Angiogenesis Inhibitors

The process by which the body makes new blood vessels is called angiogenesis. However, when new blood vessels transport oxygen and nutrients to the cancer cells of a tumor, they help the tumor to grow and spread.

The goal of drugs known as angiogenesis inhibitors is to help stop or slow the growth or spread of tumorsAn abnormal mass of tissue that results when cells divide more than they should or do not die when they should by stopping the formation of blood vessels that go to them.

How do angiogenesis inhibitors work?

Angiogenesis inhibitors stop the formation of new blood vessels in order to cut off tumors’ blood supply. They may also make the tumor’s vasculatureThe arrangement of blood vessels in an organ or other part of the body more normal so that chemotherapy drugs can get to the tumor more effectively.1,2

The Role of VEGF (vascular endothelial growth factor)

VEGF protein released from the tumor cells can attach to the VEGF receptors on blood vessel cells and help new blood vessels form around the tumors. The blood vessels, with their supply of oxygen and nutrients, can help the cancer cells grow.1,3

Blood vessel overgrowth

 

How Do Angiogenesis Inhibitors Work?

Angiogenesis inhibitors are different from other anti-cancer agents because they work on the blood vessels that feed tumors, instead of working to stop the growth of the tumor cells directly. Angiogenesis inhibitors do this by specifically recognizing and binding to VEGF so that VEGF is unable to activate the VEGF receptor to stimulate the growth of new blood vessels.

Because angiogenesis inhibitors do not kill tumors but instead prevent tumors from growing, they may need to be administered over a long period. In addition, angiogenesis inhibitors are most effective when used in combination with other therapies, and they are FDA-approved only in those combinations.1,3

Available angiogenesis inhibitors for lung cancer

Currently, two angiogenesis inhibitors are approved by the US Food and Drug Administration (FDA) for treatment of non-small cell lung cancer:

Note: Bevacizumab (Avastin®)is not approved or recommended for treating squamous cell lung cancerA type of non-small cell lung cancer that usually starts near a central bronchus. It has been found to cause serious bleeding from the lungs of squamous cell lung cancer patients.7

  • Bevacizumab (Avastin®):  Approved as first-line treatmentThe first treatment given for a disease of unresectableUnable to be removed by surgery, locally advancedHaving spread from where it started to nearby tissue or lymph nodes, recurrentHaving come back after a period of time during which the cancer could not be detected, or metastaticHaving spread from the primary site, or place where it started non–squamous non–small cell lung cancer (NSCLC) in combination with the chemotherapiesTreatment with drugs that kill cancer cells carboplatin (Paraplatin®) and paclitaxel (Taxol® or Onxol®).4,5  Bevacizumab (Avastin®) is also approved in combination with paclitaxel, carboplatin and the immunotherapy drug atezolizumab (Tecentriq®) as a first-line treatment for adult patients with metastatic non-small squamous NSCLS with no EGFR or ALK genomic mutations.6
  • Ramucirumab (Cyramza®): This drug is a VEGF Receptor 2 antagonistA substance that stops the action or effect of another substance. It is approved in combination with the chemotherapy docetaxel (Taxotere®) for the second- or subsequent-line treatmentTreatment that is usually started after the first set of treatments doesn’t work, has stopped working, or has side effects that are not tolerated of patients with metastaticHaving spread from the primary site, or place where it started non-small cell lung cancer whose disease has progressed while on or after taking platinum-based chemotherapy (for example, cisplatin (Platinol-AQ®) or carboplatin (Paraplatin®). It is approved for use with both non-squamous and squamousA type of non-small cell lung cancer that usually starts near a central bronchus histologic types. Patients with EGFR or ALK mutations should have disease progression on FDA-approved targeted therapyA type of treatment that uses drugs to attack specific types of cancer cells with less harm to normal cells for these mutations before receiving ramucirumab (Cyramza®).8

How Are They Administered?

Bevacizumab (Avastin®) is given intravenously every 3 weeks. It is given in combination with carboplatin (Paraplatin®) and paclitaxel (Taxol® or Onxol®) or carboplatin (Paraplatin®) and paclitaxel (Taxol® or Onxol®) and atezolizumab (Tecentriq®). When given on the same day as atezolizumab (Tecentriq®), the atezolizumab (Tecentriq®) is administered earlier.4

Ramucirumab (Cyramza®) is given intravenously once every 3 weeks (on day 1 of a 21-day cycle) over approximately 60 minutes. It is given before docetaxel (Taxotere®) infusion.6

What are the side effects of angiogenesis inhibitors?

Like any treatment, angiogenesis inhibitors can cause side effects. Each drug has a different set of most common side effects. It’s important to remember that just because a side effect is possible doesn’t mean that a patient will experience it. Before taking an angiogenesis inhibitor, which is approved in combination with other therapies, a patient should discuss with their healthcare team what side effects they might expect from the treatments and how to prevent or ease them. A patient should speak with their healthcare team if and when new side effects begin, as treating them early on is often more effective than trying to treat them once they have already become severe.

Bevacizumab (avastin®)

Common side effects of bevacizumab (Avastin®) include nosebleeds, headaches, high blood pressure, inflammation of the nose, too much protein in the urine, taste alteration, dry skin, rectal hemorrhage, increased tearing of the eyes, back pain, and redness and peeling of the skin. Because an angiogenesis inhibitor interferes with the formation of new blood vessels, use can lead to problems with bruising and bleeding.

Rare side effects of bevacizumab (Avastin®) include bleeding from the stomach and intestines, which can be severe. Other serious side effects may include clots in the lungs and legs, heart attacks, and strokes. It also interferes with the healing of wounds, which can cause old wounds to open up again and new wounds to have trouble closing. This can lead to perforations in the stomach or intestine.5

Ramucirumab (cyramza®)

The most common side effects seen in patients treated with the combination of ramucirumab  (Cyramza®) and docetaxel include neutropeniaA condition in which there are fewer than normal neutrophils (a type of white blood cell), leading to increased susceptibility to infection, fatigue/weakness, and stomatitisInflammation or irritation of the mucous membranes in the mouth and irritation or inflammation of other mucous membranes. Rarer side effects include febrile neutropeniaA condition marked by fever and a lower-than-normal number of neutrophils in the blood, swelling from fluid build-up in the hands and lower legs, thrombocytopeniaA condition in which there are fewer platelets in the blood than normal, increased blood pressure, increased tearing of the eyes, and nosebleeds.8

Where do angiogenesis inhibitors fit in the lung cancer treatment plan?

Bevacizumab (Avastin®) and ramucirumab (Cyramza®) fit differently in the lung cancer treatment plan. The information below summarizes how they are approved for use by the FDA, based on clinical trial experience.

  Bevacizumab (Avastin®)5,6 Ramucirumab (Cyramza®)7

Non-small cell lung cancer histologyThe study of tissues and cells under a microscope (subtype)

Lung adenocarcinomaA type of non-small cell lung cancer that usually develops in the cells lining the lungs
Large cell lung cancer
Rare subtypes
Not squamous cell lung cancer

Any kind, including squamous cell lung cancerA type of non-small cell lung cancer that usually starts near a central bronchus

Stage of disease

Unresectable, locally advanced, recurrent, or metastatic

MetastaticHaving spread from the primary site, or place where it started, to other places in the body

Timing

First-lineThe first treatment given for a disease

  • Patient has not been treated with chemotherapy beforehand

Second-line or laterTreatment that is usually started after the first set of treatments doesn’t work, has stopped working, or has side effects that are not tolerated

  • Patient’s lung cancer has progressed while on or after taking platinum-based chemotherapy

  • Patients with EGFRThe protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide or ALKA gene that the body normally produces but, when it fuses with another gene, produces an abnormal protein that leads to cancer cell growth mutations have had disease progressionContinued growth or spread of cancer while being treated with FDA-approved targeted therapyA type of treatment that uses drugs to attack specific types of cancer cells with less harm to normal cells for these mutations

Given in combination with which chemotherapy

Carboplatin (Paraplatin®) and paclitaxel (Taxol® or Onxol®)

Docetaxel (Taxotere®)

Given in combination with which chemotherapy and immunotherapy

Carboplatin (Paraplatin®) and paclitaxel (Taxol® or Onxol®) and atezolizumab (Tecentriq®)

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Finding a clinical trial that might be right for you

Clinical research is ongoing to evaluate the role of angiogenesis inhibitors in a range of other lung cancer treatment approaches, including alone or in combination with other drugs. Other angiogenesis inhibitors are also being studied.9

If you are considering participating in a clinical trial, start by asking your healthcare team whether there is one for which you might qualify in your area. In addition, here are several resources to help you find one that may be a good match for you:

Learn more about clinical trials here.

Questions to ask your healthcare team about angiogenesis inhibitor therapy

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  1. Why do you recommend an angiogenesis inhibitor for me?
  2. What treatment(s) will this be combined with?
  3. How and where will this therapy be given, and for how long?
  4. How and when will I know if the treatment is working?
  5. How often do I need to be seen between treatments for a physical exam and/or lab work?
  6. Are there any tests or procedures I will need during the treatment?
  7. What side effects can I expect?
  8. What can I do to manage these side effects?
  9. How will this treatment affect my daily life? Will I be able to work, exercise, and perform my usual activities?
  10. What tests will I need after treatment is completed?
  11. Are there any long-term health issues I should expect from treatment with an angiogenesis inhibitor?
  12. How much will my treatment cost?
  13. Who should I contact for information or if I have a problem during treatment? Who is my after-hours contact?

Updated July 16, 2019


References

  1. Angiogenesis Inhibitors. National Cancer Institute website. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet. Reviewed April 2, 2018. Accessed July 16, 2019.
  2. Jain, RK. Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy. Science. 07 Jan 2005. Vol. 307, Issue 5706, pp. 58-62. Doi: 10.1126/science.1104819. Accessed July 16, 2019.
  3. Angiogenesis Inhibitors. The University of Texas MD Anderson Cancer Center. https://www.mdanderson.org/treatment-options/angiogenesis-inhibitors.html. Copyright 2019. Accessed July 16, 2019.
  4. Lung Cancer Treatment Options. Cancer.Net website. https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/types-treatment. Approved January 2019. Accessed July 16, 2019.
  5. Avastin® (bevacizumab) [package insert]. Genentech, Inc. South San Francisco, CA. November 2014. https://www.gene.com/download/pdf/avastin_prescribing.pdf. Revised June 2019. Accessed July 16, 2019.
  6. Tecentriq® (atezolizumab) [package insert]. Genentech, Inc. South San Francisco, CA. 2016. https://www.gene.com/download/pd/tecentriq_prescribing.pdf. Revised May 2019. Accessed July 16, 2019.
  7. Avastin safety profile. Avastin website. https://www.avastin.com/hcp/safety.html. Accessed July 16, 2019.
  8. Cyramza® (ramucirumab) [package insert]. Eli Lilly and Company. Indianapolis, IN; December 2014. http://pi.lilly.com/us/cyramza-pi.pdf. Revised May 2019. Accessed Juiy 16, 2019.
  9. Clinicaltrials.gov. US National Institutes of Health website. http://clinicaltrials.gov. Accessed December 18, 2017.

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