT05633602), presented at ASCO 2025, where the combination failed to improve OS compared with standard therapy. Collectively, no VEGF plus ICI regimen has demonstrated efficacy in randomized phase III trials in the post-ICI setting. Host-derived factors such as gut microbial composition and systemic inflammatory state also modulate ICI responsiveness and contribute to resistance beyond tumor-intrinsic mechanisms. Moving forward, progress will depend on pairing biological innovation with clinical pragmatism. Innovation may include mechanism-based combinations designed to remodel the post-ICI TME, selective application of ADCs, bispecific antibodies, immune engagers, and genotype-directed therapies. Pragmatism should involve biomarker-driven enrichment strategies and resistance-type stratification. Ultimately, integrating mechanistic insight with patient-centered trial design will be essential to define where, and for whom, anti-angiogenic strategies remain clinically relevant and capable of achieving durable benefit in ICI-resistant NSCLC.

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-2025-1882/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1882/coif). H.K. receives speaking and lecture fees from MSD, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb Co., and AstraZeneca. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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/.

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Cite this article as: Kaneda H. Immune checkpoint inhibitor resistance in non-small cell lung cancer: limits of vascular endothelial growth factor inhibition and new directions. J Thorac Dis 2025;17(11):9263-9270. doi: 10.21037/jtd-2025-1882

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