Nearly 20 Years with Bevacizumab Has Brought Hope for Patients and Deeper Understanding of Solid Tumors

Tumor Neoangiogenesis

Rapidly multiplying tumor cells have significant metabolic demands. Up to a certain size of the lesion, they are capable of securing everything they need through diffusion, but later they start a signaling cascade of neoangiogenesis. New branches sprout from nearby vessels, which, though structurally imperfect, supply the growing tumor with what it needs–nutrients and oxygen.

The most significant pro-angiogenic factor in tumors is vascular endothelial growth factor VEGF-A, whose signaling is activated by binding to VEGFR1-3 receptors on endothelial cells. The effect of VEGF-A lies in stimulating the proliferation and survival of endothelial cells and increasing vascular permeability.

Targeting More Than Just New Vessels

Bevacizumab binds circulating VEGF-A. It was developed as an anti-angiogenic drug that does not have a direct cytotoxic effect. Today we know that this monoclonal antibody can influence complex interactions between various cells present in the tumor tissue and interactions with the extracellular matrix.

VEGF-A affects not only endothelial cells but also other cells within the tumor microenvironment:

• Tumor cells themselves: VEGF-A supports their proliferation, migration, and invasiveness.
• Tumor stem cells: VEGF-A maintains their “stem” properties, particularly their self-renewal capability.
• Immune cells: VEGF-A has immunosuppressive effects on dendritic cells, macrophages, and T lymphocytes, while it supports regulatory T cells and myeloid-derived suppressor cells.

The effects of inhibiting VEGF-A with bevacizumab thus extend far beyond just suppressing pathological new blood vessel formation. They are varied and likely specific to tumor type and microenvironment.

Clinical Uses

Bevacizumab is approved for treating solid tumors, including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and cervical cancer, as well as breast cancer, ovarian cancer (OC), fallopian tube cancer, and peritoneal cancer. It is typically used for advanced, inoperable, recurrent, or metastatic stages. Unlike the United States, it is not approved in the European Union for treating glioblastoma. Conversely, it is not approved in the USA for treating breast cancer.

Clinical trials preceding its registration involved over 37,000 patients, and estimates by 2020 indicated more than 3.5 million patients treated in routine oncology practice. In clinical trials, bevacizumab statistically significantly and, most importantly, clinically significantly prolonged progression-free survival, increased treatment response rates, and improved quality of life while reducing tumor size. In some indications, however, overall survival was not extended.

For most indications, bevacizumab was the first targeted treatment (e.g., in metastatic CRC or advanced RCC). As it is not primarily a cytotoxic agent, it shows very advantageous synergy with chemotherapy. Additionally, by reducing the permeability of new blood vessels, it ensures better and higher concentration delivery of cytostatics to tumor lesions.

New Role for Bevacizumab

Current clinical research focuses on the advantageous combinations of bevacizumab. Significant attention is given to its combination with immune checkpoint inhibitors. The combination of bevacizumab with atezolizumab and chemotherapy was recently approved for NSCLC, as it reduces the risk of disease progression regardless of EGFR and ALK status. Further results showing the clinical benefits of combinations with immunotherapy have emerged in clinical trials for RCC and hepatocellular carcinoma (HCC). Combinations with PARP inhibitors are being tested in OC patients.

Conclusion

Unresolved issues remain, such as the absence of suitable predictive biomarkers for treatment response, which currently hampers greater personalization, and the lack of effective approaches for overcoming secondary resistance to bevacizumab. Despite these obstacles, after nearly 20 years of experience, bevacizumab as a representative of targeted anti-angiogenic therapy is firmly established in the treatment protocols for many solid tumors. Thanks to its unique mechanism of action, suitable for combination with other anti-cancer drugs, it is expected to maintain its position in the future.

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Source: Garcia J., Hurwitz H. I., Sandler A. B. et al. Bevacizumab (Avastin^®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev 2020; 86: 102017, doi: 10.1016/j.ctrv.2020.102017.