Angiogenesis Inhibitors

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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 tumors. They are also called anti-angiogenic agents or drugs.

How do angiogenesis inhibitors work?

There is some debate about how exactly these drugs work, but theories include that they stop the formation of new blood vessels in order to cut off tumors’ blood supply, or they make the  tumor’s vasculature 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

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, 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

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 is not approved or recommended for treating squamous cell lung cancer. 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.3,5

  • Bevacizumab (Avastin®):  Approved as first-line treatment of unresectable, locally advanced, recurrent, or metastatic non–squamous non–small cell lung cancer (NSCLC) in combination with the chemotherapies carboplatin and paclitaxel.3
  • Ramucirumab (Cyramza®): Cyramza is considered a VEGF Receptor 2 antibody. It is approved in combination with the chemotherapy docetaxel for the second-line treatment of patients with metastatic non-small cell lung cancer, whose disease has progressed while on or after taking platinum-based chemotherapy (for example, cisplatin or carboplatin).

    Patients with EGFR or ALK mutations should have disease progression on FDA-approved targeted therapy for these mutations before receiving ramucirumab. It is approved for use with both non-squamous and squamous histologic types.4

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

A number of other angiogenesis inhibitors are also being studied in clinical research studies.

How Are They Administered?

Bevacizumab is given intravenously every 3 weeks over 30 to 90 minutes. It is given in combination with chemotherapy.3

Ramucirumab 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.4

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

Common side effects of bevacizumab include high blood pressure, headaches, dry skin, back pain, inflammation of the nose, and too much protein in the urine.

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 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.3

Ramucirumab

The most common side effects seen in patients treated with the combination of ramucirumab  and docetaxel include neutropenia, fatigue/weakness, and stomatitis and irritation or inflammation of other mucous membranes. Rarer side effects include febrile neutropenia, swelling from fluid build-up in the hands and lower legs, thrombocytopenia, increased blood pressure, increased tearing of the eyes, and nosebleeds.4

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®)3 Ramucirumab (Cyramza®)4
Non-small cell lung cancer histology (subtype) Adenocarcinoma
Large cell lung cancer
Rare subtypes
Not squamous cell lung cancer
Any kind, including squamous cell lung cancer
Stage of disease Advanced Metastatic
Timing

First-line

  • Patient has not been treated with chemotherapy beforehand

Second-line or later

  • Patient’s lung cancer has progressed while or after taking platinum-based chemotherapy
  • Patients with EGFR or ALK mutations have had disease progression while being treated with FDA-approved targeted therapy for these mutations

Given in combination with which chemotherapy:

Carboplatin and paclitaxel Docetaxel

A number of other angiogenesis inhibitors are also being studied in clinical research studies.

Finding a clinical research study 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 health care team about angiogenesis inhibitor therapy

Print this list

  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 February 23, 2016.


References

  1. Angiogenesis Inhibitors. National Cancer Institute website. http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibi.... Reviewed October 7, 2011. Accessed February 23, 2016.
  2. Lung Cancer Treatment Options. American Society of Clinical Oncology website. http://www.cancer.net/cancer-types/lung-cancer/treatment-options. Approved August 2015. Accessed February 23, 2016.
  3. Avastin® (bevacizumab) [package insert]. Genentech, Inc. South San Francisco, CA; November 2014. https://www.gene.com/download/pdf/avastin_prescribing.pdf. Revised December 2015. Accessed February 22, 2016.
  4. Cyramza® (ramucirumab) [package insert]. Eli Lilly and Company. Indianapolis, IN; December 2014. http://pililly.com/us/cyramza-pi.pdf. Revised April 2015. Accessed February 22, 2016.
  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 February 22, 2016.

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