Background
Immune checkpoint inhibitors (ICIs) targeting programmed cell death‑1 (PD‑1) or its ligand (PD‑L1) have become core therapy in advanced non‑small cell lung cancer (NSCLC), but outcomes remain heterogeneous in routine practice (e.g., wide ranges of overall survival [OS] across real‑world cohorts even in PD‑L1 ≥50% disease) 15. A major mechanistic and therapeutic theme in 2024–2026 literature is that angiogenesis is not only a blood‑supply program, but also an immune‑regulatory system that can block multiple steps of the cancer‑immunity cycle—creating a rationale for combining anti‑angiogenic therapy (VEGF/VEGFR inhibition) with PD‑1/PD‑L1 blockade 11920.
Mechanistic / scientific rationale: why synergy is plausible
Across recent mechanistic reviews and preclinical studies, VEGF/VEGFR inhibition is proposed to augment ICIs by remodeling the tumor microenvironment (TME) along several connected axes: vascular normalization, hypoxia relief, metabolic reprogramming, restoration of antigen presentation, and myeloid/T‑cell rebalancing 14131920.
Mechanistic pillars (TME immunomodulation)
| Pillar | What VEGF‑driven biology does | How VEGF/VEGFR blockade may help ICI response | Key sources |
|---|---|---|---|
| 1) Abnormal vasculature → poor trafficking | VEGF‑dependent vessels are leaky, disorganized, and inefficient, limiting immune cell infiltration | “Vascular normalization” (transiently) improves perfusion and immune cell access; anti‑VEGFA can reduce permeability and increase pericyte recruitment | 14 |
| 2) Hypoxia → immune suppression & PD‑L1 regulation | Hypoxia (via HIF‑1α) promotes epithelial–mesenchymal transition (EMT) and therapeutic resistance; HIF‑1α is linked with PD‑L1 expression in NSCLC | Normalization/oxygenation reduces HIF‑1α and VEGF; in KRAS‑mutant NSCLC, tumor PD‑L1 correlates with HIF‑1α, supporting joint targeting of PD‑L1 and hypoxia pathways | 14916 |
| 3) Metabolic barrier (lactate) | Hypoxia‑driven glycolysis increases lactate, which suppresses macrophages, dendritic cells (DCs), and T cells and contributes to anti‑PD‑(L)1 resistance | Reducing hypoxia can reduce lactate; lactate metabolism is itself a resistance node and therapeutic target to combine with PD‑1/PD‑L1 blockade | 2413 |
| 4) Myeloid suppression (MDSCs/TAMs) | VEGF signaling supports accumulation and suppressive programming of myeloid cells (MDSCs, M2‑like tumor‑associated macrophages [TAMs]), which inhibit T‑cell function | Anti‑angiogenic therapy plus ICIs can reduce MDSCs/Tregs and repolarize macrophages; vascular pathways like ANG2–TIE2 can drive MDSC‑mediated resistance | 461220 |
| 5) Impaired antigen presentation (DC dysfunction) | Chronic inflammatory signaling and suppressive myeloid states can reduce functional cDC1 differentiation and IL‑12 production, weakening CD8+ priming | TME normalization and immune‑supportive conditions facilitate DC maturation; DC function is highlighted as central in NSCLC and a determinant of checkpoint response | 14181920 |
Preclinical evidence that vascular normalization can enhance anti-PD-L1 response
A 2024 study using ultrasound‑stimulated microbubble cavitation to induce “sononeoperfusion” reported: reduced HIF‑1α/VEGF, decreased lactate and adenosine, fewer Tregs/MDSCs/M2‑TAMs, and increased tumor‑infiltrating CD8+ T cells producing IFN‑γ and TNF‑α—sensitizing tumors to anti‑PD‑L1 in mouse models 4. While not a VEGFR drug trial, it experimentally supports the vascular normalization logic used to justify VEGF/VEGFR + ICI strategies.
Biomarker signals supporting the biology in NSCLC
A 2025 retrospective NSCLC analysis (86 patients on anti‑PD‑1/PD‑L1 monotherapy) found higher serum total VEGF‑A and especially the pro‑angiogenic VEGF121 isoform associated with worse outcomes: VEGF121‑high had shorter progression‑free survival (PFS) (2.3 vs 3.3 months) and lower objective response rate (ORR) (9.7% vs 30.9%); VEGF121 was independently associated with shorter PFS and lower ORR 3. Separately, in KRAS‑mutant NSCLC, HIF‑1α expression correlated with tumor PD‑L1 expression (though neither predicted OS in that cohort), reinforcing a hypoxia–PD‑L1 link 16.
Clinical evidence base (efficacy and safety)
Landmark Phase 3: IMpower150
IMpower150 established proof‑of‑concept that adding VEGF inhibition (bevacizumab) to chemo‑immunotherapy can improve outcomes in first‑line metastatic nonsquamous NSCLC 29.
Key outcomes (reported across sources):
- Wild‑type population (excluding EGFR/ALK):
- Final OS analyses (web‑retrieved):
- Subgroup signals (exploratory): benefit reported in EGFR/ALK‑altered patients (after prior targeted therapy) and in liver metastases (e.g., liver metastases OS 13.2 vs 9.1 months; HR 0.54) 24.
Guideline positioning (US/China evidence retrieved):
- NCCN (Version 1.2020 “Guidelines Insights”) lists ABCP as an “other recommended” category 1 option for metastatic nonsquamous NSCLC in select patients without contraindications to immunotherapy or bevacizumab and with negative EGFR/ALK/ROS1/BRAF testing; NCCN notes panel preference for pembrolizumab/chemotherapy regimens due to tolerability/experience 39.
- CSCO 2025 lists paclitaxel + carboplatin + bevacizumab + atezolizumab as a Category II (other recommended) option for stage IV driver‑negative nonsquamous NSCLC 42.
EGFR‑mutated post‑TKI setting: ORIENT‑31
ORIENT‑31 is a double‑blind randomized phase 3 trial in China in EGFR‑mutated nonsquamous NSCLC after EGFR‑TKI progression 28. It directly targets a population with known limited ICI monotherapy benefit.
- PFS (sintilimab + bevacizumab biosimilar IBI305 + pemetrexed/cisplatin vs chemotherapy): 7.2 vs 4.3 months; HR 0.51; p<0.0001 28.
- OS (preliminary, July 2022 cutoff): numerically higher but not statistically significant (21.1 vs 19.2 months; HR 0.98), with crossover‑adjusted HRs ranging 0.79–0.84 reported 28.
- Grade ≥3 treatment‑related adverse events: 56% (quad) vs 49% (chemo) 28.
Clinical context for EGFR disease: A phase 2 trial of pembrolizumab monotherapy in TKI‑naïve EGFR‑mutant, PD‑L1+ NSCLC stopped early for lack of efficacy (the single apparent responder was later found not to truly have the EGFR mutation), illustrating intrinsic resistance of EGFR‑mutant NSCLC to PD‑1 monotherapy and motivating combinations such as ORIENT‑31 38.
VEGFR TKI + PD‑1 strategies in global Phase 3: negative/neutral results with lenvatinib
Two phase 3 trials demonstrate that VEGF/VEGFR combinations are not uniformly beneficial:
- LEAP‑006 (lenvatinib added to pembrolizumab + pemetrexed/platinum in first‑line metastatic nonsquamous NSCLC without targetable alterations): did not meet PFS endpoint (HR 0.88; 1‑sided p=0.07976) and showed no OS benefit (HR 1.05). Toxicity increased (grade ≥3 TRAEs 69.7% vs 55.6%; grade 5 5.6% vs 2.7%) 30.
- LEAP‑007 (lenvatinib + pembrolizumab vs pembrolizumab alone in PD‑L1 TPS ≥1% metastatic NSCLC): OS futility met (HR 1.10), despite modest PFS improvement (HR 0.78); grade 3–5 TRAEs 57.9% vs 24.4% 31.
Interpretation (from retrieved materials): these outcomes support a central competitive/clinical point—“anti‑angiogenic + ICI” synergy is context‑ and regimen‑dependent (agent class, dose, backbone therapy, and patient selection) rather than guaranteed 3031.
Additional anti‑angiogenic context (without ICI): bevacizumab and ramucirumab baselines
Older bevacizumab‑chemotherapy phase 3 trials establish efficacy and key risks (bleeding/hemoptysis, hypertension) that remain critical when bevacizumab is part of ICI triplets. Paclitaxel/carboplatin + bevacizumab improved OS vs chemotherapy (12.3 vs 10.3 months) but increased serious bleeding and treatment‑related deaths in that study’s context. AVAiL improved PFS but not OS 21.
For ramucirumab (anti‑VEGFR2), REVEL (docetaxel + ramucirumab, post‑platinum) improved OS modestly (10.5 vs 9.1 months; HR 0.86) but with higher grade ≥3 toxicity 32. No phase 3 ramucirumab + PD‑(L)1 NSCLC results were identified in retrieved materials 32.
Patient selection & safety: practical management constraints
Bevacizumab class safety issues that shape suitability
| Risk | Key points from retrieved guidance | Sources |
|---|---|---|
| Hemorrhage/hemoptysis | Bevacizumab contraindicated with recent hemoptysis ≥ ~2.5 mL; discontinue for grade 3–4 hemorrhage; pulmonary hemorrhage risk historically higher in squamous histology | 40 |
| Hypertension | Monitor every 2–3 weeks; severe HTN occurs more often with VEGF inhibitors; ACEi/ARB often first‑line and also help proteinuria; hold/discontinue for crisis/uncontrolled severe HTN | 4041 |
| Proteinuria | Baseline quantification and serial urinalysis; hold for ≥2 g/24h; discontinue for nephrotic syndrome; ACEi/ARB can reduce severity | 4041 |
| Myeloid/immune toxicities (conceptual) | Combining ICIs with TME‑active agents can increase adverse‑event complexity; LEAP trials show higher grade ≥3 toxicity without OS gain | 3031 |
Clinical nuance: guidelines restrict ABCP to patients without contraindications to bevacizumab and immunotherapy, and NCCN indicates it is not the “preferred” first‑line choice despite category 1 evidence—underscoring tolerability and regimen complexity as competitive disadvantages 39.
Competitive landscape & positioning versus current NSCLC standards
Benchmarking against ICI-based standards (evidence retrieved)
- Network meta‑analyses place pembrolizumab + pemetrexed + platinum among the most effective first‑line options for OS, with ABCP among top regimens in some analyses but not consistently dominant across indirect comparisons 3435.
- Dual checkpoint approaches (nivolumab + ipilimumab ± short chemotherapy) show durable long‑term benefit in PD‑L1 <1% disease (median OS 17.4 vs 11.3 months; HR 0.64; 5‑year OS 20% vs 7%), representing a non‑angiogenic competitor strategy 36.
- Real‑world OS heterogeneity after anti‑PD‑(L)1 approval highlights unmet need for better stratification and combinations in non‑responders 15.
Where VEGF+PD‑(L)1 regimens are differentiated
- PD‑L1–agnostic activity and “immune‑excluded” disease biology: IMpower150 showed benefit even in low/negative PD‑L1 subgroups (reported qualitatively in IMpower150 summaries) 29.
- Oncogene‑driven subsets (selected): ORIENT‑31 demonstrates meaningful PFS gains post‑EGFR‑TKI with a PD‑1 + anti‑VEGF + chemotherapy approach 28.
- TME‑driven resistance nodes: VEGF‑A (VEGF121) as a resistance biomarker for PD‑(L)1 monotherapy provides a patient‑selection hypothesis for anti‑VEGF combinations 3.
Pipeline mapping (12–24 month catalysts)
A drug/pipeline mapping output (USA/China) indicates substantial late‑stage activity beyond bevacizumab—especially bispecific antibodies co‑targeting PD‑(L)1 and VEGF, and multi‑kinase VEGFR TKIs designed for immunotherapy combinations 22.
| Approach | Example assets (from pipeline mapping) | Phase / status (as retrieved) | Competitive implication |
|---|---|---|---|
| PD‑1/VEGF or PD‑L1/VEGF bispecific antibodies | Ivonescimab (PD‑1/VEGF) and PM‑8002 (PD‑L1/VEGF) | Ivonescimab: approved in China and in phase 3 in USA; PM‑8002: phase 3 in China 22 | Single‑molecule “built‑in combo” may improve convenience and pharmacology vs two‑drug regimens |
| VEGFR TKIs + ICI programs | Lenvatinib, sitravatinib, axitinib (examples) | Multiple phase 2–3 programs listed 22 | LEAP‑006/007 caution that toxicity/benefit balance can be unfavorable depending on regimen/dose/backbone 3031 |
| China-specific PD‑1 ecosystems + anti‑VEGF | Multiple domestic PD‑1s (e.g., sintilimab, camrelizumab, toripalimab) alongside many bevacizumab biosimilars | Numerous approved agents and biosimilars listed 22 | Enables cost/access and rapid combinatorial development; ORIENT‑31 is a flagship example 28 |
A 2025 systematic review of ivonescimab in advanced NSCLC (retrieved) characterizes “promising activity” and manageable safety but emphasizes need for further research and long‑term outcomes (no pivotal phase 3 outcome numbers were provided in the retrieved excerpt) 33.
Future directions (2024–2026)
- Biomarker-driven use of anti‑VEGF + ICI: serum VEGF‑A isoforms (VEGF121) and hypoxia markers (HIF‑1α) are highlighted as plausible predictive tools, though validation is incomplete 31620.
- Targeting myeloid resistance programs: ANG2–TIE2 signaling in monocytic MDSCs and broader MDSC‑oriented therapeutic strategies are repeatedly framed as combination opportunities with ICIs and anti‑angiogenics 61220.
- Metabolic remodeling as a co‑strategy: lactate metabolism is positioned as an actionable resistance axis to PD‑1/PD‑L1 therapy, biologically linked to hypoxia and abnormal vasculature 213.
- Engineering approaches: nanoregulators and targeted delivery (e.g., PD‑L1‑targeted nanovesicles delivering STING agonists) illustrate the field’s push toward multi‑mechanism TME remodeling, conceptually parallel to VEGF+ICI objectives 57.
Conclusion
The scientific rationale for VEGF/VEGFR inhibition plus PD‑1/PD‑L1 blockade in NSCLC is strongly supported by contemporary TME biology: VEGF‑driven vascular dysfunction, hypoxia, lactate accumulation, dendritic cell impairment, and myeloid suppression converge to limit checkpoint efficacy, and anti‑angiogenic therapy can counter several of these barriers at once 1413181920. Clinically, the strategy is validated by IMpower150’s OS and PFS gains for ABCP in first‑line metastatic nonsquamous NSCLC 2923 and by ORIENT‑31’s major PFS improvement in EGFR‑mutant post‑TKI disease using a PD‑1 + anti‑VEGF + chemotherapy regimen 28. However, negative phase 3 lenvatinib combinations (LEAP‑006 and LEAP-007) demonstrate that benefit is not class‑automatic and that toxicity can outweigh modest efficacy gains 3031. Competitively, VEGF+ICI regimens occupy a differentiated niche for selected patients and biologic contexts, while bispecific PD‑(L)1/VEGF antibodies and China‑driven combination ecosystems represent major near‑term challengers and catalysts 2233.