Editor's Note: As the year draws to a close, reflection and progress take center stage. The "2024 Beijing Forbidden City Annual Lung Cancer Conference and the 16th Multidisciplinary Seminar on Advances in Lung Cancer Diagnosis and Treatment," jointly organized by the Beijing Tumor Prevention and Research Association, the China Association of Senior Healthcare, the Beijing Medical Love Public Welfare Foundation, and the Beijing Chen Jumei Public Welfare Foundation, was successfully held on December 13–14, 2024, in Beijing.

At the conference, Dr. Yong Song from Nanjing Jinling Hospital affiliated with Nanjing University Medical School delivered a keynote speech titled The Status and Prospects of Anti-Angiogenic Therapy in Cancer. Professor Song systematically reviewed the development of anti-angiogenic therapy for lung cancer, presented advancements in the treatment strategies of macromolecular and small-molecule anti-angiogenic drugs, and shared future directions for exploring anti-angiogenic approaches in lung cancer treatment. Oncology Frontier has compiled key insights from the presentation for our readers.

Part 1: Overview of Anti-Angiogenic Therapy for Lung Cancer

Origins and Mechanisms of Anti-Angiogenic Therapy

In 1971, Judah Folkman proposed that tumor growth depends on angiogenesis, identifying it as one of the hallmarks of malignant tumors. Angiogenesis creates a microenvironment for tumor growth and invasion and participates in multiple stages of tumor progression. Inhibiting angiogenesis has thus become a viable therapeutic strategy for cancer.

Tumor angiogenesis is driven by diverse mechanisms, including sprouting angiogenesis, bone marrow-derived vascular formation, vascular mimicry, intussusceptive angiogenesis, and tumor stem cell-derived vascular formation. These mechanisms provide critical targets for anti-angiogenic therapy.

Development Timeline

Since the 1970s, anti-angiogenic therapy for lung cancer has evolved from theoretical exploration to drug development and clinical application. Key milestones, such as the discovery of vascular endothelial growth factor A (VEGFA) and the synthesis of humanized VEGF monoclonal antibodies, have significantly advanced the field.

Part 2: Classification of Anti-Angiogenic Drugs and Clinical Research Progress

Macromolecular Anti-Angiogenic Drugs

1. First-line Combination with Chemotherapy: Overall Survival (OS) Benefit

  • ECOG 4599 Trial: This phase III multicenter clinical trial evaluated the efficacy of bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of advanced non-squamous NSCLC. The results showed a median OS of 14.2 months in the bevacizumab group compared to 10.3 months in the control group.
  • BEYOND Trial: This study explored bevacizumab combined with platinum-based doublet chemotherapy in Asian or Chinese patients with advanced non-squamous NSCLC. Results demonstrated significantly prolonged progression-free survival (PFS), higher objective response rate (ORR), and extended OS in the combination group compared to chemotherapy alone.
  • Endostar Trial: A phase III randomized, double-blind, controlled multicenter study assessed Endostar combined with NP (vinorelbine and cisplatin) in advanced NSCLC. The ORR was 35.4% in the treatment group versus 19.5% in the control group. Median time to progression (TTP) was 6.3 months versus 3.6 months, and median OS was 13.75 months versus 9.77 months, indicating favorable efficacy and safety.
  • REVEL Trial: This trial compared ramucirumab plus docetaxel versus docetaxel monotherapy in metastatic NSCLC. Results highlighted good safety and improved survival benefits with the combination therapy.

2. First-line Combination with Targeted Therapy: PFS Benefit Only

  • JO25567 Trial: This randomized, open-label phase II study compared erlotinib monotherapy with erlotinib plus bevacizumab in treatment-naïve stage IIIB/IV or postoperative recurrent non-squamous NSCLC. The combination group demonstrated better PFS and tumor response rates, though OS differences were not statistically significant.
  • NEJ026 Trial: This study evaluated bevacizumab plus erlotinib versus erlotinib monotherapy in EGFR-mutant patients. The combination group achieved significant PFS improvement, meeting the primary endpoint, but OS differences remained statistically insignificant.

3. First-line Combination with Immunotherapy: Significant Benefit for High PD-L1 Expression

  • WJOG10718L Study: For patients with PD-L1 expression ≥50%, bevacizumab combined with atezolizumab as first-line therapy achieved an ORR of 64.1% and a median PFS of 15.9 months, demonstrating excellent efficacy.
  • JVDF Trial: This study demonstrated that in NSCLC cohorts, ramucirumab combined with pembrolizumab yielded better outcomes in patients with high PD-L1 expression (TPS ≥50%) compared to those with lower PD-L1 expression (TPS 1%-49%). The overall tolerability was good.

EGFR-TKI Resistance and Combination Strategies

Results from the CheckMate 722 and Keynote 789 studies demonstrated that immune checkpoint inhibitors combined with chemotherapy offer limited efficacy post-EGFR-TKI resistance, failing to achieve significant survival benefits. However, the IMpower150 trial evaluated atezolizumab (A) combined with bevacizumab (B), carboplatin (C), and paclitaxel (P) as a first-line treatment for advanced non-squamous NSCLC. The ABCP regimen showed superior progression-free survival (PFS) compared to the BCP regimen in EGFR-mutant TKI-pretreated patients and indicated a trend toward overall survival (OS) benefits. These findings underscore the potential of anti-angiogenic and immunotherapy combinations in achieving survival benefits, though validation in large-scale phase III trials is needed.

The ORIENT-31 trial further validated the efficacy of sintilimab combined with bevacizumab and chemotherapy in TKI-resistant NSCLC. Significant PFS improvements were observed across subgroups, including patients aged ≥65, males, smokers, those with liver metastases, and T790M mutations, as well as those who received two lines of TKI treatment. Notably, sintilimab combined with chemotherapy also showed significant PFS benefits compared to chemotherapy alone in TKI-resistant NSCLC.

Post-Immunotherapy Resistance: Anti-Angiogenic Combinations as Promising Options

The MORPHEUS-Lung trial explored atezolizumab and bevacizumab (± radiotherapy) versus docetaxel in patients with metastatic NSCLC previously treated with immune checkpoint inhibitors (ICIs). The results indicated that atezolizumab combined with bevacizumab may offer a viable treatment option for patients with CPI-treated metastatic NSCLC.

For patients with advanced NSCLC lacking actionable mutations, studies such as VARGADO and research by Takehiro Tozuka demonstrated the efficacy and safety of anti-angiogenic drugs combined with chemotherapy in previously ICI- and platinum-treated metastatic NSCLC. These findings highlight the potential of such combinations in overcoming resistance.

VEGF-Based Bispecific Antibodies in Clinical Practice

Therapies Targeting PD-L1–Positive Patients

The HARMONi-2 trial, a randomized, double-blind phase III study, compared ivonescimab monotherapy with pembrolizumab monotherapy as first-line treatment for locally advanced or metastatic NSCLC with PD-L1 expression ≥1%. Results revealed a median PFS of 11.14 months in the ivonescimab group, marking the first phase III study to demonstrate superior efficacy over pembrolizumab for advanced NSCLC, establishing ivonescimab as a leading first-line option for patients with PD-L1 expression ≥1%.

Perioperative Applications in Resectable NSCLC

The AK112-205 trial assessed ivonescimab monotherapy and its combination with chemotherapy in the perioperative treatment of resectable NSCLC. The ivonescimab plus chemotherapy group achieved higher pathological complete response (pCR) and major pathological response (MPR) rates compared to monotherapy, with promising signals observed across different clinical stages and PD-L1 expression levels.

A phase II trial (NCT05756972) evaluating PM8002 combined with chemotherapy for advanced NSCLC post-EGFR-TKI failure demonstrated anti-tumor activity irrespective of PD-L1 expression. Interestingly, PD-L1 levels correlated positively with response rates, with the treatment showing manageable safety. These promising results warrant further clinical trials in NSCLC patients.

Future Directions in Anti-Angiogenic Therapy

Dr. Yong Song highlighted the need for further exploration of synergistic combination strategies in the field of macromolecular anti-angiogenic therapies to achieve enhanced efficacy.

Small-Molecule Anti-Angiogenic Drugs

Multi-Target TKIs in NSCLC

Early exploratory studies yielded limited benefits in NSCLC. However, the LUME-Lung 1 trial demonstrated that nintedanib combined with docetaxel as a second-line therapy improved median PFS by 0.7 months and extended median OS by 2.3 months in lung adenocarcinoma patients compared to chemotherapy alone. This established a survival advantage for the combination of chemotherapy and nintedanib.

The VARGADO study further confirmed the efficacy and safety of nintedanib combined with chemotherapy in metastatic NSCLC patients previously treated with ICIs and platinum-based chemotherapy, particularly in mutation-negative cases.

Apatinib

A phase II randomized controlled trial (NCT01270386) presented at the 2012 ASCO meeting evaluated apatinib versus placebo as a third-line treatment for advanced non-squamous NSCLC. The results showed that apatinib significantly improved median progression-free survival (mPFS), objective response rate (ORR), and disease control rate (DCR) compared to the placebo group, with manageable safety. This study demonstrated the efficacy and safety of apatinib for patients with advanced non-squamous NSCLC receiving third-line or later treatments.

In a retrospective study evaluating the safety and efficacy of apatinib in advanced non-squamous NSCLC after first-line treatment progression, apatinib combined with chemotherapy achieved significant improvements in PFS and overall survival (OS) compared to chemotherapy alone, with manageable safety. This combination may serve as a promising treatment option for this patient population.

Fruquintinib

A phase II randomized, double-blind, multicenter, placebo-controlled study presented at the 2016 WCLC assessed fruquintinib as a third-line treatment for advanced NSCLC. The study showed that fruquintinib significantly prolonged PFS in heavily pretreated non-squamous NSCLC patients, with adverse events being predictable and manageable.

Anlotinib

ALTER0303 Study

A phase III randomized, double-blind clinical trial explored the efficacy of anlotinib as a third-line treatment for advanced NSCLC. Results indicated that anlotinib significantly improved both PFS and OS compared to placebo, demonstrating its efficacy in this setting.

Combination with Immunotherapy

At the 2022 ESMO Asia Congress, an analysis of second-line treatment with anlotinib combined with immunotherapy for advanced NSCLC showed good efficacy and manageable safety.

SUNRISE Study

This study updated the results of sintilimab combined with anlotinib versus platinum-based chemotherapy as first-line therapy for metastatic NSCLC. The combination demonstrated longer-lasting efficacy benefits compared to chemotherapy, with a favorable safety profile. This approach holds promise as a potential first-line treatment for metastatic NSCLC.

Small-Cell Lung Cancer

The ETER701 study highlighted the significant efficacy and manageable safety of bevacizumab combined with anlotinib and chemotherapy in extensive-stage small-cell lung cancer, offering a new treatment option for this challenging disease.

Challenges in Anti-Angiogenic Therapy for Lung Cancer and Strategies for Optimization

Current Challenges

Dr. Yong Song highlighted several challenges in the clinical use of anti-angiogenic therapies for lung cancer, including:

  • Choosing between macromolecular and small-molecule drugs.
  • Identifying optimal patient populations.
  • Determining the appropriate timing for administration.

For example, in EGFR-positive NSCLC, the first-line “A+T” (angiogenesis inhibitors + TKIs) strategy remains controversial. While first-generation TKI combinations show positive PFS results and are guideline-recommended, the combination of macromolecular anti-angiogenic agents with third-generation TKIs requires further investigation. Small-molecule combinations with third-generation TKIs show initial promise but need deeper exploration.

Optimizing Strategies for TKI Slow Progression

The CTONG-1803/ALTER-L001 studies showed that in patients previously treated with first- or second-generation TKIs, the combination of EGFR-TKIs with anlotinib achieved a median PFS of 9.1 months. For patients treated with third-generation TKIs, this combination achieved a median PFS of 10.4 months. These results suggest that anlotinib combined with EGFR-TKIs offers significant efficacy and manageable toxicity for NSCLC patients experiencing slow progression, local advancement, or potential disease progression.

Exploration of Combination Therapies

  • BACH-NET Study: In real-world settings, EGFR-TKI-resistant patients treated with the ABCP (atezolizumab, bevacizumab, carboplatin, paclitaxel) regimen showed a median PFS of 5.7 months and a median OS of 16.2 months, which were inferior to results from the IMpower150 trial. This underscores the need for proactive safety management of the ABCP regimen.
  • Chemotherapy-Free Approaches: The ALTER-L038 study revealed that bevacizumab combined with anlotinib significantly improved OS in patients with advanced EGFR-mutant NSCLC after TKI resistance, with good safety profiles.

Strategies for Overcoming TKI Resistance

The ATTLAS Study was the first randomized phase III trial to confirm that the ABCP quadruple regimen provided greater clinical benefits compared to chemotherapy alone in NSCLC patients with EGFR or ALK mutations who had failed TKI therapy.

Strategies for Overcoming Immunotherapy Resistance

Overcoming resistance to immunotherapy remains a major challenge in advanced NSCLC. Multiple studies are currently investigating anti-angiogenic therapies in this setting. Future efforts should focus on:

  • Improving OS.
  • Identifying predictive biomarkers for efficacy.
  • Developing innovative combination therapy strategies.

Conclusion

Dr. Yong Song emphasized that anti-angiogenic therapies have evolved from adjunctive treatments to key therapeutic options, now fully integrated into the comprehensive management of lung cancer. The introduction of PD-(L)1/VEGF bispecific antibodies has opened a new chapter in lung cancer treatment. Meanwhile, small-molecule anti-angiogenic TKIs are gaining increasing clinical importance. With continued innovation in anti-angiogenic drugs and combination strategies, the landscape of precision medicine for lung cancer is expected to advance further, offering hope to patients worldwide.

Dr. Yong Song

  • Chief Physician, Doctoral Supervisor
  • Department of Pulmonary and Critical Care Medicine, Jinling Hospital, Nanjing University Medical School
  • Chest Oncology Center, Nanjing Tianyinshan Hospital, China Pharmaceutical University
  • Director, Nanjing University Respiratory Research Institute
  • Member, Respiratory Disease Branch, Chinese Medical Association
  • Chair, Respiratory Disease Branch, Jiangsu Medical Association
  • President-elect, Jiangsu Medical Doctor Association Respiratory Committee
  • Council Member, Chinese Society of Clinical Oncology (CSCO)
  • Editor-in-Chief, Translational Lung Cancer Research; Editorial Board Member, Chinese Medical Journal
Post Views: 721