Angiogenesis Inhibitors

As the body develops and grows, it makes new blood vessels to supply all of the cells with blood. This process is called angiogenesis. When the new blood vessels provide oxygen and nutrients to the cancer cells, they help the cancer cells grow and spread.

The goal of angiogenesis inhibitors is to help stop or slow the growth or spread of these tumorsAn abnormal mass of tissue that results when cells divide more than they should or do not die when they should. They are also called anti-angiogenic agents or drugs.

How do angiogenesis inhibitors work?

Angiogenesis inhibitors stop the formation of new blood vessels in order to cut off tumors’ blood supply, or they 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 better.1

The Role of VEGF (vascular endothelial growth factor)

VEGF proteins can attach to the VEGF receptors on blood vessel cells and help new blood vessels to form around the tumors. The blood vessels can help the cancer cells grow.1,2

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, such as bevacizumab (Avastin®), do this by specifically recognizing and binding to VEGF. When VEGF is attached to the angiogenesis inhibitor, the protein is unable to activate the VEGF receptor.

Angiogenesis inhibitors are most effective when combined with additional therapies, especially chemotherapy. Angiogenesis inhibitors do not necessarily kill tumors; they instead may prevent tumors from growing. Therefore, this type of therapy may need to be administered over a long period.1,2

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 life-threatening and fatal bleeding in the lungs of patients with squamous cell carcinoma. The high risk of bleeding is thought to be due to the central location of these tumors.3,4,5

  • 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 and paclitaxel.4
  • Ramucirumab (Cyramza®): This drug is considered a VEGF Receptor 2 antagonistA substance that stops the action or effect of another substance. It is approved in combination with the chemotherapy docetaxel for the second-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 or carboplatin). 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.6

Both of these drugs must be given in combination with chemotherapy.

A number of other angiogenesis inhibitors are also being studied in clinical trials.7

How Are They Administered?

Bevacizumab (Avastin®) is given intravenously every 3 weeks over 30 to 90 minutes. It is given in combination with chemotherapy.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 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 it will happen to you.

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.4

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.6

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

Bevacizumab and ramucirumab fit differently in the lung cancer treatment plan. The information below shows how they are approved for use by the FDA based on clinical trial experience.

  Bevacizumab (Avastin®)4 Ramucirumab (Cyramza®)6
Non-small cell lung cancer histologyThe study of tissues and cells under a microscope (subtype) 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 and paclitaxel Docetaxel

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.

If you are considering participating in a clinical trial, start by asking your doctor 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 January 5, 2018


References

  1. Angiogenesis Inhibitors. National Cancer Institute website. http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibitors. Reviewed October 7, 2011. Accessed December 4. 2017.
  2. Angiogenesis Inhibitors. The Universit of Texas MD Anderson Cancer Center. https:/www.mdanderson.org/treatment-options/angiogenesis-inhibitors.html. Copyright 2017. Accessed December 18, 2017.
  3. Lung Cancer Treatment Options. Cancer.Net website. http://www.cancer.net/cancer-types/lung-cancer/treatment-options. Approved August 2017. Accessed December 4, 2017.
  4. Avastin® (bevacizumab) [package insert]. Genentech, Inc. South San Francisco, CA; November 2014. https://www.gene.com/download/pdf/avastin_prescribing.pdf. Revised December 2016. Accessed December 4, 2017.
  5. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. Journal of Clinical Oncology. June 1, 2004: 2184-2919. doi: 10.1200/JCO.2004.11.022. http://jco.ascopubs.org/content/22/11/2184.full. Accessed December 4, 2017.
  6. Cyramza® (ramucirumab) [package insert]. Eli Lilly and Company. Indianapolis, IN; December 2014. http://pililly.com/us/cyramza-pi.pdf. Revised March 2017. Accessed December 4, 2017.
  7. Clinicaltrials.gov. US National Institutes of Health website. http://clinicaltrials.gov. Accessed December 18, 2017.

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