Author:

Adriana Albini

Abstract

_Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), was the first anti-angiogenic therapy approved for cancer treatment. Developed through decades of research on tumour-induced blood vessel formation, bevacizumab revolutionized oncology by inhibiting tumour vascularization and enhancing the efficacy of chemotherapy, radiotherapy, and immunotherapy. Approved for colorectal, lung, ovarian, renal, and liver cancers, bevacizumab has significantly improved patient outcomes. Its mechanism involves VEGF-A inhibition, leading to vascular normalization and reduced tumour perfusion. The use of bevacizumab and its fragment lucentis achieved a great success in ophthalmology

Despite its success, challenges such as acquired resistance, cost-effectiveness, and adverse effects remain. The introduction of check-point blockade immunotherapy put angiogenesis in second row, however the rationale for combination of the two approaches is bringing a revival of bevacizumab. Research is ongoing to refine combination strategies, identify predictive biomarkers, and explore applications beyond oncology,. This article reviews the scientific foundation, clinical development, and future perspectives of bevacizumab in cancer therapy._

Introduction

Bevacizumab, a pioneering anti-angiogenic therapy, has revolutionized cancer treatment by targeting vascular endothelial growth factor (VEGF) to inhibit tumor blood supply. Developed through decades of research into tumor angiogenesis, its approval marked a major milestone in oncology. Bevacizumab has been instrumental in treating various cancers, including colorectal, lung, renal, ovarian, and glioblastoma, often in combination with chemotherapy and recently immunotherapy. Beyond oncology, its application extends to ophthalmology for conditions like macular degeneration. Despite its success, challenges such as resistance mechanisms, adverse effects, and cost-effectiveness concerns continue to shape its clinical use. Ongoing research aims to refine its therapeutic potential, exploring combination strategies and biomarkers to optimize patient outcomes.

Theoretical Foundation and Early Development

Inhibition of tumor development and metastases by blocking the neoangiogenic process has been an important approach to the treatment of tumors (Albini et al 2024). The conceptual groundwork for bevacizumab began to take shape as early as the mid-20th century. In 1927, Warren Lewis, an anatomist at Johns Hopkins University, offered early evidence that different tumour types in rats exhibited distinct vascular structures, suggesting that the tumours environment played a role in blood vessel growth. A year later, J.C. Sandison advanced this understanding by introducing a transparent chamber that could be implanted in the rabbit ear. This enabled direct observation of the formation of new blood vessels in a healing wound. which allowed scientists to study how tumours interacted with blood vessels. This technique paved the way for further studies, including those by Gordon Ide and colleagues in 1939, who used Sandison's method to demonstrate that transplanted carcinomas stimulated rapid blood vessel formation, directly linking tumour growth to angiogenesis. In 1945, Glen Algire, a researcher at the US National Cancer Institute, conducted pioneering experiments that showed blood vessels growing towards tumours. By implanting transparent plastic chambers with tumour samples into mice, Algire observed that blood vessels grew rapidly toward the tumours, even faster than they would toward wounds. He hypothesized that tumours released a substance that stimulated this vascular growth. Despite these groundbreaking findings, Algire's work did not receive significant follow-up, and he himself did not pursue this line of research further. The idea that tumours might influence the vascular system lay dormant until it was revitalized by Judah Folkman in 1971. In his landmark paper published in the New England Journal of Medicine (Folkman 1971), Folkman postulated that tumours cannot grow beyond a few millimetres in size without recruiting new blood vessels to supply oxygen and nutrients. He proposed that tumours secrete a diffusible substance that stimulates the growth of new blood vessels (angiogenesis), and that blocking this process could be a strategy to inhibit tumour growth. He called this substance ‘tumour angiogenesis factor’ (TAF). He also suggested that anti-angiogenic therapy could potentially be used to treat cancer. This hypothesis, though initially met with scepticism, laid the foundation for decades of research into tumour angiogenesis and the development of anti-angiogenic therapies.

Throughout the 1970s and 1980s, significant discoveries advanced the understanding of angiogenesis. Researchers such as Hugo Armelin and Denis Gospodarowicz independently identified fibroblast growth factor (FGF), which exhibited strong mitogenic effects on various cell types, including those involved in blood vessel formation. A pivotal breakthrough came with the discovery of a protein initially named vascular permeability factor (VPF) by Ann Dvorak and Donald Senger in 1983 (Senger 1983). In 1989, Napoleone Ferrara and his team at Genentech cloned, sequenced, and characterized the vascular endothelial growth factor VEGF, revealing that it was the same as VPF. They found that VEGF is a signalling protein that binds to receptors (VEGFR-1 and VEGFR-2) on endothelial cells, facilitating new blood vessel formation (Ferrara 1989).

Recognizing VEGF's central role in tumour angiogenesis, Ferrara's research shifted towards creating antibodies to neutralize VEGF. By the late 1990s, he and his team had successfully developed bevacizumab, setting the stage for clinical trials. The creation of bevacizumab involved sophisticated bioengineering techniques to humanize the monoclonal antibody, minimizing immunogenicity while maintaining high affinity and specificity for VEGF-A, the most critical isoform of VEGF.

Mechanism of Action

Bevacizumab, marketed under the trade name Avastin, is a humanized monoclonal antibody that selectively binds to VEGF-A, preventing it from activating VEGFR-1 and VEGFR-2 on endothelial cells. This inhibition blocks the downstream signalling cascade necessary for angiogenesis, leading to the suppression of new blood vessel formation around the tumour. Furthermore, bevacizumab’s action can cause the regression of existing tumour blood vessels and normalization of the remaining vasculature.

The concept of “vascular normalization,” proposed by Rakesh Jain, has been a key element in understanding how bevacizumab enhances the efficacy of concurrent treatments (Jain 2005). The process involves strengthening the remaining vasculature, making it more efficient for delivering oxygen and drugs to the tumour. The improvement occurs within a "normalization window," during which combined therapies can be most effective. Vascular normalization addresses hypoxia (low oxygen levels) in tumours, which is a common barrier to successful cancer treatment. By enhancing drug delivery and increasing the infiltration of anti-tumour immune cells, this approach maximizes the effectiveness of chemotherapy, radiotherapy, and immunotherapy. Studies have shown that patients whose tumour vasculature normalizes the most tend to have better progression-free and overall survival rates, see for instance the studies by John Martin’s group, (Martin 2019).

Bevacizumab selectively prunes immature blood vessels and strengthens the structure of those that remain, leading to improved outcomes when used alongside conventional therapies. This effect has not only improved treatment for cancers such as lung, kidney, liver, and endometrial cancers but has also supported FDA approvals for combination therapies involving antiangiogenic agents and immune-checkpoint inhibitors, combining antiangiogenic agents and immune checkpoint inhibitors (ICIs) can counteract the immunosuppression by anti-angiogenesis and confer synergistic therapeutic benefits. As an example, several studies have demonstrated the effectiveness of anti-angiogenic drugs in combination with immune checkpoint inhibitors (ICIs) in patients with microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) or in lung cancer.

Applications Beyond Oncology

The inhibition of VEGF has proven valuable not only in treating cancer but also in managing other conditions characterized by abnormal blood vessel growth. One notable area of application is in the treatment of eye diseases. The knowledge that VEGF plays a role in pathological angiogenesis has been pivotal in developing treatments for conditions like wet age-related macular degeneration (AMD), diabetic retinopathy, and macular oedema. Anti-VEGF agents such as ranibizumab (Lucentis) and bevacizumab have become standard treatments for these conditions, effectively reducing abnormal blood vessel growth and leakage, which are hallmarks of these eye diseases. Bevacizumab, despite being developed primarily for cancer therapy, is often used off-label in ophthalmology due to its cost-effectiveness compared to other anti-VEGF drugs.

Adverse drug reactions

While bevacizumab is generally well-tolerated, it requires vigilant monitoring and management of side effects. Understanding its unique toxicity profile is essential for optimizing treatment outcomes and ensuring patient safety. Common side effects include hypertension, which is generally manageable with anti-hypertensive medications. Another common issue is proteinuria, which also requires regular monitoring. Additionally, bleeding events, ranging from minor mucosal bleeding to more serious haemorrhages, are associated with bevacizumab use.

Gastrointestinal perforation is a rare but potentially life-threatening complication, with the risk appearing to be higher in certain cancer types, such as colorectal and ovarian cancers. Thromboembolic events, including pulmonary embolism and deep vein thrombosis, have also been reported.

Comparing bevacizumab to traditional chemotherapy, it generally causes less severe systemic toxicity than cytotoxic chemotherapy. While myelosuppression is possible with bevacizumab, it is typically less severe than that seen with chemotherapy alone. Nausea and vomiting are also less common with bevacizumab monotherapy compared to many chemotherapy regimens. In terms of combination therapy, when bevacizumab is used alongside chemotherapy, there can be an increased risk of certain adverse events. The risk of fatal adverse events tends to be higher when bevacizumab is combined with platinum or taxane chemotherapy agents. Common fatal events in such combinations include hemorrhage, neutropenia, and gastrointestinal perforations.

The impact of bevacizumab on quality of life can vary among patients. Regimens containing bevacizumab may lead to decreased appetite, increased nausea/vomiting, and fatigue; however, the overall impact on quality of life may not be significantly different from chemotherapy alone in some cases.

Clinical Development and FDA Approvals for cancer

Bevacizumab’s journey to clinical success began with multiple pivotal trials across different cancer types, with the AVF2107g trial being one of the earliest and most pivotal. This Phase III study demonstrated the significant benefits of adding bevacizumab to standard chemotherapy for metastatic colorectal cancer (mCRC). Patients treated with a combination of bevacizumab, irinotecan, fluorouracil, and leucovorin saw a notable increase in median overall survival, from 15.6 months to 20.3 months. This led to the FDA's landmark approval of bevacizumab in 2004, making it the first anti-angiogenic therapy to be sanctioned for cancer treatment.

In non-small cell lung cancer (NSCLC), the pivotal study E4599 demonstrated a significant improvement in overall survival. Patients receiving bevacizumab in combination with carboplatin and paclitaxel had a median overall survival of 12.3 months compared to 10.3 months for those receiving carboplatin and paclitaxel alone. This result represented a 20% reduction in the risk of death (hazard ratio: 0.80, p=0.013). Based on these findings, the FDA approved bevacizumab for first-line treatment of unresectable, locally advanced, recurrent, or metastatic, nonsquamous NSCLC in 2006.

Bevacizumab received accelerated approval from the FDA for the treatment of recurrent glioblastoma in May 2009. This approval was based on the results of two-phase II studies: AVF3708g and NCI 06-C-0064E. The AVF3708g study was an open, multicentre trial where previously treated patients with glioblastoma received 10 mg/kg IV of bevacizumab alone or combined with irinotecan every 2 weeks. Treatment continued until disease progression or unacceptable toxicity. All patients had received prior temozolomide and radiotherapy. The FDA considered only the single-agent arm for the accelerated approval. Among 85 patients in this cohort, the objective response rate (ORR) was 25.9% (95% CI, 17-36.1), with a median response duration of 4.2 months (95% CI, 3.0-5.7). The NCI 06-C-0064E study was a single-arm study involving 56 patients with previously treated gliomas. Patients received 10 mg/kg IV of bevacizumab every 2 weeks until disease progression or unacceptable toxicity. All patients had prior temozolomide and radiation therapy. The ORR was 19.6% (95% CI, 10.9-31.3), with a median duration of response of 3.9 months (95% CI, 2.4-17.4). The accelerated approval was based on the drug's effect on progression-free survival (PFS) and objective response rates in these two studies. This approval pathway allowed for faster access to the drug for patients with this aggressive form of brain cancer, while requiring the manufacturer to conduct further studies to confirm the clinical benefit. In 2017, bevacizumab received full approval for this indication based on the results of the phase III EORTC 26101 study. This study showed that adding bevacizumab to lomustine chemotherapy reduced the risk of disease progression or death by 48% in patients with recurrent glioblastoma.

In 2009, the FDA granted approval for the use of bevacizumab in combination with interferon alfa-2a for the treatment of metastatic renal cell carcinoma (RCC). This approval was primarily based on the results of the AVOREN trial, a randomized, double-blind, placebo-controlled phase III study. The AVOREN trial demonstrated significant improvements in progression-free survival when bevacizumab was combined with interferon alfa-2a compared to interferon alfa-2a alone. The study showed a 4.8-month increase in median PFS, rising from 5.4 months with placebo plus interferon alfa-2a to 10.2 months with the combination therapy. The hazard ratio for progression was reported as 0.60 (95% confidence interval, 0.49-0.72), indicating a 40% reduction in the risk of progression or death. Additionally, the objective response rate more than doubled with the combination therapy compared to interferon alfa-2a alone. While there was a trend toward improved overall survival, the final analysis did not show a statistically significant difference between the two treatment arms, with overall survival rates of 23.3 months for those receiving bevacizumab plus interferon and 21.3 months for those receiving interferon alone. The approval was further supported by results from the Cancer and Leukemia Group B (CALGB) 90206 trial, which echoed similar improvements in PFS.

Bevacizumab received FDA approval for the treatment of advanced ovarian cancer in 2014. The approval was based on the results of several clinical trials, most notably the GOG-0218 and ICON7 studies, which demonstrated improved PFS in patients with advanced ovarian cancer when bevacizumab was added to standard chemotherapy. The GOG-0218 trial was a phase III, randomized, double-blind, placebo-controlled study that enrolled 1,873 women with newly diagnosed stage III or IV epithelial ovarian, primary peritoneal, or fallopian tube cancer. The study compared three treatment arms: standard chemotherapy alone, chemotherapy with concurrent bevacizumab, and chemotherapy with concurrent and maintenance bevacizumab. The results showed that adding bevacizumab to standard chemotherapy and continuing it as maintenance therapy significantly improved PFS compared to chemotherapy alone (14.1 months vs. 10.3 months). The ICON7 trial was a phase III study that included 1,528 women with newly diagnosed ovarian cancer. It compared standard chemotherapy to chemotherapy plus bevacizumab, followed by bevacizumab maintenance. The results aligned with those of GOG-0218, showing an improvement in progression-free survival with the addition of bevacizumab. Notably, the ICON7 trial also identified a subgroup of high-risk patients who derived greater benefit from bevacizumab, with a significant improvement in overall survival.

The approval of bevacizumab for cervical cancer in 2014 was primarily based on the results of the phase III GOG-0240 trial. This randomised, open-label study enrolled 452 women with persistent, recurrent, or metastatic cervical cancer. The study compared four treatment arms: two different chemotherapy regimens (cisplatin plus paclitaxel or topotecan plus paclitaxel) with or without bevacizumab. The primary endpoint of the study was overall survival. The results showed that he addition of bevacizumab to chemotherapy significantly improved overall survival, with a median overall survival of 16.8 months in the bevacizumab-containing arms compared to 13.3 months in the chemotherapy-alone arms. This represented a 26% reduction in the risk of death. The study also showed improvements in progression-free survival and objective response rates with the addition of bevacizumab. Based on these compelling results, the FDA granted approval for bevacizumab in combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer.

The approval of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma (HCC) in 2020 was based on the results of the IMbrave150 trial, a global, open-label, phase III study that compared the combination of atezolizumab (an anti-PD-L1 immunotherapy) and bevacizumab to sorafenib, the previous standard of care for first-line treatment of HCC. The IMbrave150 trial enrolled 501 patients with unresectable HCC who had not received prior systemic therapy. Participants were randomized in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib. The study's co-primary endpoints were overall survival and progression-free survival. At the primary analysis, after a median follow-up of 8.6 months, the combination therapy demonstrated a significant improvement in overall survival compared to sorafenib. The hazard ratio for death was 0.58 (95% CI, 0.42-0.79; p<0.001), representing a 42% reduction in the risk of death. The 12-month overall survival rate was 67.2% with atezolizumab-bevacizumab compared to 54.6% with sorafenib. Progression-free survival was also significantly improved with the combination therapy. The median PFS was 6.8 months in the atezolizumab-bevacizumab group compared to 4.3 months in the sorafenib group (HR 0.59; 95% CI, 0.47-0.76; p<0.001) (Finn 2020). The combination therapy also showed a higher objective response rate and longer duration of response compared to sorafenib. Importantly, the safety profile of atezolizumab plus bevacizumab was consistent with the known safety profiles of each agent, and no new safety signals were identified.

While bevacizumab has shown significant efficacy in many cancer types, its clinical application has also faced challenges, most notably in metastatic breast cancer (MBC). Initially, bevacizumab showed promising results in MBC, leading to its accelerated approval by the FDA in 2008. The approval was based on the E2100 study, a pivotal phase III trial. The E2100 trial compared paclitaxel alone to paclitaxel plus bevacizumab as first-line therapy for patients with metastatic breast cancer. The study showed that adding bevacizumab to paclitaxel significantly improved progression-free survival compared to paclitaxel alone (11.8 months vs 5.9 months). However, subsequent trials failed to demonstrate a consistent improvement in overall survival, raising concerns about the clinical value of bevacizumab for metastatic breast cancer. This led to the FDA's controversial decision in 2011 to withdraw its approval for this indication after thoroughly reviewing the available data. The decision was met with significant debate within the oncology community and among patient advocacy groups. The withdrawal was based on two primary factors. First, despite showing some benefit in progression-free survival, the drug did not consistently lead to longer overall survival or improved quality of life. Second, the safety profile of bevacizumab raised concerns, with side effects such as hypertension, proteinuria, and, in rare cases, serious complications like gastrointestinal perforations and haemorrhage. The FDA concluded that these risks outweighed the limited benefits observed in breast cancer patients.

The bevacizumab experience in breast cancer has had lasting impacts on the field of oncology. It has led to more stringent requirements for drug approvals, particularly for accelerated approvals based on surrogate endpoints like progression-free survival. It has also spurred further research into biomarkers that might help identify which patients are most likely to benefit from anti-angiogenic therapies, potentially leading to more personalized treatment approaches in the future.

European Approvals and International Perspective

The European contribution to the development and approval of bevacizumab has been significant, reflecting a more flexible and context-driven approach compared to the US regulatory landscape. While the FDA initially led approvals, the European Medicines Agency (EMA) not only supported early indications but also expanded bevacizumab’s use across different cancer types, considering broader criteria that emphasized regional clinical needs.

One of the key differences between the EMA and FDA's approach was evident in the approval for metastatic breast cancer. In 2007, the EMA granted approval for bevacizumab based on the E2100 trial, which showed improved progression-free survival when bevacizumab was combined with paclitaxel. Unlike the FDA, which revoked this approval in 2011, European regulators took a more nuanced stance, allowing its use with specific restrictions, emphasizing that the progression-free survival benefit was still clinically meaningful for certain patients.

European researchers have led and participated in numerous bevacizumab’s pivotal studies that have shaped bevacizumab’s clinical use. Carried out in 2006-2007, the AVADO trial was a pivotal Phase III clinical study designed to evaluate the efficacy and safety of bevacizumab in combination with docetaxel for treating HER2-negative metastatic breast cancer (Miles 2009). Conducted primarily across European centres, the trial aimed to determine whether adding bevacizumab to standard chemotherapy would improve outcomes compared to chemotherapy alone. The study enrolled 736 patients with locally recurrent or metastatic HER2-negative breast cancer who had not received prior chemotherapy for their metastatic disease. Participants were randomly assigned to one of three treatment groups: a control group receiving docetaxel with a placebo, a group receiving docetaxel with a lower dose of bevacizumab (7.5 mg/kg), and a group receiving docetaxel with a higher dose of bevacizumab (15 mg/kg). The primary goal was to assess progression-free survival, measuring the time during and after treatment in which the disease did not worsen. Secondary goals included evaluating overall survival (OS), objective response rates (ORR), and safety profiles. Results from the AVADO trial showed that adding bevacizumab to docetaxel led to a significant improvement in PFS compared to the control group. Patients in both bevacizumab groups experienced longer periods without disease progression, demonstrating that bevacizumab could effectively delay tumour growth when combined with chemotherapy. Additionally, the combination treatment led to higher objective response rates, meaning that a larger proportion of patients experienced a measurable reduction in tumour size. However, the trial did not show a significant difference in overall survival between the groups. This outcome highlighted the ongoing challenge in translating improvements in PFS into prolonged life expectancy for patients with metastatic breast cancer (Miles 2009). The safety profile of the combination therapy was consistent with known effects of bevacizumab, including increased risks of hypertension, proteinuria, fatigue, and neutropenia. These adverse effects were manageable with careful monitoring and appropriate intervention. The results of the AVADO trial played a key role in the EMA's decision to maintain approval for this indication.

Further contributions came from multinational trials conducted across Europe, which were essential in evaluating bevacizumab's effectiveness in diverse patient populations. For instance, trials like ICON7 and GOG-0218 played a critical role in solidifying the drug’s use in ovarian cancer by demonstrating that bevacizumab, when added to standard chemotherapy, significantly improved progression-free survival. These studies were influential not just in Europe but worldwide, guiding clinical practices and regulatory decisions.

European research has also focused on the optimization of bevacizumab dosing, exploring its integration with other emerging therapies such as immunotherapies and targeted treatments. Collaborative efforts involving research institutions across the continent have been pivotal in identifying potential biomarkers, refining treatment strategies, and understanding the mechanisms of resistance to bevacizumab.

Challenges: cost-effectiveness and resistance mechanisms

The high cost of bevacizumab has sparked ongoing debates regarding its cost-effectiveness, especially within healthcare systems that operate under limited resources. These discussions have focused on assessing the value bevacizumab brings in relation to its benefits in extending progression-free survival and improving quality of life, with cost-effectiveness varying significantly across different indications and healthcare contexts.

In ovarian cancer, a Canadian study published in Current Oncology Reports in 2016 (Duong 2016) found that adding bevacizumab to standard chemotherapy for high-risk-of-relapse advanced ovarian cancer yielded an incremental cost-effectiveness ratio (ICER) of $95,942 per quality-adjusted life year (QALY). While Canada does not have an officially established willingness-to-pay threshold for health technology assessments, an analysis using a $100,000 per quality-adjusted life year (QALY) benchmark suggests that adding bevacizumab to chemotherapy can be considered cost-effective for certain high-risk ovarian cancer patients. Specifically, this applies to patients with stage III suboptimally debulked disease or stage III/IV unresectable disease who are at high risk of progression. A probabilistic sensitivity analysis using this $100,000 per QALY threshold found that the combination of bevacizumab and chemotherapy was cost-effective in 56% of the simulated scenarios when compared to standard chemotherapy alone. For cervical cancer, a study published in 2022 in JCO Global Oncology (Gupta 2022) evaluated the cost-effectiveness of bevacizumab combined with standard chemotherapy for advanced and metastatic disease. The analysis, conducted in the context of India's healthcare system, found that bevacizumab resulted in a gain of 0.129 QALYs at an additional cost of $3,816 USD, leading to an ICER of $34,744 USD per QALY gained. However, this exceeded India's per-capita GDP threshold, suggesting that in this healthcare context, the treatment may not be considered cost-effective. In the treatment of hepatocellular carcinoma, a study published in 2021 in JAMA Network Open (Su 2021) assessed the cost-effectiveness of atezolizumab plus bevacizumab for unresectable disease. The combination therapy added 0.530 QALYs at an incremental cost of $89,807 compared to sorafenib, resulting in an ICER of $169,223 per QALY gained. At a willingness-to-pay threshold of $150,000/QALY, there was only a 35% probability of the combination being cost-effective, highlighting the challenges in justifying its use from a purely economic perspective.

The substantial expense associated with long-term treatment has influenced reimbursement policies in various countries, with some healthcare systems limiting coverage to specific indications where the cost-benefit ratio is deemed justifiable. As healthcare costs continue to rise globally, these economic considerations will likely play an increasingly important role in treatment decisions and policy-making regarding the use of high-cost targeted therapies like bevacizumab.

Another significant challenge in the clinical use of bevacizumab is the development of resistance. Although initial responses to the therapy can be encouraging, many patients eventually develop resistance, leading to reduced effectiveness over time. There are several mechanisms that contribute to this resistance. One common issue is the upregulation of alternative pro-angiogenic pathways that bypass the VEGF blockade. According to a 2020 review in Frontiers in Oncology, these pathways can include members of the fibroblast growth factor (FGF), ephrin, and angiopoietin families. These alternative pathways can circumvent the VEGF blockade imposed by bevacizumab and re-establish tumour neovascularization (Heibe 2020).

The recruitment of bone marrow-derived cells has been shown to promote angiogenesis independently of VEGF. A study published in Nature Communications in 2015 identified bone marrow-derived fibrocyte-like cells as contributors to acquired resistance to bevacizumab. These cells, defined as alpha-1 type I collagen-positive and CXCR4-positive, were found to be the main producers of fibroblast growth factor 2 (FGF2) in resistant tumours. This mechanism allows for angiogenesis to continue even in the presence of VEGF inhibition (Mitsuhashi 2015).

Another mechanism of resistance involves adaptations in tumour vasculature and behaviour. As described by Gabriele Bergers and Douglas Hanahan (Bergers 2008), increased pericyte coverage of tumour blood vessels can enhance vascular integrity and reduce dependence on VEGF-mediated survival signalling, thereby protecting these vessels from anti-VEGF therapy. Simultaneously, tumours may become more invasive, enabling them to access normal tissue vasculature without requiring new blood vessel formation. These complementary mechanisms allow tumours to circumvent the need for VEGF-dependent angiogenesis, effectively bypassing the anti-angiogenic effects of bevacizumab and similar therapies.

The role of tumour-associated macrophages (TAMs) in resistance to anti-angiogenic therapy has also been highlighted in research. These macrophages, particularly when M2-polarized, can stimulate angiogenesis and promote tumour progression, contributing to treatment resistance (Zhu 2017).

Research on overcoming resistance to bevacizumab focuses on combination therapies and targeting multiple pathways. Pairing bevacizumab with immune checkpoint inhibitors, like in the IMbrave150 trial, showed success in treating hepatocellular carcinoma. Other approaches include dual targeting of VEGF with FGF or Ang2 and inhibiting transcription factors like HIF-1α. Targeting myeloid cells and using dynamic biomarker monitoring are also promising strategies.

The Ang-Tie signaling pathway, which involves angiopoietins (Ang1 and Ang2) and their receptor Tie2, is crucial for regulating vascular development, stability, and permeability. Ang1 generally promotes vascular stabilization by activating Tie2, helping to maintain vessel integrity. Conversely, Ang2 can function either as an agonist or an antagonist of Tie2, depending on the physiological context, and is often associated with processes like inflammation-induced vascular permeability and tumour angiogenesis. This dual nature allows the pathway to play a role in various physiological and pathological conditions.

Given the complementary roles of the VEGF and Ang-Tie pathways in angiogenesis, targeting both pathways can enhance therapeutic outcomes. For instance, combining VEGF inhibition through bevacizumab with treatments that modulate the Ang-Tie axis may provide a more comprehensive approach to vascular regulation, potentially improving the efficacy of anti-cancer therapies. Additionally, studies have identified levels of Ang1 and Tie2 as predictive biomarkers for the effectiveness of bevacizumab in specific cancers, such as ovarian cancer. While bevacizumab primarily focuses on blocking VEGF to hinder new blood vessel formation, integrating approaches that modulate the Ang-Tie axis opens additional avenues for enhancing anti-cancer treatments through better vascular regulation and stabilization.

Biomarkers could help identify patients who are most likely to benefit from bevacizumab, making its use more targeted and cost-effective. Combined measurements of circulating Angiopoietin-1 (Ang1) and Tie2 concentrations predicted improved progression-free survival (PFS) in bevacizumab-treated patients. In both the training and validation sets, high Ang1 and low Tie2 levels were associated with significantly better PFS, with medians of 23.0 months versus 16.2 months (p=0.003). The prognostic indices from the training set effectively distinguished between high and low progression probabilities in the validation set (p=0.008), yielding similar hazard ratios (0.21 vs. 0.27) for patients with high Ang1 and low Tie2 values across treatment arms (Backen 2014). In 2023 a retrospective study published in Lancet Oncology (Zeng 2023) explored the use of artificial intelligence (AI) to predict response to atezolizumab plus bevacizumab in hepatocellular carcinoma patients. The researchers developed an AI model called ABRS-P (atezolizumab-bevacizumab response signature prediction) that could estimate treatment response directly from histological slides. Patients with ABRS-P-high tumours showed significantly longer median progression-free survival compared to those with ABRS-P-low tumours after treatment initiation. A study published in the International Journal of Gynecologic Cancer 2024 examined angiogenesis gene variants as potential biomarkers for bevacizumab toxicity in ovarian cancer patients. The researchers found borderline associations between certain VEGFA variants and residual disease, as well as a rare variant (rs114694170) with delayed toxicity after bevacizumab treatment (Polaczek 2024).

A study by Ji Won Han et al. published in 2024 in Liver Cancer investigated dynamic peripheral T-cell analysis as a potential biomarker for response to atezolizumab plus bevacizumab in hepatocellular carcinoma (Han 2024). They found that changes in CD8+ T cell populations 3 weeks after treatment initiation could potentially predict treatment response. The 2023 study by Ohnmacht et al. in Nature Communications developed the Oncology Biomarker Discovery framework (OncoBird) that revealed response patterns to cetuximab and bevacizumab in metastatic colorectal cancer. They identified several potential biomarkers, including interactions between genetic alterations and tumour subtypes, that could predict differential response to these treatments (Ohnmacht 2023).

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