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Immune Checkpoint Inhibitors: Boosting the Cancer Battle

Medically reviewed on Oct 9, 2018 by L. Anderson, PharmD

What is Immunotherapy?

You've probably heard about the new groundbreaking type of "immunotherapy" drugs used to treat and kill cancer. Immunotherapy has been the subject of numerous news articles and TV specials. In fact, in October 2018 James P. Allison, PhD from the MD Anderson Cancer Center in Houston won the 2018 Nobel Prize in Physiology or Medicine for his breakthrough discoveries in this type of immunotherapy.

These drugs aren't some kind of obscure therapy, either. Former President Jimmy Carter received one of these medications, Keytruda -- fortunately with great success -- for his skin cancer (also called melanoma) that had spread to his brain. These medications are now established therapy in the toolbox of cancer treatments.

These groundbreaking new treatments are adding months -- or even years -- to the lives of patients who have cancer. In fact, for some patients, their tumors seem to disappear. One cancer immunotherapy class is called the Immune Checkpoint Inhibitors, and they are making headlines in the medical world.

Linked: Our Immune System and Cancer

Our immune system is simply an amazing piece of human biology. The immune system helps to guard the body from infections due to bacteria, viruses, and yes, even cancer. This immune gatekeeper has a memory, too, and it can remember and 'recognize' when foreign invaders, such as cancer, attempt to inhabit our body.

However, the immune system is not perfect in fighting these intruders, and researchers are making great progress to learn why. It appears some tumors can 'turn off' the ability of cancer-fighting cells such as T-cells (a type of white blood cell) to attack these unwelcome guests.

But the new immunotherapy drug class called "Immune Checkpoint Inhibitors" is fighting back.

Drugs in this group include agents such as:

What makes them so special? How do these novel agents work?

Cancer Types Targeted by Immunotherapy

If you've been affected by cancer -- either yourself or a family member -- take time to learn more about these breakthrough treatments. Advances are being made in cancers such as:

Many other types of cancer are also under research.

While not every patient will have a response, it is important to investigate your alternatives with your doctor. Joining a groundbreaking research trial might even be an option. This could give you the opportunity to use an investigational medication that is not available otherwise.

Immune Checkpoint Inhibitors: Releasing the Brakes

The immune system needs to be able to tell the difference between foreign invaders and heathy tissue so that our cells and organs are not mistakenly attacked. To do this, our immune system has a set of "brakes", like a bike, that can help it to stop and go.

  • When the immune system "brakes" are "off", it's active and attacks cells that considered foreign invaders such as cancer. Our immune system is very good at this, but cancer is sneaky and can fool the "brakes".
  • When the T-cell is stopped ("brakes" are on) it can't fight the cancer.

However, the Immune Checkpoint Inhibitors release the "brakes" so the T-cells can now "go" find and kill the cancer cells.

Some of these checkpoints are called PD-1, PD-L1, and CTLA-4 receptors, which are protein receptors or ligands on cell surfaces. Drugs that target these checkpoints to turn "off" the "brakes" hold great promise and are now used to fight many types cancer.

FDA-Approved Immune Checkpoint Inhibitors

  • Yervoy (ipilimumab) from Bristol Myers Squibb, targets CTLA-4 and is used for advanced melanoma (skin cancer); kidney cancer when used with nivolumab (Opdivo).
  • Keytruda (pembrolizumab) from Merck, targets PD-1 ligands and is used for advanced melanoma (skin cancer); non-small cell lung cancer (NSCLC); Hodgkin's lymphoma; head and neck cancer; cervical cancer; microsatellite instability-high cancer; bladder and urinary tract cancer; primary mediastinal large B-cell lymphoma; and gastric (stomach) cancer.
  • Opdivo (nivolumab) from Bristol-Myers Squibb, targets PD-1 and is used for advanced melanoma; NSCLC; renal cell cancer; bladder, ureters and renal pelvis (urothelial) cancer; Hodgkin's Lymphoma; head and neck cancer; liver cancer; colorectal cancer; and small cell lung cancer.
  • Tecentriq (atezolizumab) from Genentech, targets PD-L1 and is used for advanced bladder cancer and NSCLC
  • Bavencio (avelumab) for Merkel cell carcinoma, a rare type of skin cancer and urothelial carcinoma (bladder cancer)
  • Imfinzi (durvalumab), also for bladder cancer, as well as to slow progression of NSCLC.

Libtayo (cemiplimab-rwlc), from Sanofi/Regneron, was first approved in Sept. 2018. Libtayo targets the PD-1 cellular pathway, and is approved to treat a type of skin cancer known as metastatic cutaneous squamous cell carcinoma (CSCC) or CSCC that is locally advanced in patients for whom surgery or radiation is not an option.

Combined use of some of these agents, such as with Opdivo and Yervoy, have also been cleared by the FDA.

Quite often these drugs are used after traditional cancer treatment has failed, but as research advances they are increasingly gaining first-line indications.

Yervoy (ipilimumab)

Yervoy, known generically as (ipilimumab), is a monoclonal antibody that attaches to the T-lymphocyte antigen 4 (CTLA-4) protein receptor to inhibit CTLA-4. This releases the "brakes" and helps to activate our immune system to attack cancer.

Melanoma is more likely to spread (metastasize) than other forms of skin cancer, and is increasing in incidence. Yervoy was the first immune checkpoint inhibitor to be FDA-approved in March of 2011 for the treatment of late-stage melanoma (skin cancer), and has since been approved to reduce the risk of melanoma returning after surgery.

Yervoy is given by intravenous injection every 3 weeks or every 12 weeks depending upon use.

Common reported side effects include rash, diarrhea, fatigue, itching, headache, nausea and weight loss. Severe immune-mediated side effects can also occur with Yervoy, which may result in the need for treatment discontinuation.

Opdivo (nivolumab)

Opdivo, known generically as nivolumab, is also an immune checkpoint inhibitor. However, Opdivo acts at a different receptor than Yervoy, and is known as a programmed death receptor-1 (PD-1) blocking antibody.

Opdivo was first approved in December 2014 to treat advanced melanoma, but since then has been cleared by the FDA to also treat:

Opdivo is given as an intravenous injection. Common side effects might include rash, itching, cough, upper respiratory tract infections, and fluid retention (edema). Severe immune-mediated side effects, a problem with all of these drugs, can occur.

Keytruda (pembolizumab)

Keytruda, generic name pembolizumab, might sound familiar to you. Approved in September, 2014, this was the immunotherapy successfully received by former President Jimmy Carter to fight off brain cancer due to metastatic melanoma (skin cancer that has spread).

Like Opdivo, Keytruda is PD-1 blocking antibody. Keytruda is FDA-approved to treat:

  • metastatic melanoma (including as a first-line agent)
  • metastatic non-small cell lung cancer (NSCLC)
  • first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC) irrespective of PD-L1 expression
  • Hodgkin's lymphoma
  • primary mediastinal large B-cell lymphoma
  • bladder and urinary tract cancer
  • cervical cancer
  • head and neck cancer
  • microsatellite instability-high cancer
  • gastric (stomach) cancer

Keytruda is given via intravenous (IV) infusion, with common side effects including edema (water retention) fatigue, itching, constipation, diarrhea, rash, and nausea. Infusion reactions with flu-like symptoms such as chills, fever, headache and weakness may occur, too, plus the immune mediated adverse reactions seen with other checkpoint inhibitors.

Tecentriq (atezolizumab) and Imifinzi (durvalumab)

Tecentriq, generic name atezolizumab was approved in May 2016 and was the first PD-1/PD-L1 inhibitor. Tecentriq is approved to treat a common type of cancer known as urothelial carcinoma, which affects the bladder, ureters and renal pelvis.

Tecentriq is also approved by the FDA for treatment of certain types of advanced non-small cell lung cancer (NSCLC).

Like other checkpoint inhibitors, Tecentriq is given by an intravenous infusion. In studies, common side effects included fatigue, decreased appetite, nausea, urinary tract infection, fever, and constipation. Tencentriq also has the potential to cause infection and more serious, but less common, immune-mediated side effects that involve healthy organs, including the lungs, colon and endocrine system.

Another PD-L1 blocker, Imfinzi (durvalumab) from AstraZeneca, was FDA-approved in May 2017 for the treatment of patients with advanced urothelial carcinoma (bladder cancer) who have ongoing disease despite use of platinum-containing chemotherapy with or without surgery.

Bavencio (avelumab)

Bavencio (avelumab), also a PD-L1 blocking antibody, received accelerated FDA-approval in March 2017 for the treatment of patients with metastatic Merkel cell carcinoma (MCC). Bavencio is the first FDA-approved treatment for metastatic MCC and is used in patients 12 years and older including those who have not received prior chemotherapy.

MCC is rare form of skin cancer most common in older patients. It appears as painless pink, red, or purple bump, often on the face, head or neck area. Most patients can get the tumor removed surgically, but more than 30% will eventually develop disease recurrence.

Approval of Bavencio was based on a study of 88 patients with metastatic MCC who had previously received chemotherapy. In 33% of patients, complete or partial shrinkage of their tumors occurred, with a response lasting for more than 12 months in 45% of patients. Common side effects include fatigue, muscle pain, diarrhea, nausea, infusion-related reactions, and rash, among others.

In May 2017, Bavencio was given accelerated approval to treat urothelial carcinoma (of the bladder, ureters and renal pelvis) as well.

Imfinzi (durvalumab)

Imfinzi (durvalumab) was approved in May 2017 for the treatment of patients with advanced urothelial carcinoma (bladder cancer) who have disease progression despite use of platinum-containing chemotherapy with or without surgery.

Imfinzi is an anti-PD-L1 in the same class of drugs as Tecentriq (atezolizumab) and Bavencio (avelumab). In clinical trials for bladder cancer, Imfinzi had an objective response rate (ORR) of 17%, regardless of PD-L1 status, with an ORR of 26.3% in patients with PD-L1 high-expressing tumors. Among 31 patients who responded to treatment, 14 patients (45%) had ongoing responses of at least 6 months and 5 patients (16%) at least 12 months. Of all evaluable patients, 2.7% achieved complete response.

In February 2018, FDA approved Imfinzi for an added use -- in patients with stage III non-small cell lung cancer(NSCLC) whose tumors cannot be removed surgically and whose cancer has not progressed after treatment with chemotherapy and radiation. In clinical trials, the lung tumors did not have significant growth (known as progression-free survival) for 16.8 months compared with 5.6 months for placebo. In studies, common side effects included cough, fatigue, inflammation in the lungs, respiratory tract infections, difficulty breathing, and rash.

How Well Do Checkpoint Inhibitors Work?

Some, but not all people, can have a positive response with checkpoint inhibitors. How well they work for an individual patient will be based on many factors:

  • their type of cancer
  • whether they express certain genetic markers on their tumors
  • their overall health at the time of treatment
  • previous cancer treatments
  • their ability to tolerate the side effects of the medication.

In some patients, tumors have regressed and disappeared with checkpoint inhibitors. But this does not necessarily mean they are "cured", that the cancer won't return, or that everyone will respond.

For example, of those people who received Keytruda in one clinical trial for melanoma, roughly 24 percent had their tumors shrink (partially or fully) lasting at least 1.4 to 8.5 months, and continued beyond this period in most patients. Unfortunately, this means that 76 percent of patients did not respond to the treatment. But this can be variable -- cancer treatment is very individual. It's important to discuss your expected treatment outcomes with your doctor.

Other Types of Cancer Immunotherapy

Research is very active in the area of cancer immunotherapy treatments. Immune checkpoint inhibitors are only one type of immunotherapy for treating cancer. Many other types of immunotherapy exist, some still under research in clinical trials and not yet approved:

Is An Oral Checkpoint Inhibitor On the Horizon?

Although research is early, in June 2016, Curis Inc. submitted an investigational new drug (IND) application to the FDA for CA-170, the first orally available, and once-daily, immune checkpoint inhibitor designed as a small molecule antagonist of immune checkpoints PD-L1 (programmed death-ligands 1) and VISTA (V-domain Ig suppressor of T cell activation). CA-170 is called a PD-L1/VISTA antagonist. Additional details of the trial can be found at www.clinicaltrials.gov (NCT02812875).

Currently, all checkpoint inhibitors are monoclonal antibodies that require intravenous (IV) infusion. However, CA-170 is being developed as an oral medication that could be used alone or in combination with other cancer treatments. Early toxicology studies show it to be safe when given in a once-daily oral dosing regimen. Curis is currently investigating CA-170 in a Phase 1 trial in patients with advanced solid tumors and lymphomas.

Another oral agent is in pre-clinical stage. CA-327 is a first-in-class, orally-available, small molecule antagonist of the immune checkpoints PD-L1 and T cell immunoglobulin and mucin domain 3 (TIM3), also from Curis. The company expects to file with FDA and initiate clinical testing in 2018.

Combining Checkpoint Inhibitors

Metastatic melanoma is particularly aggressive, and the use of dual immune checkpoint inhibition is a novel approach to treat cancer. Opdivo and Yervoy are immune checkpoint inhibitors that target different but complementary checkpoint pathways (PD-1 and CTLA-4). Future research will focus on combining many of these treatments. Research is also looking at the possibility of combining CAR T cell therapy with checkpoint inhibition to extend the activity of CAR T cell.

In January 2016, the combined use of Opdivo and Yervoy was FDA-approved for unresectable (can't be removed with surgery) or metastatic (spreading in the body) melanoma regardless of BRAF (genetic) mutational status. The Phase III study, known as the CheckMate-067, was the first study to show the success of combining two immunotherapies.

In the study, the Opdivo + Yervoy regimen prolonged progression-free survival (PFS; survival time without the melanoma worsening) by a median of 11.5 months. Opdivo used alone (monotherapy) could prolong PFS by a median of 6.9 months, with 2.9 months for Yervoy used alone. A complete response (cancer undetectable) was seen in 8.9% of patients receiving the combined regimen.

Other combined uses of Opdivo + Yervoy include metastatic colorectal (bowel) cancer and renal cell (kidney) carcinoma.

Rare safety issues with the combined use of Opdivo + Yervoy, such as serious heart side effects, were reported in Nov. 2016: sudden cardiac arrest and rapid heartbeat with organ failure were fatal.

How Can I Learn More About Immunotherapy Clinical Trials?

Your doctor might recommend that you consider enrollment is one of the many ongoing clinical trials evaluating immunotherapy. Or maybe you want to look for one yourself? This might give you the ability to receive a medication that you could not otherwise obtain. It's important to talk to your health care providers about the risks and benefits of clinical trials and if it might be a possibility. However, joining a clinical trial is not the right choice for everyone.

To learn more about available clinical trials, you can look at the National Cancer Institute's (NCI) Clinical Trial Finder on their website. Here you can search by cancer type, zip code, and even age to help further define which trials might be right for you. Your doctor might be able to recommend other clinical trials, too.

Cancer Is Smart. But We Are Smarter.

Cancer is very clever. It can learn how to evade the natural systems we have in our bodies that are there to protect us. It can set up shop from head to toe and try to evade detection. But over many years, researchers have toiled to learn about the immune system and how it's linked to cancer. Now this hard work is paying off.

Newer cancer treatments with fewer side effects and easier dosing regimens are extending survival time for some patients. But more work needs to be done, and initiatives like the Cancer Moonshot led by former Vice President Joe Biden can boost this worldwide battle.

To stay up-to-date with the latest news and approvals for cancer immunotherapy, consider these options:

  • Joining the Drugs.com Cancer Support Group
  • Join individual groups that discuss new immunotherapies like Keytruda or Opdivo.
  • Ask questions, lend support, and raise awareness to those who may have similar cancer concerns as yours.

We are smarter than cancer.

Finished: Immune Checkpoint Inhibitors: Boosting the Cancer Battle

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