Opdivo (Nivolumab): Uses, Actions, and Side Effects

What Should You Know About the Immuotherapy Drug Opdivo?

immunotherapy drug concept behind Opdivo (nivolumab)
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The immunotherapy drug Opdivo (nivolumab) is now approved for several cancers that are metastatic (such as lung cancer, melanoma, and more), and has resulted in responses previously not seen with these advanced cancers. The drug works, simplistically, by helping the body's own immune system eliminate cancer cells. Unlike chemotherapy, Opdivo targets cancer cells specifically, and often has fewer side effects than traditional chemotherapy drugs. Common side effects include a rash, electrolyte abnormalities, and inflammation in a number of different organs. Let's look at the mechanism of action of Opdivo, when and how it may be used, potential side effects, and how doctors are attempting to learn who will respond best to these drugs.

Opdivo (Nivolumab)—Definition

Opdivo (nivolumab) is considered a type of immunotherapy drug, the first drug in this category approved for lung cancer (in 2015) and also now approved for several other cancers. Immunotherapy is a relatively new type of cancer treatment which uses the immune system or principles of the immune response to fight cancer.

There are many different types or categories of treatments that are classified as immunotherapy. Opdivo is considered a "checkpoint inhibitor" (which we will discuss further below).

Opdivo (nivolumab) has been an exciting addition for treating cancer in past few years, and much of the excitement is not just hype. Some people have had responses to the medication which were almost unheard of even 5 years ago. Unfortunately, Opdivo does not work for everyone, but when it is effective it may result in a durable response (defined below). Side effects are common, but in general, are milder than side effects found with many chemotherapy regimens.

Is Opdivo (Nivolumab) a Type of Chemotherapy?

Many people are confused about how chemotherapy and immunotherapy are related. Is immunotherapy, and specifically nivolumab, a type of chemotherapy?

Sometimes, chemotherapy is used loosely to describe any type of drug given to fight cancer. In this case, immunotherapy drugs may sometimes be referred to as chemotherapy. Yet there are important differences as well. The term "chemotherapy" usually refers to the use of drugs which affect cell division of all rapidly growing cells. The well-known side effects of chemotherapy arise because, in addition to fighting cancer cells, these drugs also affect normal cells that divide rapidly. It is this action of chemotherapy on healthy cells, such as those in the bone marrow (resulting in a low white count and more), hair follicles (resulting in hair loss), and digestive tract (resulting in nausea) that results in the common side effects.

In contrast, immunotherapy drugs are designed specifically to alter the body's immune system or use substances made by the immune system to fight cancer, and does not attack all of the cells in the body. For this reason, immunotherapy drugs often have fewer side effects than traditional chemotherapy drugs.

How Opdivo (Nivolumab) Works (Mechanism of Action)

Opdivo (nivolumab) is an immunotherapy drug which is classified as a checkpoint inhibitor.

The mechanism of action of checkpoint inhibitors is easier to understand if you think of your immune system as a car, with checkpoint inhibitors being the brakes on the car. Our immune systems are designed to attack bacteria, viruses, and even cancer cells in our bodies. Our immune system already knows how to fight cancer. Just as our body fights off bacteria and viruses in our environment, it is designed to fight off foreign cells such as cancer cells.

The immune system does, however, have checks and balances. These checkpoints serve to control the immune system so it doesn't underperform or overperform. An overactive immune system, is, in fact, a problem with autoimmune diseases such as rheumatoid arthritis and lupus.

The "brakes" of the car that slow down the process are proteins referred to as checkpoint inhibitors. These checkpoint proteins slow down the immune response so that it is not overactive. One of these proteins is PD-L1. PD-L1 binds to PD-1 receptors on T cells (the cells in the immune system most active in attacking cancer), telling them to be quiet.

Cancer cells are tricky. Some cancer cells have found a way to produce a lot of PD-L1. When this binds to PD-1 receptors on the T cells, it allows the cancer cells to grow unchecked, almost like putting a mask on the cancer cells so that the immune system does not recognize and attack them.

Opdivo works by binding to and blocking the activation of PD-1 by PD-L1, essentially releasing the brakes on the car (immune system) so that it can fight the cancer. All in all, Opdivo works by taking the mask off of cancer cells so that they can no longer hide from the immune system, and end up being destroyed by our body's own immune response.

Opdivo (Nivolumab) Uses

Opdivo is usually used for stage IV (inoperable) cancers, cancers that cannot be treated with surgery and have usually spread to other parts of the body (referred to as metastatic).

What Cancers May Be Treated With Opdivo?

Opdivo (nivolumab) has been approved for the treatment of people with lung adenocarcinoma (a type of non-small cell lung cancer), squamous cell carcinoma of the lungs (another type of non-small cell lung cancer), metastatic melanoma, Hodgkin disease, head and neck cancer, Merkel cell carcinoma, and renal cell carcinoma (kidney cancer). It is also being used in clinical trials for other cancers.

How is it Given?

Opdivo is given by intravenous injection over an infusion period of about an hour. It is most often given every 2 weeks.

Alone or in Combination

Opdivo may be given alone, or in combination with other immunotherapy drugs, chemotherapy drugs, or radiation. Of note is that combination therapy may work well due to a particular mechanism. Chemotherapy or radiation therapy result in the breakdown of tumor cells. The breakdown products of these cells are then "seen" by the immune system, and by essentially priming the system, may result in immunotherapy drugs working better.

What Does “Durable Response” Mean?

Before discussing the studies on nivolumab, it’s helpful to define a term that’s used frequently when describing the response to immunotherapy drugs: the term "durable response."

A "durable response" refers to a long-lasting positive response of a tumor to a drug. There is not a specified time, but "long-lasting" usually means a minimum of 1 year and sometimes much longer.

If you see studies talking about a "durable response," this often contrasts with the typical type of response expected from chemotherapy. With stage IV solid tumors, chemotherapy can be effective but the tumor almost always becomes resistant to chemotherapy after a relatively short period of time (often defined in months). With targeted therapies, the response time is often longer, yet resistance often develops in a year's time depending on the particular drug, the type of cancer, and much more. (Some of the newer targeted therapies appear to work longer than this.)

A durable response does not mean a "cure" but it defines a response that in many ways is the closest thing we have at this time—when it works.

Immunotherapy May Continue to Work After Treatment is Done

Unlike chemotherapy and targeted therapy—which are effective only as long as a person is taking the drug—for some people who have taken Opdivo, it appears that it may continue to be effective. With non-small cell lung cancer, some people have had durable responses even after discontinuing therapy.

What Are Studies and Clinical Trials Telling Us About Opdivo?

Studies have, in general, looked at the effect of Opdivo on specific cancers rather than cancers as a whole:

  • Non-small cell lung cancer: A 2017 review of nine studies involving people with stage III and stage IV non-small cell lung cancer found that nivolumab (and Tecentriq (atezolitumab) and Keytruda (pembrolizumab) improved overall survival more than chemotherapy when used second line (and also pembrolizumab first line in PDL-1 positive tumors). In addition, people experienced fewer side effects on the checkpoint inhibitors than on chemotherapy. Opdivo may be used for either lung adenocarcinoma or squamous cell carcinoma of the lungs. Opdivo should only be used for those people who do not have targetable gene mutations or haven't responded to targeted therapy.
  • Metastatic melanoma: Opdivo is now recommended first line (as the first treatment) for metastatic melanoma.
  • Classical Hodgkin lymphoma: Opdivo may used for people with classical Hodgkin lymphoma who are not improving after a stem cell transplant and use of targeted therapy.
  • Squamous cell head and neck cancer (metastatic or recurrent).
  • Renal cell carcinoma: Opdivo is approved second line (after anti-angiogenesis inhibitor therapy) for advanced renal cell carcinoma, the most common type of kidney cancer.
  • Urothelial carcinoma: Opdivo is approved for people with this type of bladder cancer who are not improving on chemotherapy.
  • Merkel cell carcinoma
  • Colorectal cancer: One type of metastatic colon cancer after treatment with three chemotherapy drugs.
  • Hepatocellular carcinoma (liver cancer): Opdivo may be used after treatment with Nexavar (sorafenib).
  • Cancer with Brain Metastases

Cancer with Brain Metastases

Cancers with brain metastases, such as melanoma or lung cancer with brain metastases have traditionally been challenging to treat. Most chemotherapy drugs are unable to reach the central nervous system due to the presence of the blood-brain barrier, a tight network of capillaries that works to keep toxins (such as chemotherapy drugs) out of the brain. This is the reason, for example, why nivolumab is recommended first-line for people with melanoma with asymptomatic brain metastases.

When Does Immunotherapy Work Best?

The research on Opdivo and other immunotherapy drugs is still young, but with lung cancer at least, it seems that people who have smoked in the past are more likely to respond to the drug than those who have never smoked. This makes sense when thinking about the mechanism. Lung tumors in people who have smoked have a "higher mutation load." In other words, the cancer cells have more of the mutations that are found in cancer cells that occur in the process of the cell becoming cancerous. (This is not related to heredity and these mutations are not passed on in a family). Cells that have more mutations probably appear more abnormal (less like normal cells) to the immune system, making treatments that use the immune system or its principles more likely to be effective.

Tests to See if Opdivo May Be Effective

Tests that may be done to predict the response to Opdivo and other checkpoint inhibitors include:

  • PD-L1 Levels: Tests for PD-L1 levels can, in some cases, predict a response to Opdivo, but the test has many limitations as far as deciding when to use the drug. Some people who have low levels of PD-L1 may still have a very strong response to the drug.
  • Tumor Mutation Burden: Tumor mutation burden is a biomarker test that looks at the number of mutations in cancer cells. Those who have a high tumor mutation burden (defined as more than 10 mutations per megabase on Foundation testing) are more likely to respond, but as with PD-L1 testing, there are exceptions, and it is still too soon to use the test as a method of choosing treatment.

Potential Side Effects Of Opdivo (Nivolumab)

As with any cancer treatment, there are common and potential side effects to treatment with Opdivo.

Common side effects (those that occur in 10 percent or more of people) include:

  • Skin rash
  • Itching (pruritis)
  • Elevated potassium level (hyperkalemia) and low sodium level (hyponatremia)
  • Abnormal liver function tests such as ALT and alkaline phosphatase
  • Cough
  • Shortness of breath
  • Fatigue
  • Low white blood cell count
  • Muscle pain especially with lung cancer

Less common but serious adverse effects may include:

  • Almost anything that ends with the suffix "itis," a term that means inflammation; such as colitis (inflammation of the colon), pneumonitis (inflammation of the lungs), hepatitis (inflammation of the liver), nephritis (inflammation of the kidneys), pancreatitis (inflammation of the pancreas), and more
  • Eye conditions such as uveitis and dry eyes
  • Endocrine problems involving the thyroid gland, adrenal glands, and pituitary gland

Warnings While on Opdivo (Nivolumab)

People taking Opdivo should be monitored for inflammatory symptoms, and if present, the drug may need to be held or stopped. These include conditions such as pneumonitis, encephalitis, nephritis, and colitis. The drug can cause type I diabetes, and blood sugar should be monitored.

Adrenal insufficiency or adrenal fatigue can occur, and people should be aware of the potential of this condition as well as the possible symptoms.

Severe immune related rashes such as Stevens-Johnson syndrome may occur, and you should talk to your doctor about any rashes you develop.

Overall, however, severe adverse reactions necessitating stopping the drug are uncommon, occurring less than 1 percent of the time. Make sure to talk to your oncologist about other potential symptoms as well as when you should call.

A Word From Verywell

Opdivo (nivolumab) is a very new drug that is classified as a type of immunotherapy. For those in whom these drugs are effective, we have sometimes seen responses of advanced solid tumors that were unimaginable just a few years ago. That said, they do not work for everyone, and we still do not have a good way of knowing who will respond best to treatment.

Side effects are common, especially symptoms such as a rash, itching, and thyroid dysfunction. Serious adverse reactions may sometimes occur as well. In general, however, Opdivo is tolerated better than traditional chemotherapy.

There has been much excitement from the medical community for a few reasons. Opdivo can be used to treat even very advanced solid tumors. In addition, it can be effective in several different types of cancer. It's likely that new uses for the drug will be approved in the near future, and many clinical trials are in progress assessing the effect of Opdivo on a wide variety of cancer types, both alone, and in combination with other treatments.

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