Non-small cell lung cancer (NSCLC) accounts for more than 80 percent of lung cancer diagnoses. The two main types of NSCLC are squamous cell and nonsquamous cell. By the time most cases are found, they have already either advanced locally or metastasized-in other words, it is too late for surgical intervention. For many years, there was only one form of treatment for advanced non-small cell lung cancer (Stage IIIB and IV): platinum chemotherapy.
Rapid cell proliferation is a hallmark of malignant tumors, and chemotherapy works by killing off the cancer cells that grow the fastest. But these highly toxic drugs have a broad sweep and can also kill many other cells in the body, so the side effects can be significant.
More recently, a range of drugs that impact specific molecular processes have proven effective in extending survival rates in lung cancer while causing fewer side effects. Many of these new drugs are a type of cutting-edge treatment known as immunotherapy. Medications in this class seek to alter the body’s own immune response, either by ramping it up or tamping it down.
The key to immunotherapy: Your immune system
To fully appreciate the cancer immunotherapies that are making their way through clinical trials and into doctors’ offices, it’s important to first understand your immune system and how and why it’s now being used as a primary weapon in the war on cancer.
Think of your immune system as your own private militia. This remarkably effective and highly complex network of specialized white blood cells, tissues, and organs is designed to protect and defend you from daily unwanted intrusions from millions of bacteria, viruses, and other pathogens that do their best to enter your body.
The white blood cells, or leukocytes, are one of the most important parts of the immune system. The white blood cells are involved in protecting us from harmful invaders. Lymphocytes are a type of white blood cell. The two main types of lymphocytes are the B and T white blood cells. The B-cells secrete antibodies to attack foreign antigens, while the T-cells direct and regulate immune responses and attack infected cells.
In people with lung cancer, rather than being attacked by an intruder from the outside, the enemy lies within. Normally, human cells grow and divide to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place-a process called apoptosis.
When cancer develops, however, this orderly process breaks down. Cells survive when they should die, and new cells form when they are not needed. These cells clump together, forming malignant tumors that spread to the rest of the body (metastasize).
Why doesn’t the person’s immune system identify these abnormal cells and remove them from the body? Researchers have discovered that some cancer cells can trick the immune system into thinking they’re a friend, not a foe-a feat that allows them to continue multiplying and spreading unchecked.
Three novel checkpoint inhibitors
In 2015, the Food and Drug Administration approved two immunotherapy drugs known as checkpoint inhibitors as secondline treatments for advanced nonsmall cell lung cancer; that is, after standard treatments have failed.
Both of these novel drugs- pembrolizumab (Keytruda) from Merck and nivolumab (Opdivo) from Bristol-Myers Squibb-are designed to help restore the immune system’s ability to identify and destroy cancerous cells. A third drug-atezolizumab (Tecentriq) from Genentech-targets the same molecular process but works in a different way. Atezolizumab, which was approved in 2016, is also for second-line treatment of patients with advanced non-small cell lung cancer.
How they work
The immune system uses checkpoints-proteins on immune cells that must be “turned on” to attack invaders-to initiate an immune response. Some normal cells produce a checkpoint protein called PD-L1, which signals to the T-cells that they are not harmful. The T-cells deploy a protein probe, called PD-1, to determine which cells are displaying PD-L1 and should be left alone. But as a way of fooling the immune system, some cancer cells also produce PD-L1.
Nivolumab and pembrolizumab both work by latching onto the T-cells’ PD-1 protein probe, blocking its interaction with the PD-L1 probe. This action prevents the T-cells from using the probe to misidentify cancer cells as normal ones. The T-cells, which are no longer fooled by the decoy PD-L1 proteins, turn their immune system response on and mount an attack on the cancer cells.
Taking a different approach, atezolizumab works by latching onto the PD-L1 proteins. This action strips the tumors of their disguise, enabling the T-cells to identify them as cancer cells.
How effective are they?
In terms of extending survival, the benefits these drugs provide are real but are generally modest. In a key randomized controlled trial of 582 patients with advanced nonsquamous cell NSCLC, the one-year survival rate for those who received nivolumab was 51 percent, versus 39 percent for those who received standard chemotherapy (docetaxel).
Results from the trial, which were reported in The New England Journal of Medicine in 2015, also showed that the median survival among patients taking nivolumab was 12.2 months, about three months longer than for those receiving conventional treatment. Among patients whose cancer cells contained significant levels of PD-L1, the treatment was even more effective.
Findings reported in 2016 in The Lancet show that pembrolizumab also prolonged overall survival compared with docetaxel in 1,034 patients with advanced squamous cell or nonsquamous cell NSCLC. This study, which only enrolled patients with PD-L1-positive tumors, demonstrated a median overall survival of 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group. (Since its original approval in 2015, pembrolizumab has also been approved as a first-line treatment for certain patients with tumors that have high levels of PD-1/PD-L1.)
Positive results from a randomized controlled trial of atezolizumab versus the chemotherapy drug docetaxel were reported in 2017 in The Lancet. The study, which involved 1,225 patients with NSCLC, found that overall, atezolizumab-treated patients lived a median of 13.8 months-4.2 months longer than those treated with docetaxel. This study enrolled people regardless of their PD-L1 status and included squamous and nonsquamous disease types.
Unique side effects
All checkpoint inhibitors work by essentially releasing the breaks on the T-cells’ immune system response, and, as a result, normal cells can be attacked as well. These “immune-mediated” side effects differ from chemotherapy-related adverse effects and include inflammation in the lung, colon, liver, kidney, and hormone-producing glands. If these side effects become serious or life-threatening, treatment is stopped and high doses of corticosteroids are administered. Side effects more commonly associated with checkpoint inhibitors include fatigue, cough, nausea, itching, loss of appetite, and diarrhea.
The bottom line
These emerging treatments have clearly given some patients the gift of more time. And pharmaceutical companies are continuing to explore their use as both first- and second-line treatments for NSCLC, alone and in combination with chemotherapy or other medications.
Nevertheless, it is important to remember that checkpoint inhibitors don’t work in every patient, and researchers continue to study how to maximize their effectiveness and minimize side effects.
Cost, too, is an issue. All three checkpoint inhibitors cost about $150,000 annually. Insurance may cover some of the expense, but out-of-pocket costs can be high. Some patients may qualify for assistance from the pharmaceutical companies.